Subclinical hypothyroidism (SCH) contributes to obesity, with the liver acting as a crucial metabolic regulator. Thyroid-stimulating hormone (TSH) affects systemic lipid balance, potentially linking SCH to obesity. While the direct impact of TSH on hepatic lipid metabolism has been extensively documented, its role in modulating lipid dynamics in peripheral organs through liver-mediated pathways remains insufficiently understood. This study identifies TSH-stimulated hepatocyte-derived exosomes (exosomesTSH) as key mediators in liver-adipose communication, promoting triglyceride accumulation in adipocytes via the transforming growth factor-beta 1 (TGF-β1)/adipose triglyceride lipase (ATGL) axis. ExosomesTSH enhance lipid storage in adipocytes, significantly increasing triglyceride content and lipid droplet formation while reducing lipolysis, effects that are dependent on TSH receptor (TSHR) activation in hepatocytes. In vivo, exosomesTSH induce weight gain and adipose tissue expansion, impairing glucose metabolism in both chow- and high-fat diet-fed mice. Mechanistically, exosomesTSH upregulate TGF-β1 and downregulate ATGL in adipocytes, establishing the TGF-β1/ATGL pathway as essential for exosome-mediated lipid accumulation. Further, miR-139-5p is identified as a modulator of TGF-β1 expression within this pathway, with overexpression of miR-139-5p alleviating exosomesTSH-induced lipid accumulation in adipocytes. This study elucidates a novel miR-139-5p-dependent mechanism through which TSH modulates lipid metabolism via liver-derived exosomes, highlighting the pivotal role of miR-139-5p in linking SCH to adipose lipid accumulation through the TGF-β1/ATGL signaling axis.

BackgroundIn recent years, the incidence of insulin resistance is increasing, and it can cause a variety of Metabolic syndrome. Ginsenosides have been clinically proven to improve fat metabolism and reduce insulin resistance, but their components and mechanism of action are still unclear.ObjectiveGinsenoside, a bioactive compound derived from ginseng, exhibits significant potential in treating obesity, diabetes, and metabolic disorders. Despite evidence supporting its efficacy in ameliorating insulin resistance (IR) in obesity, the specific bioactive components and underlying mechanisms remain obscure. In this study, we endeavored to elucidate the potential molecular targets and pathways influenced by ginsenoside Rh3 (GRh3) to ameliorate IR in liver tissue. We employed a comprehensive approach that integrates system pharmacology and bioinformatics analysis.Materials and methodsOur methodology involved the identification of candidate targets for GRh3 and the profiling of differentially expressed genes (DEGs) related to IR in individuals with insulin resistance. The coalescence of candidate targets and DEGs facilitated the construction of a “GRh3-targets-disease” network for each tissue type, ultimately yielding 38 shared target genes. Subsequently, we conducted pathway enrichment analysis, established protein-protein interaction (PPI) networks, and identified hub targets among the GRh3 targets and IR-related DEGs. Additionally, we conducted animal experiments to corroborate the role of these hub targets in the context of GRh3.ResultsOur investigation identified a total of 38 overlapping targets as potential candidates. Notably, our analysis revealed crucial hub targets such as EGFR, SRC, ESR1, MAPK1, and CASP3, alongside implicated signaling pathways, including those related to insulin resistance, the FoxO signaling pathway, the PPAR signaling pathway, and the IL-17 signaling pathway. This study establishes a robust foundation for the mechanisms underlying GRh3’s efficacy in mitigating IR. Furthermore, these results suggest that GRh3 may serve as a representative compound within the ginsenoside family.ConclusionThis study elucidates the potential molecular targets and associated pathways through which GRh3 ameliorates IR, showcasing its multifaceted nature, spanning multiple targets, pathways, and mechanisms. These findings establish a robust foundation for subsequent experimental inquiries and clinical applications.

Background. Serum uric acid (SUA) and glycosylated hemoglobin (HbA1c) were closely related to the body’s metabolism. This study aimed to investigate the relationship between HbA1c and SUA in adults. Methods. This study selected 7293 participants aged ≥20 from 2011 to 2020 in the National Health and Nutrition Examination Survey (NHANES). The multivariate linear regression model was used to test the association between HbA1c and SUA. Subgroup analysis was performed according to age, gender, race, and body mass index (BMI). This study solved the relationship between HbA1c and SUA by fitting a smooth curve. Finally, the inflection point in the nonlinear relationship was calculated by the recursive algorithm, and the relationship between HbA1c and SUA on both sides of the inflection point was analyzed by the two-segment piecewise linear regression model. Results. All 7293 participants found a negative correlation between HbA1c and SUA by completely adjusting the model (β = −7.93 and 95% CI: −9.49–−6.37). In addition, when this study was stratified by gender, age, race, and BMI status, this negative correlation was still statistically significant. In the subgroup analysis, we found that the relationship between the two had different results due to gender differences. In men, HbA1c had a significant negative correlation with SUA. However, in women, the HbA1c value was positively correlated with SUA before 6.8%, and the HbA1c value was negatively correlated with SUA after 6.8%, which indicates that the relationship between HbA1c and SUA in women has changed in prediabetes and diabetes. Conclusion. This study shows that HbA1c is positively correlated with SUA in American adults before 7%. There is a negative correlation after the HbA1c value of 7%.

BACKGROUND AND AIM:Diabetes retinopathy (DR) is a common microvascular complication of diabetes, and it is the main cause of global vision loss. The current observational research results show that the causal relationship between Vitamin D and DR is still controversial. Therefore, we conducted a Mendelian randomization study to determine the potential causal relationship between serum 25-hydroxyvitamin D 25(OH)D and DR. METHODS AND RESULTS:In this study, we selected aggregated data on serum 25(OH)D levels (GWAS ID: ebi-a-GCST90000615) and DR (GWAS ID: finn-b-DM_RETINOPATHY) from a large-scale GWAS database. Then use MR analysis to evaluate the possible causal relationship between them. We mainly use inverse variance weighted (IVW), supplemented by MR Egger and weighted median methods. Sensitivity analysis is also used to ensure the stability of the results, such as Cochran's Q-test, MR-PRESSO, MR-Egger interception test, and retention method. The MR analysis results showed that there was no significant causal relationship between 25(OH)D and DR (OR = 1.0128, 95%CI=(0.9593,1.0693), P = 0.6447); Similarly, there was no significant causal relationship between DR and serum 25 (OH) D levels (OR = 0.9900, 95% CI=(0.9758,1.0045), P = 0.1771). CONCLUSION:Our study found no significant causal relationship between serum 25(OH)D levels and DR, and vice versa. A larger sample size randomized controlled trial is needed to further reveal its potential causal relationship.

This study aimed to evaluate the efficacy and therapeutic mechanism of parthenolide (PTL) in breast cancer (BC) through a comprehensive strategy integrating network pharmacology, single-cell RNA sequencing (scRNA-seq) and metabolomics. In network pharmacology, 70 therapeutic targets were identified, of which 16 core targets were filtered out through seven classical algorithms of Cytohubba plugin. Additionally, the hub module of PPI network was extracted using MCODE plugin. Molecular docking and molecular dynamics simulation showed a potent binding affinity between PTL and JNK, subsequently validated by MST and SPR assays. Further, Mendelian randomization analysis indicated that JNK was causally associated with BC. GO and KEGG enrichment analyses revealed that PTL counteracted BC via promoting ROS generation, inducing apoptosis and suppressing proliferation, which potentially involved the coordinated regulation of MAPK and FoxO1 pathways. Moreover, ssGSEA and scRNA-seq analysis suggested that PTL may act on T cell immune microenvironment of BC. Subsequently, these bioinformatics-based predictions were experimentally validated using in-vitro and in-vivo models. Finally, metabolome profiling unveiled that PTL remodeled the glycine, serine and threonine metabolism as well as biosynthesis of unsaturated fatty acids, and thereby contributed to BC inhibition. From molecular, immune and metabolic perspectives, this study not only provided a unique insight into the mechanistic details of PTL against BC, but also proposed a novel promising therapeutic strategy for BC.

Objective This study systematically explored the mechanism of Rhizoma Coptidis-Eupatorium fortunei in treating type 2 diabetes mellitus (T2DM) by using network pharmacology and molecular docking methods. Methods The TCMSP database was used to screen out the active ingredients and related targets of Rhizoma Coptidis-Eupatorium fortunei (R-E) drug pair. GeneCards, OMIM, DrugBank, and other databases were used to screen the related targets of T2DM, and then, the UniProt database was used to standardize the relevant targets of T2DM. Then, the Venn analysis was performed on the active ingredient-related targets and disease-related targets of R-E drugs to find the intersection targets. Using the STRING database and Cytoscape software, the PPI network and “drug-active ingredient-target-disease” network are constructed by intersecting targets and corresponding active ingredients. Through the cluster profiler package in the R software, GO function enrichment analysis and KEGG pathway enrichment analysis were carried out on the intersection targets and the screened core targets, and the prediction results were verified by molecular docking. Results Taking OB ≥ 30% and DL ≥ 0.18 as the standard, a total of 25 effective active ingredients of R-E drug pairs were screened, including berberine, palmatine, coptisine, and so on. After corresponding, 19 effective chemical components and 284 targets of the R-E drug pair were obtained. After searching multiple disease databases, 1289 T2DM-related targets were screened. After the summary, 159 common targets were obtained in this study. Finally, in the bioinformatics analysis, this study concluded that quercetin, luteolin, berberine, palmatine, and coptisine are the main chemical components of the R-E drug pair. ESR1, MAPK1, AKT1, TP53, IL6, and JUN are the important core targets. GO and KEGG enrichment analyses showed that Rhizoma Coptidis-Eupatorium fortunei could improve T2DM by regulating multiple biological processes and pathways. Molecular docking results showed that berberine, palmatine, and coptisine had higher binding to the core target, and MAPK1, AKT1, and IL6 could stably bind to the active ingredients of Rhizoma Coptidis-Eupatorium fortunei. Conclusion Rhizoma Coptidis-Eupatorium fortunei may have therapeutic effects on T2DM such as anti-inflammatory and regulating glucose and lipid metabolism through multiple components, multiple targets, and multiple signaling pathways, which provides a scientific basis for further research on the hypoglycemic effect of Rhizoma Coptidis-Eupatorium fortunei drug pair.

Ethnopharmacological relevance: Presently, insulin resistance has been a growing concern that urgently needs to be addressed, because it not only places patients at risk of developing type 2 diabetes mellitus but also results in metabolic syndrome and different aspects of cardiovascular diseases. Shenqi Jiangtang Granule (SJG) is a classic traditional Chinese medicine (TCM) prescription that is widely used to treat diabetes mellitus and its complications in clinical practice. While studies have revealed that SJG with multi-ingredients and multi-targets characteristics possesses potential anti-insulin resistance pharmacological properties, its mechanisms of action and molecular targets for the treatment of insulin resistance are still obscure, which prompt us to conduct an indepth research. Aim of the study: This study was purposed to uncover the pharmacological mechanism of SJG against insulin resistance through integrating network pharmacology and experimental validation. Materials and methods: The putative ingredients of SJG and its related targets were discerned from the TCMSP database. Subsequently, insulin resistance-associated targets were retrieved from GeneCard, OMIM, and GEO database. Compound-target, protein-protein interaction (PPI), and compound-target-pathway networks were established using Cytoscape software. GO and KEGG pathway analyses were performed to identify possible enrichment of genes with specific biological themes. Molecular docking was used to verify the correlation between the main active ingredients and hub targets. Optimal docking conformation was further analyzed by molecular dynamics (MD) simulation. Finally, the potential molecular mechanisms of SJG acting on insulin resistance, as predicted by the network pharmacology analyses, were validated experimentally in insulin resistant rat model. Results: 136 active compounds, 211 corresponding targets in addition to 1463 disease-related targets were collected, of which 94 intersection targets were obtained. 29 key targets including AKT1, VEGFA, IL-6, CASP3, and PTGS2 were identified through PPI network analysis. Hub module of PPI network was closely associated with inflammation. GO and KEGG analyses also revealed that inflammation-related pathways may be a central factor for SJG to modulate insulin resistance. Molecular docking test showed a good binding potency between primary active ingredients and core targets, and the binding mode of optimal docking conformation was stable in MD simulation. A rat model of insulin resistance was successfully induced by chronic high-fat diet (HFD) consumption. Through a series of in vivo studies, including HEC, ITT, and HOMA-IR measurement, it was revealed that SJG exhibited a beneficial effect on ameliorating insulin resistance, as demonstrated by a significant increase of GIR and a significant decrease of AUCITT and HOMA-IR index value. Further molecular biological analysis showed that SJG can decrease the mRNA expression level and serum concentration of inflammatory cytokines (TNF-alpha, IL-6, and IL-1 beta), along with suppressing the p-NF kappa B protein overexpression, indicating its antiinflammatory activity. Also, it can contribute to the reversal of the impaired hepatic insulin signaling pathway, as evidenced by up-regulated protein expression of p-Akt and GLUT2. Conclusions: Through in silico and in vivo approaches, the present study not only provides a unique insight into the possible mechanism of SJG in insulin resistance after successfully filtering out associated key target genes and signaling pathways, but also suggests a novel promising therapeutic strategy for curing insulin resistance.

Background Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by abdominal pain, diarrhea or constipation, and changes in defecation patterns. No organic disease is found to explain these symptoms by routine clinical examination. This study aims to investigate the efficacy and safety of acupuncture therapy for IBS patients compared with those of conventional treatments. We also aim to identify the optimal acupoint combination recommended for IBS and to clarify the clinical advantage of the “multiacupoint co-effect and synergistic effect.” Methods and analysis A total of 204 eligible patients who meet the Rome IV criteria for IBS will be randomly stratified into acupuncture group A, acupuncture group B, or the control group in a 1:1:1 ratio with a central web-based randomization system. The prespecified acupoints used in the control group will include bilateral Tianshu (ST25) , Shangjuxu (ST37) , Neiguan (PC6) , and Zusanli (ST36). The prespecified acupoints used in experimental group A will include bilateral Tianshu (ST25) , Shangjuxu (ST37) , and Neiguan (PC6) . The prespecified acupoints used in experimental group B will include bilateral Tianshu (ST25) , Shangjuxu (ST37) , and Zusanli (ST36) . Each patient will receive 12 acupuncture treatments over 4 weeks and will be followed up for 4 weeks. The primary outcome is the IBS-Symptom Severity Scale (IBS-SSS) score. The secondary outcomes include the Bristol Stool Form Scale (BSFS), Work and Social Adjustment Score (WSAS), IBS-Quality of Life (IBS-QOL), Self-Rating Anxiety Scale (SAS), and Self-Rating Depression Scale (SDS) scores. Both the primary outcome and the secondary outcome measures will be collected at baseline, at 2 and 4 weeks during the intervention, and at 6 weeks and 8 weeks after the intervention. Ethics and dissemination The entire project has been approved by the ethics committee of the Beijing University of Chinese Medicine (2020BZYLL0903). Discussion This is a multicenter randomized controlled trial for IBS in China. The findings may shed light on the efficacy of acupuncture as an alternative to conventional IBS treatment. The results of the trial will be disseminated in peer-reviewed publications. Trial registration Chinese Clinical Trials Register ChiCTR2000041215 . First registered on 12 December 2020. http://www.chictr.org.cn/ .

Objective: To investigate whether Gypenoside XLIX (Gyp-XLIX) can attenuate insulin resistance in vivo, and explore the possible molecular mechanism. Methods: We performed hyperinsulinemic-euglycemic clamp in overnight-fasted Sprague-Dawley rats infused with saline, or lipid with or without Gyp-XLIX. Steady-state glucose infusion rate (SSGIR) was analyzed. Plasma free fatty acid (FFA) levels were measured by using a colorimetric kit. IRS1/ PI3K/Akt and I kappa B alpha/NF-kappa B signaling pathway in the liver, gastrocnemius muscle, and epididymis fat were analyzed by western blot assay. Expressions of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6) and IL-1 beta mRNA were determined by real-time fluorescence quantitative PCR. AutoDock Vina software was used to perform molecular docking so as to evaluate the binding affinity between Gyp-XLIX and IKK beta. Results: Lipid infusion remarkably decreased SSGIR compared with saline infusion (P < 0.001), which implicated a systemic insulin resistance. However, Gyp-XLIX pretreatment partially prevented the decrease of SSGIR caused by lipid infusion (P < 0.01), suggesting that insulin resistance was alleviated by Gyp-XLIX. Additionally, Gyp-XLIX attenuated lipid-induced impairment of IRS1/ PI3K/Akt insulin signaling pathway in both liver and gastrocnemius muscle. Concomitantly, Gyp-XLIX also exerted an inhibitory potency on lipid-stimulated NF-kappa B activation and mRNA expression of proinflammatory genes (TNF-alpha, IL-1 beta, and IL-6). Molecular docking showed that Gyp-XLIX hold great potential to target IKK beta protein. Conclusion: Gyp-XLIX improved insulin sensitivity in lipid-infused rats, and the possible mechanism may involve inhibition of liver and muscle inflammation by suppressing IKK beta/NF-kappa B signaling pathway.

Objective: To investigate the efficacy of improved vacuum-assisted closure (VAC) therapy for diabetic wounds that are difficult to heal because of the presence of chronic narrow sinuses or cavities. Methods: Five patients met the inclusion criteria and were selected from the Department of Endocrinology, Shandong Provincial Hospital, affiliated to Shandong University. All the patients received improved negative-pressure wound therapy (NPWT) in addition to standard-of-care treatment. We completed intra-subject comparisons of wound growth speed [(the last depth - the depth of the wound)/interval number (mm/day)] to determine treatment effectiveness. Patients were followed up until healing. We recorded visual representations of wound progression and time to full healing. Results: All the subjects demonstrated variable degrees of improvement of wound healing at the last follow-up. Wound healing during NPWT was significantly faster than that observed during standard-of-care treatment. Conclusion: The improved VAC therapy promoted narrow fistula healing in the patients with refractory diabetic foot wounds, but the promotion and application of this technology require additional research.