Potential mechanism of pyrotinib-induced diarrhea was explored by gut microbiome and ileum metabolomics.

Pyrotinib is a novel epidermal growth factor receptor/human epidermal growth factor receptor-2 (HER2) tyrosine kinase inhibitor that exhibited clinical efficacy in patients with HER2-positive breast cancer and HER2-mutant/amplified lung cancer. However, severe diarrhea adverse responses preclude its practical use. At present, the mechanism of pyrotinib-induced diarrhea is unknown and needs further study. First, to develop a suitable and reproducible animal model, we compared the effects of different doses of pyrotinib (20, 40, 60 and 80 mg/kg) in Wistar rats. Second, we used this model to examine the intestinal toxicity of pyrotinib. Finally, the mechanism underlying pyrotinib-induced diarrhea was fully studied using gut microbiome and host intestinal tissue metabolomics profiling. Reproducible diarrhea occurred in rats when they were given an 80 mg/kg daily dose of pyrotinib. Using the pyrotinib-induced model, we observed that Lachnospiraceae and Acidaminococcaceae decreased in the pyrotinib groups, whereas Enterobacteriaceae, Helicobacteraceae and Clostridiaceae increased at the family level by 16S rRNA gene sequence. Multiple bioinformatics methods revealed that glycocholic acid, ursodeoxycholic acid and cyclic AMP increased in the pyrotinib groups, whereas kynurenic acid decreased, which may be related to the pathogenesis of pyrotinib-induced diarrhea. Additionally, pyrotinib-induced diarrhea may be associated with a number of metabolic changes mediated by the gut microbiome, such as Primary bile acid biosynthesis. We reported the establishment of a reproducible pyrotinib-induced animal model for the first time. Furthermore, we concluded from this experiment that gut microbiome imbalance and changes in related metabolites are significant contributors to pyrotinib-induced diarrhea.

Tailored to fit: China optimizes policies and regulations regarding drug registration and review to promote innovation in traditional Chinese medicine.

The classification system for drug registration and the review and approval process influence the innovation and development of pharmaceuticals. China's previous classification standards for registration of traditional Chinese medicines (TCMs) overly emphasized the material basis while neglecting the clinical value of TCM. Moreover, the review and approval system did not fully consider the characteristics of new TCM drugs, such as the clinical experience already available for many TCM formulations guided by TCM theories. This resulted in suboptimal quality and quantity in the development of new TCM drugs. Since 2019, China has introduced a series of policies and regulations aimed at reforming the classification system for registration of TCMs and establishing a review system tailored to TCM characteristics. The new classification system for registration of TCMs emphasizes that the development of new TCM drugs should be oriented towards clinical value, focusing on meeting unmet clinical needs. The policies and regulations promote the conversion of prescriptions in ancient classics into new drugs and encourages the conversion of preparations from medical facilities into new TCM drugs. Secondary development of already marketed TCM products is encouraged to enhance the advantages of their clinical use. The new review system places importance on the role of TCM theories and clinical experience in supporting the registration of new TCM drugs. These reform measures have paved a path for registration and review of the characteristics of TCMs and will positively promote the development of new TCMs.

Considering traditional Chinese medicine as adjunct therapy in the management of chronic constipation by regulating intestinal flora.

Chronic constipation is one of the most common gastrointestinal disorders worldwide. Due to changes in diet, lifestyle, and the aging population, the incidence of chronic constipation has increased year by year. It has had an impact on daily life and poses a considerable economic burden. Nowadays, many patients with chronic constipation try to seek help from complementary and alternative therapies, and traditional Chinese medicine (TCM) is often their choice. The intestinal flora play an important role in the pathogenesis of constipation by affecting the body's metabolism, secretion, and immunity. Regulating the intestinal flora and optimizing its composition might become an important prevention and treatment for chronic constipation. TCM has unique advantages in regulating the imbalance of intestinal flora, and its curative effect is precise. Therefore, we reviewed the relationship between intestinal flora and chronic constipation as well as advances in research on TCM as adjunct therapy in the management of chronic constipation by regulating intestinal flora. Some single Chinese herbs and their active ingredients (e.g., Rheum palmatum, Radix Astragalus, and Cistanche deserticola), some traditional herbal formulations (e.g., Jichuan decoction, Zengye decoction, and Zhizhu decoction) and some Chinese patent medicines (e.g., Maren pills and Shouhui Tongbian capsules) that are commonly used to treat chronic constipation by regulating intestinal flora are highlighted and summarized. Moreover, some external forms of TCM, and especially acupuncture, have also been found to improve intestinal movement and alleviate constipation symptoms by regulating intestinal flora. We hope this review can contribute to an understanding of TCM as an adjunct therapy for chronic constipation and that it can provide useful information for the development of more effective constipation therapies.

Cinobufacini Inhibits Survival and Metastasis of Hepatocellular Carcinoma via c-Met Signaling Pathway.

OBJECTIVE: To investigate the anti-tumor effects of cinobufacini (CINO) on hepatocellular carcinoma (HCC) induced by des-gamma-carboxy-prothrombin (DCP) and to uncover the underlying mechanisms. METHODS: The inhibitory effect of CINO on HCC cell proliferation was evaluated using the cell counting kit-8 method, and the apoptosis rate was quantified using flow cytometry. Immunofluorescence and Western blot analyses were used to investigate the differential expression of proteins associated with cell growth, apoptosis, migration, and invasion pathways after CINO treatment. The therapeutic potential of CINO for HCC was confirmed, and the possibility of combining cinobufacini with c-Met inhibitor for the treatment of primary HCC was further validated by in vivo experiments. RESULTS: Under the induction of DCP, CINO inhibited the activity of HCC cells, induced apoptosis, and inhibited migration and invasion. Upon the induction of DCP, CINO regulated c-Met activation and the activation of the phosphatidylinositol-3 kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) pathways. In a mouse model of HCC, CINO exhibited significant antitumor effects by inhibiting the phosphorylation of c-Met and the downstream PI3K/AKT and MEK/ERK pathways in tumor tissues. CONCLUSIONS: CINO inhibited HCC cell growth, promoted apoptosis, and suppressed HCC cell invasion and migration by targeting c-Met and PI3K/AKT and MEK/ERK signaling pathways under DCP induction.

Herbal medicines exhibit a high affinity for ACE2 in treating COVID-19.

Coronavirus Disease 2019 (COVID-19) has been an unprecedented disaster for people around the world. A point particularly worth noting is that herbal medicines have made great contributions to the prevention and treatment of COVID-19 in China. Angiotensin converting enzyme 2 (ACE2) has been identified as the critical functional receptor for SARS-CoV-2. It can bind to the receptor-binding domain (RBD) of the spike protein (S protein), which is responsible for the entry of the coronavirus into host cells. Therefore, ACE2 can be regarded as an important intervention target for COVID-19. Recently, many herbal medicines have exhibited a high affinity for ACE2 in treating COVID-19. The current work summarized these herbal medicines including formulas (such as Lianhua Qingwen capsules, Xuebijing injection, Qingfei Paidu Decoction, Huashi Baidu formula, Shufeng Jiedu capsules, and Maxing Shigan decoction), single herbs including Ephedra sinica Stapf (Mahuang), Scutellariae radix (Huangqin), Lonicera japonica (Jinyinhua), and Houttuynia cordata (Yuxingcao), and active ingredients (such as ursodeoxycholic acid, glycyrrhizic acid, glycyrrhizin, salvianolic acid, quercetin, and andrographidine C), which have exhibited a high affinity for ACE2 in treating COVID-19. We hope this work may provide meaningful and useful information on further research to investigate the mechanisms of herbal medicines against SARS-CoV-2 and follow-up drug discovery.

Cost-effectiveness analysis of neonatal hearing screening program in China: should universal screening be prioritized?

BACKGROUND: Neonatal hearing screening (NHS) has been routinely offered as a vital component of early childhood care in developed countries, whereas such a screening program is still at the pilot or preliminary stage as regards its nationwide implementation in developing countries. To provide significant evidence for health policy making in China, this study aims to determine the cost-effectiveness of NHS program implementation in case of eight provinces of China. METHODS: A cost-effectiveness model was conducted and all neonates annually born from 2007 to 2009 in eight provinces of China were simulated in this model. The model parameters were estimated from the established databases in the general hospitals or maternal and child health hospitals of these eight provinces, supplemented from the published literature. The model estimated changes in program implementation costs, disability-adjusted life years (DALYs), average cost-effectiveness ratio (ACER), and incremental cost-effectiveness ratio (ICER) for universal screening compared to targeted screening in eight provinces. RESULTS AND DISCUSSION: A multivariate sensitivity analysis was performed to determine uncertainty in health effect estimates and cost-effectiveness ratios using a probabilistic modeling technique. Targeted strategy trended to be cost-effective in Guangxi, Jiangxi, Henan, Guangdong, Zhejiang, Hebei, Shandong, and Beijing from the level of 9%, 9%, 8%, 4%, 3%, 7%, 5%, and 2%, respectively; while universal strategy trended to be cost-effective in those provinces from the level of 70%, 70%, 48%, 10%, 8%, 28%, 15%, 4%, respectively. This study showed although there was a huge disparity in the implementation of the NHS program in the surveyed provinces, both universal strategy and targeted strategy showed cost-effectiveness in those relatively developed provinces, while neither of the screening strategy showed cost-effectiveness in those relatively developing provinces. This study also showed that both strategies especially universal strategy achieve a good economic effect in the long term costs. CONCLUSIONS: Universal screening might be considered as the prioritized implementation goal especially in those relatively developed provinces of China as it provides the best health and economic effects, while targeted screening might be temporarily more realistic than universal screening in those relatively developing provinces of China.

Recent advances in Chinese patent medicines entering the international market.

As an indispensable part of Traditional Chinese medicine (TCM), Chinese patent medicines have played an important role in preventing and treating diseases in China. Since they are easy to use, easy to store, and cost-effective, Chinese patent medicines have been generally accepted and widely used in Chinese clinical practice as a vital medical resource. In recent years, as TCM has developed and it has been accepted around the world, many Chinese patent medicine companies have gained international market access and successfully registered several Chinese patent medicines as over-the-counter (OTC) or prescription drugs in regions and countries that primarily use Western medicine such as the EU, Russia, Canada, Singapore, and Vietnam. Moreover, several Chinese patent medicines have been obtained the US Food and Drug Administration (FDA) approval conducting phase II or III clinical trials in the US. The current work has focused on several Chinese patent medicines that have been successfully registered or that have been submitted for registration abroad. Summarized here are recent advances in the efficacy and molecular mechanisms of these Chinese patent medicines to treat respiratory infectious diseases (Lianhua Qingwen capsules, Jinhua Qinggan granules, and Shufeng Jiedu Capsules), cardiovascular and cerebrovascular diseases (Compound Danshen Dripping Pills, Huatuo Zaizao pills, and Tongxinluo Capsules), cancers (a Kanglaite injection and a Shenqi Fuzheng Injection), and gynecological diseases (Guizhi Fuling Capsules). The hope is that this review will contribute to a better understanding of Chinese patent medicines by people around the world.

Network pharmacology and molecular docking analysis on the mechanism of Baihe Zhimu decoction in the treatment of postpartum depression.

Baihe Zhimu decoction (BZD) has significant antidepressant properties and is widely used to treat mental diseases. However, the multitarget mechanism of BZD in postpartum depression (PPD) remains to be elucidated. Therefore, the aim of this study was to explore the molecular mechanisms of BDZ in treating PPD using network pharmacology and molecular docking. Active components and their target proteins were screened from the traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The PPD-related targets were obtained from the OMIM, CTD, and GeneCards databases. After overlap, the targets of BZD against PPD were collected. Protein-protein interaction (PPI) network and core target analyses were conducted using the STRING network platform and Cytoscape software. Moreover, molecular docking methods were used to confirm the high affinity between BZD and targets. Finally, the DAVID online tool was used to perform gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of overlapping targets. The TCMSP database showed that BZD contained 23 active ingredients in PPD. KEGG analysis showed that overlapping genes were mainly enriched in HIF-1, dopaminergic synapses, estrogen, and serotonergic synaptic signalling pathways. Combining the PPI network and KEGG enrichment analysis, we found that ESR1, MAOA, NR3C1, VEGFA, and mTOR were the key targets of PPD. In addition, molecular docking confirmed the high affinity between BZD and the PPD target. Verified by a network pharmacology approach based on data mining and molecular docking methods, the multi-target drug BZD may serve as a promising therapeutic candidate for PPD, but further in vivo/in vitro experiments are needed.

Effects of Shenling Baizhu powder on pyrotinib-induced diarrhea: analysis of gut microbiota, metabonomics, and network pharmacology.

BACKGROUND: Shenling Baizhu Powder (SBP) is a traditional Chinese medicine (TCM) prescription, which has the good efficacy on gastrointestinal toxicity. In this study, we used gut microbiota analysis, metabonomics and network pharmacology to investigate the therapeutic effect of SBP on pyrotinib-induced diarrhea. METHODS: 24 Rats were randomly divided into 4 groups: control group, SBP group (3.6 g/kg /bid SBP for 10 days), pyrotinib model group (80 mg/kg/qd pyrotinib) and pyrotinib + SBP treatment group. A 16S rRNA sequencing was used to detect the microbiome of rat fecal bowel. Metabolic profiles were collected by non-targeted metabolomics and key metabolic pathways were identified using MetaboAnalyst 5.0. The antitumor effect of SBP on cells treated with pyrotinib was measured using a CCK-8 assay. Network pharmacology was used to predict the target and action pathway of SBP in treating pyrotinib-related diarrhea. RESULTS: In vivo study indicated that SBP could significantly alleviate pyrotinib-induced diarrhea, reaching a therapeutic effect of 66.7%. SBP could regulate pyrotinib-induced microbiota disorder. LEfSe research revealed that the SBP could potentially decrease the relative abundance of Escherichia, Helicobacter and Enterobacteriaceae and increase the relative abundance of Lachnospiraceae, Bacilli, Lactobacillales etc. In addition, 25-Hydroxycholesterol, Guanidinosuccinic acid, 5-Hydroxyindolepyruvate and cAMP were selected as potential biomarkers of SBP for pyrotinib-induced diarrhea. Moreover, Spearman's analysis showed a correlation between gut microbiota and metabolite: the decreased 25-hydroxycholesterol in the pyrotinib + SBP treatment group was negatively correlated with Lachnospiraceae while positively correlated with Escherichia and Helicobacter. Meanwhile, SBP did not affect the inhibitory effect of pyrotinib on BT-474 cells and Calu-3 cells in vitro. Also, the network analysis further revealed that SBP treated pyrotinib-induced diarrhea through multiple pathways, including inflammatory bowel disease, IL-17 signaling pathway, pathogenic Escherichia coli infection and cAMP signaling pathway. CONCLUSIONS: SBP could effectively relieve pyrotinib-induced diarrhea, revealing that intestinal flora and its metabolites may be involved in this process.

Bufalin and cinobufagin induce apoptosis of human hepatocellular carcinoma cells via Fas- and mitochondria-mediated pathways.

Bufadienolides bufalin and cinobufagin are cardiotonic steroids isolated from the skin and parotid venom glands of the toad Bufo bufo gargarizans Cantor. They have been shown to induce a wide spectrum of cancer cell apoptosis. However, the detailed molecular mechanisms of inducing apoptosis in hepatocellular carcinoma (HCC) are still unclear. In the present study, the apoptosis-inducing effect of bufalin and cinobufagin on HCC cell line HepG(2) was investigated. We found bufalin and cinobufagin induced marked changes in apoptotic morphology and significantly increased the proportion of apoptotic cells. This apoptotic induction was associated with an increase in Fas, Bax and Bid expression, a decrease in Bcl-2 expression, disruption of the mitochondrial membrane potential, release of cytochrome c, activation of caspase-3, -8, -9 and -10, and the cleavage of poly(ADP-ribose)polymerase (PARP), which indicated that bufalin and cinobufagin induced apoptosis through both Fas- and mitochondria-mediated pathways. In addition, caspase activation during bufalin- and cinobufagin-induced apoptosis was further confirmed by caspase-3 inhibitor Z-DEVD-FMK, caspase-8 inhibitor Z-IETD-FMK, caspase-9 inhibitor Z-LEHD-FMK and caspase-10 inhibitor Z-AEVD-FMK. The results showed that bufalin- and cinobufagin-induced apoptosis was blocked by these inhibitors and particularly by caspase-10 inhibitor. Taken together, bufalin and cinobufagin induce apoptosis of HepG(2) cells via both Fas- and mitochondria-mediated pathways, and a Fas-mediated caspase-10-dependent pathway might play a crucial role.

Traditional Chinese medicine for treatment of novel infectious diseases: Current status and dilemma.

Traditional Chinese medicine (TCM) is a valuable form of medicine with a long history in China. It has played a significant role in the control and prevention of infectious diseases including SARS and H7N9 flu. After the outbreak of COVID-19, China's National Health Commission included TCM in the Diagnosis and Treatment Protocol for COVID-19. During the COVID-19 pandemic, three traditional Chinese medicines (Jinhua Qinggan granules, Lianhua Qingwen medicine, and a Xuebijing Injection) and three TCM preparations (a Qingfei Paidu decoction, a Huashi Baidu decoction, and a Xuanfei Baidu decoction) have been screened for their efficacy against COVID-19. More than 150 trials involving TCMs are registered in the Chinese Clinical Trial Registry (ChiCTR), and those trials cover prevention, treatment, recovery, and illnesses diagnosed in accordance with TCM principles. TCM can effectively alleviate the symptoms of patients with COVID-19, delay the disease's progression from mild to severe or critical, and reduce severe and critical all-cause mortality. The underlying mechanisms of TCM mainly involve action against SARS-CoV-2, anti-inflammatory and immunomodulatory action, and organ protection. The current work provides a brief description of the current status of and issues with TCM to treat this novel infectious disease. The hope is that TCM can help considerably to control this global epidemic.

The positive role of traditional Chinese medicine as an adjunctive therapy for cancer.

Traditional Chinese medicine (TCM), especially Chinese herbal medicines and acupuncture, has been traditionally used to treat patients with cancers in China and other East Asian countries. Numerous studies have indicated that TCM not only alleviates the symptoms (e.g., fatigue, chronic pain, anorexia/cachexia, and insomnia) of patients with cancer and improves their quality of life (QOL) but also diminishes adverse reactions and complications caused by chemotherapy, radiotherapy, or targeted-therapy. Therefore, Chinese herbal medicines and acupuncture and other alternative therapies need to be understood by TCM physicians and other health care providers. This review mainly summarizes the experimental results and conclusions from literature published since 2010, and a search of the literature as been performed in the PubMed, MEDLINE, Web of Science, Scopus, Springer, ScienceDirect, and China Hospital Knowledge Database (CHKD) databases. Some Chinese herbal medicines (e.g., Panax ginseng, Panax quinquefolius, Astragali radix, Bu-zhong-yi-qi-tang (TJ-41), Liu-jun-zi-tang (TJ-43), Shi-quan-da-bu-tang (TJ-48), and Ban-xia-xie-xin-tang (TJ-14)) and some acupuncture points (e.g., Zusanli (ST36), Zhongwan (CV12), Neiguan (PC6) and Baihui (GV20)) that are commonly used to treat cancer-related symptoms and/or to reduce the toxicity of chemotherapy, radiotherapy, or targeted-therapy are highlighted and summarized. Through a review of literature, we conclude that TCM can effectively alleviate adverse gastrointestinal reactions (including diarrhea, nausea, and vomiting) to these anti-cancer therapies, decrease the incidence of bone marrow suppression, alleviate cardiotoxicity, and protect against chemotherapy-induced peripheral neuropathy and radiation-induced pneumonitis. Moreover, TCM can alleviate epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-related acneiform eruptions, diarrhea, and other adverse reactions. The hope is that this review can contribute to an understanding of TCM as an adjuvant therapy for cancer and that it can provide useful information for the development of more effective anti-cancer therapies. However, more rigorously designed trials involving cancer treatment must be conducted in the future, including complete quality control and standardized models at the cellular, organic, animal and clinical levels, in order to study TCM in multiple forms and at multiple levels.

Anti-hepatitis B virus activities of cinobufacini and its active components bufalin and cinobufagin in HepG2.2.15 cells.

Cinobufacini (Huachansu) is a Chinese medicine prepared from the skin of Bufo bufo gargarizans Cantor (Bufonidae), which has long been used in traditional Chinese medicine (TCM). The aim of present study was to examine the anti-hepatitis B virus (HBV) activities of cinobufacini and its active components bufalin and cinobufagin in the human HBV-transfected cell line HepG2.2.15. The hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and hepatitis B core-related antigen (HBcrAg) concentrations in cell culture medium were determined by chemiluminescent enzyme immunoassay after HepG2.2.15 cells were respectively treated with different concentrations of cinobufacini, bufalin, and cinobufagin for 3 or 6 d. HBV DNA and mRNA were determined using transcription-mediated amplification and real-time polymerase chain reaction (PCR), respectively. On d 3, cinobufacini at a concentration of 1 µg/ml had no activity against HBV virological markers. However, on d 6, cinobufacini at 1 µg/ml effectively inhibited the secretion of HBsAg, HBeAg, and HBcrAg by 29.58, 32.87, and 42.52%. It was more potent than the positive control lamivudine (100 µg/ml). Bufalin and cinobufagin slightly inhibited HBV antigen secretion. Treatment with cinobufacini, bufalin, or cinobufagin had no anti-HBV effect on DNA in cell culture medium. Consistent with the HBV antigen reduction, HBV mRNA expression was markedly inhibited in comparison to the control when HepG2.2.15 cells were treated with cinobufacini, bufalin, or cinobufagin. Results suggested that cinobufacini had more potent activity against HBV antigen secretion than its components bufalin and cinobufagin and this inhibitory role was attributed to the specific inhibition of HBV mRNA expression.

[Apoptosis-inducing effect of cinobufacini on human hepatoma cell line HepG2 and its mechanism of action].

To investigate the apoptosis-inducing effect of cinobufacini (Huachansu) on human hepatoma cell line HepG2 and its possible mechanism of action, HepG2 cells were treated with different concentrations of cinobufacini. Cell proliferation was measured by methylthiazolyl tetrazolium (MTT) assay. The morphological changes of apoptosis were observed by Hoechst 33258 staining. Cell cycle distribution and apoptotic rate were evaluated by flow cytometry (FCM). Quantitative real-time RT-PCR and Western blotting analysis were used to detect the mRNA and protein expressions of apoptosis related factors Bcl-2, Bax and p53. The results indicated that cinobufacini could inhibit the proliferation of HepG2 cells in a dose and time dependent manner. Remarkable morphological changes of apoptosis including cytoplasmic and nuclear condensation and partition of cytoplasm were observed by Hoechst 33258 staining. According to FCM analysis, HepG2 cells were arrested in G2/M phase and the apoptotic rate increased with the increase of the concentration of cinobufacini. Both the mRNA and protein expressions of Bax and p53 were up-regulated while Bcl-2 expression down-regulated. Thus, cinobufacini could inhibit the proliferation and induce apoptosis of human hepatoma cell line HepG2. Furthermore, up regulation of Bax and p53 as well as down regulation of Bcl-2 expressions may be one of the important apoptotic inducing mechanisms.

Traditional Chinese medicine to treat COVID-19: the importance of evidence-based research.

Coronavirus disease 2019 (COVID-19) broke out in 2019 and spread rapidly around the world, causing a global pandemic. Traditional Chinese medicine has a history of more than 2,000 years in the prevention and treatment of epidemics and plagues. In guidelines on fighting COVID-19, the National Health Commission (NHC) has recommended some traditional Chinese medicines (TCM), including Jinhua Qinggan granules, Lianhua Qingwen capsules, XueBijing injections, a Qingfei Paidu decoction, a Huashi Baidu decoction, and a Xuanfei Baidu decoction. Based on current results, TCM has displayed some efficacy in combating COVID-19. However, TCM faces many challenges in terms of being recognized around the world. Therefore, evidence-based research is crucial to the development of TCM.

A review of traditional Chinese medicine for treatment of glioblastoma.

Glioblastoma (GBM) is the most common primary malignant intracranial tumor. Due to its high morbidity, high mortality, high recurrence rate, and low cure rate, it has brought great difficulty for treatment. Although the current treatment is multimodal, including surgical resection, radiotherapy, and chemotherapy, it does not significantly improve survival time. The dismal prognosis and inevitable recurrence as well as resistance to chemoradiotherapy may be related to its highly cellular heterogeneity and multiple subclonal populations. Traditional Chinese medicine has its own unique advantages in the prevention and treatment of it. A comprehensive literature search of anti-glioblastoma active ingredients and derivatives from traditional Chinese medicine was carried out in literature published in PubMed, Scopus, Web of Science Cochrane library, CNKI, Wanfang, and VIP database. Hence, this article systematically reviews experimental research progress of some traditional Chinese medicine in treatment of glioblastoma from two aspects: strengthening vital qi and eliminating pathogenic qi. Among, strengthening vital qi medicine includes panax ginseng, licorice, lycium barbarum, angelica sinensis; eliminating pathogenic medicine includes salvia miltiorrhiza bunge, scutellaria baicalensis, coptis rhizoma, thunder god vine, and sophora flavescens. We found that the same active ingredient can act on different signaling pathways, such as ginsenoside Rg3 inhibited proliferation and induced apoptosis via the AKT, MEK signal pathway. Hence, this multi-target, multi-level pathway may bring on a new dawn for the treatment of glioblastoma.

Regulatory effects of Ningdong granule on microglia-mediated neuroinflammation in a rat model of Tourette's syndrome.

Tourette's syndrome (TS) is an inherited neurologic disorder characterized by involuntary stereotyped motor and vocal tics. Its pathogenesis is still unclear and its treatment remains limited. Recent research has suggested the involvement of immune mechanisms in the pathophysiology of TS. Microglia are the brain's resident innate immune cells. They can mediate neuroinflammation and regulate brain development and homeostasis. A traditional Chinese medicine (TCM), Ningdong granule (NDG), has been found to be efficacious in the treatment of TS while causing few adverse reactions. In the current study, a rat model of 3,3'-iminodipropionitrile (IDPN)-induced TS was used to explore the regulating effects and mechanisms of NDG on microglia-mediated neuroinflammation. IDNP led to robust pathological changes and neurobehavioral complications, with activation of microglia in the striatum of rats with TS. After activation by IDNP, microglia strongly responded to this specific injury, and TNF-α, IL-6, and MCP-1 were released in the striatum and/or serum of rats with TS. Interestingly, NDG inhibited the activation of microglia and decreased the abnormal expression of TNF-α, IL-6, and MCP-1 in the striatum and/or serum of rats with TS, thus controlling tics. However, there were no significant changes in the striatum and/or serum of rats with TS after treatment with haloperidol. The anti-TS action of haloperidol might occur not through microglial activation and neuroinflammation but through the DAT system, thus controlling tics. In conclusion, microglia might play key roles in mediating neuroinflammatory responses in TS, triggering the release of TNF-α, IL-6, and MCP-1.NDG inhibited tics in rats with TS, and this mechanism may be associated with a reduction in the increased number of activated microglia and a decrease in the expression of pro-inflammatory cytokines and chemokines in the striatum and/or serum.

The toxicity and safety of traditional Chinese medicines: Please treat with rationality.

For a long time, many people have believed that traditional Chinese medicines (TCMs) are safe because they derive from natural products. However, this belief has been greatly challenged in recent years especially after some reports on aristolochic acid involved in the genesis of cancer. According to the Chinese pharmacopoeia, many TCMs are known to be toxic, causing damage to the nervous, liver, renal, respiratory, and reproductive system. How to reduce the toxicity of TCMs and how to avoid abuse of TCMs in daily practice is the question? Here, we will give a brief summary and some tips on these issues. First, the accurate differentiation of a specific syndrome is the foundation of an effective and individualized treatment strategy, as well as the key to applying TCMs. Second, through standard processing, proper compatibility, rational decoction, and appropriate dose for TCMs, the harm of TCMs can be effectively avoided. Third, it should be remembered that Chinese herbs cannot be taken continuously as dietary supplements. Finally, Chinese patent medicines should be used with caution. In addition, the dosage of TCMs should not exceed the limit prescribed by the current China Pharmacopoeia, which will ensure the balance of efficacy and toxicity. Taken together, it is necessary to treat the toxicity and safety of TCMs with rationality. The more toxicity we can find, the more safety patients will have.

Cinobufacini inhibits epithelial-mesenchymal transition of human hepatocellular carcinoma cells through c-Met/ERK signaling pathway.

Cinobufacini, an aqueous extract from the skins and parotid venom glands of the toad Bufo bufo gargarizans Cantor, is a well known traditional Chinese medicine widely used in clinical cancer therapy in China. Its therapeutic effect is especially pronounced in liver cancer. However, the precise mechanisms induced by cinobufacini in human hepatocellular carcinoma (HCC) cells are still not very clear. Here, we investigated the effects and mechanisms of cinobufacini on inhibiting HepG2 cells invasion and metastasis. Epithelial-mesenchymal transition (EMT) is identified as an important initiation step for HCC metastasis. After the HepG2 cells were treated with different concentrations of cinobufacini, the expression of EMT related E-cadherin was increased while N-cadherin and Vimentin were decreased, and the expression of EMT related transcription factors Snail and Twist were decreased. Moreover, the phosphorylation of c-Met was inhibited by cinobufacini, and the expression of MEK1/2 and ERK1/2, the downstream kinase of the signal transduction pathway activated by c-Met, also decreased in a dose-dependent manner with cinobufacini. In addition, after the cells were treated with different concentrations of cinobufacini, there was a significant decrease in MMP-2 and MMP-9 expression in HepG2 cells. In conclusion, the current study suggested cinobufacini could prevent HepG2 cells migration and invasion via inhibiting EMT through c-Met/ERK signaling pathway, which might provide experimental evidence for cinobufacini treatment of HCC.

Adenovirus-mediated P311 ameliorates renal fibrosis through inhibition of epithelial-mesenchymal transition via TGF-ß1-Smad-ILK pathway in unilateral ureteral obstruction rats.

Epithelial-mesenchymal transition (EMT) is a critical step and key factor during renal fibrosis. Preventing renal tubular EMT is important for delaying the progression of chronic kidney disease (CKD). P311, a highly conserved 8-kDa intracellular protein, has been indicated as an important factor in myofibroblast transformation and in the progression of fibrosis. However, the related studies on P311 on renal fibrosis are limited and the mechanisms of P311 in the progression of renal tubulointerstitial fibrosis remain largely unknown. In the present study, we examined the effect of P311 on transforming growth factor-ß1 (TGF-ß1)-mediated EMT in a rat model of unilateral ureteral occlusion (UUO) renal fibrosis. The recombinant adenovirus p311 (also called Ad-P311) was constructed and transferred it into UUO rats, the preventive effect and possible mechanism of P311 on TGF-ß1-mediated EMT were explored. The UUO model was established successfully and Ad-P311 was administered into UUO rats each week for 4 weeks, then the serum levels of Cr, blood urea nitrogen (BUN) and albumin (ALB) were evaluated. H&E staining and Masson staining were performed to observe the pathological changes of kidneys. Immunohistochemical staining and western blot analysis were used to examine the EMT markers [E-cadherin and α-smooth muscle actin (α-SMA)], and signal transducers (p-Smad2/3 and Smad7). Integrin linked kinase (ILK) as a keyintracellular mediator that controls TGF-ß1-mediated-EMT was also assayed by western blot analysis. The results showed that P311 could alleviate renal tubular damage and interstitial fibrosis improving Cr, BUN and ALB serum levels in UUO kidneys. Furthermore, P311 attenuated TGF-ß1-mediated EMT through Smad-ILK signaling pathway with an increase in α-SMA, pSmad2/3 and ILK expression, and a decrease in E-cadherin and Smad7 expression in UUO kidneys. In conclusion, P311 may be involved in the pathogenesis of renal fibrosis by blocking TGF-ß1-mediated EMT via TGF-ß1-Smad-ILK pathway in UUO kidneys. P311 may be a novel target for the control of renal fibrosis and the progression of CKD.