Natural products in traditional Chinese medicine: molecular mechanisms and therapeutic targets of renal fibrosis and state-of-the-art drug delivery systems.

Renal fibrosis (RF) is the end stage of several chronic kidney diseases. Its series of changes include excessive accumulation of extracellular matrix, epithelial-mesenchymal transition (EMT) of renal tubular cells, fibroblast activation, immune cell infiltration, and renal cell apoptosis. RF can eventually lead to renal dysfunction or even renal failure. A large body of evidence suggests that natural products in traditional Chinese medicine (TCM) have great potential for treating RF. In this article, we first describe the recent advances in RF treatment by several natural products and clarify their mechanisms of action. They can ameliorate the RF disease phenotype, which includes apoptosis, endoplasmic reticulum stress, and EMT, by affecting relevant signaling pathways and molecular targets, thereby delaying or reversing fibrosis. We also present the roles of nanodrug delivery systems, which have been explored to address the drawback of low oral bioavailability of natural products. This may provide new ideas for using natural products for RF treatment. Finally, we provide new insights into the clinical prospects of herbal natural products.

Mass spectrometry-based metabolomics for discovering active ingredients and exploring action mechanism of herbal medicine.

Natural products derived from herbal medicine are a fruitful source of lead compounds because of their structural diversity and potent bioactivities. However, despite the success of active compounds derived from herbal medicine in drug discovery, some approaches cannot effectively elucidate the overall effect and action mechanism due to their multi-component complexity. Fortunately, mass spectrometry-based metabolomics has been recognized as an effective strategy for revealing the effect and discovering active components, detailed molecular mechanisms, and multiple targets of natural products. Rapid identification of lead compounds and isolation of active components from natural products would facilitate new drug development. In this context, mass spectrometry-based metabolomics has established an integrated pharmacology framework for the discovery of bioactivity-correlated constituents, target identification, and the action mechanism of herbal medicine and natural products. High-throughput functional metabolomics techniques could be used to identify natural product structure, biological activity, efficacy mechanisms, and their mode of action on biological processes, assisting bioactive lead discovery, quality control, and accelerating discovery of novel drugs. These techniques are increasingly being developed in the era of big data and use scientific language to clarify the detailed action mechanism of herbal medicine. In this paper, the analytical characteristics and application fields of several commonly used mass spectrometers are introduced, and the application of mass spectrometry in the metabolomics of traditional Chinese medicines in recent years and its active components as well as mechanism of action are also discussed.

Mechanism of Citri Reticulatae Pericarpium as an Anticancer Agent from the Perspective of Flavonoids: A Review.

Citri Reticulatae Pericarpium (CRP), also known as "chenpi", is the most common qi-regulating drug in traditional Chinese medicine. It is often used to treat cough and indigestion, but in recent years, it has been found to have multi-faceted anti-cancer effects. This article reviews the pharmacology of CRP and the mechanism of the action of flavonoids, the key components of CRP, against cancers including breast cancer, lung cancer, prostate cancer, hepatic carcinoma, gastric cancer, colorectal cancer, esophageal cancer, cervical cancer, bladder cancer and other cancers with a high diagnosis rate. Finally, the specific roles of CRP in important phenotypes such as cell proliferation, apoptosis, autophagy and migration-invasion in cancer were analyzed, and the possible prospects and deficiencies of CRP as an anticancer agent were evaluated.

Xuefu Zhuyu decoction for nonalcoholic fatty liver disease: A protocol for systematic review and meta-analysis.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) includes nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH), which ranks only second to viral hepatitis and poses an increasingly serious challenge to global public health and economy. NAFLD has attracted more and more attention, but there is no drugs with exact curative effects are available. The commonly used drugs for the treatment of NAFLD in clinical practice are statins, such drugs, inevitably increase the burden on the live. Compared to statins, traditional Chinese medicines are believed to be "all natural" with fewer side effects, are associated with strong patient compliance. Accordingly, a great deal of clinical studies have shown that Xuefu Zhuyu decoction (XFZYD) can significantly improve the clinical symptoms and enhance the therapeutic effect. Meanwhile, a system review and meta-analysis are conducted by us to further clarify the effectiveness and safety of XFZYD for NAFLD. METHODS: We will apply to database mainly range from the English literature searches Cochrane Library, PubMed, excerpt medica database, and Web of Science to the Chinese literature China national knowledge infrastructure, Chinese biomedical literature database, VIP, and Wanfang database, randomized controlled trials (RCTs) are enrolled to evaluate the effectiveness and safety of XFZYD in the treatment of NAFLD, the enrollment of RCTs is from the establishment of the database to February 01, 2021. Simultaneously we will retrieval clinical registration tests and grey literatures. The 2 researchers worked independently on literature selection, data extraction, and quality assessment. The dichotomous data is expressed in terms of relative risk, the continuous is represented by mean difference or standard mean difference, whether there is heterogeneity is the factor that determines the synthesis of data in fixed effect model or random effect model. Alanine aminotransferase (ALT) or Aspartic acid aminotransferase (AST) coupled with Glutamyltransferase (GGT) is considered as one of the main indicators of the NAFLD, while the pathology, imaging and diagnosis of metabolic syndrome are also auxiliary results. The last, meta-analysis was conducted by RevMan software version 5.3. RESULTS: This study will provide evidence for treatment of NAFLD with XFZYD in terms of effectiveness and safety. CONCLUSION: This systematic review aims to confirm the efficacy and safety of XFZYD in the treatment of NAFLD. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/7CWRK.

Efficacy and safety of Chinese herbal footbaths for the treatment of dysmenorrhea: Protocol for a systematic review and meta-analysis.

BACKGROUND: Chinese herbal footbaths are an external therapy of traditional Chinese medicine that has been widely used to treat dysmenorrhea. This review aims to systematically evaluate its efficacy and safety for the treatment of dysmenorrhea. METHODS: Databases of PubMed, EMBASE, Cochrane Library, CIHAHL, Web of Science, Chinese National Knowledge Infrastructure(CNKI), Chinese Scientific Journals Database (VIP), Wanfang Database, China Biomedical Literature Database(CBM), and Chinese Biomedical Literature Service System (SinoMed) will be searched from the inception to September 30, 2020. The eligible randomized controlled trials (RCTs) will be identified and included. The primary outcomes include pain intensity measured by validated scales of visual analog scale, numeric rating scale, and response rate of symptom reduction. The secondary outcomes are scores on validated pain questionnaires, quality of life measured by SF-36 or other validated scales, and adverse events. Study selection, data extraction, and assessment of bias risk will be conducted by two reviewers independently. RevMan software (V.5.3.5) will be utilized to perform data synthesis. Subgroup and sensitivity analysis will be performed when necessary. The strength of the evidence will be evaluated with the Grading of Recommendations Assessment, Development and Evaluation System. RESULTS: A high-quality synthesis of current evidence of Chinese herbal footbaths for patients with dysmenorrhea will be provided in this study. CONCLUSION: This systematic review will provide evidence of whether Chinese herbal footbaths are an effective and safe intervention for the treatment of dysmenorrhea. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020188256.

Efficacy of integrative Traditional Chinese and Western medicine for the treatment of patients infected with 2019 novel coronavirus (COVID-19): A protocol for systematic review and meta analysis.

BACKGROUND: No specific anti-virus drugs or vaccines have been available for the treatment of COVID-19. Integrative traditional Chinese and western medicine has been proposed as a therapeutic option with substantial applications in China. This protocol is proposed for a systematic review and meta-analysis that aims to evaluate the efficacy of integrative traditional Chinese and western medicine treatment on patients with COVID-19. METHODS: Ten databases including PubMed, EMBASE, Cochrane Library, CIHAHL, Web of Science, Chinese National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP), Wanfang database, China Biomedical Literature Database (CBM) and Chinese Biomedical Literature Service System (SinoMed) will be searched. All published randomized controlled trials, clinical controlled trials, case-control, and case series that meet the pre-specified eligibility criteria will be included. Primary outcome measures include mortality, clinical recovery rate, duration of fever, progression rate from mild or moderate to severe, improvement of symptoms, biomarkers of laboratory examination and changes in computed tomography. Secondary outcomes include dosage of hormonotherapy, incidence and severity of adverse events and quality of life. Study selection, data extraction and assessment of bias risk will be conducted by 2 reviewers independently. RevMan software (V.5.3.5) will be used to perform data synthesis. Subgroup and sensitivity analysis will be performed when necessary. The strength of evidence will be assessed by the GRADE system. RESULTS: This study will provide a well-reported and high-quality synthesis on the efficacy of integrative traditional Chinese and western medicine treatment on patients with COVID-19. CONCLUSION: This systematic review protocol will be helpful for providing evidence of whether integrative traditional Chinese and western medicine treatment is an effective therapeutic approach for patients with COVID-19. ETHICS AND DISSEMINATION: Ethical approval is unnecessary as no individual patient or privacy data is collected. The results of this study will be disseminated in a peer-reviewed scientific journal and/or conference presentation. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020167205.

Pien-Tze-Huang protects cerebral ischemic injury by inhibiting neuronal apoptosis in acute ischemic stroke rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Pien-Tze-Huang (PZH) is a famous formula of traditional Chinese medicine used to treating stroke. However, the protective effect of PZH and its mechanisms in acute ischemic stroke remain to be explored. AIM OF THE STUDY: To investigate the protective effect of PZH on neuronal apoptosis in acute cerebral ischemic injury rats and explore its underlying mechanisms. MATERIALS AND METHODS: The effects of PZH were studied in acute ischemic stroke rats induced by transient middle cerebral artery occlusion, and the mitochondria-mediated apoptotic proteins including cytochrome C (Cyt C), Bax, Bcl-xl, P53, caspase-3, and caspase-9 as well as AKT and glycogen synthase kinase-3 beta (GSK-3ß) were assessed. RESULTS: Four days of PZH treatment (180 mg/kg) could significantly reduce cerebral infarct volume, improve neurological deficit, attenuate inflammatory response, and inhibit neuronal apoptosis in acute ischemic stroke rats. Moreover, PZH treatment significantly decreased cytosolic Cyt C, Bax, P53, cleaved caspase-3, and cleaved caspase-9 levels, but elevated mitochondrial Cyt C and Bcl-xl levels. PZH treatment also increased phosphorylation of AKT and GSK-3ß. CONCLUSION: PZH potently protects the brain from cerebral ischemia/reperfusion injury in vivo, and inhibiting mitochondria-mediated neuronal apoptosis as well as attenuating inflammatory responses may be involved in this effect. This study provides experimental basis of PZH in treating acute cerebral ischemic stroke, which would provide some novel insights for its prevention and treatment of ischemic stroke.

An herbal formula attenuates collagen-induced arthritis via inhibition of JAK2-STAT3 signaling and regulation of Th17 cells in mice.

Wenjinghuoluo prescription, a traditional Chinese medicine compound treatment of rheumatoid arthritis characterized by wind-cold-dampness arthralgia, contains five herbs, namely, C. cassia Presl., Cinnamomum cassia Presl., Paeonia lactiflora Pall., Saposhnikovia divaricate (Turcz.) Schischk., and Clematis chinensis Osbeck. We have reported that WJHL could inhibit the production of inflammatory mediators in immune cells. This study explored the effect and mechanism of WJHL on collagen-induced arthritis mice. WJHL could significantly improve clinical arthritic conditions; inhibit bone erosion and osteophyte formation in joints; decrease expression of proinflammatory cytokines (TNF-α, IL-1ß, IL-6, and IL-17); reduce protein expression levels of JAK2, p-JAK2, STAT3, p-STAT3 and gene expression levels of JAK2, STAT3, IL-17A, RORγt mRNA; elevate osteoprotegerin and Foxp3 mRNA levels and lower Th17 cell proportions in splenocytes. Results suggest that WJHL, specifically regulating the JAK2/STAT3 pathway and Th17 cells, may be a promising herbal medicine candidate for the treatment of RA.

IN VIVO EFFECT OF GUIDING-HERB RADIX PLATYCODONIS AND RADIX CYATHULAE ON PAEONIFLORIN PHARMACOKINETICS OF XUEFU ZHUYU TANG IN RATS.

BACKGROUND: Xuefu Zhuyu Tang (XFZYT), first recorded in Correction of Errors in Medical Works by Qing-ren Wang, has been proven reliable and effective for curing various diseases such as atherosclerosis, hypertension, hyperlipidemia, and angina pectoris. It consists of 11 herbs and two of them, Radix platycodonis and Radix cyathulae, have been traditionally considered as guiding herbs and deeply valued by tens of millions of Chinese medicine practitioners. Do Radix platycodonis and Radix cyathulae affect the pharmacokinetics of the effective constituent-paeoniflorin of XFZYT? If yes, in what way? This study aims to answer these questions. MATERIALS AND METHODS: The medicinal solutions of XFZYT, XFZYT without Radix platycodonis (XFZYT-JG), XFZYT without Radix cyathulae (XFZYT-NX), and XFZYT without Radix platycodonis and Radix cyathulae (XFZYT-JG-NX) were prepared and administrated to rats in the normal group and the blood-stasis model group by gavage, respectively. The blood samples of rats in the normal group were obtained 5, 10, 15, 20, 30, 45, 60, 120, and 240 minutes after gavage; whereas the blood samples of rats in the blood-stasis model group were obtained 10, 15, 20, 30, 45, 90, 150, and 240 minutes after gavage. Biological samples were processed; the assays of specificity, precision, linearity, intra-day and inter-day precisions, recovery and stability were conducted; high performance liquid chromatography was performed to detect paeoniflorin content; and DAS software was adopted to generate pharmacokinetic parameters. Mobile phase was composed of acetonitrile and water (16:84), detection wavelength was 230 nm, and riboflavin was set as internal standard substance. RESULTS: The pharmacokinetic parameters of the rats in the normal group after oral gavage of XFZYT, XFZYT-JG, XFZYT-NX, and XFZYT-JG-NX were Cmax = (0.363±0.248, 0.065±0.020, 0.099±0.033, 0.099±0.020) mg/L, Tmax = (0.276±0.084, 0.583±0.342, 0.555±0.228, 0.317±0.033)h, t1/2 = (0.501±0.241, 1.021±0.522, 0.853±0.377, 1.227±0.402) h; and AUC0-∞ = (0.381±0.415, 0.13±0.085, 0.166±0.066, 0.185±0.059) mg/L·h.; whereas the pharmacokinetic parameters for the rats in the blood-stasis model group after oral gavage of XFZYT, XFZYT-JG, XFZYT-NX, and XFZYT-JG-NX were Cmax = (0.315±0.153, 0.215±0.044, 0.228±0.056, 0.248±0.09) mg/L, Tmax = (0.5±0, 0.667±0.129, 0.5±0, 0.542±0.102) h, t1/2 = (0.408±0.146, 0.813±0.135, 0.708±0.383, 0.741±0.173) h, and AUC0-∞ = (0.306±0.157, 0.408±0.136, 0.368±0.159, 0.381±0.246) mg/L·h. CONCLUSION: The guiding herbs, Radix platycodonis and Radix cyathulae, significantly increased the absorption amount and rate of paeoniflorin in XFZYT, and accelerated its elimination from the blood.

Curcumin treatment alters ERK-1/2 signaling in vitro and inhibits nasopharyngeal carcinoma proliferation in mouse xenografts.

Curcumin, a plant phenol, has been used for centuries in traditional medicines for its anti-inflammatory and anti-neoplastic properties. The compound is believed to act on a range of proteins involved in cell cycle regulation. In this study, the effect of curcumin on ERK-1/2 pathway protein expression and on proliferation of nasopharyngeal carcinoma cells was investigated. CNE-2Z nasopharyngeal carcinoma cells were cultured with 10, 20, 40, or 80 µM curcumin for 24 h before proliferation was assessed by MTT colorimetry. Cell proliferation was increasingly inhibited as the concentration of curcumin increased (P<0.005). Additionally, Western blotting revealed that expression of p-ERK-1/2, MMP-9, and TIMP-1 was altered following curcumin treatment, also in a dose-dependent manner. Expression of p-ERK-1/2 and MMP-9 decreased, while expression of TIMP-1 increased (P<0.05). Finally, CNE-2Z cells were xenografted under the skin of 18 nude mice. Mice were treated with vehicle only (control), 24 mg/kg curcumin (low-dose group), or 50 mg/kg curcumin (high-dose group) every other day for 40 days beginning 24 h after xenografting. Compared to tumors from the control group, the volume and weight of xenograft tumors was significantly lower in both curcumin groups, with a higher magnitude of difference in the high-dose curcumin group (P<0.05). These results indicate that curcumin treatment can inhibit proliferation of nasopharyngeal carcinoma cells and alter expression of proteins in the ERK-1/2 signaling pathway. Therefore, curcumin warrants further investigation as a potential treatment for nasopharyngeal cancer.