Discovery and Validation of Traditional Chinese and Western Medicine Combination Antirheumatoid Arthritis Drugs Based on Machine Learning (Random Forest Model).

The combination of traditional Chinese medicine (TCM) and Western medicine is a promising method for treating rheumatoid arthritis (RA). Combining the two fully exploits the advantages of Western and TCM to treat RA and has the potential to greatly improve the therapeutic effect on RA. In this study, we developed a combination drug training set by using 16 characteristic variables based on the characteristics of small molecules of TCM ingredients and Food and Drug Administration-certified combination drug data downloaded from the DrugCombDB database. Furthermore, we compared the prediction and classification abilities of five models: the k-nearest neighbors, naive Bayes, support vector machine, random forest, and AdaBoost algorithms. The random forest model was selected as the classification and prediction model for Western and TCM and Western combination drugs. We collected data for 41 small molecules of TCM ingredients from the Traditional Chinese Medicine Systems Pharmacology database and 10 small molecule drugs commonly used in anti-RA treatment from the DrugBank database. Combinations of Western and TCM for anti-RA treatment were screened. Finally, the CellTiter-Glo method was used to determine the synergy of these combinations, and the 15 most predicted drug combinations were carried out experimental verification. Myricetin, rhein, nobiletin, and fisetin had high synergy with celecoxib, and rhein had high synergy with hydroxychloroquine. The preliminary findings of this study can be further applied for practical clinical anti-RA combined treatment strategies and serve as a reference for clinical treatment of RA with integrated Western and TCM.

Gynostemma pentaphyllum polysaccharides ameliorate non-alcoholic steatohepatitis in mice associated with gut microbiota and the TLR2/NLRP3 pathway.

Recent studies have revealed the pivotal role of gut microbiota in the progress of liver diseases including non-alcoholic steatohepatitis (NASH). Many natural herbs, such as Gynostemma pentaphyllum (GP), have been extensively applied in the prevention of NASH, while the bioactive components and underlying mechanism remain unclear. The aim of this study was to investigate whether the polysaccharides of GP (GPP) have a protective effect on NASH and to explore the potential mechanism underlying these effects. C57BL/6 male mice were fed with a methionine-choline-deficient (MCD) diet for 4 weeks to induce NASH and administered daily oral gavage of sodium carboxymethylcellulose (CMC-Na), low dose of GPP (LGPP), high dose of GPP (HGPP), and polyene phosphatidylcholine capsules (PPC), compared with the methionine-choline-sufficient (MCS) group. Our results showed that the symptoms of hepatic steatosis, hepatocyte ballooning, liver fibrosis, and oxidative stress could be partially recovered through the intervention of GPP with a dose-dependent effect. Furthermore, gut microbiome sequencing revealed that HGPP altered the composition of gut microbiota, mainly characterized by the enrichment of genera including Akkermansia, Lactobacillus, and A2. Moreover, hepatic transcriptome analysis indicated that the anti-inflammatory effect of HGPP might be associated with toll-like receptor (TLR) and nod-like receptor (NLR) signaling pathways. HGPP could inhibit the expression of TLR2 and downregulate the expression of the NLRP3 inflammasome, as well as the pro-inflammatory cytokine tumor necrosis factor (TNF)-α and interleukin (IL)-1ß. In summary, GPP could ameliorate NASH possibly mediated via the modulation of gut microbiota and the TLR2/NLRP3 signaling pathway, indicating that GPP could be tested as a prebiotic agent in the prevention of NASH.

Effect of exercise and diet intervention in NAFLD and NASH via GAB2 methylation.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a disorder that extends from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), which is effectively alleviated by lifestyle intervention. Nevertheless, DNA methylation mechanism underling the effect of environmental factors on NAFLD and NASH is still obscure. The aim of this study was to investigate the effect of exercise and diet intervention in NAFLD and NASH via DNA methylation of GAB2. METHODS: Methylation of genomic DNA in human NAFLD was quantified using Infinium Methylation EPIC BeadChip assay after exercise (Ex), low carbohydrate diet (LCD) and exercise plus low carbohydrate diet (ELCD) intervention. The output Idat files were processed using ChAMP package. False discovery rate on genome-wide analysis of DNA methylation (q < 0.05), and cytosine-guanine dinucleotides (CpGs) which are located in promoters were used for subsequent analysis (|Δß|≥ 0.1). K-means clustering was used to cluster differentially methylated genes according to 3D genome information from Human embryonic stem cell. To quantify DNA methylation and mRNA expression of GRB2 associated binding protein 2 (GAB2) in NASH mice after Ex, low fat diet (LFD) and exercise plus low fat diet (ELFD), MassARRAY EpiTYPER and quantitative reverse transcription polymerase chain reaction were used. RESULTS: Both LCD and ELCD intervention on human NAFLD can induce same DNA methylation alterations at critical genes in blood, e.g., GAB2, which was also validated in liver and adipose of NASH mice after LFD and ELFD intervention. Moreover, methylation of CpG units (i.e., CpG_10.11.12) inversely correlated with mRNA expression GAB2 in adipose tissue of NASH mice after ELFD intervention. CONCLUSIONS: We highlighted the susceptibility of DNA methylation in GAB2 to ELFD intervention, through which exercise and diet can protect against the progression of NAFLD and NASH on the genome level, and demonstrated that the DNA methylation variation in blood could mirror epigenetic signatures in target tissues of important biological function, i.e., liver and adipose tissue. Trial registration International Standard Randomized Controlled Trial Number Register (ISRCTN 42622771).

New insight into the divergent responses of plants to warming in the context of root endophytic bacterial and fungal communities.

Plant adaptation under climate changes is critical to the maintenance of terrestrial ecosystem structure and function. Studying the response of the endophytic community to climate warming is a novel way to reveal the mechanism of host environmental adaptability because of the prominent role endophytes play in host nutrient acquisition and stress tolerance. However, host performance was generally neglected in previous relevant research, which limits our understanding of the relationships between the endophytic community and host responses to climate warming. The present study selected two plants with different responses to climate warming. Elymus nutans is more suitable for growing in warm environments at low altitude compared to Kobresia pygmaea. K. pygmaea and E. nutans were sampled along an altitude gradient in the natural grassland of Qinghai-Tibet Plateau, China. Root endophytic bacterial and fungal communities were analyzed using high throughput sequencing. The results revealed that hosts growing in more suitable habitats held higher endophytic fungal diversity. Elevation and host identity significantly affected the composition of the root endophytic bacterial and fungal community. 16S rRNA functional prediction demonstrated that hosts that adapted to lower temperatures recruited endophytic communities with higher abundance of genes related to cold resistance. Hosts that were more suitable for warmer and drier environments recruited endophytes with higher abundance of genes associated with nutrient absorption and oxidation resistance. We associated changes in the endophytic community with hosts adaptability to climate warming and suggested a synchronism of endophytic communities and hosts in environmental adaptation.

Meta-analysis of letrozole versus clomiphene citrate in polycystic ovary syndrome.

The aim of this study was to systematically compare the clinical efficacy and safety of letrozole with clomiphene citrate for ovulation induction in women with polycystic ovary syndrome (PCOS). The Cochrane Central Register of Controlled Trials, PubMed, EMbase, CBMdisc and CNKI were searched for eligible randomized controlled trials (RCT) comparing letrozole with clomiphene citrate in PCOS patients. Two reviewers independently extracted information and evaluated methodological quality according to the Cochrane Handbook 5.0. Meta-analysis was performed with the fixed-effects model or random-effects model according to the heterogeneity. Six eligible RCT involving 841 patients were included. Letrozole was associated with a number of lower mature follicles per cycle (standardized mean difference (SMD) -1.41; 95% confidence intervales (CI) -1.54 to -1.28; P<0.00001) compared with clomiphene citrate. There were no significant differences in pregnancy rate (relative risk (RR) 0.97; 95% CI 0.79 to 1.18), abortion rate (RR 1.38; 95% CI 0.48 to -3.96) and multiple pregnancy rate (RR 0.34; 95% CI 0.07 to -1.72) between the two groups. The evidence from ovulation rates was not enough to support either letrozole or clomiphene citrate. In conclusion, letrozole is as effective as clomiphene citrate for ovulation induction in patients with PCOS.