Deciphering the pharmacological mechanisms of Shenlingbaizhu formula in antibiotic-associated diarrhea treatment: Network pharmacological analysis and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Shenlingbaizhu (SLBZ) formula, a classical traditional Chinese medicinal (TCM) formula, has been widely used for treating antibiotic-associated diarrhea (AAD). However, the underlying pharmacological mechanisms have not yet been investigated thoroughly. AIM OF THE STUDY: To explore the remission mechanism of SLBZ in the treatment of AAD, we conducted network pharmacological analysis and experimental validation in vitro and in vivo. MATERIALS AND METHODS: In this study, the main compounds of SLBZ were identified by ultra-high-performance liquid chromatography-mass spectroscopy (UHPLC-MS) and online databases. The targets of the active components and AAD-related targets were predicted by network pharmacology, and the potential targets of SLBZ against AAD were obtained. Then the core targets were recognized after Protein-Protein Interaction (PPI) analysis. Based on these, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analyses were conducted, and the key pathway was screened. Subsequently, molecular docking was performed using Auto Dock Vina to find the key components that played a crucial role in that pathway. Molecular dynamics simulation was performed by Gromacs software to detect the binding mode. Finally, the results were confirmed by in vitro and in vivo experiments. RESULTS: A total of 66 active ingredients of SLBZ were detected by UHPLC-MS, and 128 active ingredients were screened out by network pharmacological analysis. Additionally, 935 drug targets and 1686 AAD-related targets were obtained. Seventy-eight intersected genes were selected as potential therapeutic targets and 19 genes were excavated as core targets. Enrichment analysis revealed PI3K-AKT signaling pathway was the key pathway in SLBZ against AAD. Topological analysis further revealed that JAK2, MTOR, TLR4, and SYK were the key targets affected by SLBZ on the PI3K-AKT pathway, and 52 components of SLBZ were associated with them. Molecular docking and dynamics simulation revealed strong binding affinities between MTOR and diosgenin. Subsequently, after SLBZ treatment, the expression levels of JAK2, MTOR, TLR4, and SYK were found significantly upregulated in the AAD model rats (p < 0.05). The cell experiment further validated the good binding ability between MTOR and diosgenin. CONCLUSION: We demonstrate that the therapeutic effect of SLBZ on AAD was achieved in part by inhibiting the PI3K-AKT pathway.

Novel Natural Carrier-Free Self-Assembled Nanoparticles for Treatment of Ulcerative Colitis by Balancing Immune Microenvironment and Intestinal Barrier.

Ulcerative colitis (UC) is a chronic inflammatory illness affecting the colon and rectum, with current treatment methods being unable to meet the clinical needs of ulcerative colitis patients. Although nanomedicines are recognized as promising anti-inflammatory medicines, their clinical application is limited by their high cost and unpredictable safety risks. This study reveals that two natural phytochemicals, berberine (BBR) and hesperetin (HST), self-assemble directly to form binary carrier-free multi-functional spherical nanoparticles (BBR-HST NPs) through noncovalent bonds involving electrostatic interactions, π-π stacking, and hydrogen bonding. Because of their synergistic anti-inflammatory activity, berberine-hesperetin nanoparticles (BBR-HST NPs) exhibit significantly better therapeutic effects on UC and inhibitory effects on inflammation than BBR and HST at the same dose by regulating the immune microenvironment and repairing the damaged intestinal barrier. Furthermore, BBR-HST NPs exhibit good biocompatibility and biosafety. Thus, this study proves the potential of novel natural anti-inflammatory nanoparticles as therapeutic agents for UC, which could promote the progress of drug development for UC and eventually benefit patients who suffering from it.

Efficacy and safety of Weifuchun tablet for chronic atrophic gastritis: A systematic review and meta-analysis.

BACKGROUND: Chronic atrophic gastritis is a significant premalignant lesion of gastric carcinoma. There is a great need to prevent the progression to gastric carcinoma through early intervention and treatment for chronic atrophic gastritis. Weifuchun, a famous Chinese patent drug, has been widely used for chronic atrophic gastritis in China. However, it remains unclear whether Weifuchun is effective for atrophic gastritis. OBJECTIVE: To determine the effectiveness and safety of Weifuchun for chronic atrophic gastritis. METHODS: We systematically retrieved seven databases (Cochrane Library, EMBASE, PubMed, China National Knowledge Infrastructure, Wanfang database, Chinese Scientific Journals Database, and Chinese Biological Medical Database) from their inception to October 5, 2022. Methodological quality was examined using the Cochrane Risk of bias tool. We also used RevMan 5.4 software for statistical analysis to examine the effectiveness and safety of Weifuchun. RESULTS: Fifteen studies with 1,488 patients were enrolled in this meta-analysis. The study indicated that Weifuchun was more effective (RR 1.52; 95% CI 1.41, 1.63; p<0.00001) than Western medicine and other Chinese patent medicine. In addition, Weifuchun was more effective in improving gastric mucosal under gastroscopy, improving histopathologic changes of gastric mucosal, and inhibiting Helicobacter pylori. However, no significant difference in safety was examined between Weifuchun and the control group (RR 2.83; 95% CI 0.85, 9.38; P = 0.09). CONCLUSIONS: The meta-analysis revealed a significant statistical difference with Weifuchun in effectiveness compared to the control group. However, there was no significant difference in safety. Thus, more high-quality clinical studies are needed in the future. TRIAL REGISTRATION: Registration number CRD42022365703.

Research on the experience of National Master of Traditional Chinese Medicine Professor Lu ZhiZheng in treating chronic atrophic gastritis based on data mining technology.

BACKGROUND: The purpose of this research is to summarize the academic expertise of Professor Lu Zhizheng in the treatment of Chronic Atrophic Gastritis, and to explain his clinical reasoning and common prescriptions in the treatment of CAG. METHODS: Professor Lu's outpatient cases of CAG from January 2008 to December 2021 were selected, and the PageRank algorithm was applied on the FangNet platform to analyze the usage frequencies of herbs, their four natures and five flavors according to Traditional Chinese Medicine, core herbs, and herb clustering patterns, with the goal of summarizing the distinguishing features of Professor Lu's academic and clinical approach to CAG. A total of 170 patients from 252 consultations were included in this study. The prescriptions involved a total of 239 herbs, which occurred a cumulative 4339 times. The herb natures were mainly warm, neutral, and slightly cold, and the herb flavors were predominantly sweet, bitter, and pungent. The channel tropism of the selected herbs primarily targeted the spleen, stomach, and lung meridians. Herb rank analysis showed that 34 herbs, including Gancao, Taizishen, Banxia, Huanglian, Shengjiang, Baizhu, Yiyiren, Maiya, Cangzhu, and Kuxingren, were the driver herbs used by Professor Lu for the treatment of CAG. RESULTS: Herb-herb co-occurrence/exclusivity analysis revealed 10 sets of frequently used herb pairs; herb cluster analysis yielded 10 herb clusters. These results reflected the emphasis Professor Lu placed on protecting Qi and Yin while clearing damp-heat. Professor Lu Zhizheng utilized dialectics reinforced with flexible thinking in the treatment of CAG, and emphasized that identifying the pathogenesis and addressing the syndrome should be prioritized. CONCLUSIONS: The characteristic treatment strategy aimed to replenish Qi and nourish Yin, clear away damp-heat, and treat CAG patients comprehensively under the guidance of established principles.

Qu-Du-San-Jie decoction induces growth inhibition and vascular normalization in NF2-associated vestibular schwannoma.

Background: Neurofibromatosis type 2 (NF2) is a rare genetic syndrome that predisposes individuals to develop bilateral vestibular schwannomas (VSs) causing a high risk of life-threatening neurological complications. Traditional treatment options for NF2-associated VS usually cause neurological damage, and to date, there are no FDA-approved pharmacotherapies for NF2. The aim of this study was to evaluate the antitumor efficacy of Qu-Du-San-Jie (QDSJ) decoction, a traditional Chinese medicine formula, on NF2-associated VS and to investigate the potential underlying mechanisms. Methods: Ultra high-performance liquid chromatography-mass spectroscopy (UHPLC-MS) analysis was performed to identify the components of QDSJ and their targets. To determine the relationships between the putative targets of QDSJ and the differential genes of NF2-associated VS, the drug-disease crossover genes were screened using the UHPLC-MS data combined with our previous gene expression profiling data. The differentially expressed genes were imported into the STRING database to generate a PPI network. Differentially expressed gene targets and pathways were identified using GO and KEGG pathway enrichment analyses. The in vitro and in vivo drug efficacy of QDSJ decoction was tested using a patient-derived schwannoma cell line and a patient-derived xenograft mouse model, respectively. H&E staining, immunochemistry, and immunofluorescence staining were used to evaluate the cell proliferation and tumor vessels. Results: A total of 133 compounds were identified in QDSJ decoction using UHPLC-MS analysis. Network pharmacology showed that the regulation of necroptosis, apoptosis, cell cycle, angiogenesis, adherens junction, and neuroactive ligand-receptor interaction could be associated with the efficacy of QDSJ in treating NF2-associated VS. Treatment with QDSJ induced necrotic cell death and apoptosis of schwannoma cells in vitro and suppressed the tumor growth in vivo. Histopathological analysis revealed areas of cell necrosis and enlarged tumor blood vessels in the QDSJ-treated tumors. The numbers of cells positive for Cyclin D1 and Ki-67 were significantly reduced in QDSJ-treated tumors compared to control tumors. Immunofluorescence staining of CD31 and αSMA showed a decreased number and density of tumor vessels and normalized vessel structure in QDSJ-treated tumors. Conclusion: Our study demonstrates that QDSJ decoction shows significant antitumor activity against NF2-associated schwannoma and is a possible candidate for future clinical trials.

Manpixiao Decoction Halted the Malignant Transformation of Precancerous Lesions of Gastric Cancer: From Network Prediction to In-Vivo Verification.

Manpixiao decoction (MPX), a traditional Chinese medicine formula, is mainly used to improve the gastric mucosal pathology and stomach discomfort in patients with gastric precancerous lesions. Precancerous lesion of gastric cancer (PLGC) refers to intestinal metaplasia and/or dysplasia based on gastric mucosal atrophy. Effective prevention and treatment of PLGC is of great significance to reduce the incidence of gastric cancer. Because of the complexity of the etiology and pathogenesis of PLGC, there is no unified and effective treatment plan in western medicine. In recent years, traditional Chinese medicine has shown obvious advantages in the treatment of PLGC and the prevention of its further progression to gastric cancer, relying on its multi-approach and multi-target comprehensive intervention characteristics. This study is designed to examine the protective effect of MPX against PLGC and further to reveal the engaged mechanism via integrating network pharmacology and in vivo experimental evidence. Network pharmacology results demonstrated that inflammation, immune responses, and angiogenesis might be associated with the efficacy of MPX in the treatment of PLGC, in which the PI3K-Akt, cellular senescence, P53 and protein processing in endoplasmic reticulum were involved. Then, we established a rat model of PLGC using a combination of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), sodium salicylate, irregular fasting, and ranitidine, and observed the effects after MPX treatment. Our result showed that MPX improved the pathological condition of gastric mucosa in PLGC rats and reduced the incidence of gastric cancer. Next, the analysis of serum inflammatory cytokines showed that MPX reduced the inflammation-related cytokines (such as IL-1α, IL-7, CSF-1, and CSF-3) in the serum. Additionally, MPX also had a regulation effect on the "protein/protein phosphorylation-signaling pathway" network in the core region of the PLGC rats. It is showed that MPX can inhibit the phosphorylation of PI3K-AKT, and downregulates the EGFR, ß-catenin, and N-cadherin protein levels. These results indicate that MPX halted the PLGC progression through inhibiting EGFR-PI3K-AKT related epithelial-mesenchymal transition process.

Erianin, the main active ingredient of Dendrobium chrysotoxum Lindl, inhibits precancerous lesions of gastric cancer (PLGC) through suppression of the HRAS-PI3K-AKT signaling pathway as revealed by network pharmacology and in vitro experimental verification.

ETHNOPHARMACOLOGICAL RELEVANCE: Dendrobium chrysotoxum Lindl, a well-known traditional Chinese medicinal herb used in the treatment of gastric disease, is distinguished as the first of the "nine immortal grasses". Dendrobium chrysotoxum Lindl and the traditional Chinese medicine prescriptions containing Dendrobium chrysotoxum Lindl are often prescribed clinically to treat chronic gastritis and precancerous lesions of gastric cancer (PLGC), showing favorable clinical effects and medicinal value in the prevention of gastric cancer. However, the effective ingredients and pharmacological mechanisms through which Dendrobium chrysotoxum Lindl prevents and treats PLGC have not been adequately identified or interpreted. AIM OF THE STUDY: The present study aimed to evaluate the effective ingredients and pharmacological mechanisms of Dendrobium chrysotoxum Lindl in the prevention and treatment of PLGC using network pharmacology. In addition, in vitro verification was performed to evaluate the mechanism of action of Erianin, the main active ingredient in Dendrobium chrysotoxum Lindl, providing experimental evidence for the clinical use of Dendrobium chrysotoxum Lindl in the treatment of PLGC. MATERIALS AND METHODS: Using network pharmacology methods, the main ingredients in Dendrobium chrysotoxum Lindl were screened from the ETCM, BATMAN-TCM, and TCMID databases, and their potential targets were predicted using the Swiss Target Prediction platform. The targets related to PLGC were retrieved through the GeneCard database, and the targets common to the main ingredients of Dendrobium chrysotoxum Lindl and PLGC were analyzed. The protein-protein interaction (PPI) network was obtained via the STRING database and analyzed visually using Cytoscape 3.7.2. The underlying mechanisms of the common targets identified through gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were analyzed using DAVID online. The "component-target-pathway" networks of Dendrobium chrysotoxum Lindl and Erianin were visually constructed by Cytoscape 3.7.2. The biological activity evaluation of Erianin's effect on PLGC was carried out using MC cell lines, the PLGC cell model established using MNNG to induce damage in normal gastric mucosal epithelial cell (GES-1). After the intervention of different concentrations of Erianin, MC cell viability was explored using the MTT assays, cell migration was determined by wound healing assays, the cell cycle and apoptosis were analyzed using flow cytometry, and the expression levels of related proteins and their phosphorylation in the HRAS-PI3K-AKT signaling pathway were detected by Western blot. RESULTS: The "component-target-pathway" network constructed in this study showed 37 active ingredients from Dendrobium chrysotoxum Lindl and 142 overlapping targets related to both Dendrobium chrysotoxum Lindl and PLGC. The targets were associated with a variety of cancer-related signaling pathways, including Pathways in cancer, PI3K-Akt signaling pathway, Rap1 signaling pathway, Focal adhesion, Ras signaling pathway, and MAPK signaling pathway. Notably, the network showed that Erianin, the primary active ingredient from Dendrobium chrysotoxum Lindl and the component associated with the most targets, could regulate Pathways in cancer, PI3K-AKT signaling pathway, Focal adhesion, Rap1 signaling pathway, cell cycle, and RAS signaling pathway in the treatment of PLGC. Verification through in vitro experiments found that Erianin can significantly inhibit MC cell viability, inhibit cell migration, block the cell cycle in the G2/M phase, and induce cell apoptosis in a dose-dependent manner. The results of the Western blot experiment further showed that Erianin can significantly decrease the protein expression levels of HRAS, AKT, p-AKT, MDM2, Cyclin D1, and p-Gsk3ß, and increase the protein expression level of p21, which suggests that Erianin can treat PLGC by regulating the HRAS-PI3K-AKT signaling pathway. CONCLUSION: This study explained the positive characteristics of multi-component, multi-target, and multi-approach intervention with Dendrobium chrysotoxum Lindl in the treatment of PLGC. Our results suggest that Erianin may be a promising candidate in the development of prevention and treatment methods for PLGC. This study provided experimental evidence for the clinical use of Dendrobium chrysotoxum Lindl to treat PLGC and prevent gastric cancer.

The mechanisms of action of WeiChang'An Pill (WCAP) treat diarrhoea-predominant irritable bowel syndrome (IBS-D) using network pharmacology approach and in vivo studies.

ETHNOPHARMACOLOGICAL RELEVANCE: WeiChang'An Pill (WCAP) is used in Traditional Chinese Medicine (TCM) to clinically treat diarrhoea-predominant irritable bowel syndrome (IBS-D); however, the underlying pharmacological mechanisms are unclear to date. AIM OF THE STUDY: To explore the mechanism underlying the therapeutic action of WCAP in IBS-D using a network pharmacology approach and in vivo experiments. MATERIALS AND METHODS: The active compounds of WCAP were selected from the TCM Systems Pharmacology Database and TCM Integrated Database, and the potential targets were identified using the Swiss Target Prediction and Similarity Ensemble Approach (SEA) databases. The targets related to IBS-D were mined from the Therapeutic Target Database (TTD), National Center for Biotechnology Information Search database (NCBI), DrugBank database, and DisGeNET database. The intersecting protein-protein interactions (PPIs) of the drug-disease crossover genes were analysed, and the central PPI network was constructed using the String database, version 11.0, and Cytoscape version 3.7.2. Following Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes pathway analyses, the gene-pathway network was constructed for identifying the key target genes and pathways. Based on the results and existing evidence, it was selected the cyclic adenosine monophosphate (cAMP) signalling pathway for further validation using in vivo experiments. RESULTS: A total of 872 targets were identified from the 77 active compounds in WCAP, which shared 78 targets that were predicted to be related to IBS-D. Twenty-one core targets were identified from the PPI network, which was constructed from the common targets. The results of enrichment analysis revealed that HRT2B, ADRA1A, ADRA1D, and CHRM2 could be the key targets of WCAP in IBS-D, and 11 signalling pathways, including the neuroactive ligand-receptor interaction, calcium signalling, and cAMP signalling pathways, were identified as crucial for the therapeutic activity of WCAP in IBS-D. We also identified the possibility of several interactions and crosstalk between the different pathways. Subsequent molecular biology experiments revealed that the expression levels of cAMP, phospho-(Ser/Thr) protein kinase A substrates (p-PKA), 5-hydroxytryptamine, and proteins in the cAMP signalling pathway, including G protein-coupled receptor (GPCR), adenylyl cyclase 5 (AC5), and cAMP-response element binding protein (CREB), were significantly upregulated in rat models of IBS-D following treatment with WCAP (P < 0.05). However, a reverse trend was observed in the expression of nuclear factor kappa-B (NF-κB) (P < 0.05), which could be attributed to the low-grade inflammation that occurs in IBS-D. CONCLUSION: We demonstrated that WCAP may alleviate the symptoms of diarrhoea and visceral sensitivity in IBS-D by regulating the cAMP signalling pathway.

Potential effect of Maxing Shigan decoction against coronavirus disease 2019 (COVID-19) revealed by network pharmacology and experimental verification.

ETHNOPHARMACOLOGICAL RELEVANCE: Since the occurrence of coronavirus disease 2019 (COVID-19) in Wuhan, China in December 2019, COVID-19 has been quickly spreading out to other provinces and countries. Considering that traditional Chinese medicine (TCM) played an important role during outbreak of SARS and H1N1, finding potential alternative approaches for COVID-19 treatment is necessary before vaccines are developed. According to previous studies, Maxing Shigan decoction (MXSGD) present a prominent antivirus effect and is often used to treat pulmonary diseases. Furthermore, we collected 115 open prescriptions for COVID-19 therapy from the National Health Commission, State Administration of TCM and other organizations, MXSGD was identified as the key formula. However, the underlying molecular mechanism of MXSGD against COVID-19 is still unknown. AIM OF THE STUDY: The present study aimed to evaluate the therapeutic mechanism of MXSGD against COVID-19 by network pharmacology and in vitro experiment verification, and screen the potential components which could bind to key targets of COVID-19 via molecular docking method. MATERIALS AND METHODS: Multiple open-source databases related to TCM or compounds were employed to screen active ingredients and potential targets of MXSGD. Network pharmacology analysis methods were used to initially predict the antivirus and anti-inflammatory effects of MXSGD against COVID-19. IL-6 induced rat lung epithelial type Ⅱ cells (RLE-6TN) damage was established to explore the anti-inflammatory damage activity of MXSGD. After MXSGD intervention, the expression level of related proteins and their phosphorylation in the IL-6 mediated JAK-STAT signaling pathway were detected by Western blot. Molecular docking technique was used to further identify the potential substances which could bind to three key targets (ACE2, Mpro and RdRp) of COVID-19. RESULTS: In this study, 105 active ingredients and 1025 candidate targets were selected for MXSGD, 83 overlapping targets related to MXSGD and COVID-19 were identified, and the protein-protein interaction (PPI) network of MXSGD against COVID-19 was constructed. According to the results of biological enrichment analysis, 63 significant KEGG pathways were enriched, and most of them were related to signal transduction, immune system and virus infection. Furthermore, according the relationship between signal pathways, we confirmed MXSGD could effectively inhibit IL-6 mediated JAK-STAT signal pathway related protein expression level, decreased the protein expression levels of p-JAK2, p-STAT3, Bax and Caspase 3, and increased the protein expression level of Bcl-2, thereby inhibiting RLE-6TN cells damage. In addition, according to the LibDock scores screening results, the components with strong potential affinity (Top 10) with ACE2, Mpro and RdRp are mainly from glycyrrhiza uralensis (Chinese name: Gancao) and semen armeniacae amarum (Chinese name: Kuxingren). Among them, amygdalin was selected as the optimal candidate component bind to all three key targets, and euchrenone, glycyrrhizin, and glycyrol also exhibited superior affinity interactions with ACE2, Mpro and RdRp, respectively. CONCLUSION: This work explained the positive characteristics of multi-component, multi-target, and multi-approach intervention with MXSGD in combating COVID-19, and preliminary revealed the antiviral and anti-inflammatory pharmacodynamic substances and mechanism of MXSGD, which might provide insights into the vital role of TCM in the prevention and treatment of COVID-19.

Ethnobotanical survey of medicinal plants in Gaomi, China.

ETHNOPHARMACOLOGICAL RELEVANCE: The uses of medicinal plants have a long history and become one of the important sources of the health cares in Gaomi City, Shandong Province, China. However, limited studies have been done to identify these medicinal plant species and to scientifically document their associated traditional knowledge. Many species used by indigenous people could potentially represent a novel resource of medicine. The study can aid in further investigations of modern pharmacology and planning of the wild species conservation. AIM OF THE STUDY: The study aimed to investigate and record the medicinal plant taxa and their associated traditional knowledge in Gaomi City, China. MATERIALS AND METHODS: Field study was conducted from March 2018 to May 2019 with 184 residents of Gaomi City. Traditional medicinal plant specimens were collected from the field with the help of these residents and were identified and authenticated in the Herbarium of the School of Pharmacy, Binzhou Medical University. Ethnobotanical knowledge was collected by semi-structured face-to-face interviews. The quantitative data were analyzed by using the informant consensus factor (ICF) method and the number of citations. RESULTS: A total of 181 species belonging to 137 genera and 65 families were collected in Gaomi City. Asteraceae was the predominant family and Fabaceae took the second place. River basins and the southern hills in Gaomi were rich in vegetation. However, the cultivated area of medicinal plants only accounted for 10% of agricultural acreage. The main preparation method was decocting (170, 94.48%) and the most frequent mode of administration was oral (177, 97.97%). The highest numerical ICF value was recorded for treating endocrine, metabolic, and nutritional (ICF: 0.85) conditions. Seven of the medicinal plant species used by the people in Gaomi have not been reported previously in China. Verbena officinalis L. was found in Gaomi City, which is a new distribution record for this species. CONCLUSIONS: People in Gaomi hold valuable knowledge about the use of medicinal plants; however, their knowledge has not been comprehensively documented. The therapeutic uses of the documented medicinal plants will provide a basis for further pharmacological and phytochemical investigations. Additionally, the result of this study indicated that the elder people in Gaomi have more traditional knowledge of plant medicines than the younger ones.

FangNet: Mining herb hidden knowledge from TCM clinical effective formulas using structure network algorithm.

The use of herbs to treat various human diseases has been recorded for thousands of years. In Asia's current medical system, numerous herbal formulas have been repeatedly verified to confirm their effectiveness in different periods, which is a great resource for drug innovation and discovery. Through the mining of these clinical effective formulas by network pharmacology and bioinformatics analysis, important biologically active ingredients derived from these natural products might be discovered. As modern medicine requires a combination of multiple drugs for the treatment of complex diseases, previously clinical formulas are also combinations of various herbs according to the main causes and accompanying symptoms. However, the herbs that play a major role in the treatment of diseases are always unclear. Therefore, how to rank each herb's relative importance and determine the core herbs, is the first step to assisting herb selection for active ingredients discovery. To solve this problem, we built the platform FangNet, which ranks all herbs on their relative topological importance using the PageRank algorithm, based on the constructed symptom-herb network from a collection of clinical empirical prescriptions. Three types of herb hidden knowledge, including herb importance rank, herb-herb co-occurrence, and associations to symptoms, were provided in an interactive visualization. Moreover, FangNet has designed role-based permission for teams to store, analyze, and jointly interpret their clinical formulas, in an easy and secure collaboration environment, aiming at creating a central hub for massive symptom-herb connections. FangNet can be accessed at http://fangnet.org or http://fangnet.herb.ac.cn.

Shen-Fu Decoction could ameliorate intestinal permeability by regulating the intestinal expression of tight junction proteins and p-VASP in septic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Shen-Fu Decoction (SFD), a classic Traditional Chinese paired herb formulation, has been widely used for the treatment of sepsis in China. This study was carried out to assess the effects of SFD in sepsis-induced intestinal permeability and intestinal epithelial tight junction damage in rats with sepsis. MATERIALS AND METHODS: A rat model of sepsis was created by cecal ligation and puncture (CLP). Rats in Sham and CLP + vehicle groups received equal distilled water, while rats in SFD group were treated by gavage of SFD (3 mg/kg, twice a day) for 72h. Mortality, sepsis-induced peritoneal inflammation, intestinal and liver histopathology damage, intestinal permeability (serum FITC-dextran and D-lactate), serum LPS, serum inflammation (PCT, TNF-α, and IL-6), and liver function (AST and ALT) were evaluated. The levels of zonula occluden (ZO-1), Occludin, Claudin-1 were analyzed by Real-time quantitative PCR and Western blotting (WB) respectively. Vasodilator-stimulated phosphoprotein (VASP) and p-VASP in intestinal epithelium were analyzed by WB. RESULTS: Our study showed that SFD markedly reduced the mortality rate of CLP rats, prevented intestine and liver damage, relieved sepsis-induced intestinal permeability and inflammation elevation, ameliorated sepsis-induced impaired intestinal permeability by regulating the expression of ZO-1, Occludin, Claudin-1 and p-VASP. CONCLUSIONS: The herbal formula SFD may be useful for reducing sepsis-induced organic damage and mortality by ameliorating the condition of sepsis-induced intestinal permeability by regulating tight junction proteins and p-VASP.

Celastrol inhibits ezrin-mediated migration of hepatocellular carcinoma cells.

Progression of hepatocellular carcinoma involves multiple genetic and epigenetic alterations that promote cancer invasion and metastasis. Our recent study revealed that hyperphosphorylation of ezrin promotes intrahepatic metastasis in vivo and cell migration in vitro. Celastrol is a natural product from traditional Chinese medicine which has been used in treating liver cancer. However, the mechanism of action underlying celastrol treatment was less clear. Here we show that ROCK2 is a novel target of celastrol and inhibition of ROCK2 suppresses elicited ezrin activation and liver cancer cell migration. Using cell monolayer wound healing, we carried out a phenotype-based screen of natural products and discovered the efficacy of celastrol in inhibiting cell migration. The molecular target of celastrol was identified as ROCK2 using celastrol affinity pull-down assay. Our molecular docking analyses indicated celastrol binds to the active site of ROCK2 kinase. Mechanistically, celastrol inhibits the ROCK2-mediated phosphorylation of ezrin at Thr567 which harnesses liver cancer cell migration. Our findings suggest that targeting ROCK2-ezrin signaling is a potential therapeutic niche for celastrol-based intervention of cancer progression in hepatocellular carcinoma.

Association of Symptoms with Eating Habits and Food Preferences in Chronic Gastritis Patients: A Cross-Sectional Study.

PURPOSE: There is a lack of research on the relationship between symptoms and dietary factors of chronic gastritis (CG) patients, and the contribution of dietary management in relieving symptoms of CG patients has not attracted enough attention. This study aimed to identify the associations between different symptoms and dietary factors. Patients and Methods. All CG patients in this cross-sectional study were recruited from 3 hospitals in Beijing, China, from October 2015 to January 2016. Association Rule Mining analysis was performed to identify the correlations between gastrointestinal symptoms and dietary factors (including eating habits and food preferences), and subgroup analysis focused on gender differences. RESULTS: The majority of patients (58.17%) reported that their symptoms were related to dietary factors. About 53% reported that they had the habit of "eating too fast," followed by "irregular mealtimes" (29.66%) and "eating leftover food" (28.14%). Sweets (27.57%), spicy foods (25.10%), and meat (24.33%) were the most popular among all participants. Stomachache and gastric distention were the most common symptoms and were both associated with irregular mealtimes, irregular meal sizes, eating out in restaurants, meats, barbecue, fried foods, sour foods, sweets, snacks, and salty foods (support >0.05 and lift >1.0). Their most strongly associated factors were irregular meal sizes, barbecues, and snacks (lift >1.2). In addition, irregular mealtimes, salty foods, and sweet foods may be important diet factors influencing the symptoms in CG patients (support >0.05 and lift >1.0), as they were associated with almost all dyspeptic symptoms in the whole group and subgroup analyses. Furthermore, alcohol, barbecue, and spicy foods were associated with almost all symptoms for males (support >0.05 and lift >1.0), but sweets were the only dietary factor associated with all symptoms for females (support >0.05 and lift >1.0). CONCLUSION: This study has provided new data for the association of symptoms with eating habits and food preferences in CG patients. The role of individual daily management schemes, such as dietary or lifestyle programs, needs more attention.

Meta-Analysis of Paclitaxel-Based Chemotherapy Combined With Traditional Chinese Medicines for Gastric Cancer Treatment.

This study aimed to compare the efficacy and safety of traditional Chinese medicines (TCMs) combined with paclitaxel-based chemotherapy and paclitaxel-based chemotherapy alone for gastric cancer treatment. Literature searches (up to September 25, 2019) were performed using the Cochrane Library, EMBASE, PubMed, Chinese Science and Technology Journals (CQVIP), Wanfang, and China Academic Journals (CNKI) databases. Data from 14 randomized controlled trials (RCTs), with 1,109 participants, were included. The results indicated that, compared with paclitaxel-based chemotherapy alone, the combination of TCMs and paclitaxel-based chemotherapy significantly improved the tumor response rate (TRR; RR: 1.39; 95% CI: 1.24-1.57; p < 0.001, I 2 = 12%), increased the quality of life based on the Karnofsky Performance Scale score (RR: 1.53; 95% CI: 1.19-1.96; p < 0.001, I 2 = 0%), and reduced the side effects, such as neutropenia (RR: 0.68; 95% CI: 0.55-0.84; p < 0.001, I 2 = 44%), leukopenia (RR: 0.69; 95% CI: 0.54-0.90; p < 0.01, I 2 = 40%), thrombocytopenia (RR: 0.66; 95% CI: 0.46-0.96; p < 0.05, I 2 = 32%), and nausea and vomiting (RR: 0.50; 95% CI: 0.32-0.80; p < 0.01, I 2 = 85%). Hepatic dysfunction (RR: 0.63; 95% CI: 0.33-1.20; p = 0.16, I 2 = 0%), neurotoxicity (RR: 0.64; 95% CI: 0.26-1.55; p = 0.32, I 2 = 0%), and anemia (RR: 0.65; 95% CI: 0.40-1.04; p = 0.07, I 2 = 0%) were similar between the two groups. Evidence from the meta-analysis suggested that compared with paclitaxel-based chemotherapy alone, the combination of TCMs and paclitaxel-based chemotherapy may increase the TRR, improve quality of life, and reduce multiple chemotherapy-related side effects in gastric cancer patients. Additional rigorously designed large RCTs are required to confirm the efficacy and safety of this treatment.

Baicalin Induces Apoptosis and Suppresses the Cell Cycle Progression of Lung Cancer Cells Through Downregulating Akt/mTOR Signaling Pathway.

Baicalin, as a natural active ingredient extracted and isolated from the traditional Chinese medicine Scutellaria baicalensis Georgi., has been potentially used in various areas for its antioxidative, antitumor, anti-inflammatory, and anti-proliferative activities. Although several studies have reported the antitumor effects of baicalin against various cancer types, its beneficial effects on lung cancer have not yet been elucidated. Therefore, the therapeutic effects and molecular mechanisms of baicalin on lung cancer cell lines H1299 and H1650 were investigated. Here, the results of its antitumor activity were shown. We found that Akt/mTOR pathway inhibition was the essential determinant in baicalin-induced cell cycle arrest. Furthermore, when the Akt Agonist SC79 or Akt plasmid transfection was performed, the antitumor effect of baicalin was significantly abrogated in both H1299 and H1650 cells. In conclusion, we found that baicalin exerted its antitumor activity mainly by inducing Akt-dependent cell cycle arrest and promoting apoptosis, which show great potential for developing a new drug for lung cancer treatment.

Efficacy and safety of acupuncture therapy for chronic atrophic gastritis: A meta-analysis and trial sequential analysis protocol.

BACKGROUND: The proportion of application of acupuncture for chronic atrophic gastritis (CAG) is increasing over time. We will conduct this study to explore the efficacy and safety of acupuncture as a treatment method for CAG. METHODS: We will go through domestic and foreign databases until July 2019 to identify related randomized controlled trials that explored the effectiveness of acupuncture for CAG. RevMan (V.5.3) and test sequential analysis (V.0.9) will be used for mata-analysis and trial sequential analysis. RESULTS: This study will update previous evidence summaries of acupuncture and determine the efficacy and safety of acupuncture for CAG based on clinical effectiveness rate, clearance of Helicobacter pylori (H pylori) infection, and quality of life and symptom scores. CONCLUSION: This study will determine the evidence for judging whether acupuncture provides benefits in the treatment of CAG, and will support the application of acupuncture in the recovery of patients with CAG. REGISTRATION NUMBER: CRD42019127916.

Hierarchical and Complex System Entropy Clustering Analysis Based Validation for Traditional Chinese Medicine Syndrome Patterns of Chronic Atrophic Gastritis.

Objectives: Chronic atrophic gastritis (CAG) is the precancerous stage of gastric carcinoma. Traditional Chinese Medicine (TCM) has been widely used in treating CAG. This study aimed to reveal core pathogenesis of CAG by validating the TCM syndrome patterns and provide evidence for optimization of treatment strategies. Design: This is a cross-sectional study conducted in 4 hospitals in China. Hierarchical clustering analysis (HCA) and complex system entropy clustering analysis (CSECA) were performed, respectively, to achieve syndrome pattern validation. Results: Based on HCA, 15 common factors were assigned to 6 syndrome patterns: liver depression and spleen deficiency and blood stasis in the stomach collateral, internal harassment of phlegm-heat and blood stasis in the stomach collateral, phlegm-turbidity internal obstruction, spleen yang deficiency, internal harassment of phlegm-heat and spleen deficiency, and spleen qi deficiency. By CSECA, 22 common factors were assigned to 7 syndrome patterns: qi deficiency, qi stagnation, blood stasis, phlegm turbidity, heat, yang deficiency, and yin deficiency. Conclusions: Combination of qi deficiency, qi stagnation, blood stasis, phlegm turbidity, heat, yang deficiency, and yin deficiency may play a crucial role in CAG pathogenesis. In accord with this, treatment strategies by TCM herbal prescriptions should be targeted to regulating qi, activating blood, resolving turbidity, clearing heat, removing toxin, nourishing yin, and warming yang. Further explorations are needed to verify and expand the current conclusions.

Validating traditional Chinese syndrome features in varied stages of chronic gastritis malignant transformation: study protocol for a cross-sectional study.

INTRODUCTION: The transition from chronic non-atrophic gastritis (CNAG) to chronic atrophic gastritis (CAG) and gastric carcinoma (GC) is regarded as a representative disease model of gastric mucosa malignant transformation led by uncontrolled inflammation. Traditional Chinese medicine (TCM) syndrome-targeted therapies have been applied in treating chronic gastritis (CG) malignant transformation in China with satisfying efficacy. This study aims to validate TCM syndrome features in each stage of CG malignant transformation. The findings may shed light on the TCM hypothesis of CG malignant transformation, and thus optimise syndrome-targeted treatment strategies of CNAG, CAG and GC, respectively. METHODS AND ANALYSIS: The present study is a cross-sectional study conducted in China. A total of 2000 eligible patients, including 500 CNAG cases, 1000 CAG cases and 500 GC cases, will be recruited from four TCM hospitals. Primary outcome measures include the prevalence of TCM syndrome patterns in varied stages of CG malignant transformation. Secondary outcome measures include prevalence and severity of all the presenting signs and symptoms collected by using TCM four diagnostic methods. Descriptive analysis, comparative analysis and correlation analysis of all the measurement data will be performed by biostatisticians. Unsupervised data mining analyses, including exploratory factor analysis, association rule analysis, hierarchical clustering analysis, complex system entropy clustering analysis, and so on, will also be performed by data scientists respectively for in-depth analyses of TCM syndrome-related indicators. ETHICS AND DISSEMINATION: The protocol has been approved by the Ethical Review Board of Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine (No ECPJ-BDY-2014-02). All the study outcomes will be disseminated through national conference reports and in the meantime published on peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03314038; Pre-results.

Radiosensitization effect of Huaier on breast cancer cells.

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 cells to radiotherapy through regulation of the cell cycle and DNA repair pathway. Thus, Huaier may be a promising radiosensitizer for the treatment of breast cancer.