While the TyG index has been studied in relation to stroke risk, there is a lack of research integrating fat distribution indicators like Body Roundness Index (BRI) and Fat Mass Index (FMI). Additionally, comparative studies across multiple regions are scarce. This study investigates the association between obesity-related parameters and stroke incidence, examining the mediation effects of multimorbidity, using data from rural areas in China and the United Kingdom. This cohort study included 60,685 participants (6,980 from China and 53,705 from UK). The obesity-related parameters were calculated using established formulas. The TyG index was determined as ln [TG (mg/dL) × GLU (mg/dL) / 2]. Additionally, composite indices were created by multiplying the TyG index by BMI, WC, FMI, and RBI to assess obesity-related risks. Cox regression analyses were employed on the relationship between Triglyceride Glucose index related parameters and stroke risk. Multiple mediation analysis was applied to assess the contributions of multimorbidity to obesity indicators in stroke occurrence. After excluding those who developed stroke within two years of enrollment, the Chinese cohort (6,638 subjects, median follow-up 4.33 years) had 237 ischemic and 21 hemorrhagic strokes. The UK cohort (53,631 subjects, median follow-up 13.85 years) had 742 ischemic and 316 hemorrhagic strokes. Chinese residents had lower BMI but higher visceral obesity (BRI), higher prevalence of multimorbidity, and higher stroke incidence compared to UK residents. Cox analyses demonstrated significant associations between BMI/TyG indices and ischemic stroke in both Chinese and UK populations, which diminished after adjusting for multimorbidity. In the Chinese rural cohort, only TyG-BRI (HR:1.13, 95%CI:0.99–1.30) approached statistical significance after full adjustment for mediators. In contrast, in the UK cohort, significant associations persisted for most TyG Index indicators when full adjustment for mediators, including BMI (HR: 1.17, 95% CI: 1.09–1.26), TyG-BMI (HR: 1.16, 95% CI: 1.07–1.26), TyG-WC (HR: 1.13, 95% CI: 1.03–1.25), TyG-FMI (HR: 1.17, 95% CI: 1.07–1.28), and TyG-RBI (HR: 1.15, 95% CI: 1.06–1.24). TyG-BRI also showed the best predictive performance for ischemic stroke in Chinese rural residents (AUC > 0.7) and exhibited an almost linear relationship with ischemic stroke occurrence. Additionally, TyG-BRI presented a U-shaped relationship with the risk of hemorrhagic stroke incidence in the UK (p overall = 0.041, p non-linear = 0.017). Multimorbidity mediated the relationship between TyG indices, and ischemic stroke incidence in both cohorts. The mediation percentage for multimorbidity was higher than the sum of individual chronic diseases, with a higher mediation percentage in the Chinese cohort (up to 51%) compared to the UK cohort (up to 27.2%). Chinese rural residents exhibit higher levels of visceral obesity compared to residents in UK, leading to greater stroke susceptibility mediated by multimorbidity. These findings underscore the importance of comprehensive management of multimorbidity for stroke prevention. The TyG-BRI may serve as a promising predictor of ischemic stroke incidence among rural community residents.

Background: The tumor suppressor gene CDKN2A generates at least three different transcriptional variants, each of which is thought to encode a tumor suppressor. However, the inhibitory activities of these variants have not yet been compared in the same cells. Protein therapy is known to have several advantages over gene therapy. Thus, investigation of the exogenous protein molecule of the most effective suppressor may yield meaningful information regarding protein-based cancer therapy. Methods: The inhibitory effects of p16INK4a, p14ARF and p12 were studied in the human lung cancer cell line A549 which lacks the CDKN2A locus. The eukaryotic expression plasmids of the three transcriptional variants were constructed and stably transfected into the cells. RNA and protein expression by the plasmids was confirmed using RT-PCR and fluorescence immunocytochemistry, respectively. Cell growth inhibition and cell-cycle redistribution after transfection were investigated based on growth curve and flow cytometry analyses. An exogenous His-tag fusion p16INK4a protein was obtained and purified by affinity chromatography. Cell growth inhibition and cell cycle arrest induced by the expression of p16INK4a protein were measured in A549 cells transduced with the exogenous protein. Results: While all three variants suppressed cell growth, p16INK4a had the strongest effect. Marked G1-phase accumulation and S-phase inhibition were induced by p16INK4a and p14ARF but not by p12. Exogenous p16INK4a protein was successfully expressed and purified and transduction of the fusion protein into A549 cells inhibited cell growth by G1→S arrest. Conclusions: Among the three transcript variants, p16INK4a has a greater inhibitory effect than p14ARF and p12; exogenous p16INK4a protein should be further investigated for use in cancer therapy as a protein agent.

Chronic exposure to arsenic in drinking water damages cognitive function, and nerve cell apoptosis is one of the primary characteristics. The damage to mitochondrial structure and/or function is one of the main characteristics of apoptosis. Peroxisome proliferator-activated receptor γ coactivator α (PGC-1α) is involved in the regulation of mitochondrial biogenesis, energy metabolism, and apoptosis. In this study, we aimed to study the role of PGC-1α in sodium arsenite (NaAsO₂)-induced mitochondrial apoptosis in rat hippocampal cells. We discovered that increased arsenic-induced apoptosis in rat hippocampus increased with NaAsO₂ (0, 2, 10, and 50 mg/L, orally via drinking water for 12 weeks) exposure by TUNEL assay, and the structure of mitochondria was incomplete and swollen and had increased lysosomes, lipofuscins, and nuclear membrane shrinkage observed via transmission electron microscopy. Furthermore, NaAsO₂ reduced the levels of Bcl-2 and PGC-1α and increased the levels of Bax and cytochrome C expression. Moreover, correlation analysis showed that brain arsenic content was negatively correlated with PGC-1α levels and brain ATP content; PGC-1α levels were negatively correlated with apoptosis rate; and brain ATP content was positively correlated with PGC-1α levels, but no significant correlation between ATP content and apoptosis has been observed in this study. Taken together, the results of this study indicate that NaAsO₂-induced mitochondrial pathway apoptosis is related to the reduction of PGC-1α, accompanied by ATP depletion.