Identification of inhibitors from a functional food-based plant Perillae Folium against hyperuricemia via metabolomics profiling, network pharmacology and all-atom molecular dynamics simulations.

Introduction: Hyperuricemia (HUA) is a metabolic disorder caused by purine metabolism dysfunction in which the increasing purine levels can be partially attributed to seafood consumption. Perillae Folium (PF), a widely used plant in functional food, has been historically used to mitigate seafood-induced diseases. However, its efficacy against HUA and the underlying mechanism remain unclear. Methods: A network pharmacology analysis was performed to identify candidate targets and potential mechanisms involved in PF treating HUA. The candidate targets were determined based on TCMSP, SwissTargetPrediction, Open Targets Platform, GeneCards, Comparative Toxicogenomics Database, and DrugBank. The potential mechanisms were predicted via Gene Ontology (GO) and Kyoto Gene and Genome Encyclopedia (KEGG) analyses. Molecular docking in AutoDock Vina and PyRx were performed to predict the binding affinity and pose between herbal compounds and HUA-related targets. A chemical structure analysis of PF compounds was performed using OSIRIS DataWarrior and ClassyFire. We then conducted virtual pharmacokinetic and toxicity screening to filter potential inhibitors. We further performed verifications of these inhibitors' roles in HUA through molecular dynamics (MD) simulations, text-mining, and untargeted metabolomics analysis. Results: We obtained 8200 predicted binding results between 328 herbal compounds and 25 potential targets, and xanthine dehydrogenase (XDH) exhibited the highest average binding affinity. We screened out five promising ligands (scutellarein, benzyl alpha-D-mannopyranoside, elemol, diisobutyl phthalate, and (3R)-hydroxy-beta-ionone) and performed MD simulations up to 50 ns for XDH complexed to them. The scutellarein-XDH complex exhibited the most satisfactory stability. Furthermore, the text-mining study provided laboratory evidence of scutellarein's function. The metabolomics approach identified 543 compounds and confirmed the presence of scutellarein. Extending MD simulations to 200 ns further indicated the sustained impact of scutellarein on XDH structure. Conclusion: Our study provides a computational and biomedical basis for PF treating HUA and fully elucidates scutellarein's great potential as an XDH inhibitor at the molecular level, holding promise for future drug design and development.

Mechanisms of Nelumbinis folium targeting PPARγ for weight management: A molecular docking and molecular dynamics simulations study.

The lotus leaf, Nelumbinis folium (NF), has frequently appeared in obesity clinical trials as an intervention to promote weight loss and improve metabolic profiles. However, the molecular mechanisms by which it interacts with important obesity targets and pathways, such as the peroxisome proliferator-activated receptor gamma (PPARγ) within the PPAR signalling pathway, were not well understood. This study aims to screen for candidate compounds from NF with desirable pharmacokinetic properties and examine their binding feasibility at the PPARγ ligand-binding domain (LBD). Ligand- and structure-based screening of NF compounds were performed, and a consensus approach has been applied to identify druggable candidates. By examining the pharmacokinetic profiles, a large proportion of NF compounds exhibited favourable drug-likeness and oral bioavailability properties. Furthermore, the binding affinity scores and poses provided new insights on the distinctive binding behaviours of NF compounds at the LBD of PPARγ in its inactive form. Several NF compounds could bind strongly to PPARγ at sub-pockets where partial agonists and antagonists were found to bind and may induce conformational changes that influence co-repressor binding, trans-repression, and gene expression inhibition. Subsequent molecular dynamics simulations of a candidate compound (NF129 narcissin) bound to PPARγ revealed conformational stability, residue fluctuation, and binding behaviours comparable to that of the known inhibitor, SR1664. Therefore, it can be proposed that narcissin exhibits characteristics of a PPARγ antagonist. Further experimental validation to support the development of NF129 as a future anti-obesity agent is warranted.

Poria cocos compounds targeting neuropeptide Y1 receptor (Y1R) for weight management: A computational ligand- and structure-based study with molecular dynamics simulations identified beta-amyrin acetate as a putative Y1R inhibitor.

Poria cocos (PC) is a medicinal herb frequently used in weight-loss clinical trials, however the mechanisms by which its compounds target orexigenic receptors including the neuropeptide Y1 receptor (Y1R) remain largely unknown. This study aimed to screen PC compounds for favourable pharmacokinetics profiles and examine their molecular mechanisms targeting Y1R. Forty-three PC compounds were systematically sought from pharmacological databases and docked with Y1R (PDB: 5ZBQ). By comparing the relative binding affinities, pharmacokinetics and toxicity profiles, we hypothesised that compounds designated PC1 3,4-Dihydroxybenzoic acid, PC8 Vanillic acid, PC40 1-(alpha-L-Ribofuranosyl)uracil, could be potential antagonists as they contact major residues Asn283 and Asp287, similar to various potent Y1R antagonists. In addition, PC21 Poricoic acid B, PC22 Poricoic acid G and PC43 16alpha,25-Dihydroxy-24-methylene-3,4-secolanosta-4(28),7,9(11)-triene-3,21-dioic acid, contacting Asn299, Asp104 and Asp200 proximal to the extracellular surface could also interfere with agonist binding by stabilising the extracellular loop (ECL) 2 of Y1R in a closed position. Owing to their selective interaction with Phe302, an important residue in binding of selective Y1R antagonists, PC12 beta-Amyrin acetate, PC26 3-Epidehydrotumulosic acid and PC27 Cerevisterol were proposed as putative antagonists. Following the consensus approach, PC12 beta-Amyrin acetate, PC26 3-Epidehydrotumulosic acid and PC27 Cerevisterol were identified as candidate compounds due to their high affinities (-12.2, -11.0 and -10.8 kcal, respectively), high drug-likeness and low toxicity profiles. Trajectory analyses and energy contributions of PC12-Y1R complex further confirmed their structural stability and favourable binding free energies, highlighting the feasibility and possible development of PC12 beta-Amyrin acetate as a future Y1R inhibitor.

Interaction of compounds derived from the Chinese medicinal formula Huangqi Guizhi Wuwu Tang with stroke-related numbness and weakness targets: An in-silico docking and molecular dynamics study.

Huangqi Guizhi Wuwu Tang (HGWT) is a traditional Chinese herbal formula used for managing post-stroke symptoms. Existing research have supported the use of this formula particularly for stroke-related numbness and weakness (SRNW); however, their mechanisms of actions are not fully understood. This study aims to investigate the molecular mechanisms of components from HGWT targeting specific proteins related to numbness and weakness through computational docking and molecular dynamics (MD) simulations. A total of 786 compounds from HGWT were retrieved from a herbal compound database and docked against a candidate SRNW target protein, with the asernestioside B (HQ068)-mitogen-activated protein kinase 3 (MAPK3) complex predicted to exhibit the highest binding affinity (-10.4 kcal/mol) and number of ligand-receptor contacts. Subsequent molecular dynamics (MD) simulations were performed in triplicate on the apo-MAPK3 protein and asernestioside B -bound form in a solvated system for 200 ns per trajectory to ascertain the stability of the enzyme-ligand complex, and to determine the structural impact of ligand binding. The stability of the complex and overall tertiary structural changes were characterized using root-mean-square deviation (RMSD), radius of gyration (Rg), root-mean-square fluctuation (RMSF) calculations Differences in the RMSF of apo and ligand-bound MAPK3 were most prominent in three major regions: (a) activation loop Asp184:Pro213 (b) MAPK3 insertion site Gly262:Ala291 and (c) loop region at the C-terminus Tyr334:Pro356. Lower values of RMSF for the HQ068-bound protein at the activation loop suggest that HQ068 binding stabilizes MAPK3 in a different conformation in this region compared to the apo protein. Free energy calculations of the asernestioside B-MAPK3 complex revealed key residues contributing to the interaction, which include Pro264, Gln 266, Asp268 and Thr288. These key residues may play an integral role in the binding of selective modulators or substrates of extracellular signal-regulated kinase (ERK) within the MAPK cascade. Overall, this study provides a mechanistic overview of compounds from HGWT. Modelling predicted that asernestioside B may act with high potency against MAPK3, while exhibiting a favourable ADMET profile, and this compound should be explored as a potential agent to alleviate SRNW-related symptoms in future studies.

The Effects and Safety of Chinese Herbal Medicine on Blood Lipid Profiles in Placebo-Controlled Weight-Loss Trials: A Systematic Review and Meta-Analysis.

This study was conducted to assess the effects and safety of Chinese herbal medicine (CHM) on blood lipids among adults with overweight or obesity. Fourteen bibliographic databases were comprehensively searched, from their respective inceptions up to April 2021, for randomised placebo-controlled weight-loss trials using CHM formulation on total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol over ≥4 weeks. Data collection, risk of bias assessment, and statistical analyses were guided by the Cochrane Handbook (v6.1). Continuous outcomes were expressed as the mean difference with 95% confidence intervals, and categorical outcomes were expressed as a risk ratio with 95% confidence intervals. All analyses were two-tailed with a statistical significance of p < 0.05. Fifteen eligible studies with 1,533 participants were included in this meta-analysis. Findings from meta-analyses indicated that CHM interventions, compared to placebo, reduced triglyceride (MD -0.21 mmol/L, 95% CI -0.41 to -0.02, I 2 = 81%) and increased HDL cholesterol (MD 0.16 mmol/L, 95% CI 0.04 to 0.27, I 2 = 94%) over a median of 12 weeks. The reduction in total cholesterol and LDL cholesterol were not statistically significant. Furthermore, the tendency of reduced triglycerides was identified among overweight participants with high baseline triglycerides. Attrition rates and frequency of adverse events were indifferent between the two groups. CHM may provide lipid-modulating benefits on triglycerides and HDL cholesterol among participants with overweight/obesity, with the tendency for significant triglyceride reduction observed among overweight participants with high baseline triglycerides. However, rigorously conducted randomised controlled trials with larger sample sizes are required to validate these findings.

Chinese Herbal Medicine for Weight Management: A Systematic Review and Meta-Analyses of Randomised Controlled Trials.

Objective: This review investigated the effects and safety of Chinese herbal medicine (CHM) formulas on weight management. Methods: Eighteen databases in English, Chinese, Korean, and Japanese were searched from their inceptions to September 2019. The treatment groups included CHM formulations, and the control included placebo, Western medication (WM), and lifestyle intervention (LI), with or without cointerventions (WM and/or LI). Quality of studies was assessed using Cochrane Collaboration's risk of bias assessment tool. Body weight and body mass index (BMI) were analysed in RevMan v5.4.1 and expressed as mean differences with 95% confidence intervals (CI), while adverse events were expressed as risk ratio with 95% CI. Results: Thirty-nine RCTs were eligible for qualitative analysis, 34 of which were included in the meta-analyses. The majority of studies had a high or unclear risk of selection, performance, and detection bias. Twenty-five CHM studies involving cointerventions revealed that CHM had significant adjunct effects on body weight and BMI at the end of treatment compared to control. No serious adverse events were reported in the CHM groups. Conclusion: CHM indicates a promising adjunct to facilitate WM or lifestyle change for weight management. However, methodological barriers such as lack of allocation concealment and double-blinding may have led to challenges in data synthesis. More rigorously designed RCTs involving cointerventions are warranted.

Oral application of Chinese herbal medicine for allergic rhinitis: A systematic review and meta-analysis of randomized controlled trials.

Chinese herbal medicine (CHM) has long been used for allergic rhinitis (AR). This systematic review aimed to investigate the clinical effects and safety of oral CHM for AR by comparing it to Western medications (WM). Nineteen databases were searched up to May 27, 2020. Randomized controlled trials (RCTs) assessing the effects of CHM on the primary or secondary outcomes comparing to WM, in any age of the patients, were included. The pooled results were expressed as mean difference, standardized mean difference, or odds ratio with 95% confidence intervals. Eighteen RCTs were included and 17 of them were evaluated in the meta-analysis. CHM may improve total nasal symptom scores, individual symptom scores (rhinorrhea, nasal congestion, sneezing, and nasal itching), quality of life, and recurrence rate, compared to antihistamines (loratadine and chlorpheniramine). Only mild and transient adverse events of CHM were reported. However, there were no significant differences in some subgroup analyses in total nasal symptom scores, rhinorrhea, nasal obstruction, sneezing, nasal itching, and SF-36. Due to the small number of included studies, poor quality of trial design, and substantial heterogeneities, the potential of CHM for AR should be validated in large, multicenter, and well-designed RCTs in the future.