Ginsenoside Rk1 improves endothelial function in diabetes through activating peroxisome proliferator-activated receptors.

Ginsenoside Rk1, one kind of ginsenoside, is a minor ginsenoside found in Panax ginseng and used as traditional Chinese medicine for centuries. It exhibits anti-tumor and anti-aggregation effects. However, little research has been done on its effect on endothelial function. This study investigated whether ginsenoside Rk1 improved endothelial dysfunction in diabetes and the underlying mechanisms in vivo and in vitro. Male C57BL/6 mice were fed with a 12 week high-fat diet (60% kcal % fat), whereas treatment groups were orally administered with ginsenoside Rk1 (10 and 20 mg per kg per day) in the last 4 weeks. Aortas isolated from C57BL/6 mice were induced by high glucose (HG; 30 mM) and co-treated with or without ginsenoside Rk1 (1 and 10 µM) for 48 h ex vivo. Moreover, primary rat aortic endothelial cells (RAECs) were cultured and stimulated by HG (44 mM) to mimic hyperglycemia, with or without the co-treatment of ginsenoside Rk1 (10 µM) for 48 h. Endothelium-dependent relaxations of mouse aortas were damaged with elevated oxidative stress and downregulation of three isoforms of peroxisome proliferator-activated receptors (PPARs), PPAR-α, PPAR-ß/δ, and PPAR-γ, as well as endothelial nitric oxide synthase (eNOS) phosphorylation due to HG or high-fat diet stimulation, which also existed in RAECs. However, after the treatment with ginsenoside Rk1, these impairments were all ameliorated significantly. Moreover, the vaso-protective and anti-oxidative effects of ginsenoside Rk1 were abolished by PPAR antagonists (GSK0660, GW9662 or GW6471). In conclusion, this study reveals that ginsenoside Rk1 ameliorates endothelial dysfunction and suppresses oxidative stress in diabetic vasculature through activating the PPAR/eNOS pathway.

Ginsenoside Rk1 Ameliorates ER Stress-Induced Apoptosis through Directly Activating IGF-1R in Mouse Pancreatic [Formula: see text]-Cells and Diabetic Pancreas.

Hyperglycemia induces chronic stresses, such as oxidative stress and endoplasmic reticulum (ER) stress, which can result in [Formula: see text]-cell dysfunction and development of Type 2 Diabetes Mellitus (T2DM). Ginsenoside Rk1 is a minor ginsenoside isolated from Ginseng. It has been shown to exert anti-cancer, anti-inflammatory, anti-oxidant, and neuroprotective effects; however, its effects on pancreatic cells in T2DM have never been studied. This study aims to examine the novel effects of Ginsenoside Rk1 on ER stress-induced apoptosis in a pancreatic [Formula: see text]-cell line MIN6 and HFD-induced diabetic pancreas, and their underlying mechanisms. We demonstrated that Ginsenoside Rk1 alleviated ER stress-induced apoptosis in MIN6 cells, which was accomplished by directly targeting and activating insulin-like growth factor 1 receptor (IGF-1R), thus activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/Bcl-2-associated agonist of cell death (Bad)-B-cell lymphoma-2 (Bcl-2) pathway. This pathway was also confirmed in an HFD-induced diabetic pancreas. Meanwhile, the use of the IGF-1R inhibitor PQ401 abolished this anti-apoptotic effect, confirming the role of IGF-1R in mediating anti-apoptosis effects exerted by Ginsenoside Rk1. Besides, Ginsenoside Rk1 reduced pancreas weights and increased pancreatic insulin contents, suggesting that it could protect the pancreas from HFD-induced diabetes. Taken together, our study provided novel protective effects of Ginsenoside Rk1 on ER stress-induced [Formula: see text]-cell apoptosis and HFD-induced diabetic pancreases, as well as its direct target with IGF-1R, indicating that Ginsenoside Rk1 could be a potential drug for the treatment of T2DM.

Glycyrrhizic Acid and Its Derivatives: Promising Candidates for the Management of Type 2 Diabetes Mellitus and Its Complications.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease, which is characterized by hyperglycemia, chronic insulin resistance, progressive decline in ß-cell function, and defect in insulin secretion. It has become one of the leading causes of death worldwide. At present, there is no cure for T2DM, but it can be treated, and blood glucose levels can be controlled. It has been reported that diabetic patients may suffer from the adverse effects of conventional medicine. Therefore, alternative therapy, such as traditional Chinese medicine (TCM), can be used to manage and treat diabetes. In this review, glycyrrhizic acid (GL) and its derivatives are suggested to be promising candidates for the treatment of T2DM and its complications. It is the principal bioactive constituent in licorice, one type of TCM. This review comprehensively summarized the therapeutic effects and related mechanisms of GL and its derivatives in managing blood glucose levels and treating T2DM and its complications. In addition, it also discusses existing clinical trials and highlights the research gap in clinical research. In summary, this review can provide a further understanding of GL and its derivatives in T2DM as well as its complications and recent progress in the development of potential drugs targeting T2DM.

Holism of Chinese herbal medicine prescriptions for inflammatory bowel disease: A review based on clinical evidence and experimental research.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic nonspecific inflammatory disease that causes a heavy burden and lacks effective treatments. Chinese herbal medicine prescriptions (CHMPs), which are characterized by a synergistic usage of herbs, are widely used in the management of IBD. The molecular mechanisms of action of CHMP are still ambiguous as the canonical "one-compound-one-target" approach has difficulty describing the dynamic bioreactions among CHMP objects. It seems more flexible to define the holism of CHMP for IBD by employing high-throughput analysis. However, studies that discuss the development of CHMP in treating IBD in a holistic view are still lacking. PURPOSE: This review appraised preclinical and clinical research to fully describe the anti-IBD capacity of CHMPs and discussed CHMPs' holistic characteristics that can contribute to better management of IBD. METHODS & RESULTS: We screened clinical and preclinical references of CHMP being used as treatments for IBD. We discussed the complexity of IBD and the development of CHMP to present the sophistication of CHMP treatments. To describe the clinical effectiveness of CHMPs against IBD, we performed an umbrella review of CHMP-associated META analyses, in which 1174 records were filtered down to 12 references. Then, we discussed 14 kinds of CHMPs that had a long history of use and analyzed their mechanisms of action. Representative herbs were employed to provide a subordinate explanation for the whole prescription. As holism is the dominant characteristic of CHMPs, we explored applications of CHMPs for IBD with the help of omics, gut microbiome, and network pharmacology, which are potential approaches to a dynamic figure of bioactions of CHMPs. CONCLUSION: This review is the first to discuss the potential of CHMPs to manage IBD in a holistic context and will provide inspiring explanations for CHMP applications for further product transformation and application to other diseases.

Neuroendocrine-Immune Regulatory Network of Eucommia ulmoides Oliver.

Eucommia ulmoides Oliver (E. ulmoides) is a popular medicinal herb and health supplement in China, Japan, and Korea, and has a variety of pharmaceutical properties. The neuroendocrine-immune (NEI) network is crucial in maintaining homeostasis and physical or psychological functions at a holistic level, consistent with the regulatory theory of natural medicine. This review aims to systematically summarize the chemical compositions, biological roles, and pharmacological properties of E. ulmoides to build a bridge between it and NEI-associated diseases and to provide a perspective for the development of its new clinical applications. After a review of the literature, we found that E. ulmoides has effects on NEI-related diseases including cancer, neurodegenerative disease, hyperlipidemia, osteoporosis, insomnia, hypertension, diabetes mellitus, and obesity. However, clinical studies on E. ulmoides were scarce. In addition, E. ulmoides derivatives are diverse in China, and they are mainly used to enhance immunity, improve hepatic damage, strengthen bones, and lower blood pressure. Through network pharmacological analysis, we uncovered the possibility that E. ulmoides is involved in functional interactions with cancer development, insulin resistance, NAFLD, and various inflammatory pathways associated with NEI diseases. Overall, this review suggests that E. ulmoides has a wide range of applications for NEI-related diseases and provides a direction for its future research and development.

Emerging pharmacotherapy for inflammatory bowel diseases.

Inflammatory bowel disease (IBD) refers to a gamut of disorders that are characterized by chronic intestinal inflammation, including ulcerative colitis (UC) and Crohn's disease (CD), which often leads to mucosal ulceration and progressive loss of intestinal function. The etiopathogenesis of IBD has not been completely clarified, although multiple factors involving genetic modifications, host immune dysfunction, intestinal dysbiosis and environmental effects have been implicated. Currently, pharmacotherapies including both non-targeted and targeted biological agents are widely used for the clinical treatment of IBD. In addition, novel therapeutic approaches that target the intestinal microorganisms, such as fecal microbiota transplantation, antibiotics, probiotics and microbial metabolite inhibitors, are also under development. However, these treatments are either accompanied by side effects or cannot achieve complete clinical remission when used alone. The efficacy and safety of drugs are currently a clinical challenge. Thus, advanced drug delivery systems are needed for targeted delivery of drugs to the inflammatory sites and avoid absorption by healthy tissues. In this review, we have summarized the latest research on the pathogenesis of IBD and the emerging pharmacotherapies, and discussed potential therapeutic targets for innovative therapies.

The Pharmacological Rationales and Molecular Mechanisms of Ganoderma lucidum Polysaccharides for the Therapeutic Applications of Multiple Diseases.

As a versatile Chinese herb, Ganoderma lucidum (Leyss. ex Fr.) Karst (G. lucidum) has been applied to treat multiple diseases in clinics and improve the quality of life of patients. Among all of its extracts, the main bioactive components are G. lucidum polysaccharides (GLPs), which possess many therapeutic effects, such as antitumor, immunoregulatory, anti-oxidant, antidiabetic, antibacterial, and antifungal effects and neuroprotection activities. This review briefly summarized the recent studies of the pharmacological rationales of GLPs and their underlying molecular signaling transmission mechanisms in treating diseases. Until now, the clear mechanisms of GLPs for treating diseases have not been reported. In this review, we used the keywords of "Ganoderma lucidum polysaccharides" and "tumor" to search in PubMed (years of 1992-2020), then screened and obtained 160 targets of antitumor activities in the literatures. The network pharmacology and mechanism framework were employed in this study as powerful approaches to systematically analyze the complicated potential antitumor mechanisms and targets of GLPs in cancer. We then found that there are 69 targets and 21 network pathways in "Pathways in cancer". Besides, we summarized the effects of GLPs and the models and methods used in the research of GLPs. In conclusion, GLPs have been studied extensively, but more in-depth research is still needed to determine the exact mechanisms and pathways. Therefore, this review might provide new insights into the vital targets and pathways for researchers to study the pharmacological mechanisms of GLPs for the treatment of diseases.

A recent update on the use of Chinese medicine in the treatment of inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic idiopathic disease that is characterized by inflammation of the gastrointestinal tract. Proper management of IBD requires both early diagnosis and novel therapies and management programs. Many reports have suggested that Chinese medicine has unique properties favorable to the treatment of IBD. However, there are no systematic analyses on this topic. PURPOSE: This review summarizes recent studies that assessed the effects and mechanisms of Chinese medicine in the treatment of IBD in order to fully understand the advantages of Chinese medicine in the management of IBD. METHODS: A literature search was conducted using peer-reviewed and clinical databases, including PubMed, Web of Science, ClinicalTrials.gov, MEDLINE, EMBASE, Springer LINK, Wan-fang database, the Chinese Biomedicine Database, and the China National Knowledge Infrastructure (CNKI). Keywords used were inflammatory bowel disease (including Ulcerative colitis or Crohn's disease) and Chinese medicine. All selected articles were from 1997 to 2021, and each were assessed critically for our exclusion criteria. Studies describing the pathogenesis of IBD, the effects and mechanisms of Chinese medicine in the treatment of IBD, in particular their roles in immune regulation, intestinal flora regulation, and improvement of intestinal barrier function, were included. CONCLUSION: This review highlights recent progress in the use of Chinese medicine in the treatment of IBD. It also provides a reference for further evaluation and exploration of the potential of classical multi-herbal Chinese medicine in the treatment of IBD.

The key issues and development strategy of Chinese Classical Formulas pharmaceutical preparations.

It is well-known that Prof. Tu Youyou won the Nobel Prize in Physiology or Medicine in 2015 due to the research on artemisinin treating malaria, and this can be regarded as the milestone of modernization of Traditional medicine. This first Nobel Prize in Traditional Chinese medicine (TCM) has aroused profound impetus in the investigation of TCM and attracted global attention to the ancient books of TCM. Three new medicines for the treatment of COVID-19 derived from Chinese Classical Formula (, CCF) have been approved in 2021 due to their effectiveness for the treatment of COVID-19. This article introduced the research background of CCF pharmaceutical preparation (CCFPP), explained the ideas for the modernization of CCF and analyzed related issues involved in the development process of CCFPP, including the origin of medicinal materials, processing methods, dosages and the preparation process of CCF Material Reference. The strategy for industrialization was proposed in terms of the evaluation of the pharmaceutical properties, industrialization considerations, and clinical positioning of CCFPP. The key contents and requirements for the development CCFPP were also summarized according to the recently published registration guidance by the Center for Drug Evaluation in China. In addition, the safety issues of CCFPP were described, including the discussion on the non-clinical safety evaluation and analyzation on the international registration of Traditional herbal medicines. This article is aimed to provide references for enterprises, researchers, and relevant personnel of government departments that are engaged in the development of CCF to speed up the developing process of CCFPP.

Panax notoginseng Saponins Modulate the Inflammatory Response and Improve IBD-Like Symptoms via TLR/NF-[Formula: see text]B and MAPK Signaling Pathways.

Panax notoginseng saponins (PNS) are the main active ingredients of Panax notoginseng (Burk) F. H. Chen, which are used as traditional Chinese medicine for thousands of years and have various clinical effects, including anti-inflammation, anti-oxidation, and cardiovascular protection. Inflammatory bowel disease (IBD) is a complex gastrointestinal inflammatory disease that cannot be cured completely nowadays. The anti-inflammatory and protective effects of PNS were analyzed in vitro and in dextran sulfate sodium (DSS)-induced colitis mouse model. PNS inhibited the release of nitric oxide (NO), tumor necrosis factor-[Formula: see text] (TNF-[Formula: see text], interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) in Pam3CSK4-induced RAW 264.7 macrophages. In the animal study, compared with DSS-induced mice, PNS reduced the expression of pro-inflammatory cytokines (TNF-[Formula: see text], IL-6, and MCP-1) in the colon tissues. Furthermore, PNS treatment led to a remarkable reduction in the activation of the inhibitor of nuclear factor kappa-B kinase [Formula: see text]/[Formula: see text] (IKK[Formula: see text]/[Formula: see text], I[Formula: see text]B[Formula: see text] and p65 induced by DSS. On the other hand, PNS inhibited the phosphorylation of c-Jun N-terminal kinase (JNK), p38, and extracellular regulated protein kinase 1/2 (ERK1/2). Taken together, our results suggested that PNS conferred profound protection for colitis mice through the downregulation of mitogen-activated protein kinase (MAPK) and NF-[Formula: see text]B signaling pathways, which were associated with reducing inflammatory responses, alleviating tissue damage, and maintaining of intestinal integrity and functionality.

Salvia miltiorrhiza Bge. (Danshen) for Inflammatory Bowel Disease: Clinical Evidence and Network Pharmacology-Based Strategy for Developing Supplementary Medical Application.

Inflammatory bowel disease (IBD) is a non-specific colorectal disease caused by multifaceted triggers. Although conventional treatments are effective in the management of IBD, high cost and frequent side effects limit their applications and have turned sufferers toward alternative and complementary approaches. Salvia miltiorrhiza Bge (Danshen) is an herbal medicine that reportedly alleviates the symptoms of IBD. A large body of research, including clinical trials in which Danshen-based products or botanical compounds were used, has unmasked its multiple mechanisms of action, but no review has focused on its efficacy as a treatment for IBD. Here, we discussed triggers of IBD, collected relevant clinical trials and analyzed experimental reports, in which bioactive compounds of Danshen attenuated rodent colitis in the management of intestinal integrity, gut microflora, cell death, immune conditions, cytokines, and free radicals. A network pharmacology approach was applied to describe sophisticated mechanisms in a holistic view. The safety of Danshen was also discussed. This review of evidence will help to better understand the potential benefits of Danshen for IBD treatment and provide insights for the development of innovative applications of Danshen.

Anti-COVID-19 drug screening: Frontier concepts and core technologies.

The outbreak of COVID-19 has recently evolved into a global pandemic. Up to July 2020, almost every country has confirmed COVID-19 cases reported worldwide. Many leading experts have predicted that the epidemic will persist for relatively a long period of time. Thus far, there have been no remedies proven effective against the disease. As the nation where COVID-19 broke out first, China has adopted a combination of traditional Chinese medicine and western medicine to fight against the disease, and has achieved significant clinical result. Up to now, the COVID-19 pandemic has been effectively controlled in China. However, the rest of the world (except for a limited number of countries and regions) is still in deep water. This paper thoroughly summarizes interdisciplinary notions and techniques, including disease model, biochip, network pharmacology, and molecular docking technology, etc., providing a reference for researchers in the screening of drugs for COVID-19 prevention and treatment. These methodologies may facilitate researchers to screen out more potential drugs for treating COVID-19 pneumonia and to tackle this global crisis.

Reflections on treatment of COVID-19 with traditional Chinese medicine.

Coronavirus disease 2019 (COVID-19) pandemic is spreading rapidly around the globe. By the establishment of an integrative system combining both traditional Chinese medicine (TCM) and western medicine, China has achieved good clinical efficacy in the prevention and control of the pandemic. The advantages of TCM in the treatment of COVID-19 include effective relief of symptoms, retarding the development from mild and moderate to severe, improvement of cure rate, reducing death rates, and promotion of rehabilitation. Besides, according to the different severity levels of individual cases, the National Health Commission of the People's Republic of China issued treatment guidelines that provide corresponding prescriptions for patients. From the perspective of TCM, this review aims to analyze the role of a variety of TCM prescriptions in the treatment of COVID-19, focusing on the analysis of the "Three TCM prescriptions and three medicines" recommended by the Chinese authorities during the pandemic. We expect that this review will provide insights into the prevention and treatment of COVID-19 with TCM.

Gomisin M2 from Baizuan suppresses breast cancer stem cell proliferation in a zebrafish xenograft model.

Gomisin M2 isolated from Schisandra viridis A. C. Smith has potential anti-tumor effects on certain cancers, including breast cancer. However, only a few investigations have been conducted on the effects of Gomisin M2 on breast cancer stem cells (CSCs), which have the ability to self-renew and differentiate, as a possible strategy to resolve cancer cell resistance to apoptosis and to improve treatments. It is essential to investigate the effects of Gomisin M2 on breast cancer stem cells (BCSCs). In this study, we enriched breast cancer stem cells with CD44+/CD24- from MDA-MB-231 and HCC1806 cells through magnetic-activated cell sorting and cultured these in serum-free medium. The ability of Gomisin M2 to kill breast cancer stem cells was evaluated in vitro and in vivo. Gomisin M2 significantly inhibited the proliferation of the triple-negative breast cancer cell lines and mammosphere formation in breast CSCs and downregulated the Wnt/ß-catenin self-renewal pathway. Moreover, Gomisin M2 induced apoptosis and blocked the mitochondrial membrane potential of BCSCs. Gomisin M2 suppressed the proliferation of MDA-MB-231 and HCC1806 xenografts in zebrafish. Together, these findings suggest that the anti-BCSC activity of Gomisin M2 could become a promising starting point for the discovery of novel BCSC-targeting drugs.

Apoptosis effect of Aegiceras corniculatum on human colorectal cancer via activation of FoxO signaling pathway.

Aegiceras corniculatum (L.) Blanco is known to exhibit anticancer effects against different types of cancer; however, to the best of our knowledge, the anticancer activity and underlying mechanisms of action of A. corniculatum leaf extract on colorectal cancer have not been elucidated. In the present study, colony-forming assay, western blot analysis, flow cytometry, and a xenograft model were used to investigate the effects of an n-butanol extract of A. corniculatum leaves (NACL) on colorectal cancer in vitro and in vivo. The results showed that NACL inhibits the viability and proliferation of colorectal cancer cells in a dose-dependent manner. Besides, NACL also induces cell apoptosis and cell cycle arrest by activating Forkhead box proteins and controlling the cell cycle checkpoint pathways, which are associated with the caspase-dependent mitochondrial apoptotic cascades and Bcl-2 family proteins. More importantly, the tumour sizes in HT-29 xenograft nude mice decreased after treatment with NACL in vivo. These findings indicate that A. corniculatum leaf extracts have potent anticancer activities across different colorectal and other solid tumour cell lines, via regulation of the cell cycle and apoptosis; thus, it has the potential to be developed as an anticancer agent to enhance clinical standards of care for patients with colorectal cancer.