Gui Qi Zhuang Jin Decoction ameliorates mitochondrial dysfunction in sarcopenia mice via AMPK/PGC-1α/Nrf2 axis revealed by a metabolomics approach.

OBJECTIVE: Sarcopenia, as a condition of muscle mass loss and functional decline typically diagnosed in elderly individuals, severely affects human physical activity, metabolic homeostasis, and quality of life. Gui Qi Zhuang Jin Decoction (GQZJD), an approved hospital-based prescription with years of clinical application, has been demonstrated to have a notable therapeutic effect on sarcopenia. However, its potential mechanism of action in the treatment of sarcopenia remains uncertain. METHODS: Ultra-performance liquid chromatography paired with Q Exactive™ HF-X mass spectrometry (UPLC-QE-MS) was used to identify the ingredients of GQZJD. Subsequently, GQZJD observed the basic growth and muscles of the sarcopenia mouse, while the behavioral indicators were also tested. Muscle histopathology and serum oxidative stress biochemicals were also detected, and mitochondrial function and energy metabolism-related indicators in the gastrocnemius muscle were examined. Then, a metabolomics strategy was applied to predict possible pathways involving mitochondria by which GQZJD could improve sarcopenia. Finally, quantitative real-time polymerase chain reaction and western blot analyses were carried out to validate the effects of GQZJD on sarcopenia-induced mitochondrial dysfunction, together with uncovering the associated mechanisms. RESULTS: Twenty-seven ingredients absorbed into the blood (IAIBs) of GQZJD were identified using UPLC-QE-MS, which were regarded as the main active ingredients behind its sarcopenia treatment effects. GQZJD administration increased the body weight, gastrocnemius muscle mass, and autonomic activity, mitigated muscle tissue morphology and pathology; and alleviated the oxidative stress levels in sarcopenia mice. Treatment with GQZJD also decreased the mitochondrial reactive oxygen species level and serum lipid peroxide Malonaldehyde concentration. and increased the mitochondrial membrane potential, adenosine triphosphate level, 8­hydroxy-2-deoxyguanosine content, mitochondrial DNA copy number, and the mitochondrial fission factor dynamin-related protein 1. Non-targeted metabolomics suggested that the sarcopenia therapeutic effect of GQZJD on sarcopenia may occur through the glycerophospholipid metabolism, choline metabolism in cancer, phenylalanine metabolism and tyrosine metabolism pathways, implying an association with AMP-activated protein kinase (AMPK) and related signals. Further, the molecular docking results hinted that AMPK performed well in terms of binding energy with the 27 IAIBs of GQZJD (average binding energy, -7.5 kcal/mol). Finally, we determined that GQZJD significantly activated the key targets of the AMPK/peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)/nuclear factor erythroid 2-related factor 2 (Nrf2) axis.. CONCLUSIONS: Our results demonstrated that GQZJD ameliorated d-galactose-induced sarcopenia by promoting the animal behaviours, facilitating mitochondrial function and restoring mitochondrial energy metabolism. with its effects mediated by the AMPK/PGC-1α/Nrf2 axis. Over all, GQZJD represents a promising therapeutic candidate that ameliorated sarcopenia in aging mice.

Exploration of Therapeutic Strategies of Herbal Prescriptions for Carbuncle Treatment to Suggest Modern Approaches to Inflammatory Bowel Disease: Cluster and Network Analyses of the Book «Liu Juan Zi Gui Yi Fang¼.

Inflammatory bowel disease (IBD) treatments in East Asian traditional medicine (EATM) originate from principles for treating abscesses and carbuncles. Understanding the therapeutic principles of Liu Juan Zi Gui Yi Fang (GYF) is essential for optimizing EATM treatment strategies for IBD, but quantitative analysis is lacking. This study aims to extract quantitative information on therapeutic strategies from GYF and present the EATM conceptual framework for IBD treatment. Oral prescriptions for carbuncles were selected, and their constituent herbs and indications were standardized and tokenized for analysis. An EATM expert group classified prescriptions based on the similarity of herbs and indications. Hierarchical and k-means cluster analyses were performed based on herb similarity. The herb-indication (H-I) network for all prescriptions was constructed. Additionally, H-I subnetworks based on the expert group's classifications and the k-means clustering results were constructed and compared to identify treatment goals and the herbs used for each goal. The results showed that the treatment focused on abscess status, wound healing, and patient's recovery capacity, with 'fever' and 'deficiency' as the main indications addressed by tonifying and anti-inflammatory herbs. The therapeutic principles identified in this study can serve as a foundation for developing future herbal intervention units. Further preclinical and clinical research is needed to validate these findings.

Effects of Bifidobacterium bifidum tetragonum tablets and Jin Gui Ren Qi Pill on intestinal flora and metabolism in patients with diabetic kidney disease.

Objective: To investigate the effects of Bifidobacterium bifidum tetragonum tablets and Jin Gui Ren Qi Pill on intestinal flora and metabolism in patients with diabetic kidney disease. Methods: In the study conducted at Heping Hospital of Changzhi Medical College from March 2021 to December 2022, 30 cases of patients diagnosed with diabetic nephropathy were meticulously selected as study subjects. Employing a double-blind randomized table method, these patients were randomly allocated into three groups: the control group (n = 10), the Bifidobacterium bifidum tetragonum tablets group (n = 10), and the Jin Gui Ren Qi Pill group (n = 10). The control group received standard western medical treatments for diabetic nephropathy, including serum glucose, blood lipids, blood pressure management, and other conventional therapies. In addition to the standard treatments, the Bifidobacterium bifidum tetragonum tablets group received Bifidobacterium bifidum tetragonum tablets, while the Jin Gui Ren Qi Pill group received Jin Gui Ren Qi Pill. Before and after a 4-week treatment period, various baseline parameters were assessed, including fasting blood glucose, 2-h postprandial blood glucose, triglycerides, serum total cholesterol, serum low-density lipoprotein cholesterol, serum high-density lipoprotein cholesterol, random urine microalbumin/creatinine ratio (ACR), blood creatinine (SCr), and traditional Chinese medicine evidence scores. Stool specimens were collected from all three groups before and after treatment for 16S rDNA high-throughput sequencing, followed by comprehensive analyses including OUT clustering, Alpha diversity, Beta diversity, species composition analysis, LEfSe analysis, and KEGG function prediction. Spearman correlation analysis was employed to explore the relationship between intestinal flora and clinical indicators. Furthermore, fasting peripheral venous blood was collected from patients in the Bifidobacterium tetrapunctate tablets group and the control group before and after intervention to measure the optical density values of tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), and interleukin-6 (IL-6) using the Beijing Biolite ELISA kit. This study was conducted with the approval of the Ethics Committee of Changzhi Medical College. Results: 1. The 2hPBG, total cholesterol and LDL levels were observed among patients with diabetic kidney disease (DKD) across all groups: the Jin Gui Ren Qi Pill group, the Bifidobacterium bifidum tetragonum tablets group, and the control group (p < 0.05). 2. The Jin Gui Ren Qi Pill demonstrated superior efficacy in alleviating TCM symptoms and reducing the ACR compared to both the Bifidobacterium bifidum tetragonum tablets group and the control group. Conversely, Bifidobacterium bifidum tetragonum tablets exhibited a more pronounced reduction in TC levels compared to both the Jin Gui Ren Qi Pill and control groups. Notably, Bifidobacterium bifidum tetragonum tablets effectively decreased (IL-2) levels in patients with DKD. 3. Bifidobacterium bifidum tetragonum tablets also demonstrated efficacy in reducing IL-2 levels in DKD patients. 4. Analysis of intestinal microorganism abundance and diversity before and after the intervention, as well as among the three groups, revealed no significant alterations. Similarly, comparisons of ACE, Chao, Simpson, and Shannon indices showed no statistically significant differences (p > 0.05). 5. Qualitative analysis of intestinal microorganisms before and after intervention, as well as among the three groups, indicated no significant differences. Anosim test results also did not reveal qualitative distinctions (Anosim test R = 0.021, p = 0.215). 6. LEfSe analysis unveiled a noteworthy increase in Prevotella_7 abundance within the Jin Gui Ren Qi Pill group post-intervention (p < 0.05). 7. Furthermore, Chinese medicine evidence scores, body mass index, TC, and LDL levels correlated positively with the relative abundance of Tyzzerella_3 bacterial flora. Conversely, age, disease duration, and 2hPBG correlated positively with the relative abundance of Christensenellaceae_R_7 flora, while TC and LDL levels displayed a negative correlation with the relative abundance of Christensenellaceae_R_7 flora. Conclusion: The combination of Jin Gui Ren Qi Pill with western medical treatment exhibited superior efficacy in ameliorating clinical symptoms and reducing the ACR in patients with DKD compared to western medical treatment alone. Furthermore, this combination therapy led to an increase in the abundance of Prevotella_7 within the intestinal flora of patients, suggesting a potential enhancement in carbohydrate metabolism by the intestinal microbiota. On the other hand, Bifidobacterium bifidum tetragonum tablets bacterial tablets combined with western medical treatment demonstrated enhanced efficacy in reducing TC levels in DKD patients compared to western medical treatment alone. Additionally, this combination therapy effectively reduced the levels of IL-2 in DKD patients, thus mitigating inflammation in these individuals.

Next-generation bioinformatics: An ultrafast and user-friendly tool for phylogenomic data exploration.

With increasingly large genomic datasets, even routine bioinformatic tasks can be arduous, computationally demanding, and time-consuming. Additionally, most bioinformatic programs do not have a graphical user interface (GUI) and thus, require users to be minimally competent in command-line. These impediments present significant economic and technological barriers for practitioners who do not have access to advanced computational resources and support. In this issue of Molecular Ecology Resources, Handika and Esselstyn developed an ultrafast and memory-efficient bioinformatic tool, SEGUL, that performs common manipulations and calculations of summary statistics on phylogenomic datasets. SEGUL has two main features that distinguish it from other bioinformatic programs: (1) it is based on the recently emergent, high-performance programming language Rust, and (2) it has a GUI written using Flutter, a cross-platform programming framework that also supports mobile operating systems (mobile iOS, iPadOS and Android). By leveraging and combining the power of Rust and Flutter, SEGUL achieves significantly faster computation times and lower memory usage across different platforms and CPU architectures compared to similar programs. The unique and innovative features of SEGUL pave the way for a new era of bioinformatics that can be more energy-efficient, inclusive, and available to a broader swathe of users.

Exploring the Mechanism of Shen Qi Gui Oral Liquid against Chemotherapy-Induced Myelosuppression in Cancer Patients Based on Network Pharmacology and Molecular Docking.

BACKGROUND: Shen Qi Gui oral liquid (SQG) may be beneficial for chemotherapyinduced myelosuppression (CIM). However, the underlying mechanism of CIM treated with SQG is still lacking. METHODS: A total of 27 blood samples from cancer patients were selected to perform RNA-seq to obtain the Differentially Expressed Genes (DEGs). Then, the active components and target genes of SQG were acquired. Next, the drug targets and DEGs were intersected to obtain the intersection genes, followed by functional enrichment analysis and construction of a drug-compoundgene- disease network. Subsequently, core genes were selected. Then, immune cell infiltration, molecular docking, pharmacokinetic and toxicity prediction, and RT-qPCR were performed. RESULTS: A total of 1,341 DEGs, 51 active compounds, and 264 target genes were identified. Then, 30 intersection genes were acquired. Next, a drug-compound-gene-disease network was constructed, and 7 core genes were acquired. Immune infiltration analysis exhibited that only T follicular helper cells were significantly increased in the CIM group, which was significantly negatively correlated with MAPK1, MAPK14, MCL1, PTEN, and PTGS2. The luteolin, quercetin, and beta-sitosterol showed better affinity with core genes. Luteolin and quercetin, which satisfied Lipinski's rule of five, were likely absorbed by the gastrointestinal system. Toxicity predictions showed that neither luteolin nor quercetin exhibited carcinogenicity or hepatotoxicity. CONCLUSION: PTEN, PTGS2, CCL2, FOS, MCL1, MAPK1, and MAPK14 were identified as the core genes in CIM patients, which were involved in the MAPK and PI3K-Akt signaling pathways. Luteolin and quercetin may be the promising drugs against CIM.

A simple MATLAB toolbox for analyzing calcium imaging data in vitro and in vivo.

BACKGROUND: Fluorescence imaging of calcium dynamics in neuronal populations is powerful because it offers a way of relating the activity of individual cells to the broader population of nearby cells. The method's growth across neuroscience has particularly been driven by the introduction of sophisticated mathematical techniques related to motion correction, image registration, cell detection, spike estimation, and population characterization. However, for many researchers, making good use of these techniques has been difficult because they have been devised by different workers and impose differing - and sometimes stringent - technical requirements on those who seek to use them. NEW METHOD: We have built a simple toolbox of analysis routines that encompass the complete workflow for analyzing calcium imaging data. The workflow begins with preprocessing of data, includes motion correction and longitudinal image registration, detects active cells using constrained non-negative matrix factorization, and offers multiple options for estimating spike times and characterizing population activity. The routines can be navigated through a simple graphical user interface. Although written in MATLAB, a standalone version for researchers who do not have access to MATLAB is included. RESULTS: We have used the toolbox on two very different preparations: spontaneously active brain slices and microendoscopic imaging from deep structures in awake behaving mice. In both cases, the toolbox offered a seamless flow from raw data all the way through to prepared graphs. CONCLUSION: The field of calcium imaging has benefited from the development of numerous innovative mathematical techniques. Here we offer a simple toolbox that allows ordinary researchers to fully exploit these techniques.

Unveiling bacterial communication with a MATLAB GUI implementing the diffusion-based quorum sensing model.

Bacteria employ quorum sensing as a remarkable mechanism for coordinating behaviors and communicating within their communities. In this study, we introduce a MATLAB Graphical User Interface (GUI) that offers a versatile platform for exploring the dynamics of quorum sensing. Our computational framework allows for the assessment of quorum sensing, the investigation of parameter dependencies, and the prediction of minimum biofilm thickness required for its initiation. A pivotal observation from our simulations underscores the pivotal role of the diffusion coefficient in quorum sensing, surpassing the influence of bacterial cell dimensions. Varying the diffusion coefficient reveals significant fluctuations in autoinducer concentration, highlighting its centrality in shaping bacterial communication. Additionally, our GUI facilitates the prediction of the minimum biofilm thickness necessary to trigger quorum sensing, a parameter contingent on the diffusion coefficient. This feature provides valuable insights into spatial constraints governing quorum sensing initiation. The interplay between production rates and cell concentrations emerges as another critical facet of our study. We observe that higher production rates or cell concentrations expedite quorum sensing, underscoring the intricate relationship between cell communication and population dynamics in bacterial communities. While our simulations align with mathematical models reported in the literature, we acknowledge the complexity of living organisms, emphasizing the value of our GUI for standardizing results and facilitating early assessments of quorum sensing. This computational approach offers a window into the environmental conditions conducive to quorum sensing initiation, encompassing parameters such as the diffusion coefficient, cell concentration, and biofilm thickness. In conclusion, our MATLAB GUI serves as a versatile tool for understanding the diverse aspects of quorum sensing especially for non-biologists. The insights gained from this computational framework advance our understanding of bacterial communication, providing researchers with the means to explore diverse ecological contexts where quorum sensing plays a pivotal role.

Large-scale analysis of neural activity and connectivity from high-density electroencephalographic data.

INTRODUCTION: High-density electroencephalography (hdEEG) is a technique used for the characterization of the neural activity and connectivity in the human brain. The analysis of EEG data involves several steps, including signal pre-processing, head modelling, source localization and activity/connectivity quantification. Visual check of the analysis steps is often necessary, making the process time- and resource-consuming and, therefore, not feasible for large datasets. FINDINGS: Here we present the Noninvasive Electrophysiology Toolbox (NET), an open-source software for large-scale analysis of hdEEG data, running on the cross-platform MATLAB environment. NET combines all the tools required for a complete hdEEG analysis workflow, from raw signals to final measured values. By relying on reconstructed neural signals in the brain, NET can perform traditional analyses of time-locked neural responses, as well as more advanced functional connectivity and brain mapping analyses. The extracted quantitative neural data can be exported to provide broad compatibility with other software. CONCLUSIONS: NET is freely available (https://github.com/bind-group-kul/net) under the GNU public license for non-commercial use and open-source development, together with a graphical user interface (GUI) and a user tutorial. While NET can be used interactively with the GUI, it is primarily aimed at unsupervised automation to process large hdEEG datasets efficiently. Its implementation creates indeed a highly customizable program suitable for analysis automation and tight integration into existing workflows.

Dang-Gui-Si-Ni decoction facilitates wound healing in diabetic foot ulcers by regulating expression of AGEs/RAGE/TGF-ß/Smad2/3.

Diabetic foot ulcer (DFU) is a predominant complication of diabetes mellitus with poor prognosis accompanied by high amputation and mortality rates. Dang-Gui-Si-Ni decoction (DSD), as a classic formula with a long history in China, has been found to improve DFU symptoms. However, mechanism of DSD for DFU therapy remains unclear with no systematic elaboration. In vivo, following establishment of DFU rat model, DSD intervention with low, medium and high doses was done, with Metformin (DM) as a positive control group. With wound healing detection, pathological changes by HE staining, inflammatory factor expression by ELISA and qRT-PCR, oxidative stress levels by ELISA, and AGEs/RAGE/TGF-ß/Smad2/3 expression by Western blot were performed. In vitro, intervention with LY2109761 (TGF-ß pathway inhibitor) based on DSD treatment in human dermal fibroblast-adult (HDF-a) cells was made. Cell viability by CCK8, migration ability by cell scratch, apoptosis by flow cytometry, and AGEs/RAGE/TGF-ß/Smad2/3 expression by Western blot were measured. DFU rats exhibited elevated AGEs/RAGE expression, whereas decreased TGF-ß1 and p-Smad3/Smad3 protein expression, accompanied by higher IL-1ß, IL-6, TNF-α levels, and oxidative stress. DSD intervention reversed above effects. Glucose induction caused lower cell viability, migration, TGF-ß1 and p-Smad3/Smad3 protein expression, with increased apoptosis and AGEs/RAGE expression in HDF-a cells. These effects were reversed after DSD intervention, and further LY2109761 intervention inhibited DSD effects in cells. DSD intervention may facilitate wound healing in DFU by regulating expression of AGEs/RAGE/TGF-ß/Smad2/3, providing scientific experimental evidence for DSD clinical application for DFU therapy.

Genito-urinary infectious adverse events related to sodium glucose cotransporter-2 inhibitors: a network meta-analysis and meta-regression.

INTRODUCTION: Sodium glucose cotransporter-2 inhibitors (SGLT2is) are an emerging class of drugs with wide indications. Controversial evidence exists regarding the risk of urinary tract infection (UTI) and genital infections (GI) with SGLT2is paving way for undertaking this network meta-analysis and meta-regression study. METHODS: Data from randomized trials evaluating SGLT2is reporting the number of patients with UTI and GI were included. Odds ratios (OR) with 95% confidence intervals (95% CI) were the effect estimates. Meta-regression analysis identified risk factors. Number needed to harm (NNH) was estimated. RESULTS: Two hundred and sixty-four articles were included [UTI (213 studies; 150,140 participants) and GI (188 studies; 121,275 participants)]. An increased risk of UTI (OR: 1.11; 95% CI: 1.06, 1.16) and GI (OR: 3.5, 95% CI: 3.1, 3.9) was observed. Men showed a lower risk of UTI (OR: 0.2; 95% CI: 0.2, 0.3) and GI (OR: 0.4; 95% CI: 0.4, 0.5). Meta-regression analyses revealed BMI ≥ 30 kg/m2 and duration of SGLT2i treatment for ≥6 months as risk factors. NNH was 16 for UTI and 25 for GI. CONCLUSION: SGLT2is increase the risk of UTI and GI that needs to be incorporated in the treatment guidelines with precautions in high-risk patients. PROSPECTIVE PROTOCOL REGISTRATION: https://osf.io/5fwyk.

AI-Assisted Detection of Interproximal, Occlusal, and Secondary Caries on Bite-Wing Radiographs: A Single-Shot Deep Learning Approach.

Tooth decay is a common oral disease worldwide, but errors in diagnosis can often be made in dental clinics, which can lead to a delay in treatment. This study aims to use artificial intelligence (AI) for the automated detection and localization of secondary, occlusal, and interproximal (D1, D2, D3) caries types on bite-wing radiographs. The eight hundred and sixty bite-wing radiographs were collected from the School of Dentistry database. Pre-processing and data augmentation operations were performed. Interproximal (D1, D2, D3), secondary, and occlusal caries on bite-wing radiographs were annotated by two oral radiologists. The data were split into 80% for training, 10% for validation, and 10% for testing. The AI-based training process was conducted using the YOLOv8 algorithm. A clinical decision support system interface was designed using the Python PyQT5 library, allowing for the use of dental caries detection without the need for complex programming procedures. In the test images, the average precision, average sensitivity, and average F1 score values for secondary, occlusal, and interproximal caries were obtained as 0.977, 0.932, and 0.954, respectively. The AI-based dental caries detection system yielded highly successful results in the test, receiving full approval from dentists for clinical use. YOLOv8 has the potential to increase sensitivity and reliability while reducing the burden on dentists and can prevent diagnostic errors in dental clinics.

CHARMM-GUI Membrane Builder for Lipid Droplet Modeling and Simulation.

Lipid droplets (LDs) are organelles that are necessary for eukaryotic and prokaryotic metabolism and energy storage. They have a unique structure consisting of a spherical phospholipid monolayer encasing neutral lipids such as triacylglycerol (TAG). LDs have garnered increased interest for their implications in disease and for drug delivery applications. Consequently, there is an increased need for tools to study their structure, composition, and dynamics in biological contexts. In this work, we utilize CHARMM-GUI Membrane Builder to simulate and analyze LDs with and without a plant LD protein, oleosin. The results show that Membrane Builder can generate biologically relevant all-atom LD systems with relatively short equilibration times using a new TAG library having optimized headgroup parameters. TAG molecules originally inserted into a lipid bilayer aggregate in the membrane center, forming a TAG-only core flanked by two monolayers. The TAG-only core thickness stably grows with increasing TAG mole fraction. A 70 % TAG system has a core that is thick enough to house oleosin without its interactions with the distal leaflet or disruption of its secondary structure. We hope that Membrane Builder can aid in the future study of LD systems, including their structure and dynamics with and without proteins.

Ling-Gui-Zhu-Gan decoction ameliorates nonalcoholic fatty liver disease via modulating the gut microbiota.

Numerous studies have supported that nonalcoholic fatty liver disease (NAFLD) is highly associated with gut microbiota dysbiosis. Ling-Gui-Zhu-Gan decoction (LG) has been clinically used to treat NAFLD, but the underlying mechanism remains unknown. This study investigated the therapeutic effect and mechanisms of LG in mice with NAFLD induced by a high-fat diet (HD). An HD-induced NAFLD mice model was established to evaluate the efficacy of LG followed by biochemical and histopathological analysis. Metagenomics, metabolomics, and transcriptomics were used to explore the structure and metabolism of the gut microbiota. LG significantly improved hepatic function and decreased lipid droplet accumulation in HD-induced NAFLD mice. LG reversed the structure of the gut microbiota that is damaged by HD and improved intestinal barrier function. Meanwhile, the LG group showed a lower total blood bile acids (BAs) concentration, a shifted BAs composition, and a higher fecal short-chain fatty acids (SCFAs) concentration. Furthermore, LG could regulate the hepatic expression of genes associated with the primary BAs biosynthesis pathway and peroxisome proliferator-activated receptor (PPAR) signaling pathway. Our study suggested that LG could ameliorate NAFLD by altering the structure and metabolism of gut microbiota, while BAs and SCFAs are considered possible mediating substances. IMPORTANCE: Until now, there has still been no study on the gut microbiota and metabolomics of Ling-Gui-Zhu-Gan decoction (LG) in nonalcoholic fatty liver disease (NAFLD) mouse models. Our study is the first to report on the reshaping of the structure and metabolism of the gut microbiota by LG, as well as explore the potential mechanism underlying the improvement of NAFLD. Specifically, our study demonstrates the potential of gut microbial-derived short-chain fatty acids (SCFAs) and blood bile acids (BAs) as mediators of LG therapy for NAFLD in animal models. Based on the results of transcriptomics, we further verified that LG attenuates NAFLD by restoring the metabolic disorder of BAs via the up-regulation of Fgf15/FXR in the ileum and down-regulation of CYP7A1/FXR in the liver. LG also reduces lipogenesis in NAFLD mice by mediating the peroxisome proliferator-activated receptor (PPAR) signaling pathway, which then contributes to reducing hepatic inflammation and improving intestinal barrier function to treat NAFLD.

Efficacy and safety of Shen Gui capsules for chronic heart failure: a systematic review and meta-analysis.

Background: Although Shen Gui capsules (SGCP) are widely used as an adjuvant treatment for chronic heart failure (CHF), their clinical efficacy and safety remain controversial. Purpose: To assess the efficacy and safety of SGCP in the treatment of CHF through a systematic review and meta-analysis, to provide high-quality evidence for evidence-based medicine. Methods: Seven databases were searched for randomized controlled trials (RCTs) assessing SGCP for CHF, from inception to 9 January 2023. RCT quality of evidence was evaluated using the Cochrane Handbook for the Evaluation of Intervention Systems to assess risk of bias and Grading of Recommendations Assessment, Development, and Evaluation. A meta-analysis with subgroup and sensitivity analyses was performed using Review Manager 5.4 and Stata 12. Results: Nine RCTs representing 888 patients with CHF were included in the review. Meta-analysis revealed that SGCP combined with conventional heart failure therapy is more advantageous for improving left ventricular ejection fraction [LVEF; mean difference (MD) = 5.26, 95% confidence interval (CI) (3.78, 6.74), p < 0.0000] and increasing effective rate [relative risk (RR) = 1.21, 95%CI (1.14, 1.29), p < 0.001] compared with conventional therapy alone. The experimental treatment also reduced brain natriuretic peptide [MD = -100.15, 95%CI (-157.83, -42.47), p = 0.0007], left ventricular end-diastolic diameter [MD = -1.93, 95%CI (-3.22, -0.64), p = 0.003], and hypersensitive C-reactive protein [MD = -2.70, 95%CI (-3.12,-2.28), p < 0.001] compared with the control group. However, there was not a statistically significant difference in tumor necrosis factor-α [MD = -14.16, 95%CI (-34.04, 5.73), p = 0.16] or left ventricular end-systolic diameter [MD = -1.56, 95%CI (-3.13, 0.01), p = 0.05]. Nor was there a statistically significant between-groups difference in incidence of adverse events (p > 0.05). Conclusion: SGCP combined with conventional heart failure therapy can improve LVEF and increase the effective rate to safely treat patients with CHF. However, further high-quality studies are needed to confirm these findings, due to the overall low quality of evidence in this literature.Clinical Trial Registration: https://www.crd.york.ac.uk/PROSPERO/logout.php, PROSPERO [CRD42023390409].

AutoEpiCollect, a Novel Machine Learning-Based GUI Software for Vaccine Design: Application to Pan-Cancer Vaccine Design Targeting PIK3CA Neoantigens.

Previous epitope-based cancer vaccines have focused on analyzing a limited number of mutated epitopes and clinical variables preliminarily to experimental trials. As a result, relatively few positive clinical outcomes have been observed in epitope-based cancer vaccines. Further efforts are required to diversify the selection of mutated epitopes tailored to cancers with different genetic signatures. To address this, we developed the first version of AutoEpiCollect, a user-friendly GUI software, capable of generating safe and immunogenic epitopes from missense mutations in any oncogene of interest. This software incorporates a novel, machine learning-driven epitope ranking method, leveraging a probabilistic logistic regression model that is trained on experimental T-cell assay data. Users can freely download AutoEpiCollectGUI with its user guide for installing and running the software on GitHub. We used AutoEpiCollect to design a pan-cancer vaccine targeting missense mutations found in the proto-oncogene PIK3CA, which encodes the p110ɑ catalytic subunit of the PI3K kinase protein. We selected PIK3CA as our gene target due to its widespread prevalence as an oncokinase across various cancer types and its lack of presence as a gene target in clinical trials. After entering 49 distinct point mutations into AutoEpiCollect, we acquired 361 MHC Class I epitope/HLA pairs and 219 MHC Class II epitope/HLA pairs. From the 49 input point mutations, we identified MHC Class I epitopes targeting 34 of these mutations and MHC Class II epitopes targeting 11 mutations. Furthermore, to assess the potential impact of our pan-cancer vaccine, we employed PCOptim and PCOptim-CD to streamline our epitope list and attain optimized vaccine population coverage. We achieved a world population coverage of 98.09% for MHC Class I data and 81.81% for MHC Class II data. We used three of our predicted immunogenic epitopes to further construct 3D models of peptide-HLA and peptide-HLA-TCR complexes to analyze the epitope binding potential and TCR interactions. Future studies could aim to validate AutoEpiCollect's vaccine design in murine models affected by PIK3CA-mutated or other mutated tumor cells located in various tissue types. AutoEpiCollect streamlines the preclinical vaccine development process, saving time for thorough testing of vaccinations in experimental trials.

Dang-Gui-Bu-Xue decoction improves wound healing in diabetic rats by the activation of Notch signaling.

Diabetes serves as a severe chronic disease that severely affects the normal life of human beings. Diabetes causes the complication of diabetic wound dysfunction, which is characterized by sustained inflammation, altered angiogenesis, delayed epithelialization and abnormal secretion of protease. Dang-Gui-Bu-Xue decoction (DBD) is a Chinese traditional medicine that comprises Radix Astragali and Radix Angelicae sinensis and is widely applied in treatment of multiple diseases owing to its functions against inflammation, lipid peroxidation and oxidative stress. Nevertheless, the impact of DBD on diabetic wound healing remains elusive. In this study, we aimed to explore the function of DBD in the regulation of wound healing. We observed that the gavage administration of DBD reduced the wound area, inflammatory infiltration, inflammatory factor levesl, and enhanced granulation tissue formation, wound extracellular matrix (ECM) production, and CD31 accumulation in the diabetic rat wound model, and the co-treatment of gavage administration and the external administration of gauze containing DBD further improved the wound healing effect, while the combination of Notch signaling inhibitor DAPT ((N- [N- (3, 5-difluorophenacetyl)-l-alanyl]-s-phenylglycinet-butyl ester)) could attenuate the improvement. Regarding to the mechanism, the expression levels of Notch1, Delta-like canonical Notch ligand 4 (Dll4), Jagged1, and Hairy Enhancer of Split-1 (Hes1) were increased by DBD, while the treatment of DAPT impaired the effect in the rats. Furthermore, we found that the high glucose (HG)-inhibited viability and tube formation were induced by DBD in human umbilical vein endothelial cells (HUVECs), in which DAPT could reverse this effect. Therefore, we concluded that DBD contributed to wound healing by the activation of Notch signaling. Our finding provides new insight into the potential role of DBD in promoting diabetic wound healing.

Synergistic impact of Gui Zhi Shao Yao Zhi Mu Decoction and leflunomide on gut microbiota in rheumatoid arthritis: insights from 16S rDNA sequencing.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease with complex pathogenesis, including alterations in the gut microbiota. Gui Zhi Shao Yao Zhi Mu Decoction (GSZD), a traditional Chinese herbal formula, has shown efficacy in RA treatment, but its impact on intestinal microflora remains unclear. This study aimed to investigate the effects of GSZD combined with leflunomide on the gut microbiota of RA patients. METHODS: The study enrolled 48 RA patients who were randomly assigned to either a control group receiving leflunomide or a treatment group receiving GSZD combined with leflunomide for 12 weeks. Gut microbiota composition was analyzed pre- and post-intervention using 16S rDNA sequencing. Changes in microbial diversity, abundance, and metabolic functions were assessed. RESULTS: Post-treatment, both groups exhibited significant alterations in gut microbiota composition. GSZD combined with leflunomide led to an increased Bacteroidetes/Firmicutes ratio and a reduction in Actinobacteria compared to leflunomide alone. This was associated with beneficial shifts in microbial genera and metabolic pathways, suggesting improved gut health and systemic immune modulation. CONCLUSION: GSZD combined with leflunomide significantly modulates the gut microbiota in RA patients. This study provides insights into the mechanisms underlying the therapeutic effects of GSZD and highlights the potential of integrating traditional Chinese medicine with conventional treatments in managing RA.

VSpipe-GUI, an Interactive Graphical User Interface for Virtual Screening and Hit Selection.

Virtual screening of large chemical libraries is essential to support computer-aided drug development, providing a rapid and low-cost approach for further experimental validation. However, existing computational packages are often for specialised users or platform limited. Previously, we developed VSpipe, an open-source semi-automated pipeline for structure-based virtual screening. We have now improved and expanded the initial command-line version into an interactive graphical user interface: VSpipe-GUI, a cross-platform open-source Python toolkit functional in various operating systems (e.g., Linux distributions, Windows, and Mac OS X). The new implementation is more user-friendly and accessible, and considerably faster than the previous version when AutoDock Vina is used for docking. Importantly, we have introduced a new compound selection module (i.e., spatial filtering) that allows filtering of docked compounds based on specified features at the target binding site. We have tested the new VSpipe-GUI on the Hepatitis C Virus NS3 (HCV NS3) protease as the target protein. The pocket-based and interaction-based modes of the spatial filtering module showed efficient and specific selection of ligands from the virtual screening that interact with the HCV NS3 catalytic serine 139.

Fingerprint analysis of dang-gui-Si-Ni decoction and its anticoagulant activity in vivo-in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Dang-Gui-Si-Ni (DGSN) decoction is a classic prescription in the clinical practice of traditional Chinese Medicine (TCM). DGSN decoction is often used to relieve symptoms of cold coagulation and blood stasis recorded by Treatise on Febrile Diseases (Shang Han Lun) and treat Raynaud's disease, dysmenorrhea, arthritis, migraine in TCM clinic. Accumulated evidences have suggested that this diseases are related to microcirculation disturbance. However, the anticoagulant activity and underlying mechanisms of DGSN decoction responsible for the therapeutic not well understood. AIM OF THE STUDY: The fingerprint and anticoagulant activity in vivo-in vitro of DGSN decoction were evaluated to strengthen the quality control and activity study of formulas. MATERIALS AND METHODS: The chemical components of DGSN decoction were analyzed by HPLC and its fingerprint similarity were evaluated by "Chinese Medicine Chromatographic Fingerprint Similarity Evaluation Software (2012 Edition)". The anticoagulant activity of DGSN decoction was assessed by measuring four coagulation factors (PT, TT, APTT, FIB) in vitro. Zebrafish thrombosis model induced by punatinib was established to evaluate the activity of improving microvascular hemodynamics in vivo. Quantitative real-time polymerase chain reaction (q-PCR) were adopted to compare the changes in the RNA expression levels of coagulation factor II (FII), VII (FVII), IX (FIX) and X (FX) in zebrafish thrombosis model. RESULTS: The fingerprint similarity evaluation method of DGSN decoction was established. The results showed that 18 samples had higher similarity (S1-S18 > 0.878). Pharmacodynamic results showed that DGSN decoction could extend PT, TT and APTT, and reduce FIB content in vitro. Meanwhile, it markedly enhanced the cardiac output and blood flow velocity at low dosage (500 µg mL-1) in vivo. q-PCR data demonstrated that DGSN decoction (500 µg mL-1) could downregulate the RNA expression of FII, FVII, FIX and FX. Interestingly, there were a bidirectional regulation of FII, FIX and FX in a certain concentration range. In general, DGSN decoction can significantly improve hemodynamics and downregulate coagulation factors, and the results were consistent both in vitro - in vivo. CONCLUSION: The fingerprint study provide a new perspective for improving the quality control of DGSN decoction. DGSN decoction possess anticoagulant activity by regulating multiple coagulation factors simultaneously. Thus, it has the potential to develop into the novel raw material of anticoagulant drugs.

Gui ShenWan prevent premature ovarian insufficiency by modulating autophagy and angiogenesis via facilitating VDR.

ETHNOPHARMACOLOGICAL RELEVANCE: Gui Shen Wan (GSW) stands out as a promising therapeutic approach for addressing Premature Ovarian Insufficiency (POI). With deep roots in traditional medicine, GSW highlights the ethnopharmacological significance of herbal interventions in addressing nuanced aspects of women's health, with a specific emphasis on ovarian functionality. Recognizing the importance of GSW in gynecological contexts resonates with a rich tradition of using botanical formulations to navigate the intricacies of reproductive health. Delving into GSW's potential for treating POI emphasizes the crucial role of ethnopharmacological insights in guiding modern research endeavors. AIM OF THE STUDY: GSW is extensively utilized in gynecological disorders and has recently emerged as a potential therapeutic approach for POI. The present investigation aimed to assess the efficacy of GSW in treating POI in rats and elucidate its underlying molecular mechanisms. MATERIALS AND METHODS: The study employed GSW for POI treatment in rats. GSW, prepared as pills, underwent HPLC fingerprinting for quality control. Reagents and drugs, including VCD and dehydroepiandrosterone (DHEA), were sourced from reputable providers. Eighty Sprague-Dawley rats were categorized into groups for POI induction and treatment. Ovarian tissue underwent HE staining, immunohistochemical staining, Western Blot, qRT-PCR, and vaginal secretion testing. ELISA was utilized for target molecule detection. This methodology ensures a robust and reliable experimental framework. RESULTS: The results highlight a robust collaborative improvement in POI among rats subjected to combined GSW and DHEA treatment. Particularly noteworthy is the substantial enhancement in the expression of vascular regeneration-related molecules-VDR-Klotho-VEGFR-accompanied by a significant elevation in autophagy levels. Post-GSW administration, rat ovarian morphology demonstrated increased stability, hormone levels exhibited more consistent maintenance, and there was a marked reduction in inflammatory response compared to other groups (p < 0.01). Furthermore, GSW intervention resulted in a more pronounced upregulation of ovarian autophagy (p < 0.05). CONCLUSION: By modulating VDR-Klotho signaling, GSW exerts regulatory control over ovarian autophagy and vascular regeneration, thereby mitigating the occurrence and progression of POI in rats.