The ginsenoside metabolite compound K stimulates glucagon-like peptide-1 secretion in NCI-H716 cells by regulating the RhoA/ROCKs/YAP signaling pathway and cytoskeleton formation.

Ginsenoside Rb1 has been shown to have antidiabetic and anti-inflammatory effects. Its major metabolite, compound K (CK), can stimulate the secretion of glucagon-like peptide-1 (GLP1), a gastrointestinal hormone that plays a vital role in regulating glucose metabolism. However, the mechanism underlying the regulation of GLP1 secretion by compound K has not been fully explored. This study was designed to investigate whether CK ameliorates incretin impairment by regulating the RhoA/ROCKs/YAP signaling pathway and cytoskeleton formation in NCI-H716 cells. Using NCI-H716 cells as a model cell line for GLP1 secretion, we analyzed the effect of CK on the expression of RhoA/ROCK/YAP pathway components. Our results suggest that the effect of CK on GLP1 secretion depends on the anti-inflammatory effect of CK. We also demonstrated that CK can affect the RhoA/ROCK/YAP pathway, which is downstream of transforming growth factor ß1 (TGFß1), by maintaining the capacity of intestinal differentiation. In addition, this effect was mediated by regulating F/G-actin dynamics. These results provide not only the mechanistic insight for the effect of CK on intestinal L cells but also the molecular basis for the further development of CK as a potential therapeutic agent to treat type 2 diabetes mellitus (T2D).

A CT-based radiomics model for predicting lymph node metastasis in hepatic alveolar echinococcosis patients to support lymph node dissection.

BACKGROUND: Hepatic alveolar echinococcosis (AE) is a severe zoonotic parasitic disease, and accurate preoperative prediction of lymph node (LN) metastasis in AE patients is crucial for disease management, but it remains an unresolved challenge. The aim of this study was to establish a radiomics model for the preoperative prediction of LN metastasis in hepatic AE patients. METHODS: A total of 100 hepatic AE patients who underwent hepatectomy and hepatoduodenal ligament LN dissection at Qinghai Provincial People's Hospital between January 2016 and August 2023 were included in the study. The patients were randomly divided into a training set and a validation set at an 8:2 ratio. Radiomic features were extracted from three-dimensional images of the hepatoduodenal ligament LNs delineated on arterial phase computed tomography (CT) scans of hepatic AE patients. Least absolute shrinkage and selection operator (LASSO) regression was applied for data dimensionality reduction and feature selection. Multivariate logistic regression analysis was performed to develop a prediction model, and the predictive performance of the model was evaluated using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). RESULTS: A total of 7 radiomics features associated with LN status were selected using LASSO regression. The classification performances of the training set and validation set were consistent, with area under the operating characteristic curve (AUC) values of 0.928 and 0.890, respectively. The model also demonstrated good stability in subsequent validation. CONCLUSION: In this study, we established and evaluated a radiomics-based prediction model for LN metastasis in patients with hepatic AE using CT imaging. Our findings may provide a valuable reference for clinicians to determine the occurrence of LN metastasis in hepatic AE patients preoperatively, and help guide the implementation of individualized surgical plans to improve patient prognosis.

Reciprocal regulation of SIRT1 and AMPK by Ginsenoside compound K impedes the conversion from plasma cells to mitigate for podocyte injury in MRL/lpr mice in a B cell-specific manner.

Background: Deposition of immune complexes drives podocyte injury acting in the initial phase of lupus nephritis (LN), a process mediated by B cell involvement. Accordingly, targeting B cell subsets represents a potential therapeutic approach for LN. Ginsenoside compound K (CK), a bioavailable component of ginseng, possesses nephritis benefits in lupus-prone mice; however, the underlying mechanisms involving B cell subpopulations remain elusive. Methods: Female MRL/lpr mice were administered CK (40 mg/kg) intragastrically for 10 weeks, followed by measurements of anti-dsDNA antibodies, inflammatory chemokines, and metabolite profiles on renal samples. Podocyte function and ultrastructure were detected. Publicly available single-cell RNA sequencing data and flow cytometry analysis were employed to investigate B cell subpopulations. Metabolomics analysis was adopted. SIRT1 and AMPK expression were analyzed by immunoblotting and immunofluorescence assays. Results: CK reduced proteinuria and protected podocyte ultrastructure in MRL/lpr mice by suppressing circulating anti-dsDNA antibodies and mitigating systemic inflammation. It activated B cell-specific SIRT1 and AMPK with Rhamnose accumulation, hindering the conversion of renal B cells into plasma cells. This cascade facilitated the resolution of local renal inflammation. CK facilitated the clearance of deposited immune complexes, thus reinstating podocyte morphology and mobility by normalizing the expression of nephrin and SYNPO. Conclusions: Our study reveals the synergistic interplay between SIRT1 and AMPK, orchestrating the restoration of renal B cell subsets. This process effectively mitigates immune complex deposition and preserves podocyte function. Accordingly, CK emerges as a promising therapeutic agent, potentially alleviating the hyperactivity of renal B cell subsets during LN.

A Unified Interactive Model Evaluation for Classification, Object Detection, and Instance Segmentation in Computer Vision.

Existing model evaluation tools mainly focus on evaluating classification models, leaving a gap in evaluating more complex models, such as object detection. In this paper, we develop an open-source visual analysis tool, Uni-Evaluator, to support a unified model evaluation for classification, object detection, and instance segmentation in computer vision. The key idea behind our method is to formulate both discrete and continuous predictions in different tasks as unified probability distributions. Based on these distributions, we develop 1) a matrix-based visualization to provide an overview of model performance; 2) a table visualization to identify the problematic data subsets where the model performs poorly; 3) a grid visualization to display the samples of interest. These visualizations work together to facilitate the model evaluation from a global overview to individual samples. Two case studies demonstrate the effectiveness of Uni-Evaluator in evaluating model performance and making informed improvements.

Apigenin ameliorates lupus nephritis by inhibiting SAT3 signaling in CD8+ T cells.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by widespread organ and tissue involvement, with lupus nephritis (LN) being one of its most severe complications. Dietary flavonoids, as for their anti-inflammatory and antioxidant properties, have shown therapeutic potential under various inflammatory conditions. Apigenin (AP) is one of the most studied phenolics and is found in many fruits, vegetables and herbs. This study aimed to investigate the therapeutic effects and underlying mechanisms of apigenin on LN. We evaluated the effects of apigenin on MRL/lpr mice, a well-established model for spontaneous LN. Apigenin treatment improved peripheral blood profiles, reduced serum inflammatory cytokines (IL-6, IFN-γ, IL-17, TGF-ß), lowered levels of autoantibodies (ANA, anti-dsDNA) and alleviated renal damage caused by autoantibodies and inflammatory cell infiltration. The results of immunohistochemistry and transcriptome analysis showed that AP could inhibit the infiltration of CD8+ cells in renal tissues. Single-cell sequencing public data from LN patients identified cytotoxic T lymphocytes (CTLs) as the primary CD8+ T cell subtype in the kidneys, with their differentiation regulated by STAT3. In this study, cell experiments demonstrated that AP can induce apoptosis in CD8+ T cells and reduce their recruitment of macrophages by inhibiting the STAT3/IL-17 signaling pathway. These findings highlight that a diet rich in dietary flavonoids, particularly apigenin, can offer therapeutic benefits for patients with SLE.

Visual Analysis of Neural Architecture Spaces for Summarizing Design Principles.

Recent advances in artificial intelligence largely benefit from better neural network architectures. These architectures are a product of a costly process of trial-and-error. To ease this process, we develop ArchExplorer, a visual analysis method for understanding a neural architecture space and summarizing design principles. The key idea behind our method is to make the architecture space explainable by exploiting structural distances between architectures. We formulate the pairwise distance calculation as solving an all-pairs shortest path problem. To improve efficiency, we decompose this problem into a set of single-source shortest path problems. The time complexity is reduced from O(kn2N) to O(knN). Architectures are hierarchically clustered according to the distances between them. A circle-packing-based architecture visualization has been developed to convey both the global relationships between clusters and local neighborhoods of the architectures in each cluster. Two case studies and a post-analysis are presented to demonstrate the effectiveness of ArchExplorer in summarizing design principles and selecting better-performing architectures.

Assessment of bidirectional relationships between depression and rheumatoid arthritis among adults: a two-sample Mendelian randomization study.

OBJECTIVE: Increasing evidence shows that depression is associated with rheumatoid arthritis (RA). However, the causality and direction of this association remain unclear, because links between the two diseases might be caused by shared environmental confounding factors. Our study aims to understand a putative causal link between the two diseases. METHODS: We retrieved summary statistics from meta-analyses of non-overlapping genome-wide association studies (GWASes) for depression (n = 807,553, 246,363 cases and 561,190 controls) and RA (n = 58,284, 14,361 cases and 42,923 controls). We combined Mendelian randomization (MR) estimates from each genetic instrument using inverse-variance weighted (IVW) meta-analysis, with alternate methods (e.g., simple median approach, weighted median approach, and MR-Egger regression) and conducted sensitivity analyses to assess the robustness of MR analyses. RESULTS: We found no evidence of causal relationships between depression and RA across all MR methods (IVW OR, 1.028 for RA; 95% CI, 0.821-1.287; P = 0.810) or vice versa (IVW OR, 0.999 for depression; 95% CI, 0.984-1.014; P = 0.932), indicating the links between the two diseases might be due to confounders. CONCLUSION: Despite the results, to optimize treatment outcomes of RA patients, we still emphasize depression should be managed as part of routine clinical care to optimize treatment outcomes of RA.

Fasudil compensates podocyte injury via CaMK4/Rho GTPases signal and actin cytoskeleton-dependent activation of YAP in MRL/lpr mice.

Deposition of immune complexes in the glomerulus leads to irreversible renal damage in lupus nephritis (LN), of which podocyte malfunction arises earlier. Fasudil, the only Rho GTPases inhibitor approved in clinical settings, possesses well-established renoprotective actions; yet, no studies addressed the amelioration derived from fasudil in LN. To clarify, we investigated whether fasudil exerted renal remission in lupus-prone mice. In this study, fasudil (20 mg/kg) was intraperitoneally administered to female MRL/lpr mice for 10 weeks. We report that fasudil administration swept antibodies (anti-dsDNA) and attenuated systemic inflammatory response in MRL/lpr mice, accompanied by preserving podocyte ultrastructure and averting immune complex deposition. Mechanistically, it repressed the expression of CaMK4 in glomerulopathy by preserving nephrin and synaptopodin expression. And fasudil further blocked cytoskeletal breakage in the Rho GTPases-dependent action. Further analyses showed that beneficial actions of fasudil on the podocytes required intra-nuclear YAP activation underlying actin dynamics. In addition, in vitro assays revealed that fasudil normalized the motile imbalance by suppressing intracellular calcium enrichment, thereby contributing to the resistance of apoptosis in podocytes. Altogether, our findings suggest that the precise manners of crosstalks between cytoskeletal assembly and YAP activation underlying the upstream CaMK4/Rho GTPases signal in podocytes is a reliable target for podocytopathies treatment, and fasudil might serve as a promising therapeutic agent to compensate for the podocyte injury in LN.

Curcumin Compensates GLP-1 Deficiency via the Microbiota-Bile Acids Axis and Modulation in Functional Crosstalk between TGR5 and FXR in ob/ob Mice.

SCOPE: Glucagon-like peptide-1 (GLP-1) deficiency occurs in obesity-related pathologies due to defects in the intestinal lumen. And expanding the L-cell population has emerged as a promising avenue to elevate GLP-1 secretion to tackle metabolic disorders. Curcumin (Cur), the principal active component of spice turmeric, possesses well-established anti-obesity properties. To clarify, the study investigates whether Cur promotes GLP-1 secretion built upon the L-cell expansion. METHODS AND RESULTS: Cur (60 mg kg-1 ) is administered orally to male ob/ob mice for 8 weeks. Cur ameliorates obesity and impaires glucose tolerance through increasing energy expenditure in ob/ob mice, accompanied by the maintenance of crypt architecture and gut permeability. It refines the microbial structure and bile acid (BA) profiles, resulting in deoxycholic acid (DCA) accumulation by weakening the enrichment of Lactobacillus. Further analyses show radically different properties of Cur on the intestine function of TGR5 and FXR (i.e., activation and repression). Cur amplifies L-cell number to promote GLP-1 secretion in ob/ob mice. CONCLUSIONS: The findings suggest that Cur may act as a natural TGR5 agonist and FXR antagonist to improve obesity by enhancing GLP-1 release from L-cell expansion via the gut microbiota-BAs-TGR5/FXR axis, and it may serve as a promising therapeutic agent to compensate obesity-related metabolic disorders.

Jieduquyuziyin prescription enhances CD11a and CD70 DNA methylation of CD4+ T cells via miR-29b-sp1/DNMT1 pathway in MRL/lpr mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Jieduquyuziyin prescription (JP) is a traditional Chinese medicine utilized to treat systemic lupus erythematosus (SLE). Its efficacy has been confirmed through clinical trials and empirical evidence, leading to its authorized use in Chinese hospitals. The development of JP exemplifies the integration of traditional wisdom and scientific approaches, demonstrating the interdisciplinary essence of ethnopharmacology. These results emphasize the potential value of traditional medicine in addressing autoimmune disorders. AIM OF THE STUDY: This study aims to address the effect of JP in MRL/lpr mice and elucidate the pharmacological mechanism by which JP targets CD11a and CD70 DNA methylation via the miR-29b-sp1/DNMT1 pathway. MATERIALS AND METHODS: MRL/lpr mice were divided into three groups: the model group (received distilled water), the positive group (administered AAV/miR-29b-3p inhibitor), and the JP group (treated with JP decoction). C57BL/6 mice were constituted as a control group. Through ELISA assay, serum and urine samples were assessed for anti-dsDNA, TNF-α, TGF-ß, IL-2, and UP. HE and Masson staining were conducted to reveal renal pathology. Genome DNA was extracted from CD4+ T cells of mice spleens to evaluate methylation level. The methylation of CD11a, CD70, and CD40L promoter regions was analyzed by targeted bisulfate sequencing. Their expression at the mRNA and protein levels was examined using quantitative real-time PCR, western blot analysis, immunohistochemistry, and immunofluorescence staining of kidney tissues. Furthermore, the molecular mechanisms underlying the regulation of the miR-29b-sp1/DNMT1 pathway by JP were explored with Jurkat cells transfected with miR-inhibitors or miR-mimics. RESULTS: Mice treated with JP exhibited a significant decrease in anti-dsDNA, TNF-α, TGF-ß, and UP, accompanied by a significant increase in IL-2. HE staining revealed JP effectively mitigated renal inflammatory response, while Masson staining indicated a reduction in collagen fiber content. In addition, JP exhibited a significant impact on the global hypomethylation of SLE, as evidenced by the induction of high methylation levels of CD11a and CD70 promoter regions, mediated through the miR-29b-sp1/DNMT1 pathway. CONCLUSION: Our findings demonstrate JP exerts a protective effect against spontaneous SLE development, attenuates renal pathological changes, and functions as a miRNA inhibitor to enhance CD11a and CD70 DNA methylation through the modulation of the miR-29b-sp1/DNMT1 pathway.

Systemic lupus erythematosus and the risk of cardiovascular diseases: A two-sample Mendelian randomization study.

Background: Previous observational studies have suggested that the causal role of systemic lupus erythematosus (SLE) in the risk of cardiovascular diseases (CVDs) remained inconsistent. In this study, we aimed to investigate the causal relationship between SLE and CVDs by two-sample Mendelian randomization (MR) analysis. Methods: Genetic instruments for SLE were obtained from a public genome-wide association study (GWAS) with 4,036 patients with SLE and 6,959 controls. Summary statistical data for CVDs, including coronary artery disease (CAD), myocardial infarction (MI), atrial fibrillation (AF), ischemic stroke (IS), and its subtypes, were identified from other available GWAS meta-analyses. The inverse-variance weighted (IVW) method was used as the primary method to estimate the causal effect. The simple- and weighted-median method, MR-Egger method, and MR pleiotropy residual sum and outlier (MR-PRESSO) were provided as a supplement to the IVW method. Besides, we performed sensitivity analyses, including Cochran's Q test, MR-Egger intercept test, and leave-one-out analysis, to evaluate the robustness of the results. Results: A total of 15 single-nucleotide polymorphisms (SNPs) were identified after excluding linkage disequilibrium (LD) and potential confounding factors. According to the IVW results, our MR study indicated that genetically predicted SLE was not causally connected with the risk of CVDs [CAD: odds ratio (OR) = 1.005, 95% confidence interval (CI) = 0.986-1.024, p-value = 0.619; MI: OR = 1.002, 95% CI = 0.982-1.023, p-value = 0.854; AF: OR = 0.998, 95% CI = 0.982-1.014, p-value = 0.795; IS: OR = 1.006, 95% CI = 0.984-1.028, p-value = 0.621; cardioembolic stroke (CES): OR = 0.992, 95% CI = 0.949-1.036, p-value = 0.707; small vessel stroke (SVS): OR = 1.014, 95% CI = 0.964-1.067, p-value = 0.589; large artery stroke (LAS): OR = 1.030, 95% CI = 0.968-1.096, p-value = 0.352]. Analogical findings could be observed in supplementary MR methods. Sensitivity analyses suggested that the causal estimates were robust. Conclusion: Our two-sample MR analysis provided no evidence that genetically determined SLE was causally associated with the risk of CVDs.

Ginsenoside compound K increases glucagon-like peptide-1 release and L-cell abundance in db/db mice through TGR5/YAP signaling.

BACKGROUND: Incretin impairment refers to L-cell-derived glucagon-like peptide-1 (GLP-1) deficiency, commonly observed in patients with type 2 diabetes mellitus (T2DM). Promoting the enteroendocrine L-cell population to elevate GLP-1 secretory capacity represents a potential therapeutic strategy for T2DM. It has been established that ginsenoside compound K (CK) could stimulate GLP-1 secretion; however, the underlying mechanisms remain elusive. METHODS: CK was intragastrically administered to male db/db mice for 4 weeks that subsequently underwent oral glucose tolerance testing. Serum samples were collected to measure the GLP-1 secretion, insulin level, inflammatory factors, and bile acid (BA) profiles. Ileum epithelial injury was detected by Hematoxylin and Eosin (H&E) and Masson staining. Gene markers associated with L-cell differentiation were evaluated by RT-PCR, and L-cells were labeled by Gcg via immunofluorescence assays. TGR5 and YAP expression was analyzed by immunoblotting and immunofluorescence assays. RESULTS: Compound K attenuated hyperglycemia and inflammation in db/db mice and upregulated TGR5 expression by increasing lithocholic acid (LCA) and deoxycholic acid (DCA) levels in response to ileum epithelium injury. Meanwhile, fibrosis was alleviated, and the crypt architecture was restored, with increased L-cell abundance and serum GLP-1 levels. The upregulation in genes associated with L-cell differentiation promoted transformation into L-cells. Further mechanistic analyses showed that the effects of CK on the L-cell population required YAP activation, which triggered actin cytoskeleton dynamics. CONCLUSIONS: Our results indicate that TGR5 could modulate the abundance of L-cells to enhance GLP-1 release through YAP-driven intestinal regeneration in db/db mice. Accordingly, CK has huge prospects for application to alleviate incretin impairment in T2DM.

Compound K attenuates hyperglycemia by enhancing glucagon-like peptide-1 secretion through activating TGR5 via the remodeling of gut microbiota and bile acid metabolism.

Background: Incretin impairment, characterized by insufficient secretion of L-cell-derived glucagon-like peptide-1 (GLP-1), is a defining step of type 2 diabetes mellitus (T2DM). Ginsenoside compound K (CK) can stimulate GLP-1 secretion; however, the potential mechanism underlying this effect has not been established. Methods: CK (40 mg/kg) was administered orally to male db/db mice for 4 weeks. The body weight, oral glucose tolerance, GLP-1 secretion, gut microbiota sequencing, bile acid (BA) profiles, and BA synthesis markers of each subject were then analyzed. Moreover, TGR5 expression was evaluated by immunoblotting and immunofluorescence, and L-cell lineage markers involved in L-cell abundance were analyzed. Results: CK ameliorated obesity and impaired glucose tolerance in db/db mice by altering the gut microbiota, especially Ruminococcaceae family, and this changed microbe was positively correlated with secondary BA synthesis. Additionally, CK treatment resulted in the up-regulation of CYP7B1 and CYP27A1 and the down-regulation of CYP8B1, thereby shifting BA biosynthesis from the classical pathway to the alternative pathway. CK altered the BA pool by mainly increasing LCA and DCA. Furthermore, CK induced L-cell number expansion leading to enhanced GLP-1 release through TGR5 activation. These increases were supported by the upregulation of genes governing GLP-1 secretion and L-cell differentiation. Conclusions: The results indicate that CK improves glucose homeostasis by increasing L-cell numbers, which enhances GLP-1 release through a mechanism partially mediated by the gut microbiota-BA-TGR5 pathway. Therefore, that therapeutic attempts with CK might be useful for patients with T2DM.

Physical Activity and Systemic Lupus Erythematosus Among European Populations: A Two-Sample Mendelian Randomization Study.

Background: The causal relationship between physical activity (PA) and systemic lupus erythematosus (SLE) remains uncertain. We aimed to assess the causal effect of PA on SLE by two-sample Mendelian randomization (MR) study. Methods: Summary statistics of SLE were obtained from a genome-wide association study (GWAS) meta-analysis of European descent, including 4,036 cases and 6,959 controls. Genetic instruments for PA, including MVPA, VPA, SSOE, and average acceleration, were identified from a large-scale GWAS meta-analysis among 377,234 individuals of European ancestry from United Kingdom biobank and Atherosclerosis Risk in Communities (ARIC) study, and another GWAS with 91,105 European participants was employed for sedentary behavior. The two-sample MR study was conducted to estimate causal relationship between PA and SLE, with the inverse-variance weighted (IVW) method, simple- and weighted-median method. Moreover, MR-Egger regression, MR-PRESSO and leave-one-out analysis were performed to evaluate the potential pleiotropy effect. Results: In the end, we totally selected 37 SNPs (15 SNPs for MVPA, 5 SNPs for VPA, 9 SNPs for SSOE, 5 SNPs for average acceleration and 3 SNPs for sedentary behavior). According to the IVW results, as the primary method, we found that genetically predicted PA was not causally associated with risk of SLE (MVPA: OR 0.44, 95% CI 0.09-2.10, p = 0.305; VPA: OR 0.20, 95% CI 0.00-18.97, p = 0.490; SSOE: OR 0.96, 95% CI 0.03-29.24, p = 0.983; average acceleration: OR 0.91, 95% CI 0.79-1.05, p = 0.190; sedentary behavior: OR 1.54, 95% CI 0.35-6.81, p = 0.572). MR-Egger, MR-PRESSO, and leave-one-out analysis did not indicate horizontal pleiotropy. Conclusions: Our MR study suggested that genetically predicted PA was not causally associated with SLE among the European populations.