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Though significant correlations between rheumatoid arthritis (RA) and hypothyroidism have been found in earlier observational studies, their underlying causal relationship is still unknown. Mendelian randomization (MR) was used in the current study to assess the bidirectional causation between RA and hypothyroidism. We gathered summary data from genome-wide association studies (GWASs) of RA and hypothyroidism in people of European descent. Then, using data from the FinnGen consortium, we replicated our findings. Three approaches were employed to assess the causal link between RA and hypothyroidism: MR-Egger, weighted median (WM), and inverse variance weighted (IVW). The pleiotropy and heterogeneity were examined using a variety of techniques, including the MR-Egger intercept, the MR-PRESSO approach, the leave-one-out method, and the Cochran's Q test. The study looked at a bidirectional incidental relationship between RA and hypothyroidism. The risk of hypothyroidism increased with RA (IVW odds ratio (OR) = 1.28, 95% confidence interval (CI) = 1.18-1.39, = 8.30E-10), as did the risk of secondary hypothyroidism (IVW OR = 1.12, 95% CI = 1.05-1.21, = 9.64E-4). The results of reverse MR analysis revealed that hypothyroidism (IVW OR = 1.68, 95% CI = 1.51-1.88, = 4.87E-21) and secondary hypothyroidism (IVW OR = 1.74, 95% CI = 1.50-2.01, = 1.91E-13) were linked to an increased risk of RA. Additionally, we obtain the same results in the duplicated datasets as well, which makes our results even more reliable. This study revealed no evidence of horizontal pleiotropy. The present study established a bidirectional causal link between RA and hypothyroidism. However, it differs slightly from the findings of prior observational studies, suggesting that future research should concentrate on the interaction mechanisms between RA and hypothyroidism.

Data sharing has become a transformative force in the global financial ecosystem, driving the evolution from open banking to open finance. In this study, we develop a diffusion model using evolutionary game theory on complex networks to explore how data sharing influences lenders’ micro-level decision-making and promotes the macro-level diffusion of open finance. Combined with empirical observations from China’s open banking initiatives, our findings reveal that the diffusion rate of open finance remains suboptimal, with lenders adopting open finance not yet realizing significant profit advantages over traditional practices. Furthermore, sensitivity tests performed through univariate analysis show that increasing either the proportion of data sharing active borrowers or their degree of data sharing plays a critical role in accelerating open finance diffusion, following distinct nonlinear exponential and linear growth trends, respectively. Notably, data sharing active borrowers dominating the market benefit from the inclusivity of open finance, where lenders’ profits are enhanced with a higher degree of data sharing. Thus, a mutually beneficial outcome arises when both the proportion of data sharing active borrowers and their degree of data sharing are maximized. We further perform several analyses to highlight the robustness of our main results, including analyzing the effects of lender strategy updates and government subsidies and extending a hybrid model that combines small-world and scale-free networks. This article suggests that policymakers should mandate secure data sharing ecosystems through privacy-centric regulation while implementing incentives like early adopter subsidies to accelerate open finance diffusion. Financial institutions must concurrently develop robust data guardianship systems using advanced encryption and federated learning technologies, transforming shared data into personalized credit innovations. These findings offer global implications, demonstrating how strategic data sharing frameworks can drive financial innovation, financial inclusion, and consumer protection across diverse regulatory regimes.

Background Fibroblast growth factor 21 (FGF21) is a promising candidate for treating metabolic disorder diseases and has been used in phase II clinical trials. Currently, metabolic diseases are prevalent worldwide, underscoring the significant market potential of FGF21. Therefore, the production of FGF21 must be effectively improved to meet market demand. Results Herein, to investigate the impact of vectors and host cells on FGF21 expression, we successfully engineered strains that exhibit a high yield of FGF21. Surprisingly, the data revealed that vectors with various copy numbers significantly impact the expression of FGF21, and the results showed a 4.35-fold increase in expression levels. Furthermore, the performance of the double promoter and tandem gene expression construction design surpassed that of the conventional construction method, with a maximum difference of 2.67 times. Conclusion By exploring engineered vectors and host cells, we successfully achieved high-yield production of the FGF21 strain. This breakthrough lays a solid foundation for the future industrialization of FGF21. Additionally, FGF21 can be easily, quickly and efficiently expressed, providing a better tool and platform for the research and application of more recombinant proteins.

Cancer therapy-related cardiovascular toxicity (CTR-CVT) is now recognised as one of the leading causes of long-term morbidity and mortality in cancer patients. To date, potential overlapping cardiotoxicity mechanism(s) across different chemotherapeutic classes have not been elucidated. Doxorubicin, an anthracycline, and Carfilzomib, a proteasome inhibitor, are both known to cause heart failure in some patients. Given this common cardiotoxic effect of these chemotherapies, we aimed to investigate differential and common mechanism(s) associated with Doxorubicin and Carfilzomib-induced cardiac dysfunction. Primary human cardiomyocyte-like cells (HCM-ls) were treated with 1 µM of either Doxorubicin or Carfilzomib for 72 h. Both Doxorubicin and Carfilzomib induced a significant reduction in HCM cell viability and cell damage. DNA methylation analysis performed using MethylationEPIC array showed distinct and common changes induced by Doxorubicin and Carfilzomib (10,270 or approximately 12.9% of the DMPs for either treatment overlapped). RNA-seq analyses identified 5,643 differentially expressed genes (DEGs) that were commonly dysregulated for both treatments. Pathway analysis revealed that the PI3K-Akt signalling pathway was the most significantly enriched pathway with common DEGs, shared between Doxorubicin and Carfilzomib. We identified that there are shared cardiotoxicity mechanisms for Doxorubicin and Carfilzomib pathways that can be potential therapeutic targets for treatments across 2 classes of anti-cancer agents.

Background Androgen receptor (AR) signalling is critical to the initiation and progression of prostate cancer (PCa). Transcriptional activity of AR involves chromatin recruitment of co-activators, including the p300/CBP-associated factor (PCAF). Distinct miRNA expression profiles have been identified in PCa cells during the development and progression of the disease. Whether miRNAs regulate PCAF expression in PCa cells to regulate AR transcriptional activity is still unclear. Methods Expression of PCAF was investigated in several PCa cell lines by qRT-PCR, Western blot, and immunocytochemistry. The effects of PCAF expression on AR-regulated transcriptional activity and cell growth in PCa cells were determined by chromatin immunoprecipitation, reporter gene construct analysis, and MTS assay. Targeting of PCAF by miR-17-5p was evaluated using the luciferase reporter assay. Results PCAF was upregulated in several PCa cell lines. Upregulation of PCAF promoted AR transcriptional activation and cell growth in cultured PCa cells. Expression of PCAF in PCa cells was associated with the downregulation of miR-17-5p. Targeting of the 3’-untranslated region of PCAF mRNA by miR-17-5p caused translational suppression and RNA degradation, and, consequently, modulation of AR transcriptional activity in PCa cells. Conclusions PCAF is upregulated in cultured PCa cells, and upregulation of PCAF is associated with the downregulation of miR-17-5p. Targeting of PCAF by miR-17-5p modulates AR transcriptional activity and cell growth in cultured PCa cells.

The NF-kB pathway is key to epithelial immune defense and has been implicated in secretion of antimicrobial peptides, release of cytokines/chemokines to mobilize immune effector cells, and activation of adaptive immunity. The expression of many inflammatory genes following infection involves the remodeling of the chromatin structure. We reported here that histone deacetylases (HDACs) and NF-kB signaling coordinate expression of CX3CL1 in epithelial cells following Cryptosporidium parvum infection. Upregulation of CX3CL1 was detected in cultured human biliary epithelial cells following infection. Expression of miR-424 and miR-503 was downregulated, and was involved in the induction of CX3CL1 in infected cells. C. parvum infection suppressed transcription of the mir-424-503 gene in a NF-kB- and HDAC-dependent manner. Increased promoter recruitment of NF-kB p50 and HDACs, and decreased promoter H3 acetylation associated with the mir-424-503 gene were observed in infected cells. Upregulation of CX3CL1 in biliary epithelial cells and increased infiltration of CX3CR1(+) cells were detected during C. parvum infection in vivo. Induction of CX3CL1 and downregulation of miR-424 and miR-503 were also detected in epithelial cells in response to LPS stimulation. The above results indicate that HDACs and NF-kB signaling coordinate epithelial expression of CX3CL1 to promote mucosal antimicrobial defense through suppression of the mir-424-503 gene.

Background Diastolic dysfunction (DD), a hallmark of obesity and primary defect in heart failure with preserved ejection fraction, is a predictor of future cardiovascular events. We previously reported that linagliptin, a dipeptidyl peptidase-4 inhibitor, improved DD in Zucker Obese rats, a genetic model of obesity and hypertension. Here we investigated the cardioprotective effects of linagliptin on development of DD in western diet (WD)-fed mice, a clinically relevant model of overnutrition and activation of the renin-angiotensin-aldosterone system. Methods Female C56Bl/6 J mice were fed an obesogenic WD high in fat and simple sugars, and supplemented or not with linagliptin for 16 weeks. Results WD induced oxidative stress, inflammation, upregulation of Angiotensin II type 1 receptor and mineralocorticoid receptor (MR) expression, interstitial fibrosis, ultrastructural abnormalities and DD. Linagliptin inhibited cardiac DPP-4 activity and prevented molecular impairments and associated functional and structural abnormalities. Further, WD upregulated the expression of TRAF3IP2, a cytoplasmic adapter molecule and a regulator of multiple inflammatory mediators. Linagliptin inhibited its expression, activation of its downstream signaling intermediates NF-κB, AP-1 and p38-MAPK, and induction of multiple inflammatory mediators and growth factors that are known to contribute to development and progression of hypertrophy, fibrosis and contractile dysfunction. Linagliptin also inhibited WD-induced collagens I and III expression. Supporting these in vivo observations, linagliptin inhibited aldosterone-mediated MR-dependent oxidative stress, upregulation of TRAF3IP2, proinflammatory cytokine, and growth factor expression, and collagen induction in cultured primary cardiac fibroblasts. More importantly, linagliptin inhibited aldosterone-induced fibroblast activation and migration. Conclusions Together, these in vivo and in vitro results suggest that inhibition of DPP-4 activity by linagliptin reverses WD-induced DD, possibly by targeting TRAF3IP2 expression and its downstream inflammatory signaling.

Obesity is associated with significant metabolic co-morbidities, such as diabetes, hypertension, and dyslipidaemia, as well as a range of cardiovascular diseases, all of which lead to increased hospitalisations, morbidity, and mortality. Adipose tissue dysfunction caused by chronic nutrient stress can result in oxidative stress, mitochondrial dysfunction, inflammation, hypoxia, and insulin resistance. Thus, we hypothesised that reducing adipose tissue oxidative stress via adipose tissue-targeted overexpression of the antioxidant mitochondrial catalase (mCAT) may improve systemic metabolic function. We crossed mCAT (floxed) and Adipoq-Cre mice to generate mice overexpressing catalase with a mitochondrial targeting sequence predominantly in adipose tissue, designated AdipoQ-mCAT. Under normal diet conditions, the AdipoQ-mCAT transgenic mice demonstrated increased weight gain, adipocyte remodelling, and metabolic dysfunction compared to the wild-type mice. Under obesogenic dietary conditions (16 weeks of high fat/high sucrose feeding), the AdipoQ-mCAT mice did not result in incremental impairment of adipose structure and function but in fact, were protected from further metabolic impairment compared to the obese wild-type mice. While AdipoQ-mCAT overexpression was unable to improve systemic metabolic function per se, our results highlight the critical role of physiological H2O2 signalling in metabolism and adipose tissue function.

Secreted frizzled-related protein 5 (SFRP5) is a novel anti-inflammatory adipokine that may play a role in cardiovascular development and disease. However, there is yet to be a comprehensive investigation into whether circulating SFRP5 can be a biomarker for cardiac function. Plasma SFRP5 levels were measured via ELISA in 262 patients admitted to a cardiology unit. Plasma SFRP5 levels were significantly lower in patients with a history of heart failure (HF), coronary artery disease (CAD), and atrial fibrillation (AF; p = 0.001). In univariate analyses, SFRP5 levels were also significantly positively correlated with left ventricular ejection fraction (LVEF) (r = 0.52, p < 0.001) and negatively correlated with E/E’ (r = −0.30, p < 0.001). Patients with HF, CAD, low LVEF, low triglycerides, high CRP, and high eGFR were associated with lower SFRP5 levels independent of age, BMI, or diabetes after multivariate analysis (overall model r = 0.729, SE = 0.638). Our results show that low plasma SFRP5 levels are independently associated with the presence of HF, CAD, and, importantly, impaired LV function. These results suggest a potential role of SFRP5 as a biomarker, as well as a mediator of cardiac dysfunction independent of obesity and metabolic regulation.

Abstract Disclosure: D. Chen: None. J. Habibi: None. L. Xie: None. G. Jia: None. Sphingomyelinases facilitate ceramide production and are essential for cell turnover, vesicle inward budding, and exosome release. Recent data suggest a distinct role for neutral sphingomyelinase (nSMase) in regulating ceramide-dependent exosome release and its connection to metabolic syndrome. We have recently demonstrated that elevated exosomal CD36 in endothelial cells is associated with increased skeletal muscle lipid disorders and insulin resistance. Here, we further investigated whether nSMase inhibition with GW4869, would attenuate Western diet (WD)-induced release of exosomal CD36, skeletal muscle lipid metabolic disorders and insulin resistance. Six week-old female C57BL/6L mice were fed either a WD containing excess fat (46%) and fructose (17.5%) for 16 weeks or a standard chow diet. Mice were variably treated with GW4869 (2.0 μg/g body weight, intraperitoneal injection every 48 h for 12 weeks). WD feeding increased nSMase2 expression and the plasma release of exosomal CD36, while causing glucose intolerance, HOMA-IR, and insulin resistance index, respectively. Moreover, these functional abnormalities were associated with reduced glucose transporter type 4 expression in conjunction with impaired insulin metabolic signaling in phosphoinositide 3-kinases/protein kinase B in skeletal muscle. GW4869 treatment prevented the WD-induced increases in in vivo glucose intolerance and tissue insulin resistance. GW4869 also inhibited WD-induced increases in the plasma release of exosomal CD36, skeletal muscle CD36 expression, lipid accumulation, oxidative stress, and mitochondrial dysfunction. These findings indicate that targeting nSMase prevents Western diet-induced increases in skeletal muscle lipid metabolic disorders and insulin resistance by attenuating the plasma release of exosomal CD36, skeletal muscle CD36 expression, and related tissue oxidative stress and mitochondria dysfunction. Presentation: Monday, July 14, 2025