The role of bile acid metabolism within the skeletal muscle microenvironment in sarcopenia remains unclear. This study investigated bile acid alterations and the function of the ATP Binding Cassette Subfamily B Member 1 (ABCB1) transporter in muscle microvascular endothelial cells (MMECs) during aging. Using a sarcopenic mouse model stratified by muscle density, we found elevated deoxycholic acid (DCA) and lithocholic acid (LCA) levels but reduced tauroursodeoxycholic acid (TUDCA) levels in muscle, correlating with downregulated ABCB1/P-glycoprotein expression. In vitro, inhibition of ABCB1 in MMECs impaired bile acid efflux, promoted inflammation, and compromised endothelial health. Conditioned medium from these MMECs reduced the viability, proliferation, and differentiation of C2C12 myoblasts, downregulated myogenic factors, and increased atrophy markers. Furthermore, we identified miR-135a-5p as a direct upstream regulator of ABCB1 in MMECs, and demonstrated that it mediates bile acid efflux impairment and subsequent myoblast dysfunction. Our findings reveal a novel "bile acid-MMEC-muscle" axis in sarcopenia, where miR-135a-5p-mediated ABCB1 downregulation in MMECs disrupts the local bile acid milieu and impairs muscle regeneration, highlighting ABCB1 as a potential therapeutic target for aging-related muscle loss.

BACKGROUND AND PURPOSE:Acetaminophen (APAP)-induced hepatotoxicity represents a critical medical emergency due to the rapid progression. To date, practical and feasible early interventions are limited. This study aimed to explore whether farnesoid X receptor (FXR, NR1H4) alleviates APAP-induced acute liver injury and whether this effect is mediated by fibroblast growth factor 2 (FGF2) activation to promote liver regeneration. METHODS:The difference in FXR expression between healthy subjects and patients with APAP-induced acute liver injury was analyzed through the Gene Expression Omnibus (GEO) database. The adeno-associated virus-8-mediated FXR (AAV-FXR) was injected through the tail vein into mice to establish the mouse FXR-overexpressed model. pcDNA-FXR, siFXR or siFGF2 plasmids were transfected into AML-12 cells. H&E staining, quantitative real-time PCR, Western blotting, immunofluorescence staining, DCFH-DA staining, and TUNEL staining were applied to determine the effects of FXR and FGF2. RESULTS:FXR was significantly reduced in hepatic tissues of patients with APAP-induced acute liver injury compared to normal hepatic tissues. FXR overexpression attenuated APAP-induced liver injury by inhibiting inflammation, oxidative stress and apoptosis, while promoting liver regeneration. Furthermore, FXR overexpression upregulated FGF2 expression, and its pro-regenerative effect against APAP-induced acute liver injury is dependent on FGF2. In contrast, FXR or FGF2 knockdown resulted in opposite effects. CONCLUSIONS:FXR alleviated APAP-induced acute liver injury by mitigating inflammation, oxidative stress and apoptosis, as well as promoting liver regeneration. This pro-regenerative effect of FXR is dependent on FGF2 activation.

BACKGROUND:Brusatol (BRU), a major bioactive quassinoid isolated from Brucea javanica, has shown potential in the treatment of inflammatory diseases. As mitochondrial dysfunction has been implicated in chronic inflammatory disorders, modulation of mitochondrial homeostasis may offer a potential approach for the treatment of rheumatoid arthritis (RA) and atherosclerosis (AS). PURPOSE:To develop a novel BRU derivative through rational modification at the C11‑hydroxyl group and to compare the therapeutic effects of BRU and its derivative BRUD in experimental models of RA and AS, with particular focus on mitochondrial regulation and Drp1-associated signaling. STUDY DESIGN:This study combined in vivo and in vitro experiments to evaluate the pharmacological effects of BRU and BRUD and investigate the underlying mechanisms. METHODS:The chemical constituents of BRU and BRUD were confirmed by HPLC and NMR spectroscopy (1H and 13C). Their effects were evaluated in vivo using collagen-induced arthritis (CIA) rats and apolipoprotein E-deficient (ApoE-/-) mice, and in vitro using RA fibroblast-like synoviocytes (RA-FLS), as well as IL-8-stimulated normal endothelial cells (ECs) and smooth muscle cells (SMCs). Cell viability, apoptosis, migration, invasion, adhesion, and tube formation assays were performed to assess cellular responses. Histological, biochemical, flow cytometric, confocal imaging, Western blot, molecular docking/molecular dynamics, surface plasmon resonance (SPR), and Drp1 overexpression rescue assays were performed to assess disease phenotypes, mitochondrial alterations, and Drp1-associated signaling. RESULTS:In vivo studies demonstrated that both compounds ameliorated joint damage in CIA rats and reduced atherosclerotic lesion burden in ApoE-/- mice. In vitro, BRUD more effectively inhibited pathogenic FLS activation than BRU, and restored normal EC and SMC function. Mechanistically, the stronger activity of BRUD was associated with attenuation of Drp1-related mitochondrial fission, accompanied by reduced mtROS levels and restoration of ΔΨm. CONCLUSIONS:These findings suggest that BRUD exhibits improved activity compared with BRU in RA and AS models, with protective effects associated with modulation of mitochondrial dysfunction, supporting its further evaluation as a lead compound.

Alcoholic liver disease (ALD) continues to put forward a significant challenge to global public health, however up to date, effective therapeutic targets have yet to be elucidated. Although farnesoid X receptor (FXR) is recognized as a master regulator of hepatic metabolic homeostasis, its involvement in the pathogenesis of ALD has not been fully elucidated. This study aimed to investigate the effects of FXR overexpression on ethanol-induced liver injury and to explore whether its hepatoprotective mechanism involves the inhibition of the PERK–CHOP pathway. An experimental model of FXR overexpression was established in mice via tail vein injection of the lentiviral vector encoding FXR. Morphological alterations were examined by H&E and Oil Red O staining. Key indicators including endoplasmic reticulum (ER) stress-associated proteins (GRP78, p-PERK, ATF4, CHOP), oxidative stress (ROS, MDA, SOD), and apoptosis (Bax, Bcl-2) were analyzed using qRT-PCR, Western blot and immunofluorescence. The results indicated that ethanol exposure provoked significant hepatic injury, as reflected by a marked elevation in ALT and AST, widespread microvesicular steatosis, and a significant increase in apoptotic hepatocytes. These pathological changes were accompanied by robust activation of the PERK–CHOP signaling pathway, as evidenced by the increased expression of GRP78, p-PERK, ATF4, CHOP. In contrast, targeted overexpression of FXR profoundly attenuated the severity of ethanol-induced liver injury. Mechanistically, FXR overexpression effectively suppressed the activation of the PERK–CHOP pathway. This inhibitory effect translated into a marked reduction in ER stress markers, restoration of antioxidant defenses (evidenced by diminished ROS and MDA alongside recovered SOD activity), and a significant decrease in hepatocyte apoptosis. In conclusion, FXR overexpression confers substantial protection against ALD. This beneficial effect is achieved primarily through the suppression of the PERK–CHOP pathway, which in turn alleviates ER stress, oxidative injury and hepatocyte apoptosis.

BACKGROUND:Double negative B (DNB) cells are a subset of mature B cells which does't express IgD and CD27 on surface. It is significantly expanded in various inflammatory related diseases. However, roles of DNB cells in atherosclerosis still remain unclear. Our objective is to evaluate the association between DNB cells and atherosclerosis and its severity. METHODS:A total of 138 patients who visited the Second Hospital of Dalian Medical University from June 2024 to December 2024 due to chest tightness and pain were enrolled. According to the results of coronary angiography examination, patients were divided into coronary heart disease (CHD) group and non-CHD group. The proportion of DNB cells in peripheral blood was detected using flow cytometry. Logistic regression and receiver operator characteristic (ROC) curve were utilized to explore the predictive value of the proportion of DNB cells for CHD and its severity. Moreover, atherosclerotic mice models were further constructed to explore the correlation between the proportion of DNB cells and atherosclerosis. To further reveal the potential mechanism, DNB cells were sorted for transcriptome sequencing analysis. RESULTS:Comparing with the non-CHD group, patients in the CHD group had a higher proportion of DNB cells (13.76 ± 5.48vs.7.58 ± 2.84, P < 0.001). Logistic regression model showed that the proportion of DNB cells was an independent risk factor for CHD (OR:1.455, 95%CI:1.224-1.730). ROC curve indicated that the proportion of DNB cells had favor predictive value for CHD, better than hsCRP (high sensitivity C-reactive protein) (0.859 vs. 0.699). Our above findings were further validated in animal models. Comparing with the control group, the proportion of DNB cells in peripheral blood and spleen of atherosclerosis mice was increased and positively correlated with plaque area, blood lipids and inflammatory cytokines levels. GO and KEGG enrichment analyses revealed significant enrichment of inflammation- and chemokine-related pathways, with IL-6 participating in the greatest number of inflammatory cascades. Notably, CXCR4, which was strongly correlated with IL-6, may modulate IL-6 secretion via the MAPK and NF-κB signaling axes. CONCLUSIONS:DNB cells correlate with atherosclerosis severity, potentially via CXCR4/IL6-mediated inflammation. Underlying mechanisms require further elucidation.

BACKGROUND:Alcoholic liver disease (ALD) represents a major risk that threatens human health worldwide and lacks effective therapies. Alcohol-induced inflammation and oxidative stress can trigger and aggravate liver steatosis and promote the development of diseases such as alcoholic liver fibrosis without effective treatment. Bruceine A (BA), a compound extracted from traditional Chinese medicine Brucea javanica, exhibits various activities in multiple diseases. PURPOSE:This study aimed to investigate the hepatoprotective effect of BA and its underlying mechanism involving the farnesoid X receptor (FXR) / forkhead box A2 (FOXA2) pathway. STUDY DESIGN AND METHODS:Here, a mouse model of ALD was established with a Lieber-DeCarli liquid diet including 5% ethanol (v/v). Molecular dynamics simulations and cellular thermal shift assay (CETSA) were performed to assess the binding of BA to FXR. Chromatin immunoprecipitation-qPCR (ChIP-qPCR) and dual-luciferase reporter assays were performed to examine the transcriptional regulation of FOXA2 by FXR. RESULTS:The results showed that BA alleviated ethanol-induced liver injury and lipid accumulation, and reduced oxidative stress. BA exhibited affinity for FXR and attenuated ethanol-induced FXR inactivation. FXR bound to the promoter fragments of FOXA2 and enhanced its transcriptional activity and positively affected the expression level of FOXA2. Silencing FOXA2 attenuated the protective effect of BA against hepatic lipid deposition and oxidative stress in vitro. CONCLUSION:We first demonstrated that RBA could alleviate ALD, and further verified that RBA exerted protective effects through modulating FXR-FOXA2-mediated lipid metabolism and oxidative stress in vivo and in vitro.

Background: Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by the presence of pathogenic autoantibodies and a substantial influx of immune cells into skin lesions. However, the role of eosinophils in BP remains inadequately elucidated. Objective: We sought to determine the pathologic involvement of eosinophils and eosinophil extracellular traps (EETs) in BP. Methods: Human samples collected from BP patients and healthy controls were utilized to explore the potential role of eosinophils and their EETs in BP patients through serologic detection, flow cytometry, and immunofluorescence. Naive CD4+ T cells isolated from healthy donors were stimulated and subjected to further analysis via RNA sequencing. We additionally evaluated the potential of targeting EETs in BP180immunized BP-like mice and in in vitro settings. Results: We found that elevated levels of eosinophils and EETs in BP patients correlated with disease severity. The DNA components within EETs played a crucial role in driving the differentiation of naive CD4+ T cells into follicular helper T (Tfh) cells by activating coil domains containing 25 (CCDC25). Treatment with DNase I, which disrupts the structural integrity of EETs, or neutralizing antibody against CCDC25 reduced the expansion of Tfh cells and suppressed the production of autoantibodies in BP180-immunized BP-like mouse models. Additionally, we discovered that EETs induced the N6-methyladenosine methylation of the transcription factor musculoaponeurotic fibrosarcoma (MAF) via the DNACCDC25-VIRMA pathway, thereby enhancing its mRNA stability and promoting Tfh cell differentiation. Conclusion: Our study revealed a previously unrecognized mechanism by which EETs trigger abnormal Tfh cell differentiation through CCDC25, followed by Vir-like m6A methyltransferase-associated protein (VIRMA)-mediated N6-methyladenosine modification of MAF. These insights provide promising avenues for the development of targeted therapeutic interventions in the field of BP and potentially other autoimmune diseases.

Cholestasis, a major driver of liver disease progression, is characterized by toxic bile acid accumulation due to impaired bile flow, potentially leading to hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. To date, the pathogenesis of cholestasis has remained incompletely understood. In the present study, we investigated the role of farnesoid X receptor (FXR) in modulating the NLR family CARD domain-containing protein 4 (NLRC4) inflammasome activity using in vitro (AML-12 hepatocytes) and in vivo (C57BL/6 mice) models of lithocholic acid (LCA)-induced cholestasis. LCA suppressed FXR expression, downregulated bile acid transporters (Bsep, Mrp2, Ntcp), and elevated serum biomarkers of liver injury. Through restored hepatic function by FXR lentiviral vectors, FXR overexpression reduced bile acid accumulation and mitigated inflammation and oxidative stress. In addition, FXR overexpression suppressed bile acid synthesis enzymes (Cyp7a1, Cyp8b1) by upregulating Shp and Fgf15, while enhancing detoxification through Ugt1a1 and Sult2a1. Interestingly, molecular docking analysis and Co-IP experiments demonstrated a direct interaction between FXR and NLRC4. Furthermore, FXR overexpression significantly inhibited NLRC4 inflammasome activation and decreased the expression of NLRC4, caspase-1, IL-1β, and IL-18, thereby attenuating inflammation and oxidative stress. Conversely, FXR knockdown reversed these effects. In addition, to delineate the contribution of NLRC4 inflammasome activation to IL-18 and IL-1β elevation, NLRC4-targeting siRNA-mediated knockdown and NLRC4-encoding plasmid-driven overexpression strategies were systematically employed. Furthermore, DCFH-DA staining was adopted to visualize reactive oxygen species (ROS). In conclusion, for the first time, we found that FXR overexpression alleviates LCA-induced cholestasis by regulating bile acid metabolism and inhibiting NLRC4 inflammasome activation, providing a novel therapeutic strategy for drug development targeting the FXR-NLRC4 axis.

BACKGROUND:Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells (HSCs), characterized by ineffective hematopoiesis and a high risk of progression to acute myeloid leukemia. Elucidating the mechanism underlying the dysfunction of MDS-HSCs is crucial for exploring the pathogenesis of the syndrome. While previous studies have implicated mesenchymal stem cells (MSCs), a principal component of the bone marrow (BM) microenvironment, in the inhibition of normal hematopoiesis, the precise molecular mechanisms have not been fully elucidated. In this study, we investigated the effects of MSCs from MDS patients on hematopoietic functions of HSCs from a metabolic perspective. METHODS:MSCs were isolated from BM of MDS patients. The proliferation, apoptosis, differentiation and support for hematopoiesis of these cells were analyzed using CCK-8 assay, FC and induction medium and CFU (colony forming units) assay, respectively. Expression levels of metabolic molecules were used as indicators to screen MSCs with different metabolic pathways and were detected by RT-PCR and Western blotting. Exosome derived from MSCs were isolated from the culture supernatant and confirmed by Transmission Electron Microscope, Dynamic Light Scattering and Western blotting. The effects of these exosomes on HSCs were analyzed using the same methods as those used to assess MSCs function. RESULTS:Our findings demonstrated that MDS-MSCs exhibited significant functional impairments, including reduced proliferation, impaired differentiation, diminished support for hematopoiesis, and increased apoptosis. Notably, we observed an upregulation of lipid metabolism in these MSCs, which appears to contribute to their dysfunction. Intriguingly, the aberrant lipid metabolic profile can be effectively reversed by the administration of etomoxir (ETO), an inhibitor of carnitine palmitoyltransferase 1A (CPT-1A). Furthermore, MSCs with enhanced lipid metabolism could transmit this dysfunction to HSCs through the secretion of exosomes that are enriched in CPT-1A. CONCLUSIONS:We suggest that the MDS BM microenvironment disrupts MSCs metabolism by increasing the expression of CPT-1A, which impairs the ability to support normal HSCs. Interestingly, the suppressive effect is mediated by exosomes rich in CPT-1A, which derived from MSCs. These findings provide novel insights into MDS MSCs-metabolism-Exosome axis in ineffective hematopoiesis and offer new strategies for the treatment of MDS.

Metabolic Syndrome (MetS), as a syndrome characterized by low-grade inflammation and energy metabolism disorders, is considered to be an important systemic risk factor for knee osteoarthritis (KOA). Our previous study showed that the protein level of serum resistin was positively correlated with the degree of metabolic disorder in MetS-OA. However, whether Resistin promotes the progression of KOA synovitis and the underlying mechanisms remain unclear. This study mainly investigateswhether there were metabolism disorder which promote inflammatory and catabolic phenotype in fibroblast-like synoviocytes (FLS) from KOA patients with MetS (MetS-KOA-FLS), and the roles and mechanisim of resistin in MetS-KOA-FLS. Comparative analysis of synovium and FLS from MetS-associated KOA (MetS-KOA) and non-MetS-associated KOA (nMetS-KOA) of females to detect the differences in inflammation, catabolism and glycolipid metabolism. Serum from MetS-KOA stimulated nMetS-KOA-FLS to detect the effect of MetS microenvironment on inflammation, catabolism and glycolipid metabolism of nMetS-KOA-FLS. Resistin stimulated MetS-KOA-FLS to explore the effect of resistin on inflammation and catabolism of MetS-KOA-FLS and its specific mechanism. Compared with nMetS-KOA-FLS, MetS-KOA-FLS expressed higher inflammatory related factors, catabolic enzymes, and showed stronger adhesive and invasive ability. Resistin was found to be an important factor in the serum and internal environment of MetS-KOA patients, and it mediated the differences in fatty acid oxidation (FAO) between the two groups. Resistin activated the PKA/CREB pathway through CAP1 and upregulated FAO, promoting the inflammatory and catabolic phenotype of MetS-KOA-FLS. This study clarifies the mechanism by which MetS causes synovitis from a metabolic perspective and provides new ideas for further research and treatment of MetS-KOA.

Cholestasis arises as a clinical syndrome triggered by the accumulation and aggregation of bile acids. Currently, there are only a few treatment options available for cholestasis. Therefore, it is necessary to explore novel therapeutic strategies. β-sitosterol (SIT), the phytosterol most abundantly found in plants, exhibits diverse pharmacological activities. This study examined SIT's protective role against hepatotoxicity and cholestasis induced by lithocholic acid (LCA). LCA was administered twice a day to male C57BL/6 mice for four days to cause hepatotoxicity and cholestasis. Assessment of the improvement in cholestasis following SIT treatment used H&E staining and serum biomarkers. Mice hepatocyte culture, real-time PCR, immunofluorescence staining, and Western blot were utilized to clarify the mechanisms of SIT hepatoprotection. Furthermore, molecular docking and dual-luciferase reporter gene analysis were utilized to show that SIT would activate the farnesoid X receptor (FXR). In vivo, SIT reduced bile acid accumulation by inducing the bile salt export pump (Bsep), multidrug resistance-related protein 2 (Mrp2), and reduced hepatic uptake of bile acids by inhibiting Na+/taurocholate co-transporting polypeptide (Ntcp), and cholesterol 7α-hydroxylase (Cyp7a1) and oxysterol 12α-hydroxylase (Cyp8b1) while in vitro, it restored FXR expression and transcriptional activity. Besides, SIT decreased hepatic inflammation by suppressing the inflammatory genes NF-κB p65 and p-NF-κB p65, TNF-α, IL-6, and IL-1β. However, the hepatoprotective effects of SIT were abolished by the FXR antagonist guggulsterone in vivo and FXR siRNA in vitro, confirming FXR-dependent mechanisms. In conclusion, SIT protects against LCA-induced hepatotoxicity and cholestasis via FXR activation. These findings highlight SIT as a promising therapeutic candidate for cholestasis.

Mitochondria, as the “energy factories” of cells, are vital for maintaining cell life and function. Mitochondria are highly mobile organelles within cells, constantly changing their morphology through fusion and fission processes to achieve dynamic transitions between interconnected network structures and fragmented states. This phenomenon is known as mitochondrial dynamics. Disorders in mitochondrial dynamics contribute to the onset of autoimmune conditions such as rheumatoid arthritis, multiple sclerosis, myasthenia gravis, and systemic lupus erythematosus, among others. This article aims to review the roles of mitochondrial dynamics disorders in autoimmune diseases and small molecule drugs targeting mitochondrial dynamic proteins, with the ultimate goal of aiding the development of new clinical treatments.

Mesenchymal stem cells (MSCs) are widely used in treating autoimmune diseases. However, replicative senescence limits the quantity and quality of MSCs during population doublings in vitro. Transcription factor SOX4 is a crucial regulator of cell fate and stemness. This study aims to explore the role of SOX4 in senescence of MSCs and enhance their therapeutic efficacy in systemic lupus erythematosus (SLE). In early-passage MSCs (P3), late-passage MSCs (P8), SOX4 downregulated P3-MSCs or SOX4 overexpressed P8-MSCs, cell morphology, mitochondrial reactive oxygen species (mtROS), senescence-associated β-galactosidase (SA-β-Gal) activity, cell proliferation rate, senescence-associated secretory phenotype (SASP) factors, cell cycle suppressors, the immunosuppressive effects on T cell activation and proliferation and the expression levels of SOX4 were determined. Imiquimod induced SLE mice were transplanted with P3-MSCs and P8-MSCs or control and SOX4 overexpressed P8-MSCs, and clinical symptoms were assessed. Compared to P3-MSCs, P8-MSCs display a senescent phenotype, increased mtROS, SA-β-Gal activity, SASP factors, and cell cycle suppressors p53, p21, and p16. Additionally, P8-MSCs have a reduced immunosuppressive function on T cell activation and proliferation, and express lower levels of SOX4. Downregulation of SOX4 in P3-MSCs promotes cellular senescence and impairs their immunosuppressive function. Conversely, overexpression of SOX4 in P8-MSCs ameliorates cellular senescence and enhances their immunosuppressive function. Furthermore, transplantation of P3-MSCs or SOX4-overexpressing P8-MSCs demonstrates greater therapeutic significantly efficacy in SLE mice compared to P8-MSCs. Taken together, these findings suggest that downregulation of SOX4 induces senescence in MSCs and impairs their immunosuppressive function. Targeting SOX4 in MSCs may therefore represent a promising therapeutic approach for the treatment of SLE.

The malignant transformation risk and high misdiagnosis rate of discoid lupus erythematosus (DLE) render it an urgent necessity to deeply explore its pathogenesis and biomarkers. This research, through the combined analysis of transcriptome data and single-cell sequencing data, commencing from the highly infiltrated T cells in DLE and the significant inflammation and cytokine correlation manifested by T cells, undertakes re-clustering analysis of T cells and identifies the stress response state T cells (TSTR) that are abundantly infiltrated in the dermis of DLE. Furthermore, by screening for the common genes among the differentially expressed genes in the transcriptome, the differentially expressed genes of T cells in single-cell sequencing, and the key module genes in WGCNA, CXCL13, GNLY, IFI6, IFI27, IFI44, IFI44L, MX1, and TIGIT are ultimately extracted as the key disease genes of DLE, and these genes are closely associated with the mechanism regulating T cell function. Specifically, through supplementary validation of gene expression using the psoriasis dataset, the distinctively high expression characteristics of CXCL13 and GNLY in DLE were revealed, thereby corroborating their central status as characteristic markers of DLE.

BackgroundSystemic inflammation, immune and nutrition status are closely linked to the occurrence and development of coronary heart disease (CHD). Pan-immune-inflammation value (PIV) is a new method for evaluating systemic inflammation and immune status. Our objective is to explore the connection between PIV and CHD especially in elderly people, as well as the diagnostic value of PIV combined with controlling nutritional status (COUNT) score for CHD.MethodsParticipants eligible for the study were sourced from NHANES data from 1999 to 2018. Logistic regression models were employed to evaluate the link between PIV and CHD. Additionally, restricted cubic spline was utilized to explore the correlations. Subgroup analysis was adopted in order to ensure the credibility of the results. The receiver operator characteristic (ROC) curve was used to explore the predictive value of PIV combined with COUNT score for CHD.Results41,713 individuals qualified for analysis. The individuals with CHD had higher levels of PIV. In the logistic regression model, PIV was positively related to CHD [Q4 vs. Q1, OR = 1.23 (1.03–1.48, P < 0.001)]. Restricted cubic spline indicated a positive non-linear relationship (P for overall <0.001, P for non-linear = 0.009). However, restricted cubic spline shows that this positive correlation is only significant in the elderly population aged 60 and above. Subgroup analysis shows that the relationship between PIV and CHD is more significant in the elderly population (P < 0.001). The ROC curve shows that PIV has better diagnostic value for CHD than other common inflammatory indicators. Furthermore, the combination of PIV and COUNT score is superior to PIV or COUNT score.ConclusionsA positive link between PIV and CHD, especially in the elderly. The combination of PIV and COUNT score has better diagnostic value for CHD.

Nail-patella syndrome (NPS; OMIM #161200) is an autosomal dominant disorder characterized by developmental defects in dorsal limb structures, kidneys, and eyes. The incidence of NPS is attributed to variations in the LMX1B gene. In this report, we present a novel LMX1B variation identified in a Chinese family affected by NPS. The proband, a 15-year-old male, exhibited a history of proteinuria and microscopic hematuria accompanied by renal dysfunction, nail dysplasia, bilateral patellar dysplasia, bilateral shoulder and elbow joint dysplasia and iliac horns. Histological examination revealed mild glomerular lesions. Under electron microscopy, irregular thickening of the glomerular basement membrane was observed, characterized by an appearance resembling occasional electron lucent areas ("moth-eaten" appearance) and the presence of disorganized collagen fiber bundles. Pathological findings were consistent with NPS. Genetic analysis identified a novel heterozygous variant, c.791 A>C, p.(Gln264Pro), in the patient, his father and younger brother. This new variant has been annotated as potentially pathogenic according to the recommendation of the American Society for Medical Genetics and Genomics. This represents the first report of a novel variation in the LMX1B gene. These findings expand the spectrum of variations associated with LMX1B in NPS.

Introduction:The number of circulating follicular helper T (cTfh) and peripheral helper T (Tph) cells is elevated in rheumatoid arthritis (RA), yet the molecular mechanisms mediating their specific contributions to RA pathology remain unclear. In this study, we explored the distinct function of cTfh and Tph cells based on metabolism patterns in RA. Methods:Peripheral CD4+ T cells from RA patients were treated with CXCL13 or CCL2, glycolysis inhibitor 2-DG or mitochondria-targeted antioxidant MitoQ in vitro. Collagen induced arthritis (CIA) mice were treated with 2-DG or MitoQ in vivo. The frequency, transcription factors, functional molecules, cellular senescence, glycolytic activity and mitochondrial ROS (mtROS) of cTfh and Tph cells were assessed. Joint inflammation, CD4+PD-1+ T cells, glycolytic enzymes or IL-1β and IL-6 in ankle joints of CIA mice were detected. Results:We found that in RA patients, in comparison with Tph cells, cTfh cells show higher levels of Bcl6 and BATF, B helper-related molecules, and glycolytic activity. While Tph cells exhibit higher levels of Blimp1 and T-bet, cytotoxicity-related molecules and mtROS, and more significant cellular senescence characteristics. In addition, CXCL13, the ligand for CXCR5, increases the expression of key glycolytic enzymes in RA cTfh cells, while CCL2 increases mtROS in RA Tph cells. 2-DG reduces the expression of B helper-related molecules cells, and MitoQ mitigates cytotoxic activity of cTfh and Tph cells. Both treatments ameliorate RA symptoms and decrease the number of cTfh and Tph cells in CIA mice. Conclusion:Our study suggests that in RA patients, cTfh cells display a more robust B helper-associated function, potentially linked to the CXCL13-CXCR5 axis enhancing glycolysis. Tph cells, on the other hand, show greater cytotoxic activity, possibly due to the CCL2-CCR2 axis increasing mtROS production. Targeting glycolysis or mtROS may offer a novel therapeutic strategy for RA patients.

BackgroundMagnesium is an essential immune nutrient for the body, and recent studies have found that it plays an important role in osteoarthritis (OA). Magnesium depletion score(MDS) is a new method for evaluating the magnesium status of the body. Our objective is to explore the association between MDS and the incidence of OA, as well as the relationship between MDS and mortality in patients with OA.MethodsEligible participants were obtained from NHANES from 2005 to 2018. Logistic regression models were employed to evaluate the link between MDS and the incidence of OA. Cox regression models were employed to evaluate the link between MDS and mortality among OA patients. In addition, restricted cubic spline was utilized to explore the correlation between MDS and the incidence of OA, as well as the relationship between MDS and mortality in patients with OA. Subgroup analysis were adopted in order to ensure the credibility of the results in different subgroups, including age, gender, race, education level, BMI, smoking, diabetes and hypertension.Results19,394 individuals qualified for analysis, including 3,256 OA patients. After excluding missing follow-up data, 630 all-cause deaths and 172 cardiovascular deaths (CVDs) were observed in 3,250 OA patients. The individuals with OA had higher levels of MDS. In the logistic regression model, MDS was positively related to OA (MDS≥3 vs. MDS=0, OR =1.83 (1.46-2.30, P<0.001)). Besides, a positive association was observed between MDS and all-cause mortality [MDS≥3 vs. MDS=0, HR =2.56 (1.49-4.41, P<0.001)] and CVDs [MDS≥3 vs. MDS=0, HR =3.00 (1.13-7.98, P=0.01)] in cox regression models. In addition, a 1-unit rise in MDS was significantly linked to an increased risk of mortality. Restricted cubic spline indicated a positive relationship between MDS and incidence and mortality of OA. Subgroup analysis demonstrated that the results are stable in different subgroups.ConclusionsMDS is positively correlated with the incidence and mortality of OA. Optimizing the nutritional status of magnesium may bring benefits to OA patients.