フアイアの中国語発音（ピンイン）である「Huaier」がそのまま英語名になります。「Huaier」と入力し、PubMedで検索される論文にインパクトファクター（IF）を加えて並べました。最近は信頼度の低い英文雑誌も多数存在します。そこで論文の信頼性と採択の難易度のパラメーターになるインパクトファクター（IF）を付加しました。

また、英文に限らず中国語のフアイアに関する論文のＰＤＦファイルは、以下からダウンロード可能です。（スマートフォン利用不可。パソコンからでしか閲覧できません）

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Reduction of FoxP3 + Tregs by an Immunosuppressive Protocol of Rapamycin Plus Thymalfasin and Huaier Extract Predicts Positive Survival Benefits in a Rat Model of Hepatocellular Carcinoma

Ann Transl Med 2020 Apr;8(7):472. doi: 10.21037/atm.2020.03.129.　IF 3.689

Abstract

Background: Investigate immunoregulation and anti-tumor immunity of FoxP3+Tregs after treatment with rapamycin (RAPA/SRL) plus thymalfasin (Zadaxin) and Huaier extract (PS-T) in a hepatocellular carcinoma (HCC) rat model simulating HCC relapse after liver transplant (LT).

Methods: We successfully established a rat model simulating HCC relapse after LT using an optimized chemical induction method with TACROLIMUS, methylprednisolone, and diethylnitrosamine as identified by visible liver nodules and hematoxylin-eosin staining. The model rats were then treated with RAPA, Zadaxin, and PS-T. Immune status changes were analyzed by flow cytometry, and protein expression of Akt and mTOR was determined by western blotting. Cytokines were measured by ELISAs.

Results:Combined therapy by RAPA plus Zadaxin and PS-T obviously alleviated hepatic pathological changes and significantly decreased the levels of FoxP3+Tregs in peripheral blood, the spleen, and the liver (P<0.05) and expression of mTOR protein (P<0.01) in the liver, obviously improved survival time (P=0.02). Moreover, the levels of CD8+T cells were increased significantly to almost normal levels (P<0.05) in comparison with no SRL monotherapy protocols. Inhibitory cytokines were also decreased in accordance with FoxP3+Tregs. Significant decreases of IL-10 and TGF-β were observed after SRL-based therapy (P<0.01) in comparison with the other groups. Serum alpha fetoprotein (AFP) and vascular endothelial growth factor (VEGF) levels were also decreased significantly (P<0.05). FoxP3+Tregs showed a negative correlation with CD8+ and CD4+/CD8+T cells and a positive correlation with AFP, and VEGF (P<0.05).

Conclusions: SRL-based therapy reduces FoxP3+Tregs to decrease secreted inhibitory cytokines which may enhancement the viability and number of CD8+T cells to exert anti-tumor effects that are mainly mediated through the AKT-mTOR signaling pathway.

 

 

Huaier Extract Restrains Pancreatic Cancer by Suppressing Wnt/β-catenin Pathway

Biomed Pharmacother. 2020 Apr 8;127:110126. doi: 10.1016/j.biopha.2020.110126. Online ahead of print. IF 3.743

Abstract

Pancreatic cancer is a lethal disease, and new treatments need to be explored. Huaier extract is a traditional Chinese medicine that has been found to exert antitumor properties in some cancers. However, the role of Huaier extract in pancreatic cancer has not been examined. In this study, we found that the proliferation, migration, invasion and EMT (epithelial-mesenchymal transition) of pancreatic cancer cells were suppressed by treatment with Huaier extract and that apoptosis increased. We also observed that expression of β-catenin was inhibited by Huaier extract. Furthermore, an animal study showed that Huaier extract slowed tumor growth in pancreatic cancer. Our results reveal that Huaier extract suppresses pancreatic cancer by inhibiting Wnt/β-catenin pathway both in vitro and in vivo.

 

 

Huai Qi Huang-induced Apoptosis via Down-regulating PRKCH and Inhibiting RAF/MEK/ERK Pathway in Ph + Leukemia Cells

Curr Med Sci. 2020 Apr;40(2):354-362.doi: 10.1007/s11596-020-2181-5. Epub 2020 Apr 26. IF 0.948

Abstract

Imatinib mesylate (IM) is the first-line treatment for Philadelphia (Ph) chromosomal positive leukemia by inhibiting phosphorylation of substrates via binding to the ABL kinase domain. Because of the drug resistance, side effects and the high cost of IM, it is necessary to find anti-cancer drugs with relatively low toxicity and cost, and enhanced efficacy, such as traditional Chinese medicines (TCMs). As one of TCMs, Huai Qi Huang (HQH) was chosen to treat BV173 and K562 cells. Various concentrations of HQH were added to cells for 24-72 h. Co-treatment of HQH and trametinib, an MEK inhibitor, was used to verify the synergistic effects on cell viability and apoptosis. Knockdown and overexpression of mitogen-activated protein kinase kinase 4 (MEK4) were implemented to demonstrate the role of MEK in cell apoptosis. Cell viability and apoptosis were measured by cell counting kit-8 assay (CCK8) and flow cytometry, respectively. Western blotting and real-time quantitative PCR (RT-qPCR) were used to assess protein and mRNA expression levels, respectively. The results showed that HQH inhibited survival and promoted apoptosis of BV173 and K562 cells in a dose-dependent manner, accompanied with down-regulation of PRKCH mRNA as well as CRAF, MEK4, phospho-ERK (pERK) and BCL2 proteins, and up-regulation of cleaved caspase3 protein. Co-treatment of HQH and trametinib had a synergistic effect on inhibiting survival and promoting apoptosis. MEK4 knockdown increased apoptosis, and had a synergistic effect with HQH. In contrast, MEK4 overexpression decreased apoptosis, and had the opposite effect with HQH. Collectively, the results of this study may identify a therapeutic mechanism of HQH on promoting apoptosis, and provide a potential option for treatment of Ph+ leukemia.

 

 

Huai Qi Huang Potentiates Dexamethasone-Mediated Lethality in Acute Lymphoblastic Leukemia Cells by Upregulating Glucocorticoid Receptor α

Med Sci Monit. 2020 Feb 17;26:e921649. doi: 10.12659/MSM.921649. IF 1.980

Abstract

BACKGROUND Glucocorticoids are important components of a number of chemotherapeutic regimens used to treat pediatric acute lymphoblastic leukemia (ALL). A primary cause of treatment failure of ALL is acquired resistance to glucocorticoids. Recently, traditional Chinese medicines were effectively used to treat solid tumors. Thus, the aim of this study was to investigate whether Huai Qi Huang (HQH), a traditional Chinese medicine, increased the efficacy of glucocorticoids in the treatment of ALL, and if so, to determine the underlying mechanism. MATERIAL AND METHODS Various concentrations of HQH were used to treat Jurkat and Nalm-6 cells for 24 to 72 hours. Subsequently, cells were co-treated with HQH and the glucocorticoid receptor agonist, dexamethasone (DEX), or a MEK inhibitor (PD98059) to verify the synergistic effects on apoptosis in Jurkat and Nalm-6 cells for 24 hours. Cell Counting Kit-8 assay and flow cytometry were used to measure cell viability and apoptosis, respectively. Protein and mRNA expression levels were assessed using western blotting and quantitative polymerase chain reaction. RESULTS The results revealed that cell survival was reduced and apoptosis was increased as the HQH concentration was increased, and this was accompanied with increases in the levels of BAX, cleaved-caspase-3 and glucocorticoid receptor alpha (GRalpha) and decreases in the levels of Bcl-2 and phospho-ERK (pERK). Glucocorticoid receptor ß (GRß) and total ERK (t-ERK) had no significant changes. Combined treatment with HQH and DEX or PD98059 increased apoptosis in Jurkat and Nalm-6 cells, and concurrently increased BAX, cleaved-caspase-3, GILZ, NFKBIA, and GRalpha and decreased Bcl-2 and pERK. CONCLUSIONS HQH enhanced the sensitivity of ALL cells to glucocorticoids by increasing the expression of GRalpha and inhibiting the MEK/ERK pathway, thus providing a rational foundation for the treatment of ALL with HQH.

 

 

A Clinical Study on the Use of Huaier Granules in Post-Surgical Treatment of Triple-Negative Breast Cancer

Gland Surg 2019 Dec;8(6):758-765. doi: 10.21037/gs.2019.12.08. IF 1.870

Abstract

Background: In recent years, traditional Chinese medicine (TCM) has been developing rapidly in cancer treatment. Huaier is a widely used fungus by TCM to treat different kinds of cancers. Its good efficacy in prevention of tumor recurrence and metastasis has been proven by a large number of clinical studies. In order to further investigate the efficacy and safety of Huaier granules in post-surgical therapy for stage I-III triple-negative breast cancer (TNBC) patients, we performed a case-control clinical study to observe its effects on the post-surgical safety and survival rates of these patients.

Methods: Two hundred and one TNBC patients underwent modified radical mastectomy were selected, they were admitted to our hospital between October 2010 to September 2014. The patients were randomly allocated to the experimental group (101 cases) or the control group (100 cases). Patients in the experimental group were treated with Huaier granules, by orally taking 20 g each time with 3 times a day. Medication was started during chemotherapy or at the time in 6 or 18 months after it. The control group did not receive any TCM preparations during this process. The disease-free survival (DFS) and overall survival (OS) were measured as the main outcome.

Results: The median follow-up time was 46 months. For the 100 patients in control group, 5-year DFS and OS was 82% and 86% respectively, while 87.1% and 90.1% for the 101 patients in the experimental group. The difference was not statistically significant. However, stage III patients in the control group showed a 5-year DFS of 53.8% and OS of 65.4%, which were significantly lower than that of stage III patients in the experimental group as 81.3% and 87.5%. In the experimental group, 10 patients with 6-month medication showed disease progression, whereas only 3 patients with 18-month medication showed disease progression. This difference was statistically significant as well.

Conclusions: Huaier granules could play an important role in post-surgical adjuvant therapy of TNBC patients, specially by effectively increasing the DFS and OS of breast cancer patients at middle to advanced stage.

 

 

Risk Factors and Clinical Characteristics of Tacrolimus-Induced Acute Nephrotoxicity in Children With Nephrotic Syndrome: A Retrospective Case-Control Study

Eur J Clin Pharmacol. 2020 Feb;76(2):277-284. doi: 10.1007/s00228-019-02781-3. Epub 2019 Nov 19. IF 2.774

Abstract

Purpose: Acute nephrotoxicity is a common adverse reaction of tacrolimus therapy; however, its risk factors in pediatric nephrotic syndrome (NS) remain to be evaluated. The objective of this study was to investigate the risk factors and characteristics of tacrolimus-induced acute nephrotoxicity in children with NS.

Methods: Past records of children with NS admitted to our hospital from 2014 to 2018 were reviewed. The incidence and characteristics of nephrotoxicity were analyzed. Multivariate logistic regression analysis was used to identify the risk factors of nephrotoxicity. A clinically applicable risk score was developed and validated.

Results: Tacrolimus-induced nephrotoxicity occurred in 25 of 129 patients, 13 patients were grade 1, and the renal function was recovered in 22 patients. Multivariate regression analysis showed that the maximum trough concentrations (C12h) of tacrolimus (OR, 1.48; 95% CI, 1.16 to 1.88; P < 0.001), huaiqihuang granules (OR, 0.095; 95% CI, 0.014 to 0.66; P = 0.017), and diarrhea (OR, 22.00; 95% CI, 1.58 to 306.92; P = 0.022) were independently associated with tacrolimus-induced nephrotoxicity. The maximum C12h were significantly higher in patients with nephrotoxicity (median 9.0 ng/ml) and the cut-off value for acute nephrotoxicity was 6.5 ng/ml. The area under the receiver operating characteristic curve was 0.821 for the proposed model based on the observations used to create the model and 0.817 obtained from k-fold cross-validation. Conclusions: High trough concentration of tacrolimus and diarrhea can potentiate the risk of tacrolimus-induced acute nephrotoxicity in children with NS, while huaiqihuang granules can protect this condition.

 

 

Huaier Extract Suppresses Non-Small Cell Lung Cancer Progression Through Activating NLRP3-dependent Pyroptosis

Anat Rec (Hoboken). 2019 Nov 6. doi: 10.1002/ar.24307. Online ahead of print.IF 1.328

Abstract

Recent studies have reported the anticancer activity of huaier extract in various human malignancies. However, little is known about the effect of huaier extract in non-small cell lung cancer (NSCLC) and its underlying mechanism. The current study aimed to investigate whether huaier extract affects the progression of NSCLC. mRNA and proteins expression of pyroptotic-related genes (NLRP3, caspase-1, IL-1β, and IL-18) in NSCLC tissues and cells were, respectively, detected by qRT-PCR and western blot. The effects of huaier extract on NSCLC cell viability and cytotoxicity were evaluated by CCK-8 assay, colony formation assay, and LDH detection kit. Besides, we established a xenograft model to assess the antitumor effect of huaier extract on tumor growth in vivo.

Our results showed that the expression of pyroptotic-related genes was downregulated in NSCLC tissues and cell lines. Huaier extract pretreatment inhibited cell viability and the percentage of colony formation of H520 and H358 cells, and upregulated the expression of pyroptotic-related genes. Mechanistically, huaier extract exhibited antitumor effect in NSCLC via inducing NLRP3-dependent pyroptosis in vitro and in vivo. In conclusion, our finding confirmed that huaier extract played an antitumor role in NSCLC progression through promoting pyroptotic cell death, which provided a new potential strategy for NSCLC clinical treatment.

 

 

HP-1 Inhibits the Progression of ccRCC and Enhances Sunitinib Therapeutic Effects by Suppressing EMT

Carbohydr Polym. 2019 Nov 1;223:115109. doi: 10.1016/j.carbpol.2019.115109. Epub 2019 Jul 19. IF 6.044

Abstract

Trametes robiniophila Murr (Huaier) has been used for many years as an adjuvant treatment for tumors. Sunitinib is the first-line therapy for end-stage renal cancer, but its side effects and drug resistance limit its clinical application. Cell counting kit- 8 (CCK-8), colony formation, scratch, and Transwell assays showed that Huaier polysaccharide (HP-1) reduced tumor progression. Its combination with sunitinib elicited stronger antitumor effects, including induction of apoptosis and cycle arrest. HP-1-induced effects depended on CIP2A downregulation and suppression of the EMT process. Moreover, qPCR and western blotting experiments showed that CIP2A downregulation was particularly pronounced after treatment with the combination therapy and was associated with EMT suppression. In addition, the HP-1/sunitinib combination inhibited the PI3K/Akt/VEGFR pathway, reducing the expression of pathway-related proteins. The HP-1-induced enhancement of sunitinib effects on tumor growth were also observed in vivo in a xenograft mouse model. Overall, these results indicated that HP-1 exerted antitumor effects against clear cell renal cell carcinoma (ccRCC) and enhanced the therapeutic efficacy of sunitinib.

 

 

Effectiveness of Huai Qi Huang Granules on Juvenile Collagen-induced Arthritis and Its Influence on Pyroptosis Pathway in Synovial Tissue

Curr Med Sci. 2019 Oct;39(5):784-793. doi: 10.1007/s11596-019-2106-3. Epub 2019 Oct 14. IF 0.957

Abstract

Huai Qi Huang (HQH) exerts great effects in clinic, such as anti-inflammation, immune-regulation, anti-cancer, and so on. However, the mechanism by which HQH protects juvenile idiopathic arthritis (JIA) is obscure. Thus, we explored deeply the protective mechanisms in juvenile collagen-induced arthritis (CIA) rat model. Pyroptosis is Gasdermin D (GSDMD)-dependent programmed cell death, involved in many diseases, such as sepsis. We investigated whether GSDMD-induced pyroptosis take part in mechanisms of juvenile CIA arthritis. Juvenile Wistar rats (3-4 weeks) were injected intradermally with fully emulsified bovine type II collagen and complete Freund’s adjuvant to establish CIA rat models. Later, the CIA rats received oral administration of HQH (4.16 g/kg) once a day from the day 21 of modeling, with the treatment lasting for 28 days. Varieties of indicators were measured for evaluation of anti-inflammation effect of HQH, including hind paw swelling, arthritis scores, micro CT, and histopathological changes and the level of pro-inflammatory cytokines in the serum, including tumor necrosis factor alpha (TNF-±) and interleukin-18 (IL-18). The expression of GSDMD and caspase-1 in the joint synovial tissues was detected. The results demonstrated that the expression of the pyroptotic protein GSDMD and its upstream caspase-1 was significantly increased in the synovial tissues of CIA rats. The treatment of HQH ameliorated the symptoms in CIA rats, reduced levels of pro-inflammatory cytokines and hind paw swelling, down-regulated the expression of GDSMD and caspase-1. GSDMD-induced pyroptosis participated in the pathogenesis of CIA rats. The study supported that HQH can effectively improve joints inflammation of juvenile collagen-induced arthritis rats by inhibiting pyroptosis pathway in the joint synovial tissues.

 

 

The Synergistic Antitumor Effect of Huaier Combined With 5-Florouracil in Human Cholangiocarcinoma Cells

BMC Complement Altern Med. 2019 Aug 7;19(1):203. doi: 10.1186/s12906-019-2614-5. IF 1.68

Abstract

Background: 5-Florouracil (5-FU) is a commonly used chemotherapeutic drug for cholangiocarcinoma, whereas it has unsatisfactory effect, and patients often have chemo-resistance to it. The combination of chemotherapeutic agents and traditional Chinese medicine has already exhibited a promising application in oncotherapy. Huaier extract (Huaier) has been used in clinical practice widely, exhibiting good anti-tumor effect. This paper aims to investigate the possibility of combination 5-FU and Huaier as a treatment for cholangiocarcinoma. Methods: A series of experiments were performed on the Huh28 cells in vitro, which involved cell proliferation, colony formation, apoptosis, cell cycle, migratory and invasive tests. Besides, western blots were also performed to examine the potential mechanism of 5-FU. Results: The combination effect (antagonism, synergy or additive) was assessed using Chou-Talalay method. Using the CCK-8 and Colony formation assay, the anti-proliferation effect of 5-FU combined with Huaier was observed. Apoptosis inducing and cell cycle arrest effect of the combination of two drugs were assessed by flow cytometry. To determine the combined treatment on cell immigration and invasion ability, wound healing and Transwell assay were performed. The above experiment results suggest that the combined 5-FU and Huaier, compared with treatment using either drug alone, exhibited stronger effects in anti-proliferation, cycle arrest, apoptosis-induced and anti-metastasis. Further, western blot results reveal that the inhibition of STAT3 and its target genes (e.g. Ki67, Cyclin D1, Bcl-2 and MMP-2) might be set as the potential therapeutic targets. Besides, the inhibition of combination treatment in proteins expression associated with proliferation, apoptosis, cell cycle and metastasis was consistent with that of previous phenotypic experiments. Conclusions: Huaier combined with 5-FU exhibited a synergistic anti-tumor effect in Huh28 cell. Furthermore, the mechanisms might be associated with the activation and translocation of STAT3, as well as its downstream genes.

 

 

A Polysaccharide From Huaier Ameliorates Cisplatin Nephrotoxicity by Decreasing Oxidative Stress and Apoptosis via PI3K/AKT Signaling

Int J Biol Macromol. 2019 Oct 15;139:932-943. doi: 10.1016/j.ijbiomac.2019.07.219. Epub 2019 Aug 1.IF 4.748

Abstract

Cisplatin (CP), a common chemotherapy drug used in treatment of malignant tumors. Due to various side effects such as nephrotoxicity (kidney damage), it’s efficiency and therapeutic application are limited. This study focuses on finding a suitable drug that would attenuate the side effects like kidney damage, caused by CP. Huaier polysaccharide (HP-1), an extraction of Trametes robiniophila Murr, with a molecular weight of 3 × 104 Da. Previous studies have shown that HP-1, exhibits anti-tumor potential and immunomodulatory effects. We hypothesized that HP-1 has the effect of attenuating the nephrotoxicity caused by CP chemotherapy and protecting renal function. Through our experiments, we observed that HP-1 can attenuate the level of oxidative stress, inflammation and mitochondrial dysfunction, thereby reducing kidney damage. In vitro, we observed that HP-1 significantly inhibits CP-induced renal tubular cell apoptosis and cell cycle arrest. In addition, HP-1 also affects the expression level of the protein by regulating the PI3K/Akt/mTOR signaling pathway and thus attenuates the side effects induced by cisplatin. Therefore, HP-1 may be a potential drug for preventing CP-induced renal damage.

 

 

Unusual and Highly Bioactive Sesterterpenes Synthesized by Pleurotus ostreatus During Coculture With Trametes robiniophila Murr

Appl Environ Microbiol. 2019 Jul 1;85(14):e00293-19. doi: 10.1128/AEM.00293-19. Print 2019 Jul 15. IF 3.960

Abstract

Candida albicans and Cryptococcus neoformans, human-pathogenic fungi found worldwide, are receiving increasing attention due to high morbidity and mortality in immunocompromised patients. In the present work, 110 fungus pairs were constructed by coculturing 16 wood-decaying basidiomycetes, among which coculture of Trametes robiniophila Murr and Pleurotus ostreatus was found to strongly inhibit pathogenic fungi through bioactivity-guided assays. A combination of metabolomics and molecular network analysis revealed that 44 features were either newly synthesized or produced at high levels in this coculture system and that 6 of the features that belonged to a family of novel and unusual linear sesterterpenes contributed to high activity with MICs of 1 to 32 μg/ml against pathogenic fungi. Furthermore, dynamic 13C-labeling analysis revealed an association between induced features and the corresponding fungi. Unusual sesterterpenes were 13C labeled only in P. ostreatus in a time course after stimulation by the coculture, suggesting that these sesterterpenes were synthesized by P. ostreatus instead of T. robiniophila Murr. Sesterterpene compounds 1 to 3 were renamed postrediene A to C. Real-time reverse transcription-quantitative PCR (RT-qPCR) analysis revealed that transcriptional levels of three genes encoding terpene synthase, farnesyl-diphosphate farnesyltransferase, and oxidase were found to be 8.2-fold, 88.7-fold, and 21.6-fold higher, respectively, in the coculture than in the monoculture, indicating that biosynthetic gene cluster 10 was most likely responsible for the synthesis of these sesterterpenes. A putative biosynthetic pathway of postrediene A to postrediene C was then proposed based on structures of sesterterpenes and molecular network analysis.IMPORTANCE A number of gene clusters involved in biosynthesis of secondary metabolites are presumably silent or expressed at low levels under conditions of standard laboratory cultivation, resulting in a large gap between the pool of discovered metabolites and genome capability. This work mimicked naturally occurring competition by construction of an artificial coculture of basidiomycete fungi for the identification of secondary metabolites with novel scaffolds and excellent bioactivity. Unusual linear sesterterpenes of postrediene A to C synthesized by P. ostreatus not only were promising lead drugs against human-pathogenic fungi but also highlighted a distinct pathway for sesterterpene biosynthesis in basidiomycetes. The current work provides an important basis for uncovering novel gene functions involved in sesterterpene synthesis and for gaining insights into the mechanism of silent gene activation in fungal defense.

 

 

Huaier polysaccharide inhibits the stem-like characteristics of ERα-36high triple negative breast cancer cells via inactivation of the ERα-36 signaling pathway.

Int J Biol Sci. 2019 May 20;15(7):1358-1367. doi: 10.7150/ijbs.27360. eCollection 2019. IF 4.067

Abstract

Biomed Pharmacother. 2019 Jun 12;117:109071. doi: 10.1016/j.biopha.2019.109071. IF 3.743

Abstract

 

 

Effects of adjuvant traditional Chinese medicine therapy on long-term survival in patients with hepatocellular carcinoma.

Phytomedicine. 2019 May 11;62:152930. doi: 10.1016/j.phymed.2019.152930. IF 4.183

Abstract

 

 

Trametes robiniophila Murr: a traditional Chinese medicine with potent anti-tumor effects.

Cancer Manag Res. 2019 Feb 14;11:1541-1549. 　 IF3.702

Pan J1,2, Yang C1,2, Jiang Z1,2, Huang J1,2.

Abstract

Trametes robiniophila Murr also known as Huaier, one of the traditional Chinese medicines, has been shown an effective adjuvant of cancer therapy. Accumulating evidence suggests that the anti-cancer effects of Huaier can be briefly divided into two aspects: the direct effects on tumor cells and the indirect effects on immune cells. In vitro and in vivo experiment showed Huaier directly inhibited tumor cell proliferation, induced tumor cell death, prevented metastasis and interfered with angiogenesis via various signaling pathways. The immunomodulatory effect of Huaier is associated with enhancement of the number and function of CD4+ T cells and NK cells, regulation of the polarization and function of macrophages, and elevated secretion of immune stimulatory cytokines. In this review, the anti-cancer effects and combined treatments of Huaier with other anti-cancer therapies, and the underlying mechanisms are summarized and discussed.

 

 

Identifying Clonal Origin of Multifocal Hepatocellular Carcinoma and Its Clinical Implications.

Clin Transl Gastroenterol. 2019 Feb;10(2) IF4.621

Xie DY¹, Fan HK², Ren ZG¹, Fan J^2,3, Gao Q^2,4.Author information

Abstract

Hepatocellular carcinoma (HCC) is characterized by high prevalence of multifocality. Multifocal HCC can arise synchronously or metachronously either from intrahepatic metastasis (IM) or multicentric occurrence (MO). To date, there have been no established criteria to accurately distinguish whether multifocal HCC originates from IM or MO. Histopathological features remain the most convenient strategy but with subjectivity and limited accuracy. Various molecular biological techniques involving assessment of TP53 mutation status, hepatitis B virus integration sites, and chromosomal alterations have been applied to determine the clonal origin. The introduction of next-generation sequencing facilitates a more comprehensive annotation of intertumor heterogeneity, resulting in more sensitive and accurate clonal discrimination. Generally, MO-HCC has better overall survival than IM-HCC after curative resection. Adjuvant antiviral treatment has been proved to decrease post-treatment recurrence probably by reducing MO-HCC recurrence, whereas adjuvant sorafenib treatment targeting prior micrometastasis failed to reduce IM-HCC recurrence. Recent studies recommended transcatheter arterial chemoembolization (TACE) and traditional Chinese medicine Huaier granule as effective adjuvant treatments probably by preventing IM and both types of recurrences respectively. Immunotherapy that inhibits immune checkpoint interaction may be an optimal choice for both MO- and IM-HCC. In the future, effective personalized therapy against multifocal HCC may be achieved. metastasis of GC cells via a c-Myc-Bmi1-mediated approach, providing a new perspective for our understanding of the anti-tumour effects of Huaier. These results suggest that Huaier n-butanol extract could be an attractive therapeutic adjuvant for the treatment of human GC.

 

 

Huaier n-butanol extract suppresses proliferation and metastasis of gastric cancer via c-Myc-Bmi1 axis.

Sci Rep. 2019 Jan 24;9(1):447　 IF4.12

Wang Y¹, Lv H¹, Xu Z^1,2, Sun J², Ni Y², Chen Z¹, Cheng X^3,4.

Abstract

Gastric cancer (GC) ranks as the third leading cause of cancer-related mortality worldwide, and approximately 42% of all cases diagnosed each year worldwide are diagnosed in China. A large number of clinical applications have revealed that Trametes robiniophila Μurr. (Huaier) exhibits an anti-tumour effect. However, loss of the bioactive components of Huaier during the extraction procedure with water is unavoidable, and the underlying mechanism of the anti-cancer effect of Huaier remains poorly understood. In this study, we investigated the anti-cancer effect of Huaier n-butanol extract, which contained 51.4% total flavonoids, on HGC27, MGC803, and AGS human GC cell lines in vitro. At a low concentration, Huaier n-butanol extract inhibited the growth of these GC cell types, induced cell cycle arrest and reduced cell metastasis. Moreover, Huaier n-butanol extract suppressed the c-Myc-Bmi1 signalling pathway, and overexpression of Bmi1 reversed the effects of Huaier n-butanol extract on GC cells. Thus, our findings indicate that Huaier n-butanol extract suppresses the proliferation and metastasis of GC cells via a c-Myc-Bmi1-mediated approach, providing a new perspective for our understanding of the anti-tumour effects of Huaier. These results suggest that Huaier n-butanol extract could be an attractive therapeutic adjuvant for the treatment of human GC.

 

 

An immune-stimulating proteoglycan from the medicinal mushroomHuaier up-regulates NF-κB and MAPK signaling via Toll-like receptor 4.

J Biol Chem. 2019 Jan 2.　 IF4.01

Yang A¹, Fan H², Zhao Y¹, Chen X¹, Zhu Z¹, Zha X³, Zhao Y⁴, Chai X¹, Li J¹, Tu P⁵, Hu Z¹.

Abstract

Trametes robiniophila Murr. (Huaier) is a mushroom with a long history of use as a medicinal ingredient in China and exhibits good clinical efficacy in cancer management. However, the antitumor components of Huaier and the underlying molecular mechanisms remain poorly understood. Here, we isolated a proteoglycan with a molecular weight of approximately 5.59 × 10⁴ Da from Huaier aqueous extract. We named this proteoglycan TPG-1, and using FTIR and additional biochemical analyses, we determined that its total carbohydrate and protein compositions are 43.9% and 41.2%, respectively. Using biochemical assays and immunoblotting, we found that exposing murine RAW264.7 macrophages to TPG-1 promotes the production of nitric oxide (NO), tumor necrosis factor α (TNF-α), and interleukin-6 (IL-6) through Toll-like receptor 4 (TLR4)-dependent activation of NF-κB and mitogen-activated protein kinase (MAPK) signaling. Of note, the TPG-1 treatment significantly inhibited the tumorigenesis of human hepatoma HepG2 cells likely at least in part by increasing serum levels of TNF-α and promoting leukocyte infiltration into tumors in nude mice. TPG-1 also exhibited good antitumor activity in hepatoma H22-bearing mice and had no obvious adverse effects in these mice. We conclude that TPG-1 exerts antitumor activity partially through an immune-potentiating effect due to activation of the TLR4-NF-kB/MAPK signaling cassette. Therefore, TPG-1 may be a promising candidate drug for cancer immunotherapy. This study has identified the TPG-1 proteoglycan as an antitumor agent and provided insights into TPG-1’s molecular mechanism, suggesting a potential utility for applying this agent in cancer therapy.

Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

 

 

Apoptosis of hepatocarcinoma cells Hepg2 induced by Huaier extract through regulation of HBx and CEACAM1 gene expression.

J Biol Regul Homeost Agents. 2018 Nov-Dec;32(6):1389-1398.　 IF1.397

Zhong LH¹, Zhu LY¹, Zhao YY², Wang W³, Lu BL¹, Wang Y⁴, Cheng Y¹, Ma YJ¹.

Abstract

Huaier can effectively inhibit the growth of tumor cells by enhancing the immune system. However, the mechanism of its function is still not clear. The current study aimed to explore the possible mechanism of Huaier in inhibiting human hepatocarcinoma cells by observing its effect on proliferation and invasion in hepatocarcinoma cells, HepG2 and HepG2-X, which stably express the HBx gene, and by comparing the levels of mRNA transcription and protein expression of HBx and CEACAM1 in HepG2 cells and HepG2-X cells when treated with different concentrations of Huaier. HepG2 cells and HepG2-X cells were treated with 0, 1.5, 3.0, and 6.0 g/L-1 Huaier extract in vitro. MTT assay was used to measure the inhibition of cell proliferation. The transwell cell model coated with Matrigel glue was used to detect the invasion of HepG2 and HepG2-X cells in vitro. Flowcytometry was used to observe changes in cell cycle. Real-time PCR and Western blot were used to detect HBx and CEREAM1 mRNA transcription and protein expression separately. Huaier extract can inhibit HepG2 and HepG2-X cell proliferation in a time- and dose-dependent manner. The A value of HepG2-X cells in each group was higher than that of HepG2 cells. Compared with the control group, the invasion ability of HepG2 and HepG2-X cells decreased significantly after treatment with Huaier extract, in a dose-dependent manner. The cell cycle of HepG2 and HepG2-X was arrested at S phase. The distribution of G0/G1 phase decreased gradually with the increase of the concentration of Huaier extract, and the proportion of G0/G1 phase distribution declined. After treating with Huaier extract, mRNA transcription and protein expression of HBx in HepG2 and HepG2-X declined, while those of CEACAM1 increased, reflecting a dose-dependent manner (P less than 0.05). Therefore, we concluded that the inhibitory effect of Huaier extract on hepatocarcinoma cell proliferation might function through down regulation of HBx gene expression and upregulation of CEACAM1 gene expression.

 

 

Huaier Augmented the Chemotherapeutic Sensitivity of Oxaliplatin via Downregulation of YAP in Hepatocellular Carcinoma.

J Cancer. 2018 Oct 10;9(21):3962-3970. IF3.249

Tao Y¹, Shan L¹, Xu X¹, Jiang H¹, Chen R¹, Qian Z¹, Yang Z^1,2, Liang B³, Zheng H³, Cai F³, Yu Y^1,4, Ma L³.

Abstract

For unresectable Hepatocellular carcinoma (HCC), chemotherapy is still an important treatment strategy. Oxaliplatin (Oxa) is an effective treatment of HCC after sorafenib treatment failure. However, the intrinsic or acquired resistance of Oxa affected the chemotherapeutic sensitivity. By analyzing the data of GEO Database, we found that Oxa aberrantly increased the expression of Cysteine-rich61 (Cyr61) in HCC cell lines. Subsequently, in Bel-7404 and SMMC-7721 cells after treated with Oxa, it was verified that the expression of Cyr61 and Yes-associated protein (YAP) was increased. Moreover, we found that blockade of YAP promoted Oxa-induced cell apoptosis for the first time. Meanwhile, our previous study demonstrated that Huaier (HE) inhibited the expression of YAP. Further study found that combination treatment of Oxa and HE had a significantly synergistic anti-cancer effect and significantly inhibited the expression of YAP and apoptosis related proteins. Taken together, we have observed that overexpression of YAP significantly reduced the chemotherapeutic sensitivity of Oxa in HCC for the first time. Combination treatment of Oxa and HE solved this problem.

 

 

The Anticancer Effect of Huaier Extract in Renal Cancer 786-O Cells.

Pharmacology. 2018;102(5-6):316-323.　 IF 1.615

Wei C^1,2, Liu Z¹, Li L¹, Zhang Y², Fang Z¹, Fan Y³.

Abstract

BACKGROUND:

Trametes robiniophila Murr (Huaier) has been used as an adjuvant therapy of tumor in traditional Chinese medicine for many years, but the underlying mechanisms are largely unknown. In the present study, we tested the inhibitory effect of Huaier extract on renal cancer 786-O cells and explored the possible mechanisms.

METHODS:

786-O cells were treated by gradient concentrations of Huaier extract, cell viability, invasion, migration and apoptosis were assessed by cell counting kit 8, cell scratch, transwell, and flow cytometry assay in vitro. The changes in protein level were detected by western blot analysis. Finally, the anticancer effect of Huaier was tested in vivo by nude mouse tumorigenicity assay.

RESULTS:

Viability of 786-O cells was suppressed by Huaier in a time- and dose-dependent manner; cell invasion and migration were also dramatically inhibited. Flow cytometry assays showed that Huaier could induce cell apoptosis. Western blotting analysis indicated that Huaier suppressed the activation of PI3K/AKT/mTOR/p70S6K/4E-BP1 signaling pathway. We also found that Huaier could partly reverse the epithelialmesenchymal transition (EMT) process. In vivo experiment indicated that tumor growth in the xenograft mouse model was suppressed by Huaier.

CONCLUSION:

Huaier plays an anticancer effect partially through the suppression of the PI3K/AKT/mTOR/p70S6K/4E-BP1 pathway and by reversing the EMT process. Huaier may act as an effective agent for treating renal cell carcinoma.

 

 

Efficacy of Huaier granule in patients with breast cancer.

Clin Transl Oncol. 2018 Oct 1　 IF2.392

Zhang Y¹, Wang X², Chen T³.

Abstract

BACKGROUND:

Huaier extract has been demonstrated to exhibit potent anti-tumor effects in various types of cancer cells. However, the clinical benefit of Huaier granule in breast cancer has not been reported. In this study, we aimed to evaluate the efficacy of Huaiergranule in breast cancer patients.

METHODS:

Our study included 284 breast cancer patients treated with or without Huaier granule between January 2005 and October 2016 at Qilu Hospital, Shandong University, Jinan, China. Retrospective data obtained included demographics, clinicopathological characteristics, disease-free survival (DFS), serum concentrations of tumor markers, the Karnofsky performance scale (KPS), and incidences of emotional symptoms. DFS was the main outcome measure.

RESULTS:

Of the patients included, 144 were classified into the control group and 140 into the Huaier group. Baseline characteristics were well balanced between the study arms. Median DFS was 91.43 months for control group and 112.61 months for Huaier group (hazard ratio (HR) = 2.97, 95% confidence interval (CI) = 1.57-5.61, p < 0.01). After Huaier granule treatment, the serum levels of tumor markers could be reduced to the normal range. In addition, breast cancer patients with Huaier granule treatment had higher KPS scores and less emotional symptoms.

CONCLUSIONS:

Our data demonstrated that patients orally administrated Huaier granule got longer DFS. Furthermore, Huaier granule could reduce serum tumor markers, improve the functional status, and decrease the incidences of emotional symptoms in breast cancer patients. Therefore, Huaier granule was an effective therapy for women with breast cancer.

 

 

A Randomized, Double-Blind, Controlled Clinical Study on the Curative Effect of Huaier on Mild-to-Moderate Psoriasis and an Experimental Study on the Proliferation of Hacat Cells.

Biomed Res Int. 2018 Aug 29;2018:2372895.　 IF2.583

Su D¹, Zhang X², Zhang L³, Zhou J³, Zhang F¹.

Abstract

The antitumor effects of Huaier have been recently revealed. However, no research has been conducted on the effects of Huaier on keratinocyte proliferation and for the treatment of psoriasis. Hacat cells were treated with different concentrations of Huaier for different periods of times. The effects on cell proliferation and vitality and on the cell cycle were detected. Patients with mild-to-moderate psoriasis were randomized and divided into two groups in a double-blind manner. The experimental group was given sugar-free Yinxie granules and Huaiqihuang (HQH) granules, and the control group was given sugar-free Yinxie granules and placebo. After 4 weeks, various therapeutic indexes were compared. Huaier significantly inhibited Hacat cell proliferation, suppressed vitality, and blocked the cell cycle in the G1 phase compared with the control group (P < 0.01, respectively). After treatment for 4 weeks, the number of patients between the two groups that experienced a 50% reduction in the Psoriasis Area and Severity Index (PASI 50), PASI 75 and PASI 90, was significantly different (P <0.01). The body surface area (BSA) affected by psoriasis and static physician’s global assessment (sPGA) was significantly reduced (P < 0.01); additionally, a significant improvement in the Dermatology Life Quality Index (DLQI) (P < 0.01) was observed. Huaier has shown promising effects in both clinical and experimental setting in this preliminary study and it might provide some benefit in the treatment of psoriasis vulgaris in the future.

 

 

Novel strategy of sirolimus plus thymalfasin and huaier granule on tumor recurrence of hepatocellular carcinoma beyond the UCSF criteria following liver transplantation: A single center experience.

Oncol Lett. 2018 Oct;16(4):4407-4417.　 IF 1.664

Zhou L^1,2, Pan LC^1,2, Zheng YG^1,2, Du GS¹, Fu XQ¹, Zhu ZD¹, Song JY¹, Liu ZJ¹, Su XZ², Chen W², Zheng DH¹, Suo LL¹, Yang SZ¹.

Abstract

Although liver transplantation (LT) lengthens the survival time of patients with hepatocellular carcinoma (HCC), LT patients exhibit a high recurrence rate; particularly those that had advanced HCC associated with the tumor biological characteristics and long-term application of immunosuppressants. A consensus on optimal prophylaxis and treatment for recurrent HCC following LT does not currently exist. The present study retrospectively analyzed data from 36 non-University of California at San Francisco criteria-eligible patients with advanced HCC who underwent LT, and then treated them with sirolimus (SRL)-based therapy with thymalfasin and huaier granules (SRL+, n=18), or with tacrolimus-based therapy (controls; n=18). The SRL+ group had significantly longer recurrence times (P=0.008) and survival times (P<0.0001) (OS, 1-year: 100%, 3-year: 94.4%, 5-year: 77.8%; DFS, 1-year: 88.9%, 3-year: 55.6%, 5-year: 50.0%). Furthermore, compared with pre-LT values and the control group, the SRL+ group had significantly lower serum α-fetoprotein (AFP) levels (both P<0.0001) and percentage of Forkhead box P3 (FoxP3)⁺ Treg lymphocytes (P<0.001) during the first year. In the SRL+ group, FoxP3⁺/cluster of differentiation (CD)8⁺ Treg lymphocyte percentages decreased significantly following LT (P<0.001); however, CD8⁺/CD3⁺ T-cells significantly increased (P<0.001). Levels of serum AFP and FoxP3⁺ Treg cells increased when tumors relapsed, and decreased to near-normal when relapse foci were cured or stabilized. SRL+ therapy may decrease AFP and Treg levels, while increasing CD8⁺ T cells, indicating an associated mechanism among them. In conclusion, SRL+ therapy appears to be safe and effective in preventing HCC recurrence following LT with no significant adverse events, and warrants further investigation.

 

 

Traditional Chinese Medicine Extract from Huaier Increases the Expression of Duffy Antigen Receptor for Chemokines and Reduces the Expression of Its Ligands.

Anal Cell Pathol (Amst). 2018 Jul 24;2018:6756092.　 IF1.547

Chen Y^#1, Chen Q^#1, Xie F¹, Peng H², Wu Y¹, Zhong S¹, Wang Z¹, Li W³, Xie W¹.

Abstract

AIMS:

The aim of the present study is to investigate whether the aqueous extract from Huaier, a traditional Chinese medicine (TCM), can affect the expression of Duffy antigen receptor for chemokines (DARC) and its ligands. Moreover, we compare the status of DARC in primary and metastatic breast cancer tissues from the same patient.

METHODS:

Immunohistochemistry was used to detect the expression of DARC in primary and metastatic focuses in 30 patients with breast cancer. The effect of Huaier aqueous extract on the expression of DARC and its ligands was investigated by quantitative real-time polymerase chain reaction, Western blotting, and enzyme-linked immunosorbent assay.

RESULTS:

The expression score of DARC in primary focuses was significantly higher than that in metastatic focuses, while changes of ER, PR, and HER2 receptors were not significantly different between primary and metastatic focuses. Huaier aqueous extract promoted the expression of DARC and reduced the secretion of CC chemokine ligand 2 (CCL-2), CXC chemokine ligand 8 (CXCL-8, IL-8), matrix metalloproteinase 2 (MMP-2), and CXC chemokine ligand 1 (CXCL-1).

CONCLUSION:

The present study demonstrates that difference in expression level of DARC between primary and metastatic focuses of breast cancer was significant, while differences in expression of ER, PR, and HER2 between primary and metastatic focuses were not significant. DARC may play a negative role in the metastasis of breast cancer. Traditional Chinese medicine extract from Huaier can increase DARC expression and reduce the expression of its ligands such as CCL-2, IL-8, MMP-2, and CXCL-1.

 

 

Effect of Huaier granule on recurrence after curative resection of HCC: a multicentre, randomised clinical trial.

Gut. 2018 Nov;67(11):2006-2016.　 IF17.943

Chen Q^#1, Shu C^#2,3,4, Laurence AD⁵, Chen Y^3,6,7, Peng BG⁸, Zhen ZJ⁹, Cai JQ¹⁰, Ding YT¹¹, Li LQ¹², Zhang YB¹³, Zheng QC¹⁴, Xu GL¹⁵, Li B¹⁶, Zhou WP¹⁷, Cai SW¹⁸, Wang XY¹⁹, Wen H²⁰, Peng XY²¹, Zhang XW²², Dai CL²³, Bie P²⁴, Xing BC²⁵, Fu ZR²⁶, Liu LX²⁷, Mu Y²⁸, Zhang L²⁹, Zhang QS³⁰, Jiang B³¹, Qian HX³², Wang YJ³³, Liu JF³⁴, Qin XH³⁵, Li Q³⁶, Yin P², Zhang ZW^3,6,7, Chen XP^3,6,7.

Abstract

OBJECTIVE:

There is little evidence that adjuvant therapy after radical surgical resection of hepatocellular carcinoma (HCC) improves recurrence-free survival (RFS) or overall survival (OS). We conducted a multicentre, randomised, controlled, phase IV trial evaluating the benefit of an aqueous extract of Trametes robinophila Murr (Huaier granule) to address this unmet need.

DESIGN AND RESULTS:

A total of 1044 patients were randomised in 2:1 ratio to receive either Huaier or no further treatment (controls) for a maximum of 96 weeks. The primary endpoint was RFS. Secondary endpoints included OS and tumour extrahepatic recurrence rate (ERR). The Huaier (n=686) and control groups (n=316) had a mean RFS of 75.5 weeks and 68.5 weeks, respectively (HR 0.67; 95% CI 0.55 to 0.81). The difference in the RFS rate between Huaier and control groups was 62.39% and 49.05% (95% CI 6.74 to 19.94; p=0.0001); this led to an OS rate in the Huaier and control groups of 95.19% and 91.46%, respectively (95% CI 0.26 to 7.21; p=0.0207). The tumour ERR between Huaier and control groups was 8.60% and 13.61% (95% CI -12.59 to -2.50; p=0.0018), respectively.

CONCLUSIONS:

This is the first nationwide multicentre study, involving 39 centres and 1044 patients, to prove the effectiveness of Huaier granule as adjuvant therapy for HCC after curative liver resection. It demonstrated a significant prolongation of RFS and reduced extrahepatic recurrence in Huaier group.

TRIAL REGISTRATION:

NCT01770431; Post-results.

 

 

The effects of polysaccharides from Auricularia auricula (Huaier) in adjuvant anti-gastrointestinal cancer therapy: A systematic review and network meta-analysis.

Pharmacol Res. 2018 Jun;132:80-89.　 IF4.897

Ma Y¹, Wang C², Zhang Q³, Peng X¹, Feng Y⁴, Meng X⁵.

Abstract

The aim of this study was to assess the comparative efficacy and safety of polysaccharides from Auricularia auricula (Huaier) for patients with gastrointestinal cancers (GICs) through a systematic review and network meta-analysis. We performed a network meta-analysis to identify evidence from clinical trials. We searched databases for publications up to February 2018. The prespecified primary efficacy outcomes were clinical therapeutic effects, which included the treatment response rate, 0.5-year overall survival rate, 1-year overall survival rate, 2-year overall survival rate, KPS improved rate and AFP decreased rate. The safety outcomes were the side effects of Huaier. The secondary efficacy outcome was immune function. Subgroup analyses and meta-regression were performed according to the various cancer types in all of the efficacy and safety outcomes. The study is registered with PROSPERO (CRD42018086481). A total of 33 trials, involving 2884 patients and 10 treatment arms, were eligible. Huaier significantly increased the treatment response rate (2.48, 1.83-3.35) and survival rate (0.5-year, 1-year and 2-year) and improved immune function without increasing the incidence of adverse effects. Significant efficacy was observed in most subgroups. Network meta-analysis revealed that Huaier was very suitable for combination therapy with TACE and ¹²⁵I particle implantation. Similarly, Huaier also had a good adjuvant therapeutic effect on enhancing platinum (L-OHP and DDP) and adriamycin (ADM). Huaier offers clear advantages for patients with GICs. Moreover, patients should be encouraged to accept Huaier treatment, especially HCC patients undergoing combination therapy with TACE and ¹²⁵I particle implantation.

 

 

Huaier suppresses proliferative and metastatic potential of prostate cancer PC3 cells via downregulation of Lamin B1 and induction of autophagy.

Oncol Rep. 2018 Jun;39(6):3055-3063. IF2.976

Yang A¹, Zhao Y¹, Wang Y², Zha X³, Zhao Y¹, Tu P¹, Hu Z¹.

Abstract

Prostate cancer is one of the most common malignancies occurring in males. Although large advances have been made in the pathogenesis of prostate cancer, the development of drugs with high efficacy and low toxicity for the treatment of prostate cancer is urgently needed. Recently, more and more attention has been paid to the antitumor effect of Traditional Chinese Medicine (TCM) worldwide. Trametes robiniophila Murr. (Huaier) has been applied as a type of TCM drug for ~1,600 years. Huaier exhibits excellent clinical efficacy in the treatment of cancer, including prostate cancer. However, the mechanisms underlying the anti-prostate cancer effect of Huaier remain largely unclear. In the present study, we revealed that Huaier aqueous extract inhibited the proliferative and metastatic capabilities of human prostate cancer PC3 cells through CCK-8 assay, in vitro scratch assay and Transwell assay. Moreover, decreased Lamin B1 was implicated in Huaier-induced suppression of proliferative and metastatic potential of PC3 cells. Intriguingly, we demonstrated that Huaier treatment induced autophagic cell death in PC3 cells. This study sheds new light on the mechanisms underlying the activity of Huaier against prostate cancer and provides a new theoretical basis for the clinical application of Huaier in prostate cancer.

 

 

Bi-directional solid fermentation products of Trametes robiniophila Murr with Radix Isatidis inhibit proliferation and metastasis of breast cancer cells.

J Chin Med Assoc. 2018 Jun;81(6):520-530. 　IF1.66

Liu Z¹, Tang Y², Zhou R¹, Shi X¹, Zhang H¹, Liu T¹, Lian Z³, Shi X⁴.

Abstract

BACKGROUND:

The bi-directional solid fermentation product extract of Trametes robiniophila Murr (Huaier) with Radix Isatidis (TIF) has been shown to have good anti-tumor activity. However, the mechanisms of this activity are still unknown. In the present study, we aimed to investigate its inhibitory effect on both SK-BR-3 and MDA-MB-231 cells, and explore the possible mechanisms of its anti-cancer effect in vitro.

METHODS:

The experiment comprised a control group, Radix Isatidis group, Huaier group, and TIF group. The cell viability was measured by MTT and the distribution of cell cycle and apoptosis levels were analyzed by flow cytometry. Cell scratch, Transwell, and adhesion assays were used to measure the effects of the test compounds on the migration, invasion, and adhesion capability of SK-BR-3 and MDA-MB-231 cells. The effects of TIF on the mRNA and protein expression related to apoptosis and migration were measured by using semi-quantitative RT-PCR and western blotting.

RESULTS:

TIF strongly inhibited the cell proliferation of the SK-BR-3 and MDA-MB-231 cells in a time-dependent manner and induced G2/M arrest and apoptosis. Furthermore, TIF significantly inhibited the proliferation, migration, invasion, and adhesion capabilities of SK-BR-3 and MDA-MB-231 cells. Compared with other treatments, the anticancer effect of TIF were stronger in MDA-MB-231 cells. Semi-quantitative RT-PCR suggested that TIF may upregulate the expression of p53 and caspase-3 to inhibit cell proliferation, and downregulate the expression of MMP-9/Snail and MMP-9/MMP-2 to inhibit the migration, invasion, and adhesion capabilities of SK-BR-3 and MDA-MB-231 cells. Western blotting results showed that TIF increased the expression of p53 protein and decreased the expression of MMP-9 protein in SK-BR-3 and MDA-MB-231 cells.

CONCLUSION:

The results indicated that the bi-directional solid fermentation may enhance the efficacy of Huaier in MDA-MB-231 cells and that TIF may be an effective complementary medicine for cancer treatment.

 

 

Huaier Granule extract inhibit the proliferation and metastasis of lung cancer cells through down-regulation of MTDH, JAK2/STAT3 and MAPK signaling pathways.

Biomed Pharmacother. 2018 May;101:311-321. IF3.457

Chen Y¹, Wu H², Wang X³, Wang C⁴, Gan L⁴, Zhu J³, Tong J³, Li Z⁵.

Abstract

Although the effect of Huaier has been widely studied, its role and its molecular mechanism in lung cancer are not clear. In this study, we explored the inhibitory effect of Huaier on lung cancer cells and its molecular mechanism. The cell viability, migration and invasion were analyzed by CCK-8 and BrdU cell proliferation assay kits, Transwell and colony forming assay. The cell cycle and apoptosis were analyzed by flow cytometry. The experimental results showed that the viability, migration and invasion of A549 and NCI-H1650 cells were inhibited by Huaier in a dose and time-dependent manner. Huaier induced cell apoptosis and the cells were blocked in the S phase to inhibit cell proliferation. Western blotting results showed that Huaier inhibited the expression of MTDH and increased the proportion of Bax/Bcl-2, it could also promote the expression of Cleaved Caspase-3 and increase the activity of Caspase-3, promote cell apoptosis and inhibit cell proliferation. Huaier inhibited the metastasis and invasion of lung cancer cells by inhibiting the expression levels of EMT related proteins, it also inhibited the expression of JAK2/STAT3 and MAPK signaling pathways. Therefore, our results showed that Huaier may inhibit the proliferation and metastasis of lung cancer cells through multiple targets, it had the potential for treatment of lung cancer.

 

 

Pretreatment of Huaiqihuang Extractum Protects Against Cisplatin-Induced Nephrotoxicity

Sci Rep . 2018 May 9;8(1):7333. doi: 10.1038/s41598-018-25610-6. IF 4.525

Abstract

Cisplatin is a commonly used chemotherapeutic agent in the treatment of different types of malignant tumors, but nephrotoxicity limits its usage. Therefore, in this study, we aimed to determine the possible protective effect of Huaiqihuang (HQH) extractum, a kind of Chinese herbal complex that consists of Trametes robiniophila Murr., Lycium barbarum and Polygonatum sibiricum, against nephrotoxicity induced by cisplatin in mice. We found that pretreatment with HQH significantly attenuated the cisplatin-induced increase in blood urea nitrogen (BUN), interstitial congestion, acute renal tubular injury and tubular cell apoptosis and necroptosis. It was further shown that HQH administration reduced cisplatin-induced release and nuclear-cytoplasmic translocation of HMGB1 and inactivated its downstream signaling molecules, TLR4 and NFκB, in renal tubular cells; as a result, HQH repressed cisplatin-induced TNF-α production. As dexamethasone (Dex) exerts renoprotective effects in severe Acute kidney injury (AKI), we compared it with HQH and found that HQH showed similar renoprotective effects to dexamethasone via similar mechanisms. Considering the potential side effects of corticosteroids, reducing the effectiveness of treatment and shortening survival in solid tumor patients, we suggest administration of HQH as a potential adjuvant for cisplatin therapy in solid tumor patients to preserve renal function.

 

 

Huai Qi Huang Corrects the Balance of Th1/Th2 and Treg/Th17 in an Ovalbumin-Induced Asthma Mouse Model

Biosci Rep. 2017 Dec 22;37(6):BSR20171071. doi: 10.1042/BSR20171071. Print 2017 Dec 22. IF 2.520

Abstract

The present study is designed to determine whether Huai Qi Huang has immunoregulatory effects on the (helper T (Th)) Th1/Th2 and regulatory T cell (Treg)/Th17 balance in ovalbumin (OVA)-induced asthma model mice. Asthma model mice were constructed by OVA treatment and Huai Qi Huang was administered. The amount of migrated inflammatory cells in the bronchoalveolar lavage fluid (BALF) from the OVA mice was counted. The total IgE in the sera was detected by the IgE ELISA kit. Cell suspensions from the lung were stained with antibodies specific for CD4 and the master transcription factors for Th1 (T-box expressed in T cells (T-bet)), Th2 (GATA-binding protein 3 (Gata-3)), Th17 (retinoic acid related orphan receptor γt (RORγt)), and Treg (forkhead box p3 (Foxp3)). The left lobe of the lung was used to prepare a single-cell suspension for flow cytometry to determine whether Huai Qi Huang influenced CD4+ T-cell subsets. Histological analyses were performed by using Hematoxylin and Eosin staining. The mRNA expression levels of the transcription factors were detected by using qRT-PCR. Huai Qi Huang inhibited infiltration of inflammatory cells into the lung, reduced influx of eosinophils (EOSs), lymphocytes (LYMs), neutrophils (NEUs), and macrophages (MACs) in the BALF, and decreased IgE in the serum in OVA-treated mice. Huai Qi Huang could regulate Th1/Th2 and Treg/Th17 via the re-balance of cytokine profiles and change the mRNA expression levels of the transcription factors, T-bet/Gata-3 and Foxp3/RORγt in OVA-treated mice. Our results showed that Huai Qi Huang could correct the imbalance of Th1/Th2 and Treg/Th17 in OVA-induced asthma model mice, indicating its effects on inhibiting the development and severity of asthma.

 

 

Huaier Restrains Proliferative and Migratory Potential of Hepatocellular Carcinoma Cells Partially Through Decreased Yes-Associated Protein 1.

J Cancer. 2017 Nov 6;8(19):4087-4097　3.182

Shan L¹, Li Y², Jiang H¹, Tao Y¹, Qian Z¹, Li L³, Cai F³, Ma L³, Yu Y¹.

Abstract

In China, Trametes robiniophila Murr (Huaier), a traditional Chinese herbal medicine, has been widely used in adjuvant therapies of hepatocellular carcinoma (HCC). However, the molecular mechanisms have not been fully understood. The aims of this study are to investigate the functions and mechanisms of Huaier on inhibiting proliferation and migration of HCC cells. Firstly, cell counting kit-8 (CCK-8) and colony formation shown Huaier inhibited proliferation of HCC Bel-7404, Bel-7402 and SMMC-7721 cells in a dose-dependent manner, and this inhibition might be due to Huaier decreased the expressions of the proliferating cell nuclear antigen (PCNA), the nuclear proliferation related antigen (Ki-67) and CyclinD1 detected by western blotting analysis. Notably, we also found Huaier treatment did not cause any cytotoxicity to normal human hepatocyte L-02 cells. Next, we found Huaier dose-dependently decreased Bcl-2 expression and increased Bax expression in Bel-7404 cells. The activities of cleaved caspase substrates had also been enhanced after Huaier treatment, suggesting Huaier treatment could induce HCC cell apoptosis. Then, the inhibitory effects of Huaier on migration of Bel-7404, Bel-7402 and SMMC-7721 cells via inhibiting Epithelial mesenchymal transition (EMT) had also been proved. Moreover, we confirmed yes-associated protein 1 (YAP1) was up-regulated in HCC cells and tissues, and overexpression of YAP1 promoted HCC cell proliferation and migration. Then, western blot and immunefluorescence shown Huaier had the inhibitory effects on YAP1 in HCC cells. On the other hand, human liver cancer tissue microarray (TMA) shown YAP1 expression was closely to clinic. Our study also confirmed Huaier had the inhibitory effects on YAP1 in xenograft mice models, it could be because Huaier treatment translocated YAP1 from nucleus to cytoplasm, and further promoted phosphorylation of YAP1 to be degraded by ubiquitination. Hence, we conclude that Huaier may restrain the proliferation and migration of HCC cells via down-regulation of YAP1. In summary, our study reveals the potential mechanisms of Huaier on inhibiting proliferation and migration of HCC cells. Importantly, for the first time, we found that Huaier can inhibit YAP1 expression in this anti-tumor process. We believe this finding is beneficial for the clinical applications of Huaier and the targeted therapies for HCC.

 

 

Aqueous Huaier Extract Suppresses Gastric Cancer Metastasis and Epithelial to Mesenchymal Transition by Targeting Twist.

J Cancer. 2017 Oct 19;8(18):3876-3886. IF 3.182

Xu Z¹, Zheng G¹, Wang Y², Zhang C³, Yu J¹, Teng F¹, Lv H², Cheng X¹.

Abstract

Trametes robiniophila Murr. (Huaier) is a widely used anti-cancer agent in China. Strong evidence for the anti-proliferative activity of Huaier has been reported; however, its anti-metastatic potential against gastric cancer (GC) as well as its underlying mechanism of action are unknown. Here, we show that treatment with an aqueous Huaier extract over a range of concentrations significantly suppressed both the invasiveness and migratory ability of GC cells. Huaier could also partly reverse the epithelial-mesenchymal transition (EMT), as characterized by increased expression of the epithelial marker E-cadherin and decreased expression of the mesenchymal markers N-cadherin and vimentin. In addition, Huaier-treated cells expressed lower levels of Twist compared to untreated controls, and overexpression of Twist via transfection could partially abolish the anti-metastatic activity of Huaier. Furthermore, elevated Twist expression was correlated with an advanced TNM stage, a high rate of lymph node metastasis, and reduced disease-free survival in GC patients. These findings reveal a novel anti-metastatic mechanism for Huaier, which inhibits the EMT by targeting Twist, suggesting its potential application against a GC relapse.

 

 

Huaier Extract Inhibits Breast Cancer Progression Through a LncRNA-H19/MiR-675-5p Pathway.

Cell Physiol Biochem. 2017;44(2):581-593.　 IF5.5

Wang J¹, Wang X¹, Chen T², Jiang L¹, Yang Q^1,3.

Abstract

BACKGROUND/AIMS:

Increasing evidence indicates that Huaier extract has promising therapeutic effects against cancer. However, the mechanisms that underlie its anti-tumor effects remain unclear. In recent years, various studies have shown that long noncoding RNAs (lncRNAs) play a critical role in the regulation of cancer development and progression. Here, we explored the role of lncRNAs in Huaier-induced tumor suppression.

METHODS:

Microarray profiling was performed to identify the candidate lncRNAs affected by Huaier extract. Quantitative realtime PCR (qPCR) was used to evaluate the transfection efficiency and the influence of Huaier extract on H19 expression. The effect of Huaierextract on the cell viability was examined by MTT. Moreover, the rates of apoptotic cells were detected using flow-cytometric analysis. Western blot analysis was applied to show the protein levels of CBL.

RESULTS:

Microarray data derived from Huaier-treated breast cancer cells identified H19 as a potential target. Huaier extract reduced the expression of H19. The over-expression of H19 inhibited the cytotoxic effects of Huaier extract; in contrast, reduced H19 expression enhanced the function of Huaier extract. MiR-675-5p was identified as a mature product of H19. Moreover, Huaier extract reduced the miR-675-5p expression. Upregulating miR-675-5p reversed the inhibitory effects of Huaier extract, whereas downregulating miR-675-5p sensitized breast cancer cells to the effect of Huaier extract. In addition, Huaier extract increased the expression of CBL protein, a direct target of miR-675-5p.

CONCLUSION:

Collectively, the data demonstrate that Huaier extract reduces viability and induces apoptosis in breast cancer cells via H19-miR-675-5p-CBL axis regulation.

 

 

Huaier extract enhances the treatment efficacy of paclitaxel in breast cancer cells via the NF-κB/IκBα pathway.

Oncol Rep. 2017 Dec;38(6):3455-3464.　 IF2.976

Yang L¹, Song Z¹, Wang X¹, Yang W¹, Wang M¹, Liu H¹.

Abstract

Breast cancer is considered as the most common malignant disease in women. Huaier extract, a type of traditional Chinese medicine, has been found to have antitumor activity. In the present study, we aimed to investigate whether the combined treatments of paclitaxel and Huaier extract may improve treatment efficacy in breast cancer cells. Human breast cancer cell lines MCF-7 and MDA-MB-231 were used to evaluate the antitumor efficacy of Huaier extract and paclitaxel both in vitro and in vivo. Using proliferation assays and flow cytometry, we found that both Huaier extract and paclitaxel decreased cell viability and induced cell apoptosis in a time- and dose-dependent manner. The combined treatments were more effective than monotherapy. Huaier extract induced cycle arrest in the G0/G1 phase, and paclitaxel arrested the cell cycle in the G2/M phase. Furthermore, the results of real-time PCR and western blotting revealed that Huaier extract decreased p65 and c-Met expression and increased IκBα expression, while paclitaxel increased p65 expression and reduced IκBα and c-Met expression. Consistent with the in vitro results, both Huaier extract and paclitaxel exerted a significant inhibitory effect on xenografted tumor growth, and the combined therapies revealed the most marked inhibitory effect. Collectively, our results indicated that Huaier extract increased the antitumor effect of paclitaxel therapy in breast cancer cells. The molecular mechanisms may be involved in the inhibition of the NF-κB pathway and c-Met expression.

 

 

Effect of Huaier On the Proliferation of Mesangial Cells in Anti-Thy-1 Nephritis.

Cell Physiol Biochem. 2017;42(6):2441-2452.　 IF5.5

Bai J, Geng W, Mei Y, Wu L, Duan S, Dong Z, Fu B, Wang Y, Zhu F, Cai G, Feng Z, Lin S, Chen X.

Abstract

BACKGROUND/AIMS:

To determine whether an aqueous extract of Trametes robiniophila Murr. (Huaier) suppresses anti-Thy-1 mesangial proliferative glomerulonephritis (MsPGN) in vivo and platelet-derived growth factor (PDGF)-BB-induced mesangial cell proliferation in vitro.

METHODS:

Male Wistar rats were randomly categorized into 5 groups: Sham, Thy-1, and 3 Huaier-treated groups (low, medium, and high dose). Two weeks after treatment, urinary proteins were quantified and renal pathological changes were examined. MAX interactor 1 (Mxi-1) and proliferating cell nuclear antigen (PCNA) expression levels in isolated glomeruli, rat mesangial cell viability, cell-cycle distribution, and cell-cycle pathways were assessed.

RESULTS:

Huaier diminished the proliferative damages and urinary protein secretion in Thy-1 rats. PCNA was downregulated, whereas Mxi-1 was upregulated in the isolated glomeruli of Huaier-treated groups compared with the Thy-1 group. Huaier inhibited PDGF-BB- stimulated proliferation of rat mesangial cells in a time- and dose-dependent manner (50% inhibitory concentration = 6.19 mg/mL) and induced G2 cell-cycle arrest. Cell-cycle pathway proteins were downregulated, whereas Mxi-1 was upregulated in Huaier-treated mesangial cells compared with PDGF-BB-stimulated cells.

CONCLUSION:

Huaier reduces urinary protein excretion and relieves hyperplasia in mesangial cells in anti-Thy-1 MsPGN as well as inhibits PDGF-BB-stimulated proliferation and DNA synthesis of rat mesangial cells in vitro, suggesting its novel therapeutic potential in MsPGN.

 

 

PET Imaging on Dynamic Metabolic Changes after Combination Therapy of Paclitaxel and the Traditional Chinese Medicine in Breast Cancer-Bearing Mice.

Mol Imaging Biol. 2018 Apr;20(2):309-317.　 IF3.608

Chen Y^1,2,3,4, Wang L^1,2,3,4, Liu H^1,2,3,4, Song F^1,2,3,4, Xu C^1,2,3,4, Zhang K^1,2,3,4, Chen Q^1,2,3,4, Wu S^1,2,3,4, Zhu Y^1,2,3,4, Dong Y⁵, Zhou M^1,2,3,4,6, Zhang H^1,2,3,4, Tian M^7,8,9,10.

Abstract

PURPOSE:

The aim of the study was to non-invasively evaluate the anticancer activity of a traditional Chinese medicine-Huaier, combined with paclitaxel (PTX) in breast cancer bearing mice by detecting dynamic metabolic changes with positron emission tomography (PET).

PROCEDURES:

Balb/c nude mice were randomly divided into one of the four groups: Huaier, PTX, PTX + Huaier, or the control. PET imaging with 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) was performed to monitor the metabolic changes in BT474 (luminal B) and MDA-MB-231 (triple-negative) breast cancer xenografts. Immunohistochemistry (IHC) study was performed immediately after the final PET scan to assess the expressions of phosphatidylinositol 3-kinase (PI3K), phospho-AKT (p-AKT), caspase-3, and vascular endothelial growth factor (VEGF).

RESULTS:

Compared to the control group, [¹⁸F]FDG accumulation demonstrated a significant decrease in PTX + Huaier (p < 0.01) or Huaier group (p < 0.05), which was consistent to the decreased expression of PI3K (p < 0.05) and p-AKT (p < 0.05) in the breast cancer xenografts.

CONCLUSION:

The therapeutic effect of Huaier combined with PTX was superior than the PTX alone in BT474 and MDA-MB-231 breast cancer-bearing mice. [¹⁸F]FDG PET imaging could be a potential non-invasive approach to assess the metabolic changes after chemotherapy combined with traditional Chinese medicine in the breast cancer.

 

 

Huaier extract restrains the proliferative potential of endocrine-resistant breast cancer cells through increased ATM by suppressing miR-203.

Sci Rep. 2017 Aug 4;7(1):7313.　 IF4.122

Gao S¹, Li X¹, Ding X², Jiang L³, Yang Q^4,5.

Abstract

Endocrine therapy is one of the main treatments for breast cancer patients in the early stages. Tamoxifen and fulvestrant are the major drugs of endocrine therapy for breast cancer patients. However, acquired drug resistance often caused treatment failure and relapse for patients, which is a major clinical problem. We investigated whether Huaier extract had effects on endocrine-resistant breast cancer cells. In our study, we aimed to demonstrate the inhibitory effects of Huaier extract on tamoxifen-resistant cells (M7-TR) and fulvestrant-resistant cells (M7-FR). Using MTT and clone formation assays, we found that Huaier extract could inhibit the proliferation in M7-TR and M7-FR cells. Flow cytometry and western blotting illustrated that Huaier extract could induce G0/G1 arrest in both endocrine-resistant breast cancer cells. Mechanistically, we present that Huaier extract significantly increased ataxia telangiectasia mutation (ATM) via down-regulation of miR-203. Huaier extract also had the inhibitory effects on tumour growth in vivo in a xenograft mouse model. These results demonstrated that Huaier extract could inhibit the proliferation of M7-TR and M7-FR cells by increasing ATM via suppression of miR-203.

 

 

Beneficial Effects of Huaiqihuang on Hyperglycemia-Induced MPC5 Podocyte Dysfunction Through the Suppression of Mitochondrial Dysfunction and Endoplasmic Reticulum Stress

Mol Med Rep. 2017 Aug;16(2):1465-1471.doi: 10.3892/mmr.2017.6753. Epub 2017 Jun 12. IF1.880

Abstract

The present study was performed to investigate the effect of Huaiqihuang (HQH) on hyperglycemia (HG)-induced mitochondrial dysfunction and endoplasmic reticulum (ER) stress in MPC5 podocytes. The effects of HQH and HG on cell viability were assessed using an MTT assay. mRNA and protein expression levels were evaluated using reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. Cell apoptosis was assessed using terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling, whereas reactive oxygen species production and alterations in mitochondrial membrane potential were assessed using flow cytometry. DNA damage was evaluated using a comet assay. The results demonstrated that treatment of podocytes with HQH markedly suppressed the HG induced generation of reactive oxygen species. HQH also significantly improved mitochondrial membrane potential in podocytes exposed to HG. When the podocytes were treated with HG, Ca2+ levels were significantly increased, compared with those in the control group, whereas treatment of the podocytes with HQH significantly reversed the HG induced upregulation of Ca2+ secretion. Treatment of the podocytes with HQH significantly reversed the HG induced upregulation of glucose related protein 78 (GRP78) and C/EBP homologous protein, which were used as indicators of ER stress. Furthermore, GRP78 loss of function attenuated HG induced podocyte dysfunction, including cell apoptosis and DNA damage. In conclusion, beneficial effects of HQH on HG induced MPC5 podocyte dysfunction were observed, and occurred through the suppression of mitochondrial dysfunction and ER stress.

 

 

Transarterial chemoembolization combined with Huaier granule for the treatment of primary hepatic carcinoma: Safety and efficacy.

Medicine (Baltimore). 2017 Jul;96(29):e7589.　最新のＩＦなし

Zhao GS¹, Liu Y, Zhang Q, Li C, Zhang YW, Ren ZZ, Zhou J, Zhang M.

Abstract

To evaluate the safety and efficacy of transarterial arterial chemoembolization (TACE) with gelatin sponge particles (GSPs-TACE) and Huaier granule to treat primary hepatic carcinoma (PHC).A series of 62 patients with PHC were included between June 2009 and December 2011, and randomly assigned to a control (n = 31) or an experimental group (n = 31). The control patients received TACE with 350 to 560 μm GSPs plus lobaplatin chemotherapy. Patients in the experimental group received TACE plus Huaier granule. Treatment safety and mid-to-long-term efficacy were evaluated.Follow-up ranged from 12 to 24 months with a mean of 28.7 months. The 6- and 12-month overall survivals were 100% and 93.5% in the experimental group and 90.3% and 80.6% in control group, respectively. The difference in overall survival at 12 months was significant (χ = 5.213, P < .05), but the difference in median survival in the experimental group (20.6 months) and control group (17.1 months) patients was not significant (χ = 0.745, P > .05). The number of TACE procedures in the experimental group (2.9 ± 8.7) and control group (4.1 ± 7.3) patients was significantly different (χ = 7.262, P < .05). The 6-month (87.1% vs. 73.3%, χ = 5.945) and 12-month (72.4% vs. 64.3%, χ = 6.384) tumor objective response rates in the experimental and control groups were significantly different (P < .05). There were no statistically significant differences in the occurrence of treatment-related adverse reactions in the 2 groups.Transarterial chemoembolization with GSPs and Huaier granule was safe and effective for treating PHC patients.

 

 

Killing effects of Huaier Granule combined with DC-CIK on nude mice transplanted with colon carcinoma cell line.

Oncotarget. 2017 Jul 11;8(28):46081-46089.　 最新のＩＦなし

Sun WW^1,2, Dou JX³, Zhang L³, Qiao LK⁴, Shen N³, Zhao Q⁵, Gao WY¹.

Abstract

This study aims to compare the efficacy of different treatments for nude mice transplanted with HT-29 colon carcinoma cell line. BalB/C nude mice were transplanted with HT-29 colon carcinoma cell line and randomly divided into four groups, with 5 mice in each group: blank control group, DC-CIK group, Huaier Granule group, and Huaier Granule group combined with DC-CIK group (combined treatment group). For DC-CIK group and combined treatment group, 1×106 DC-CIK cells were injected via the tail vein 4 days after transplantation. The injection was performed twice weekly for a total of 2 weeks. For Huaier Granule group and combined treatment group, Huaier Granule was administered at the dose of 20 g/60 g, by dissolving 20 g of Huaier granules in 600 ml of pure water. Intragastric administration of 0.2 ml of granules was performed once daily for 3 weeks. For the blank control group, equal volume of normal saline was given. Tumor size and body weight of nude mice were measured every 2 days during the 3-week treatment. The mice were sacrificed at the end of treatment to harvest tumors. Key genes of the signaling pathway were detected by RT-PCR. At the end of treatment, mice in combined treatment group, DC-CIK group and Huaier Granule group remained stable emotionally with normal mobility and water and food intake. However, in the blank control group, the mobility was restricted starting from the third week and the mice were on the verge of dying. The expression of PI3KR1, Akt, Wnt1, CTTNB1, Notch1, Notch2 and Notch3 genes were all downregulated significantly in the combined treatment group compared with DC-CIK group and Huaier Granule group (P<0.05). Therefore, the combined treatment of Huaier Granule combined with DC-CIK achieved the best effect in nude mice transplanted with HT-29 colon carcinoma cell line.

 

 

Huaier aqueous extract protects against dextran sulfate sodium-induced experimental colitis in mice by inhibiting NLRP3 inflammasome activation.

Oncotarget. 2017 May 16;8(20):32937-32945.　 最新のＩＦなし

Wang L¹, Yu Z², Wei C³, Zhang L^1,4, Song H², Chen B¹, Yang Q^1,4.

Abstract

The use of Trametes robiniophila Murr. (Huaier) as a complementary therapy for cancer has recently become increasingly common in China. However, whether Huaier can regulate host immune responses, especially innate immunity, remains largely unknown. The NLRP3 inflammasome is a multimeric complex consisting of NLRP3, ASC and caspase-1. NLRP3 inflammasomes respond to a variety of endogenous (damage-associated molecular patterns) and exogenous (pathogen-associated molecular patterns) stimuli, and play crucial roles in host defense against pathogens and multiple diseases such as ulcerative colitis (UC). In this study, we investigated the anti-inflammatory effect of Huaier in dextran sulfate sodium (DSS)-induced murine colitis and revealed the underlying mechanisms by targeting NLRP3 inflammasomes. In C57BL/6 mice, oral administration of Huaier attenuated DSS-induced colon shortening and colonic pathological damage. Furthermore, we analyzed the effect of Huaier on NLRP3 inflammasome activation in macrophages. Huaierinhibited NLRP3 inflammasome activation-induced IL-1β secretion and caspase-1 cleavage. Moreover, Huaier decreased NLRP3 protein expression via promoting NLRP3 degradation through the autophagy lysosome pathway. Therefore, our findings demonstrate a novel function for Huaier in the regulation of NLRP3 inflammasome activation and suggest a potential role for Huaier in NLRP3 inflammasome-associated diseases.

 

 

Huaiqihuang Granules () Reduce Proteinuria by Enhancing Nephrin Expression and Regulating Necrosis Factor κB Signaling Pathway in Adriamycin-Induced Nephropathy

Chin J Integr Med . 2017 Apr;23(4):279-287. doi: 10.1007/s11655-015-2293-0. Epub 2015 Oct 10.IF 1.445

Abstract

Objective: To investigate the effects of Huaiqihuang Granules (, HQH), a mixture of Chinese herbs including Trametes robiniophila Murr, Fructus Lycii and Polygonatum sibiricum, on adriamycininduced nephropathy (ADRN) in rats and its underlying mechanisms.

Methods

Rats with ADRN were divided into four groups: the sham group, the model group (distilled water), the low-dose HQH-treated (2 g/kg) group, and the high-dose HQH-treated (4 g/kg) group. Body weight and 24-h urinary protein (Upro) were checked every week. After 5-week intervention, at the end of the study, the rats were sacrificed and blood samples were collected for examination of biochemical parameters, including glomerular morphological makers, podocyte shape, cellular apoptosis, expressions of nephrin, inflammatory and apoptosis markers.

Results

HQH ameliorated the rat’s general status, proteinuria, renal morphological appearance and glomerulosclerosis. The decreased expression of nephrin in ADRN rats was increased by HQH, as well as the impaired podocyte foot process fusion. Cytosolic levels of p65 and inhibitor of nuclear factor κBα (IκBα) were decreased in ADRN rats, and recovered by the treatment of HQH. Consistently, the induced expression of tumor necrosis factor α (TNF-α), phosphorylated nuclear factor κB p65 (p-NFκB p65) and IκBα in ADRN were markedly suppressed by HQH. In addition, induction of Bax, cleaved caspase-3 and cytochrome C in ADRN rats were suppressed by HQH, indicating the amelioration of apoptosis.

Conclusion

HQH could ameliorate renal impairments in ADRN rats by increasing nephrin expression, inhibiting NF-κB signaling pathway via the down-regulation of p-NF-κB p65 and p-IκBα, and suppression of glomerular and tubular apoptosis.

 

 

Huaier restrains proliferative and invasive potential of human hepatoma SKHEP-1 cells partially through decreased Lamin B1 and elevated NOV.

Sci Rep. 2016 Aug 9;6:31298.　 IF4.122

Hu Z¹, Yang A^1,2, Su G^1,2, Zhao Y¹, Wang Y³, Chai X¹, Tu P¹.

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cause of malignancy-related mortality worldwide. It is urgently needed to develop potential drugs with good efficacy and low toxicity for HCC treatment. The anti-tumor effect of Traditional Chinese Medicine (TCM) has received increasing attention worldwide. Trametes robiniophila Murr. (Huaier) has been used in TCM for approximately 1,600 years. Clinically, Huaier has satisfactory therapeutic effects in cancer treatment, especially in HCC. However, the mechanisms underlying the anti-cancer effect of Huaier remain ill defined. Herein we have demonstrated that Huaier dramatically inhibited cell proliferation and induced apoptosis in human hepatoma cell line SKHEP-1. Importantly, Huaier restrained the metastatic capability of SKHEP-1 cells. Mechanistically, down-regulation of Lamin B1 and up-regulation of Nephroblastoma overexpressed (NOV) were at least partially responsible for the inhibitory effect of Huaier on the proliferative and invasive capacity of SKHEP-1 cells. Our finding provided new insights into mechanisms of anti-HCC effect of Huaier and suggested a new scientific basis for clinical medication.

 

 

A polysaccharide from Huaier induced apoptosis in MCF-7 breast cancer cells via down-regulation of MTDH protein.

Carbohydr Polym. 2016 Oct 20;151:1027-1033.　 IF5.158

Luo Z¹, Hu X², Xiong H³, Qiu H³, Yuan X³, Zhu F⁴, Wang Y⁵, Zou Y⁶.

Abstract

In this study, one homogeneous polysaccharide (SP1), with a molecular weight of 56kDa, was isolated from the Huaier fruiting bodies. It had a backbone consisting of 1,4-linked-β-d-Galp and 1,3,6-linked-β-d-Galp residues, which was terminated with 1-linked-α-d-Glcp and 1-linked-α-l-Araf terminal at O-3 position of 1,3,6-linked-β-d-Galp unit along the main chain in the ratio of 1.1:2.0:1.1:1.1. MTT assay showed that shMTDH or SP1 (100, 200 and 400μg/ml) was able to suppress the proliferation of MCF-7 cells, due to a significant increase in the number of apoptotic cells as determined by flow cytometric analysis. Furthermore, Western blot analysis revealed that SP1 or shMTDH treatment led to a rise of ratio between proapoptotic Bax and antiapoptotic Bcl-2 protein in MCF-7 cells. In addition, carcinogene MTDH protein expression in MCF-7 cells received SP1 (100, 200 and 400μg/mL) or shMTDH treatment was also repressed after 48h incubation. Taken together, these findings indicated that SP1 has anticancer potential in the treatment of human breast cancer.

 

 

Huaier aqueous extract inhibits proliferation and metastasis of tuberous sclerosis complex cell models through downregulation of JAK2/STAT3 and MAPK signaling pathways.

Oncol Rep. 2016 Sep;36(3):1491-8.　 IF2.976

Yang A¹, Fan H², Zhao Y¹, Zha X³, Zhang H⁴, Hu Z¹, Tu P¹.

Abstract

Tuberous sclerosis complex (TSC) is a genetic disorder with formation of benign tumors in many different organs. It has attracted increasing attention from researchers to search for therapeutic drugs for TSC patients. Traditional Chinese medicine (TCM) has become an important source for finding antitumor drugs. Trametes robiniophila Μurr. (Huaier) is a kind of officinal fungi in China and has been applied in TCM for approximately 1,600 years. A large number of clinical applications have revealed that Huaier has good antitumor effect. In this study, we have investigated the effects of Huaier aqueous extract on two TSC cell models, including inhibition of proliferation, induction of apoptosis, cell cycle arrest, and anti-metastasis. We demonstrated that Huaier aqueous extract inhibited JAK2/STAT3 and MAPK signaling pathways in a dose-dependent manner. Therefore, based on the low toxicity and the multi-targets of Huaier treatment, Huaier may be a promising therapeutic drug for TSC.

 

 

Huaier polysaccharide induces apoptosis in hepatocellular carcinoma cells through p38 MAPK.

Oncol Lett. 2016 Aug;12(2):1058-1066. IF1.664

Bao H¹, Liu P¹, Jiang K², Zhang X¹, Xie L¹, Wang Z¹, Gong P¹.

Abstract

The underlying mechanism of the antitumor activity of Huaier polysaccharide (HP) remains to be explored. The present study aimed to investigate the inhibitory effect of HP on hepatocellular carcinoma (HCC) cells, and to explore the possible mechanisms of its anticancer effect. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, while apoptotic nuclear changes were observed using Hoechst 33258 staining. The distribution of cell cycle and apoptosis were analyzed by flow cytometry, and western blotting was used to test the apoptotic pathways. Apoptosis and mitogen-activated protein kinase (MAPK) inhibitors were used to investigate the mechanism of apoptosis. HP triggered cell cycle arrest and apoptosis in HepG2 and Huh7 cells. Both the extrinsic and intrinsic apoptotic pathways were activated after HP treatment. Furthermore, HP enhanced the three major MAPK pathways (extracellular signal-regulated kinase, c-Jun N-terminal kinase and p38 MAPK) and inhibited the AKT/mechanistic target of rapamycin signaling pathway in HCC cells. Notably, the inactivation of p38 MAPK impaired the HP-induced cell death. HP exerted its antitumor effect on HCC cells through the regulation of the expression of the apoptosis-related proteins B-cell lymphoma (Bcl)-2, Bcl-2-associated X protein and survivin. The present study provides evidence that HP induces apoptosis in HCC cells and demonstrated the role of p38 MAPK in HP-triggered cancer cell death.

 

 

Huaiqihuang May Protect From Proteinuria by Resisting MPC5 Podocyte Damage via Targeting p-ERK/CHOP Pathway

Bosn J Basic Med Sci. 2016 Aug 2;16(3):193-200. doi: 10.17305/bjbms.2016.887. Epub 2016 May 17. IF 1.458

Abstract

The purpose of this study was to investigate the potential effects of Huaiqihuang (HQH) granule, a Chinese herbal medicine, in treating proteinuria and to reveal its possible mechanism. MPC5 podocytes were cultured in vitro at 37°C and induced with tunicamycin (TM). The TM-induced cells were treated with HQH at different concentrations. The cell proliferation was detected using the MTT assay. The optimal effective dose of HQH for MPC5 cells was determined by the MTT assay and LDH assay respectively. The influences of HQH on the proteinuria-related protein expression and the signaling pathway associated protein expression were also detected using quantitative reverse transcription PCR and Western blotting analysis. The results showed that the MPC5 cell model was successfully constructed in vitro. The HQH application could improve the harmful effects induced by TM on the MPC5 cells, including promoted cell proliferation and suppressed cell apoptosis. Furthermore, the protein expression, including podocin, nephrin, and synaptopodin was down-regulated by the TM treatment in the MPC5 cells. On contrary, the expression of these proteins was up-regulated after the HQH application. Also, the effect of TM on integrin α3 and integrin β1 expressions was also reversed by the HQH treatment. Moreover, the HQH application decreased the expression of p-ERK and DNA-damage-inducible transcript 3 (DDIT3 or CHOP) in the MPC5 cells, which was opposite to the effect observed in the cells treated with TM. Taken together, our study suggest that HQH application may protect podocytes from TM damage by suppressing the p-ERK/CHOP signaling pathway.

 

 

Study on effect and mechanism of Huaier aqueous extract on growth and invasion of human prostate cancer PC3 cells.

Zhongguo Zhong Yao Za Zhi. 2016 Jul;41(14):2701-2705.　最新のＩＦなし

[Article in Chinese]

Yang AL^1,2, Hu ZD¹, Tu PF¹.

Abstract

The purpose of this study was to investigate the effect and mechanism of Huaier aqueous extracton growth and invasion of human prostate cancer PC3 cells. CCK-8 assay was used to evaluate the inhibitory effect of Huaier aqueous extract on proliferation of PC3 cells. The effects of Huaier aqueous extract on cell cycle and apoptosis of PC3 cells were analyzed by flow cytometry. Moreover, wound healing assay and Transwell assay were performed to determine the effect of Huaier aqueous extract on invasion and migration abilities of PC3 cells. PC3 cells treated with Huaier aqueous extract were subjected to western blotting for protein levels of EMT markers and phosphorylation levels of key proteins in MAPK pathway. Results revealed that Huaier aqueous extract significantly inhibited the proliferation of PC3 cells in a dose-dependent and time-dependent manner. Huaier aqueous extract dramatically increased the apoptosisrate and induced S-phase arrest in PC3 cells.Furthermore, Huaier suppressed invasion and migration abilities of PC3 cells, and facilitated MET process of PC3 cells via down-regulation of N-cadherin and TCF8/ZEB1 and up-regulation of E-cadherin. In addition, Huaier reduced the phosphorylation of JNK and ERK. Therefore, the regulatory effects of Huaier on EMT and MAPK pathway may be responsible for the suppressive effect of Huaier on growth and invasion of PC3 cells.

 

 

Effect of Huai Qi Huang on Epithelial-Mesenchymal Transition of Renal Tubular Epithelial Cells Through miR-200a

Evid Based Complement Alternat Med. 2016;2016:8612190. doi: 10.1155/2016/8612190. Epub 2016 Jan 14. IF 1.984

Abstract

Epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells is a vital mechanism of renal fibrosis. Mounting evidence suggests that miR-200a expression decreases in tubular epithelial cells in unilateral ureteral obstruction (UUO) rats. Moreover, it has been demonstrated that Huai Qi Huang (HQH) can ameliorate tubulointerstitial damage in adriamycin nephrosis and delay kidney dysfunction in primary glomerular disease. However, the effect of HQH on EMT of tubular epithelial cells in UUO rats and its molecular mechanism is unclear. In order to explore the effect of HQH on EMT and its molecular mechanism in renal fibrosis, in vitro and in vivo experiments were performed in our study. Our results showed that HQH increased miR-200a expression in UUO rats and in TGF-β1 stimulated NRK-52E cells. Meanwhile, HQH decreased ZEB1 and ZEB2 (the transcriptional repressors of E-cadherin), α-SMA expression in renal tubular epithelial cells in vitro and in vivo. Furthermore, we found that HQH protected kidney from fibrosis in UUO rats. The results demonstrated that HQH regulated miR-200a/ZEBs pathway and inhibited EMT process, which may be a mechanism of protecting effect on tubular cells in renal fibrosis.

 

 

Research progress on anti-tumor effect of Huaier.

[Article in Chinese]

Zhongguo Zhong Yao Za Zhi. 2015 Dec;40(24):4805-10.　最新のＩＦなし

Yang AL, Hu ZD, Tu PF.

Abstract

Huaier (Trametes robiniophila) has been widely used as an adjuvant drug for cancer treatment in China. The anti-cancer effect of Huaierextract has been confirmed in liver cancer, lung cancer, breast cancer, ovarian cancer, gastric cancer, and so on. The main mechanisms by which Huaier exerts an anti-neoplastic effect include inhibition of the growth and proliferation of cancer cells, induction of apoptosis of cancer cells, suppression of angiogenesis, inhibition of the invasion and migration of cancer cells, regulation of oncogenes and tumor suppressor genes expression, improving immunity, and reversal of drug resistance in cancer cells. In order to provide references for further study and clinical application on anti-tumor effect of Huaier, the latest research progress on anti-tumor effect of Huaier in recent years is summarized in this paper.

 

 

Huaier aqueous extract sensitizes cells to rapamycin and cisplatin through activating mTOR signaling.

J Ethnopharmacol. 2016 Jun 20;186:143-150.　 IF3.115

Hu Z¹, Yang A², Fan H³, Wang Y⁴, Zhao Y¹, Zha X⁵, Zhang H⁶, Tu P⁷.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE:

Traditional Chinese Medicine (TCM) has been increasingly used to treat cancers. Trametes robiniophila Murr. (Huaier) is a medicinal fungus for treatment of inflammation and cancer. Huaier Granule has great clinical effect in various types of cancers, including liver cancer, lung cancer, gastric cancer, and breast cancer.

AIM OF THE STUDY:

The present study was performed to determine the therapeutical effect of Huaier on cancers caused by aberrant mTOR signaling in vitro and in vivo, investigate the combination effect of Huaier and rapamycin or cisplatin on cell viability, and explore its underlying mechanism.

MATERIALS AND METHODS:

The therapeutical effect of Huaier on cancers caused by aberrant mTOR signaling and the underlying mechanism of combination effect of Huaier and rapamycin or cisplatin on cell viability were investigated in mouse embryonic fibroblasts, rat uterine leiomyoma cells, human hepatoma cells, human lung carcinoma cells, and xenograft tumor model by cell viability assay and immunoblotting.

RESULTS:

Activation of mTOR sensitizes cells to Huaier treatment. Huaier inhibits tumorigenic capacity of cells with activated mTOR in vivo. Moreover, activation of mTOR signaling induced by Huaier contributes to the increased sensitivity of cells to rapamycin or cisplatin in response to Huaier treatment.

CONCLUSIONS:

Huaier may be a potential drug for the treatment of cancers caused by aberrant mTOR signaling. The combination of Huaier and rapamycin may be a candidate regimen in the treatment of these cancers.

 

 

Huaier extract synergizes with tamoxifen to induce autophagy and apoptosis in ER-positive breast cancer cells.

Oncotarget. 2016 May 3;7(18):26003-15.　最新のＩＦなし

Qi W¹, Sun M², Kong X³, Li Y¹, Wang X¹, Lv S¹, Ding X⁴, Gao S¹, Cun J¹, Cai C¹, Wang X¹, Chen J¹, Yin A⁵, Yang Q^1,6.

Abstract

Tamoxifen (TAM) is the most widely used endocrine therapy for estrogen receptor (ER)-positive breast cancer patients, but side effects and the gradual development of insensitivity limit its application. We investigated whether Huaier extract, a traditional Chinese medicine, in combination with TAM would improve treatment efficacy in ER-positive breast cancers. MTT, colony formation, and invasion and migration assays revealed that the combined treatment had stronger anticancer effects than either treatment alone. Huaier extract enhanced TAM-induced autophagy, apoptosis, and G0/G1 cell cycle arrest, as measured by acidic vesicular organelle (AVO) staining, TUNEL, flow cytometry, and western blot. Additionally, combined treatment inhibited tumorigenesis and metastasis by suppressing the AKT/mTOR signaling pathway. Huaier extract also enhanced the inhibitory effects of TAM on tumor growth in vivo in a xenograft mouse model. These results show that Huaier extract synergizes with TAM to induce autophagy and apoptosis in ER-positive breast cancer cells by suppressing the AKT/mTOR pathway.

 

 

Radiosensitization effect of Huaier on breast cancer cells.

Oncol Rep. 2016 May;35(5):2843-50.　最新のＩＦなし

Ding X¹, Yang Q², Kong X³, Haffty BG⁴, Gao S², Moran MS⁵.

Abstract

Radiotherapy is a critical treatment strategy for breast cancer. However, its wide application is sometimes restricted by radioresistance and radiotoxicity. Trametes robiniophila Murr. (Huaier), an officinal fungus used as a traditional Chinese medicine (TCM), is reported to have multi-biological functions during cancer treatment. Yet, its radiosensitization effects have not been evaluated to date. In the present study, using HTA 2.0 transcriptome microarray assay, Huaier was found to downregulate genes related to the cell cycle, cell division, cell cycle phases and DNA repair. This investigation utilized a colony formation assay to confirm the ability of Huaier to sensitize breast cancer cells to radiotherapy. Flow cytometry, immunofluorescence staining and western blotting were used to illustrate the sensitization mechanism. Our findings suggest that Huaier causes G0/G1 arrest through downregulation of cell cycle-regulating proteins in MCF-7 and MDA-MB-468 cells, prolongs the persistence of γ-H2Ax foci after radiotherapy and interferes with the homologous recombination (HR) pathway of DNA repair by downregulating RAD51. These results suggest that Huaier has the ability to sensitize breast cancer cellsto radiotherapy through regulation of the cell cycle and DNA repair pathway. Thus, Huaier may be a promising radiosensitizer for the treatment of breast cancer.

 

 

Huaier extract suppresses breast cancer via regulating tumor-associated macrophages.

Sci Rep. 2016 Feb 1;6:20049.　 IF4.122

Li Y¹, Qi W¹, Song X¹, Lv S¹, Zhang H¹, Yang Q^1,2.

Abstract

Macrophages in tumor microenvironment are mostly M2-polarized – and have been reported to promote tumorigenesis, which are also defined as tumor-associated macrophages (TAMs). Here, we examined the regulatory effects of Huaier extract on TAMs using RAW264.7 murine macrophage cell line. Our data demonstrated that Huaier extract could inhibit the infiltration of macrophages into tumor microenvironment in a dose-dependent manner. By performing RT-PCR, immunofluorescence and phagocytosis assay, we were able to find that Huaier extract could regulate the polarization of macrophages, with decreased M2-polarization and increased phagocytosis of RAW264.7 cells. Moreover, we identified that Huaier extract could suppress macrophages-induced angiogenesis by using HUVEC migration assay, tube formation and chorioallantoic membrane assay. Additionally, western blotting showed decreased expression of MMP2, MMP9 and VEGF with the use of Huaier extract. Finally, we found that Huaier extract could inhibit M2-macrophages infiltration and angiogenesis through treating 4T1 tumor bearing mice with Huaier extract. Our study revealed a novel mechanism of the anti-tumor effect of Huaier extract which inhibited angiogenesis by targeting TAMs. These findings provided that Huaier was a promising drug for clinical treatment of breast cancer.

 

 

Hepatocellular Carcinoma Patients May Benefit From Postoperative Huaier Aqueous Extract After Liver Transplantation.

Transplant Proc. 2015 Dec;47(10):2920-4.　 IF0.806

Lei JY¹, Yan LN², Zhu JQ³, Wang WT⁴.

Abstract

BACKGROUND:

Liver transplantation has been the first choice for most early- or intermediate-stage hepatocellular carcinoma (HCC) cases. However, postoperative anti-HCC therapies remain controversial. In this study, we aimed to evaluate the safety and efficacy of Huaier aqueous extract (Jinke), when used as an adjuvant postoperative anti-HCC therapy.

METHODS:

We retrospectively collected the clinical and follow-up data of HCC patients who underwent liver transplantation at our center. We divided them into 2 groups: a control liver transplantation group and a Huaier treatment group. The baseline characteristics, tumor characteristics, intraoperative data, postoperative recovery, long-term overall survival rate, and tumor-free survival rate were compared between the 2 groups.

RESULTS:

Fifty-three patients were included in our study, including 28 patients who underwent postoperative Huaier therapy and 25 patients who underwent liver transplantation without postoperative Huaier therapy. The baseline and tumor characteristics were similar between the 2 groups. None of the patients in the Huaier group experienced any severe adverse events. The long-term predictive overall survival was similar between the 2 groups (P = .202). However, the Huaier group had a higher predictive tumor-free survival rate than the control group (P = .029). And the 10- and 30-month predictive tumor recurrence rates were 17.9% and 35.7% in the Huaiergroup, which were significantly lower than those in the control group (60% and 64%; P < .05).

CONCLUSIONS:

HCC patients may benefit from Huaier therapy after liver transplantation, but a longer follow-up time and larger cohort study may be necessary to be sure.

 

 

Effect of Huaier on the proliferation and apoptosis of human gastric cancer cells through modulation of the PI3K/AKT signaling pathway.

Exp Ther Med. 2015 Sep;10(3):1212-1218.　 IF1.41

Xie HX¹, Xu ZY¹, Tang JN¹, DU YA², Huang L², Yu PF², Cheng XD¹.

Abstract

The aim of the present study was to investigate the effect of Huaier on the proliferation and apoptosis of the MKN45 and SGC7901 gastric cancer cell lines. The MTT assay was used to measure the effects of Huaier on the growth of the cells, while cell cycle distribution and apoptosis levels were analyzed using flow cytometry. Western blotting was used to assess the levels of proteins associated with the apoptotic pathway. It was found that cell survival decreased with the increase in the concentration of Huaier, and the apoptosis rates were increased in a dose-dependent manner both in MKN45 and SGC7901 cells. The number of cells in the G2/M phase in the Huaier-treated groups was increased in a dose-dependent manner compared with that in the control group. Huaier inhibited phosphorylated- (p-)AKT1, phosphatidylinositol 3-kinase (PI3K), pyruvate dehydrogenase kinase isoform 1, p-phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase and B-cell lymphoma 2 expression and upregulated cleaved-caspase-9 expression in a dose-dependent manner. In conclusion, Huaier can strongly inhibit gastric cancer cell proliferation by inhibiting cyclin B1 expression, promoting G2/M-phase arrest and modulating the PI3K/AKT signaling pathway, and can induce gastric cancer cell apoptosis by modulating the PI3K/AKT signaling pathway in dose-dependent manner.

 

 

Huaier Aqueous Extract Induces Hepatocellular Carcinoma Cells Arrest in S Phase via JNK Signaling Pathway.

Evid Based Complement Alternat Med. 2015;2015:171356.　 IF2.064

Zhang C¹, Zhang J¹, Li X², Sun N¹, Yu R¹, Zhao B¹, Yu D³, Cheng Y¹, Liu Y¹.

Abstract

Huaier aqueous extract, the main active constituent of Huaier proteoglycan, has antihepatocarcinoma activity in experimental and clinical settings. However, the potential and associated antihepatoma mechanisms of Huaier extract are not yet fully understood. Therefore, in this study, we aimed to elucidate the inhibitory proliferation effect of Huaier extract on apoptosis and cycle of HepG2 and Bel-7402 cells. Our data demonstrated that incubation with Huaier extract resulted in a marked decrease in cell viability dose-dependently. Flow cytometric analysis showed that a 48 h treatment of Huaier extract caused cell apoptosis. Typical apoptotic nucleus alterations were observed with fluorescence microscope after Hoechst staining. Immunoblot analysis further demonstrated that Huaierextract activated caspase 3 and PARP. Additionally, Huaier extract inhibited the activity of p-ERK, p-p38, and p-JNK in terms of MAPK. Furthermore, Huaier extract induced HCC cells arrest in S phase and decreased the cycle related protein expression of β-catenin and cyclin D1. Studies with JNK specific inhibitor, SP600125, showed that Huaier extract induced S phase arrest and decreased β-catenin and cyclin D1 expression via JNK signaling pathway. In conclusion, we verify that Huaier extract causes cell apoptosis and induces hepatocellular carcinoma cells arrest in S phase via JNK pathway, which advances our understanding on the molecular mechanisms of Huaier extract in hepatocarcinoma management.

 

 

Huaier aqueous extract inhibits cervical cancer cell proliferation via JNK/p38 pathway.

Int J Oncol. 2015 Sep;47(3):1054-60.　 IF3.333

Yan L¹, Liu X¹, Yin A¹, Wei Y¹, Yang Q², Kong B¹.

Abstract

Although the anticancer effects of Huaier extract have been widely investigated, including anti-proliferate, anti-angiogenic and anti-metastatic activities, the mechanisms are not well understood. This study aimed to elucidate the inhibitory effect of Huaier extract on tumor growth in cervical cancer cells and its molecular mechanisms. Cell viability and motility were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony assays, migration, and invasive assays, respectively. The distribution of the cell cycle was analyzed by flow cytometry. Huaier inhibited cell viability of SiHa and C33A cells in a time- and dose-dependent manner; cell migration and invasiveness were also suppressed; Huaier was able to cause G2/M cell cycle arrest in C33A cells. The western blot results confirmed Huaier dose-dependently increased expression of phosphorylated c-Jun N-terminal kinase (JNK), p-38 and downregulated the expression of phosphorylated extracellular signal-regulated kinase (ERK) in a time- and dose-dependently manner. In vivo experiments showed that Huaier significantly suppressed the tumor volume of SiHa cell xenografts. These data suggest that Huaier may inhibit tumor proliferation in cervical cancer via the JNK/p38 signaling pathway.

 

 

Huaier Extract Induces Autophagic Cell Death by Inhibiting the mTOR/S6K Pathway in Breast Cancer Cells.

PLoS One. 2015 Jul 2;10(7):e0131771.　 IF2.766

Wang X¹, Qi W², Li Y², Zhang N¹, Dong L¹, Sun M¹, Cun J¹, Zhang Y³, Lv S², Yang Q⁴.

Abstract

Huaier extract is attracting increased attention due to its biological activities, including antitumor, anti-parasite and immunomodulatory effects. Here, we investigated the role of autophagy in Huaier-induced cytotoxicity in MDA-MB-231, MDA-MB-468 and MCF7 breast cancer cells. Huaier treatment inhibited cell viability in all three cell lines and induced various large membranous vacuoles in the cytoplasm. In addition, electron microscopy, MDC staining, accumulated expression of autophagy markers and flow cytometry revealed that Huaier extract triggered autophagy. Inhibition of autophagy attenuated Huaier-induced cell death. Furthermore, Huaier extract inhibited the mammalian target of the rapamycin (mTOR)/S6K pathway in breast cancer cells. After implanting MDA-MB-231 cells subcutaneously into the right flank of BALB/c nu/nu mice, Huaier extract induced autophagy and effectively inhibited xenograft tumor growth. This study is the first to show that Huaier-induced cytotoxicity is partially mediated through autophagic cell death in breast cancer cells through suppression of the mTOR/S6K pathway.

 

 

Triplet anti-tumor therapy based on thymosin α-1 attenuates incidence of hepatoma and serum alpha-fetoprotein level in rat hepatoma model.

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2015 Jun;31(6):744-8.　最新のＩＦなし

[Article in Chinese]

Fu X¹, Wei Y², Zheng D³, Zhou L³, Zhu Z³, Song J³, Feng L³, Du G³.

Abstract

OBJECTIVE:

To explore the impact of triple anti-tumor therapy based on thymosin α1 (Tα1) combined with Huaier granule(HG) and sirolimus on the level of serum alpha-fetoprotein (AFP) in rat models of liver cancer.

METHODS:

Ninety Sprague-Dawley rats were randomly divided into triple anti-tumor therapy group, Tα1 group, HG group, sirolimus group, positive control and blank control groups, with 15 rats in each group. Except the blank control group, the rats in the other groups were induced using diethylnitrosamine (DEN) to establish liver cancer models. After DEN treatment, the triple therapy group underwent 0.8 mg/kg Tα1 subcutaneous injection (from once a day for two weeks to twice a week since the third week), 0.35 g/kg HG gavage (three times a day) and 1 mg/kg sirolimus gavage (once a day). The dose of the rest single drug groups were the same with that of the triple therapy group. The positive control and blank control groups were not treated with the drugs. The treatment lasted 20 weeks. Then, the behavior of the rats were observed at the different time points, and the level of serum AFP in the rats were detected at 6, 16, 18, 20 weeks, respectively.

RESULTS:

The typical symptoms of liver cancer were seen in the DEN-induced rats at 16 weeks. Since the tenth week, 6 rats died one after another. Pathological section of rat liver tissue suggested that the rat models were established successfully. According to the incidence rate of liver cancer and the survival rate at 20 weeks, the triple anti-tumor therapy was significantly superior to the single drug treatments. In addition, the triple anti-tumor therapy significantly reduced the level of serum AFP in the rats.

CONCLUSION:

The triple anti-tumor therapy can significantly prolong the survival time of rats with liver cancer, decrease the cancer incidence rate and the level of serum AFP.

 

 

The anticancer effect of Huaier (Review).

Oncol Rep. 2015 Jul;34(1):12-21.　 976

Song X¹, Li Y¹, Zhang H¹, Yang Q¹.

Abstract

Trametes robiniophila Murr. (Huaier) is a sandy beige mushroom found on the trunks of trees and has been widely used in traditional Chinese medicine (TCM) for ~1,600 years. The anticancer effects of Huaier have attracted increasing worldwide interest in recent years. Accumulating evidence suggests that the anticancer mechanism of Huaier may be associated with various biological activities, such as inhibition of cell proliferation, anti-metastasis, interference with tumor angiogenesis and tumor-specific immunomodulatory effect. Animal and experimental studies suggest that Huaier is a promising anticancer agent. Further clinical research is warranted to illustrate the untapped chemopreventive and therapeutic potential of Huaier either alone or in conjunction with existing therapies.

 

 

Huaier Cream Protects against Adriamycin-Induced Nephropathy by Restoring Mitochondrial Function via PGC-1α Upregulation.

PPAR Res. 2015;2015:720383.　 IF3.386

Che R¹, Zhu C², Ding G², Zhao M², Bai M², Jia Z², Zhang A², Huang S².

Abstract

The mechanism by which Huaier, a Chinese traditional medicine, protects podocytes remains unclear. We designed the present study to examine whether mitochondrial function restored by PGC-1α serves as the major target of Huaier cream in protecting ADR nephropathy. After ADR administration, the podocytes exhibited remarkable cell injury and mitochondrial dysfunction. Additionally, ADR also reduced PGC-1α both in vivo and in vitro. Following the Huaier treatment, the notable downregulation of PGC-1α and its downstream molecule mitochondrial transcription factor A (TFAM) were almost entirely blocked. Correspondingly, Huaier markedly ameliorated ADR-induced podocyte injury and mitochondrial dysfunction in both rat kidneys and incubated cells as it inhibited the decrease of nephrin and podocin expression, mtDNA copy number, MMP, and ATP content. Transmission electron microscopy result also showed that Huaier protected mitochondria against ADR-induced severe mitophagy and abnormal changes of ultrastructural morphology. In conclusion, Huaier can protect podocytes against ADR-induced cytotoxicity possibly by reversing the dysfunction of mitochondria via PGC-1α overexpression, which may be a novel therapeutic drug target in glomerular diseases.

 

 

Identification of multi-target effects of Huaier aqueous extract via microarray profiling in triple-negative breast cancer cells.

Int J Oncol. 2015 May;46(5):2047-56.　 IF3.333

Kong X¹, Ding X², Yang Q¹.

Abstract

Breast cancer is one of the most common malignant tumors in the world. Long-term maintenance treatment is important for breast cancer. However, effective maintenance treatment is lacking for triple-negative breast cancer (TNBC). Traditional Chinese medicine (TCM) has shown its potential anticancer roles as an effective maintenance treatment for TNBC. However its mechanisms remained unclear. In this study, we detected the differentially expressed genes (DEGs) after treatment with Huaier aqueous extract by using microarray profiling in MDA-MB-231 cells. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and gene-gene interaction network were conducted to confirm the altered biological functions induced by Huaier extract. Screening of DEGs gave 387 genes (226 upregulated and 161 downregulated) in MDA-MB-231 cells which were regulated significantly by Huaier extract. GO and KEGG pathway analysis suggested that a number of functions were affected by Huaier, including proliferation, apoptosis, migration, and angiogenesis. Gene-gene interaction network showed the detailed molecular signal-net. Based on microarray data, we studied several functions of Huaier extract and in return verified the results of microarray profiling. This study had important guidance roles and indicated new research directions.

 

 

Huaier aqueous extract induces apoptosis of human fibrosarcoma HT1080 cells through the mitochondrial pathway.

Oncol Lett. 2015 Apr;9(4):1590-1596.　 IF1.664

Cui Y¹, Meng H², Liu W³, Wang H², Liu Q¹.

Abstract

In recent years, aqueous extract of Trametes robiniophila Murr. (Huaier), a traditional Chinese medicine, has been frequently used in China for complementary cancer therapy. However, the mechanisms underlying its anticancer effects have yet to be elucidated. The present study aimed to evaluate the ability of Huaier extract to inhibit proliferation, promote apoptosis and suppress mobility in the fibrosarcoma HT1080 cell line in vitro. The cells were treated with gradient doses of Huaier extract at concentrations of 0, 4, 8 or 16 mg/ml for 24, 48 or 72 h. The cell viability and motility were measured in vitro using MTT, invasive, migration and scratch assays. The distribution of the cell cycle and the extent of cellular apoptosis were analyzed by flow cytometry. The apoptotic pathways were detected using a mitochondrial membrane potential transition assay and western blotting. The results revealed that the cellular viability decreased significantly with increasing concentrations of Huaier extract. In addition, cell invasiveness and migration were also suppressed significantly. It was demonstrated that Huaier extract induced G₂ cell-cycle arrest and cellular apoptosis in a time- and dose-dependent manner. The decreased mitochondrial membrane potential, the downregulation of B-cell lymphoma 2 and pro-caspase-3, and upregulation of Bcl-2-associated X protein, cleaved caspase-9 and caspase-3 suggested that Huaier extract induced the apoptosis of HT1080 cells through the mitochondrial pathway. The results of the present study indicate that Huaier extract is a potential complementary agent for the treatment of fibrosarcoma.

 

 

A Huaier polysaccharide reduced metastasis of human hepatocellular carcinoma SMMC-7721 cellsvia modulating AUF-1 signaling pathway.

Tumour Biol. 2015 Aug;36(8):6285-93.　最新のＩＦなし

Li C¹, Wu X, Zhang H, Yang G, Hao M, Sheng S, Sun Y, Long J, Hu C, Sun X, Li L, Zheng J.

Abstract

TP-1 is a polysaccharide from one famous fungus Huaier. Treatment with TP-1 significantly inhibited the cell growth, adhesion, migration, and motility of SMMC-7721 cells in a dose-dependent manner. Real-time quantitative RT-PCR revealed a dose-dependent decrease in RNA-binding factor 1 (AUF-1) and astrocyte elevated gene-1 (AEG-1) messenger RNA (mRNA) levels in TP-1-treated SMMC-7721 cells, which is consistent with their protein expression detected by Western blotting. On the contrary, microRNA-122 (miR-122) expression increased in SMMC-7721 cells following TP-1 treatment. Moreover, TP-1 treatment at three doses apparently increased epithelial marker E-cadherin protein expression but decreased the mesenchymal marker N-cadherin protein level. In addition, the hematoxylin-eosin (H & E) staining showed that the TP-1 significantly inhibited the lung metastasis of liver cancer in mice orthotopic implanted with SMMC-7721 tumor tissue. Taken together, these findings proved the inhibitory effect of TP-1 on the growth and metastasis of SMMC-7721 cells, and TP-1 might be offered for future application as a powerful chemopreventive agent against hepatocellular carcinoma (HCC) metastasis.

 

 

A Huaier polysaccharide restrains hepatocellular carcinoma growth and metastasis by suppression angiogenesis.

Int J Biol Macromol. 2015 Apr;75:115-20.　 IF3.909

Li C¹, Wu X², Zhang H¹, Yang G¹, Hao M¹, Sheng S¹, Sun Y¹, Long J¹, Hu C¹, Sun X³, Li L⁴, Zheng J⁵.

Abstract

Hepatocellular carcinoma (HCC) is a highly metastatic cancer. Huaier polysaccharide (TP-1) is a naturally occurring bioactive macromolecule, found in Huaier fungus and has been shown to exert in vitro antitumor and antimetastasis for HCC, but no study has addressed in vivo efficacy and mechanisms of action. Presently, we found that TP-1 at doses of 0.5, 1 and 2mg/kg significantly inhibited tumor growth and metastasis to the lung in mice bearing HCC SMMC-7721 tumors without toxicity. The analysis of tumors by immunohistochemistry demonstrated that TP-1 inhibited PCNA expression, increased the number of TUNEL-positive cells and reduced microvessel density (MVD) to achieve this effect. Furthermore, TP-1 administration reduced the protein expression of hypoxia-inducible factor (HIF)-1alpha, vascular endothelial growth factor (VEGF), AUF-1 and AEG-1, in tumor tissues. Taken together, our data suggested that the antitumor and anti-metastatic activities of TP-1 might be at least partially through down-regulation of HIF-1alpha/VEGF and AUF-1/AEG-1 signaling pathways.

 

 

Apolysaccharide from mushroom Huaier retards human hepatocellular carcinoma growth, angiogenesis, and metastasis in nude mice.

Tumour Biol. 2015 Apr;36(4):2929-36.　最新のＩＦなし

Zou Y¹, Xiong H, Xiong H, Lu T, Zhu F, Luo Z, Yuan X, Wang Y.

Mushroom Huaier has become a focus of interest in the treatment of hepatocellular carcinoma (HCC). Presently, we isolated and purified one polysaccharide from this mushroom. This study aimed to investigate the effects of SP1 on tumor growth and metastasis in a HCC xenograft model and explore its possible mechanism of action. Our results showed that SP1 not only significantly inhibited the proliferation of SMMC-7721 cells in vitro at the concentration ranging from 0 to 800 μg/ml but also suppressed the HCC tumor growth and metastatic nodules to the lung in SMMC-7721-bearing mice by oral administration at three doses of 30, 60, and 120 mg/kg. Concomitantly, immunohistochemistry analysis of tumor tissues identified that SP1 administration at three doses significantly inhibited the in vivo cancer cell proliferation and microvessel density (MVD) formation, evidenced by a low proliferating cell nuclear antigen (PCNA) and CD34 expression, but increased the percentage of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells. Keeping in line with this observation, SP1 treatment decreased serum matrix metalloproteinase (MMP) 2 and vascular endothelial growth factor (VEGF) levels, downregulated the protein expression of hypoxia-inducible factor (HIF)-1alpha, VEGF, MMP2, bcl-2, N-cadherin, signal transducer and activator of transcription 3 (STAT3), and metadherin (MTDH), and upregulated bax and NE-cadherin protein expression in tumor tissues. Taken together, our data suggest that SP1 appears to be a promising chemopreventive agent for the tumorigenesis and metastasis in patients with HCC, especially at advanced stages.

 

 

A Huaier polysaccharide inhibits hepatocellular carcinoma growth and metastasis.

Tumour Biol. 2015 Mar;36(3):1739-45.　最新のＩＦなし

Li C¹, Wu X, Zhang H, Yang G, Hao M, Sheng S, Sun Y, Long J, Hu C, Sun X, Li L, Zheng J.

Abstract

This study was carried out to evaluate the effects of a Huaier polysaccharide (TP-1) on the tumor growth and immune function in hepatocellular carcinoma (HCC) H22-based mouse in vivo. Results showed that TP-1 was capable of repressing transplanted H22 solid hepatic tumor cell growth in vivo, prolonging the live time of mice bearing ascetic H22 tumors, and repressing the pulmonary metastasis of H22-bearing mice. Moreover, the relative weight of immune organ (spleen and thymus) and lymphocyte proliferation were improved after TP-1 treatment. Furthermore, the treatment with TP-1 could promote immune-stimulating serum cytokines, such as IL-2 and IFN-γ, but inhibit immune-suppressing serum cytokines IL-10 secretion in H22-bearing mice. Besides, the percentage of CD4+ T cells and NK cells was increased, whereas the number of CD8+ T cells decreased in tumor-bearing mice following TP-1 administration. In addition, this compound displayed little toxic effects to major organ of tumor-bearing mice at the therapeutic dose, such as the liver and kidney. This experimental finding suggested that TP-1 exhibited prominent antitumor activities in vivo via enhancement of host immune system function in H22 tumor-bearing mice. This product could be developed individually as a safe and potent biological response modifier for HCC therapy.

 

 

Huaier aqueous extract inhibits stem-like characteristics of MCF7 breast cancer cells via inactivation of hedgehog pathway.

Tumour Biol. 2014 Nov;35(11):10805-13.　最新のＩＦなし

Wang X¹, Zhang N, Huo Q, Sun M, Dong L, Zhang Y, Xu G, Yang Q.

Abstract

The theory of targeting cancer stem-like cells (CSCs) provides novel strategy for cancer treatment. In the present study, we examined the inhibitory effect of Huaier aqueous extract on eradicating breast cancer stem cells and explored the underlying mechanisms. Our data demonstrated that various concentrations of Huaier extract significantly decreased the viabilities, numbers, and sizes of mammospheres. After incubation with Huaier extract for 24 h, the clonogenicity of MCF7 cell line was obviously impaired, along with less holoclones. In addition, Huaier extract reduced the number of cells expressing CD44+/CD24- and decreased the level of stem cell markers (OCT-4, NESTIN, and NANOG). The hedgehog (Hh), notch, and Wnt/β-catenin pathways were essential stem cell signaling pathways involved in regulating CSC renewal and maintenance. We reported that the inhibitory effect of Huaier extract was partly depended on the inactivation of Hh pathway. These findings provided experimental evidence that Huaier extract was a promising therapeutic drug for eliminating the breast cancer stem cells.

 

 

Preliminary Study of Huai Qi Huang Granules Delay the Development of Primary Glomerular Diseases in Human

Ren Fail. 2014 Oct;36(9):1407-10. doi: 10.3109/0886022X.2014.952746.IF 1.678

Abstract

Objective: To evaluate the effects of Huai Qi Huang (HQH) granules on primary glomerulonephritis patients, and to discuss its possible mechanisms. Method: Sixteen patients diagnosed with primary glomerular disease between December 2011 and December 2012 were enrolled. Their blood and urine samples were collected at day 0 (the baseline levels), 30, and 90 of receiving HQH granules orally. Levels of creatinine and cystatin C (Cys-C) in serum and urine, and total protein and albumin in urine were measured by automatic biochemical analyzer. Neutrophil gelatinase-associated lipocalin (NGAL) in serum and urine was tested by ELISA; serum malondialdehyde (MDA) was measured by thiobarbituric acid method, the erythrocyte count in urine was calculated under light microscope. Results: Serum levels of creatinine, MDA, Cys-C and NGAL at day 30 and 90 were significantly lower than the baseline levels. Urinary levels of Cys-C, NGAL, total protein, albumin and erythrocyte counts were also decreased; level of estimated glomerular filtration (eGFR) was increased. Conclusion: HQH granules have certain effect on delaying the development of primary glomerular disease with mild proteinuria and hematuresis in patients. This study may supply a new treatment for primary glomerular diseases.

 

 

Optimization of polysaccharides extraction from Trametes robiniophila and its antioxidant activities.

Carbohydr Polym. 2014 Oct 13;111:324-32.　 IF5.158

Wang Y¹, Liu Y², Hu Y³.

Abstract

Based on a single-factor experiment, Box-Behnken design was used to optimize the ultrasound-assisted extraction process of Trametes robiniophila (Huaier) polysaccharides (HPs). The optimum conditions were predicted as follows: ratio of water to raw material, 46.0 mL/g; extraction temperature, 68.9 °C; ultrasonic power, 51.3 W; and extraction time, 36.8 min. Under these conditions, the highest yield of HPs obtained was 36.8 ± 0.12%, which was in good agreement with the predicted value 36.6%. Additionally, chemical analysis of HPs showed a high content (85.3 ± 1.3%) of carbohydrates containing fucose, arabinose, xylose, mannose, galactose and glucose, with molar percentages 5.82%, 13.11%, 16.88%, 15.85%, 11.40% and 36.94%, respectively. Besides, HPs demonstrated appreciable antioxidant potential on ABTS, superoxide anion and hydroxyl radicals in vitro. These may further provide theoretical basis for the widely application of HPs in medicine and health care products.

 

 

Huaier suppresses proliferation and induces apoptosis in human pulmonary cancer cells via upregulation of miR-26b-5p.

FEBS Lett. 2014 Jun 5;588(12):2107-14.　 IF2.999

Wu T¹, Chen W², Liu S³, Lu H⁴, Wang H⁵, Kong D⁵, Huang X⁶, Kong Q⁷, Ning Y⁸, Lu Z⁹.

Abstract

Various studies have reported that Huaier possesses anti-tumor effects. However, the mechanisms are not completely elucidated. Here, we found 66 differentially expressed miRNAs in Huaier-treated pulmonary adenocarcinoma A549 cells, with upregulation of miR-26b-5p. Transfection of A549 cells with miR-26b-5p mimic inhibited proliferation and induced apoptosis, while transfection of Huaier-treated A549 cells with a miR-26b-5p inhibitor reversed the effects of Huaier. EZH2 was verified as the target of miR-26b-5p. Thus, our findings indicate that Huaier might suppress proliferation and induce apoptosis in lung cancer cells via a miR-26b-5p-EZH2-mediated approach, which provides a new perspective for understanding the anti-tumor effects of Huaier.

 

 

Astrocyte elevated gene-1 (AEG-1) shRNA　sensitizes Huaier polysaccharide (HP)-induced anti-metastatic potency via inactivating downstream P13K/Akt pathway as well as augmenting cell-mediated immune response.

Tumour Biol. 2014 May;35(5):4219-24.　最新のＩＦなし

Zheng J¹, Li C, Wu X, Liu M, Sun X, Yang Y, Hao M, Sheng S, Sun Y, Zhang H, Long J, Liang Y, Hu C.

Abstract

Astrocyte elevated gene-1 (AEG-1) is an important force in the development and progression of hepatocellular carcinoma (HCC). To extend our study, we examined here the role of AEG-1 in anti-metastatic effects of Huaier polysaccharide (HP) on the human HCC MHCC97-H cell line. AEG-1 shRNA contributed to the anti-proliferation effect of HP on MHCC97-H cells. Furthermore, results of Transwell insert chambers showed that low expression of AEG-1 could effectively facilitate HP to suppress MHCC97-H cell migration and invasion. We achieved this by reducing phosphoinositide 3-kinases (P13K) and phosphorylated Akt (pAkt) expression as well as enhancing natural killer (NK) cell activity. Taken together, our data strongly suggested that AEG-1 shRNA could block the carcinogenesis and progression of MHCC97-H cells and highlight the therapeutic potential of HP in HCC treatment, at least by part, by inhibiting the activation of the PI3K/Akt pathway and enhancing the NK cell-mediated immune response. These findings may provide a new strategy for HCC treatment.

 

 

Huaier polysaccharides suppresses hepatocarcinoma MHCC97-H cell metastasis via inactivation of EMT and AEG-1 pathway.

Int J Biol Macromol. 2014 Mar;64:106-10.　 IF3.909

Zheng J¹, Li C², Wu X³, Liu M⁴, Sun X⁵, Yang Y³, Hao M², Sheng S², Sun Y², Zhang H², Long J², Liang Y⁶, Hu C².

Abstract

We have recently reported that astrocyte elevated gene-1 (AEG-1) might be an epithelial-mesenchymal transition (EMT) associated biomarker in human hepatocellular carcinoma (HCC), and play an important role in the progression of hepatocellular carcinoma. To extend our study, we examined here the anti-invasive and metastatic effects of Huaier polysaccharide (HP) on human HCC cell line MHCC97-H and explored its possible mechanism of action. Treatment with HP dose-dependently inhibited the proliferation, adhesion, migration and invasion of MHCC97-H cells in vitro. This was achieved not only by reducing the expression of AEG-1 and N-cadherin, but also by enhancing E-cadherin expression. Therefore, these data suggested that HP can inhibit the growth and metastatic potential of MHCC97-H cells through modulation of the AEG-1/EMT pathway.

 

 

Huai Qi Huang Ameliorates Proteinuria and Hematuria in Mild IgA Nephropathy Patients: A Prospective Randomized Controlled Study

J Formos Med Assoc. 2013 Dec;112(12):766-72. IF 2.844

Abstract

Background/purpose: Huai Qi Huang (HQH) is a compound Chinese herbal medicine that contains Trametes robiniophila murr, wolfberry fruit, and Polygonatum. In the present study, we investigated the effects of HQH on patients with mild immunoglobulin A nephropathy (IgAN) through a prospective randomized controlled study. Methods: Forty-five adults diagnosed with IgAN according to renal pathology, who had hematuria or/and proteinuria (≤ 2 g/day), were randomly assigned to receive HQH or no treatment for 12 weeks. Twenty-four hour urinary protein excretion and hematuria were measured at Weeks 0, 4, 8, and 12. The rate of complete remission of proteinuria and hematuria was evaluated. Any adverse events induced by HQH were also observed during the treatment period. Results: Twenty-four hour urinary protein excretion was significantly reduced by HQH treatment compared with that in the control group at Weeks 8 and 12. A much higher rate of complete remission of proteinuria was observed in the HQH group than in control group at Week 12. HQH administration also obviously reduced the extent of hematuria compared with that in the control group at Week 12. HQH treatment dramatically increased the rate of complete remission of hematuria compared with that in control group at Weeks 8 and 12. No obvious adverse events caused by HQH were observed. Conclusion: HQH could be a new conservative therapy for IgAN patients who cannot tolerate steroids and immunosuppressive agents. The relapse rate after discontinuing treatment still needs further investigation.

 

 

Huaier aqueous extract suppresses human breast cancer cell proliferation through inhibition of estrogen receptor α signaling.

Int J Oncol. 2013 Jul;43(1):321-8.　 IF3.333

Wang X¹, Zhang N, Huo Q, Sun M, Lv S, Yang Q.

Abstract

Estrogen receptor α (ERα) has been reported to play a critical role in promoting the growth of breast tumor cells. In the present study, we explored the effect of Huaier extract on estrogen receptor α signaling in breast cancer cell lines. Our data demonstrated that Huaierextract effectively inhibited the proliferation of the MCF-7, T47D and ZR-75-1 human breast cancer cell lines. For the mechanism analysis, we demonstrated that Huaier extract significantly reduced the mRNA and protein levels of ERα in all three ERα-positive cell lines. The downregulation of

ERα protein levels was correlated with activation of the proteasomes. We demonstrated that Huaier extract markedly decreased the expression of both ERα and its downstream genes, inhibited the estrogen-stimulated proliferation and reversed the estrogen-induced activation of the nuclear factor κB (NFκB) pathway. Our study provides evidence that Huaier extract is a novel estrogen receptor modulator and is a promising drug for the prevention and treatment of ERα-positive human breast cancers.

 

 

Huaier aqueous extract inhibits ovarian cancer cell motility via the AKT/GSK3β/β-catenin pathway.

PLoS One. 2013 May 8;8(5):e63731.　 IF2.766

Yan X¹, Lyu T, Jia N, Yu Y, Hua K, Feng W.

Abstract

Traditional Chinese medicine has gained popularity due to its ability to kill tumor cells. Recently, the apoptotic and anti-angiogenic effects of Trametes robiniophila murr (Huaier) have been investigated. The aim of this study was to investigate its effect on cell mobility and tumor growth in ovarian cancer. Cell viability and motility were measured using SRB, scratch and migration assays. Cell apoptosis was analysed by annexin V/PI staining. Using a reverse-phase protein array (RPPA) assay, we analyzed the levels of 153 proteins and/or phosphorylations in Huaier-treated and untreated cells. Huaier inhibited cell viability and induced both early and late apoptosis in SKOV3, SKOV3.ip1 and Hey cells in a time- and dose-dependent manner. Cell invasiveness and migration were also suppressed significantly. The RPPA results showed significant differences (of at least 30%; P <0.05) in the levels of 7 molecules in SKOV3 cells and 10 in SKOV3.ip1 cells between the untreated and treated cells. Most of the molecules identified play roles in cell proliferation, apoptosis or cell adhesion/invasion. Western blot analysis further validated that Huaier treatment resulted in decreased AKT phosphorylation, enhanced expression of total GSK3β, inhibition of the phosphorylation of GSK3β on S9, reduction of both cytoplasmic β-catenin expression and nuclear β-catenin translocation, and transcriptional repression of several Wnt/β-catenin target genes (DIXDC1, LRP6, WNT5A, and cyclin D1). After knocking down GSK3β, β-catenin expression could not be inhibited by Huaier. Finally, Huaier inhibited the growth of ovarian tumor xenografts in vivo. These studies indicate that Huaier inhibits tumor cell mobility in ovarian cancer via the AKT/GSK3β/β-catenin signaling pathway.

 

 

Effects of Huaier aqueous extract on proliferation and apoptosis in the melanoma cell line A875.

Acta Histochem. 2013 Sep;115(7):705-11.　 IF1.652

Zhang F¹, Zhang Z, Liu Z.

Abstract

In recent years, an aqueous extract of the fungus Trametes robiniophila Murriell 1907 (Huaier) has been commonly used in China for complementary cancer therapy. However, the mechanisms of its anticancer effects are largely unknown. In the present study, we aimed to investigate the effects of Huaier extract on the inhibition of proliferation and promotion of apoptosis in a melanoma cell line, A875, and to explore the possible mechanisms of its anticancer effects. Cell proliferation was measured using a Cell Counting Kit-8 (CCK8) and PCNA-Western blot. The cell cycle distribution, and apoptosis levels were analyzed by flow cytometry, and Western blot was used to test the apoptotic pathways. We found that Huaier extract strongly inhibited cell proliferation of the A875 melanoma cells and induced G2/M arrest and apoptosis in a time- and dose-dependent manner. P53 expression was increased and cell apoptosis executed by caspase-3. Down-regulation of Bcl-2 and up-regulation of Bcl2-associated X protein (BAX) indicated that Huaier extract induced apoptosis through the mitochondrial pathway. As expected, the inhibitor Huaier decreased melanoma cell line A875 proliferation, and induced apoptosis in a time- and dose-dependent manner. Our findings indicate that Huaier extract is an effective complementary agent for cancer treatment of melanoma.

 

 

Huaier aqueous extract inhibits colorectal cancer stem cell growth partially via downregulation of the Wnt/β-catenin pathway.

Oncol Lett. 2013 Apr;5(4):1171-1176.　 IF1.664

Zhang T¹, Wang K, Zhang J, Wang X, Chen Z, Ni C, Qiu F, Huang J.

Abstract

The existence of cancer stem cells (CSCs) is central to the pathogenesis and therapy resistance of colorectal cancer. The aim of this study was to evaluate whether Huaier aqueous extract, a Chinese medicine, has efficacy against CSCs and to investigate the mechanisms of its anticancer effects. It was observed that the Huaier extract significantly inhibited the spheroid formation potential (P<0.05) and decreased the aldehyde dehydrogenase (ALDH)-positive cell population in colorectal primary cancer cells (P<0.05). Western blotting analysis and Wnt/β-catenin reporter assays revealed that the Huaier extract downregulated the Wnt/β-catenin self-renewal pathway. This is the first study to demonstrate that Huaier aqueous extract acts as an effective agent for eradicating colorectal CSCs and identifies the Wnt/β-catenin pathway as its potential target, which may be a new approach for colorectal cancer therapy.

 

 

A polysaccharide from the fungi of Huaier exhibits anti-tumor potential and immunomodulatory effects.

Carbohydr Polym. 2013 Jan 30;92(1):577-82.　 IF5.158

Sun Y¹, Sun T, Wang F, Zhang J, Li C, Chen X, Li Q, Sun S.

Abstract

A neutral water-soluble polysaccharide (W-NTRP), with a molecular weight of 2.5 × 10(4)Da, was isolated from the fruit bodies of Trametes robiniophila (Huaier). Gas chromatography (GC) results indicated that W-NTRP was determined to be galactose (Gal), arabinose (Ara) and glucose (Glc), with a relative molar ratio of 4.2:2.5:0.7. Its antitumor and immunomodulatory activity were evaluated in vitro. W-NTRP showed remarkable inhibitory effect on three human cholangiocarcinoma cell lines (QBC939, Sk-ChA-1 and MZ-ChA-1), with respective IC(50) values of 47.8, 75.9, and 43.7 μg/mL, but had no cytotoxicity to L-929 normal cells. Furthermore, W-NTRP had proliferation promoting effect on mouse splenocytes with or without concanavalin A (ConA) or lipopolysaccharide (LPS) in a bell-shaped dose-response manner. In addition, W-NTRP could prominently stimulate macrophages to produce nitric oxide (NO) through the up-regulation of inducible NO synthase (iNOS) activity. These results suggest that W-NTRP could be explored as a potential antitumor agent for cholangiocarcinoma.

 

 

In vitro and in vivo treatments of Echinococcus granulosus with Huaier aqueous extract and albendazole liposome.

Parasitol Res. 2013 Jan;112(1):193-8.　 IF2.558

Lv H¹, Jiang Y, Liao M, Sun H, Zhang S, Peng X.

Abstract

The aim of this study was to investigate the in vitro and in vivo efficacies of chemotherapy employing albendazole liposome (L-ABZ), Huaier aqueous extract, and a Huaier aqueous extract/L-ABZ combination against Echinococcus granulosus. Protoscolices of E. granulosus were incubated in vitro with the two drugs, either separately or in combination, at the following final concentrations: 2 mg/mL Huaier aqueous extract, 10 μg/mL L-ABZ, and 2 mg/mL Huaier aqueous extract + 10 μg/mL L-ABZ. Huaier aqueous extract and L-ABZ displayed slower protoscolicidal activity when applied separately than when used in combination. The maximum protoscolicidal effect was found with the combination Huaier aqueous extract + L-ABZ. Despite the low Huaier aqueous extract + L-ABZ concentrations used, protoscolex viability dropped rapidly. In vivo studies were performed on mice injected with protoscolices of E. granulosus. Huaieraqueous extract and L-ABZ were administered three times a week for a period of 4 months by the oral route. Huaier aqueous extract in E. granulosus-infected mice was effective. Combined application of both drugs did increase the treatment efficacy. In conclusion, the outcomes obtained clearly demonstrated that in vitro and in vivo treatment with Huaier aqueous extract and L-ABZ is effective against E. granulosus.

 

 

Anti-angiogenic and antitumor activities of Huaier aqueous extract.

Oncol Rep. 2012 Oct;28(4):1167-75.　最新のＩＦなし

Wang X¹, Zhang N, Huo Q, Yang Q.

Abstract

Traditional Chinese medicine, a rich source of potent cancer chemopreventive agents, is attracting increasing attention worldwide. Recently, the anticancer activity of Trametes robiniophila Μurr. (Huaier) has been widely investigated. However, the mechanisms are not yet fully understood. This study aimed to elucidate the inhibitory effect of Huaier extract on angiogenesis and tumor growth. Incubation with Huaier extract inhibited the proliferation of human umbilical vein endothelial cells (HUVECs) and mouse mammary tumor cells (4T1). In addition, treatment with Huaier extract decreased the motility and tube formation of HUVECs in a dose-dependent manner in vitro. As determined by western blot analysis, Huaier extract dose-dependently decreased the levels of phosphorylated extracellular signal-regulated kinase (ERK), transcription factor p65, c-Jun N-terminal kinase (JNK), signal transducer and activator of transcription 3 (STAT3) and the expression of vascular endothelial growth factor (VEGF). In ex vivo experiments, new vessel growth was suppressed as shown by chick embryo chorioallantoic membrane (CAM) and rat aortic ring assays in the presence of Huaier extract. To further evaluate the inhibitory effect, 4T1 cells were injected subcutaneously into BALB/c mice. The administration of Huaier extract suppressed tumor volume, decreased microvessel density and induced apoptosis. These data suggest that Huaier extract may serve as a potent anti-angiogenic and antitumor agent.

 

 

Anticancer effects of Huaier are associated with down-regulation of P53.

Asian Pac J Cancer Prev. 2011;12(9):2251-4.　最新のＩＦなし

Xu X¹, Wei Q, Wang K, Ling Q, Xie H, Zhou L, Zheng S.

Abstract

This study was designed to explore the mechanism of Huaier anticancer effects on experimental hepatocellular cancer (HCC) development. Seventy five rats were divided into 5 groups, administered N-nitrosodiethylamine (groups B, C, D and E) or natural saline (group A). Rats in group C and E were also given Huaier. At the 15 week sacrifice point, the HCC incidence of group C was lower than group correlating with serum AFP. The serum ALT concentration (98.9% greater) and P53 mRNA levels (23.2%) were higher in Group B than group C. Longer term survival rates between group D and E were not significantly different. Huaier can protect liver from chemical injury and furthermore HCC development, possibly with involvement of down-regulation of P53.

 

 

Huaier aqueous extract inhibits proliferation of breast cancer cells by inducing apoptosis.

Cancer Sci. 2010 Nov;101(11):2375-83.　 IF4.372

Zhang N¹, Kong X, Yan S, Yuan C, Yang Q.

Abstract

Aqueous extract of Trametes robiniophila murr (Huaier) has been commonly used in China for cancer complementary therapy in recent years; however, the mechanisms of its anticancer effects are largely unknown. In the present study, we aim to investigate its inhibitory effect on both MCF-7 and MDA-MB-231 cells, and explore the possible mechanisms of its anticancer effect. Cell viability and motility were measured by MTT and invasive assays, migration and scratch assays in vitro, respectively. The distribution of cell cycle, PI-Annexin-V staining and Rhodamine 123 assay were analyzed by flow cytometry, and western blot were used to test the apoptotic pathways. We found that Huaier extract could strongly inhibit cell viability of MCF-7 and MDA-MB-231 cells in a time- and dose-dependent manner; however, MDA-MB-231 cells showed more susceptibility to the treatment. Furthermore, cell invasiveness and migration were also suppressed with exposure to Huaier extract. We also indicated that Huaier could induce G0/G1 cell-cycle arrest, p53 accumulation and activation selectively in MCF-7 cells. Inspiringly, the PI-Annexin-V staining assay and western blot analysis confirmed cell apoptosis executed by caspase-3. Decreased mitochondrial membrane potential by Rhodamine 123 assay and down-regulation of Bcl-2 and up-regulation of BCL2-associated X protein (BAX) indicated that Huaier induced apoptosis through the mitochondrial pathway. Caspase activation during Huaier-induced apoptosis was confirmed by pan-caspase inhibitor, Z-VAD-fmk. As expected, the inhibitor decreased Huaier-induced apoptosis in both cell lines. Based on our findings, Huaier can induce cell apoptosis in both ER-positive and ER-negative breast cancer cell lines and is an effective complementary agent for breast cancer treatment.

 

 

Inhibitory effect of extract of fungi o fHuaier on hepatocellular carcinoma cells.

J Huazhong Univ Sci Technolog Med Sci. 2009 Apr;29(2):198-201.　 IF0.948

Ren J¹, Zheng C, Feng G, Liang H, Xia X, Fang J, Duan X, Zhao H.

Abstract

This study investigated the inhibitory effect of the extract of fungi of Huaier (EFH) on the growth of hepatocellular carcinoma (HCC) cells. Hep-G2 cells, a human HCC cell line, were cultured in DMEM containing 10% fetal bovine serum and treated with EFH of different concentrations (1, 2, 4, 8 mg/mL) for 24, 48 and 72 h respectively. The apoptosis rate of the cells was flow cytometrically measured. Thirty-six tumor-bearing New Zealand rabbits were randomly divided into 3 groups: group A (control group), in which the rabbits were infused with 0.2 mL/kg normal saline via the hepatic artery; group B (transhepatic artery chemoembolization [TACE] group), in which the rabbits were given lipiodol at 0.2 mL/kg plus MMC at 0.5 mg/kg via the hepatic artery; group C (TACE+EFH group), in which EFH (500 mg/kg) were orally administered after TACE. Two weeks after TACE, the rabbits were sacrificed and the implanted tumors were sampled. The tumor volume and the necrosis rate were determined. The tumor tissues were immunohistochemically detected for the expressions of factor VIII, VEGF, P53, Bax and Bcl-2. The microvessel density (MVD) was calculated by counting the factor VIII-positive endothelial cells. Our results showed that after treatment with EFH, the apoptosis rate of Hep-G2 cells was enhanced in a concentration- and time-dependent manner. Two weeks after the treatment, the average tumor volume, the necrosis rate and the growth rate of the implanted tumor in group C were significantly different from those in groups A and B (P<0.05). MVD and VEGF expressions were significantly decreased in the group C when compared with those in groups B (P<0.05 for all). The Bax expression was weakest in group A and strongest in group C. The expressions of P53 and Bcl-2 were minimal in group C and maximal in group A. There were significant differences in the expressions of P53, Bax and Bcl-2 among the 3 groups (P<0.05 for all) and there was significant difference between group B and group C (P<0.05). It was concluded that EFH could suppress not only the growth of HCC cells but also tumor angiogenesis and it can induce the apoptosis of HCC cells. EFH serves as an alternative for the treatment of HCC.