Mendelian randomization analysis separated the independent impact of childhood obesity and adult obesity on socioeconomic status, psychological status, and substance use.

Background: Obesity is linked to a variety of psychosocial and behavioral outcomes but the causalities remain unclear yet. Determining the causalities and distinguishing between the separate effects of childhood and adult obesity is critical to develop more targeted strategies to prevent adverse outcomes. Methods: With single nucleotide polymorphisms (SNPs) used as genetic variables, we employed univariable Mendelian randomization (UVMR) to explore the causalities between childhood and adult body mass index (BMI) and socioeconomic status, psychological status, and substance use. Genetic data for childhood and adult BMI came respectively from 47,541 children aged 10 years and 339,224 adult participants. The outcome data were obtained from corresponding consortia. The direct impact of childhood BMI and adult BMI was then examined using a multivariable MR (MVMR). Results: UVMR found that higher childhood BMI was linked causally to lower household income (ß = -0.06, 95 % CI = -0.08 âˆ¼ -0.03, P = 4.86 × 10-5), decreased subjective well-being (ß = -0.07, 95 % CI = -0.12 âˆ¼ -0.03, P = 1.74 × 10-3), and an increased tendency of smoking regularly (OR = 1.12, 95 % CI = 1.04-1.20, P = 1.52 × 10-3). Similar results were observed in adult BMI. MVMR further revealed that after adjusting with adult BMI, childhood BMI remained an isolated impact on household income. The impacts of adult BMI on the outcomes were diminished when adjusting with childhood BMI. Conclusion: The findings indicate the impacts of childhood obesity on subjective well-being and smoking initiation are a result of higher BMI sustaining into adulthood, whereas the effect on household income is attributed to a lasting impact of obesity in early life. The results would help facilitate more targeted strategies for obesity management to prevent adverse outcomes.

Progranulinopathy: A diverse realm of disorders linked to progranulin imbalances.

Progranulin (PGRN), encoded by the GRN gene in humans, was originally isolated as a secreted growth factor that implicates in a multitude of processes ranging from regulation of tumorigenesis, inflammation to neural proliferation. Compelling evidence indicating that GRN mutation can lead to various common neuronal degenerative diseases and rare lysosomal storage diseases. These findings have unveiled a critical role for PGRN as a lysosomal protein in maintaining lysosomal function. The phenotypic spectrum of PGRN imbalance has expanded to encompass a broad spectrum of diseases, including autoimmune diseases, metabolic, musculoskeletal and cardiovascular diseases. These diseases collectively referred to as Progranulinopathy- a term encompasses the wide spectrum of disorders influenced by PGRN imbalance. Unlike its known extracellular function as a growth factor-like molecule associated with multiple membrane receptors, PGRN also serves as an intracellular co-chaperone engaged in the folding and traffic of its associated proteins, particularly the lysosomal hydrolases. This chaperone activity is required for PGRN to exert its diverse functions across a broad range of diseases, encompassing both the central nervous system and peripheral systems. In this comprehensive review, we present an update of the emerging role of PGRN in Progranulinopathy, with special focus on elucidating the intricate interplay between PGRN and a diverse array of proteins at various levels, ranging from extracellular fluids and intracellular components, as well as various pathophysiological processes involved. This review seeks to offer a comprehensive grasp of PGRN's diverse functions, aiming to unveil intricate mechanisms behind Progranulinopathy and open doors for future research endeavors.

CircIRAK3 exerts negative feedback regulation on inflammation by binding to HNRNP U and destabilizing proinflammatory cytokine mRNA in osteoarthritis and chondrogenesis.

Osteoarthritis (OA) is the most prevalent age-related and degenerative joint disease with limited treatment options. Previous studies have identified the therapeutic effects of mesenchymal stem cells (MSCs) therapy. Nevertheless, chronic inflammation impedes MSCs therapeutic effect. There have been reports suggesting that circular RNAs (circRNAs) are involved in OA and chondrogenesis. The combination of MSCs and circRNAs in therapies appears to be a promising option. In this study, we identified circIRAK3 as a significant regulator in cartilage degeneration and chondrogenesis through high-throughput sequencing analyses. We observed increased circIRAK3 in OA cartilage and during MSCs chondrogenesis. Knockdown of circIRAK3 resulted in excessive apoptosis, inhibited proliferation, and degradation of chondrocytes, along with the inhibition of MSCs chondrogenesis. Mechanistically, circIRAK3 bound to HNRNP U and competitively prevented its binding to IL-1ß, TNFα, and IL6 mRNA, thereby promoting mRNA degradation. Notably, circIRAK3 expression in plasma increased with higher OARSI scores. Intra-articular injection of adeno-associated virus-circIRAK3 delayed cartilage degeneration and reduced inflammation in DMM mouse model. Our study highlights a compensatory regulation network of circIRAK3 in chondrocytes in response to inflammation. CircIRAK3 has the potential to serve as a new therapeutic target for OA. Furthermore, therapies targeting circIRAK3 combined with MSCs hold promise.

FUNDC1/PFKP-mediated mitophagy induced by KD025 ameliorates cartilage degeneration in osteoarthritis.

Osteoarthritis (OA) is the most common joint disease, but no disease-modifying drugs have been approved for OA treatment. Mitophagy participates in mitochondrial homeostasis regulation by selectively clearing dysfunctional mitochondria, which might contribute to cartilage degeneration in OA. Here, we provide evidence of impaired mitophagy in OA chondrocytes, which exacerbates chondrocyte degeneration. Among the several classic mitophagy-regulating pathways and receptors, we found that FUNDC1 plays a key role in preserving chondrocyte homeostasis by inducing mitophagy. FUNDC1 knockdown in vitro and knockout in vivo decreased mitophagy and exacerbated mitochondrial dysfunction, exacerbating chondrocyte degeneration and OA progression. FUNDC1 overexpression via intra-articular injection of adeno-associated virus alleviated cartilage degeneration in OA. Mechanistically, our study demonstrated that PFKP interacts with and dephosphorylates FUNDC1 to induce mitophagy in chondrocytes. Further analysis identified KD025 as a candidate drug for restoring chondrocyte mitophagy by increasing the FUNDC1-PFKP interaction and thus alleviating cartilage degeneration in mice with DMM-induced OA. Our study highlights the role of the FUNDC1-PFKP interaction in chondrocyte homeostasis via mitophagy induction and identifies KD025 as a promising agent for treating OA by increasing chondrocyte mitophagy.

Causal relationship between 14 site-specific cancers and venous thromboembolism.

Background: It has been observed that cancer and venous thromboembolism (VTE) are associated, but anticancer therapy may violate the causality. Therefore, this study aimed to elucidate the causal relationship of various cancers to VTE using Mendelian randomization (MR). Methods: Three MR methods were used to estimate causal effects: Inverse variance weighted (IVW), MR-Egger and weighted median. Sensitivity analyses included Cochran's Q-test, MR-Egger intercept test and MR-PRESSO. Gene ontology enrichment analysis was performed to elucidate the underlying mechanisms of VTE development in cancer patients. Results: The primary IVW approach showed that non-Hodgkin's lymphoma (NHL) might increase the risk of VTE (odds ratio [OR]: 1.20, 95% confidence interval [95% CI]: 1.00-1.44, p = 0.045), while melanoma possibly reduced the risk of VTE (OR: 0.89, 95% CI: 0.82-0.97, p = 0.006), although there was no significance after adjustment for multiple testing. No association was observed between VTE risk and other site-specific cancers. Gene ontology enrichment analysis revealed that vitamin D played an important role in the development of VTE in cancer patients. Conclusions: Our findings suggested that genetically predicted NHL was associated with higher VTE risk, whereas melanoma had lower VTE risk compared with other site-specific cancers. Moreover, this study suggested that anticancer therapy and increased extensive examination might play a more important role in VTE development than the nature of cancer.