Associations between cardiovascular diseases and cancer mortality: insights from a retrospective cohort analysis of NHANES data.

BACKGROUND: This study explored the association of cardiovascular disease (CVD) with cancer mortality risk in individuals with or without a history of cancer, to better understand the interplay between CVD and cancer outcomes. METHODS: Utilizing data from the National Health and Nutrition Examination Survey (NHANES) spanning 1999 to 2018, a retrospective cohort analysis was conducted. This analysis accounted for the survey's complex design to ensure national representativeness. The association of CVD with cancer mortality was assessed through multivariable Cox proportional hazards models. RESULTS: The present study included 59,653 participants, of whom 54,095 did not have cancer and 5558 had a history of cancer. In individuals without cancer, heart failure (HF) was associated with an increased risk of mortality from cancer (HR, 1.36; 95% CI, 1.09-1.69; P = 0.005). In participants with cancer, HF correlated with a higher risk of mortality from cancer (HR, 1.76; 95% CI, 1.32-2.34; P < 0.001). Diabetes (DM), hypertension (HBP) and coronary heart disease (CHD) were not significantly associated with an increased risk of mortality from cancer. Significant differences were observed in the interaction between cancer and CHD (HR, 0.68; 95% CI, 0.53-0.87; P = 0.002). For cancer and HBP, a similar trend was noted (HR, 0.75; 95% CI, 0.62-0.91; P = 0.003). No significant differences were found in interactions between HF, DM and cancer. CONCLUSIONS: HF was associated with an increased risk of mortality from cancer, regardless of cancer history, while HBP, CHD and DM showed no significant association. These findings underscore the importance of understanding the mechanisms behind the increased risk of cancer mortality following HF.

Associations of different type of physical activity with all-cause mortality in hypertension participants.

Few studies explored the association of different type of physical activity with all-cause mortality in hypertension (HBP) participants. A retrospective cohort analysis was performed using National Health and Nutrition Examination Survey (NHANES) data to explore association of moderate-intensity physical activity (MPA), vigorous-intensity physical activity (VPA), sedentary behavior with mortality in HBP individuals. Among 10,913 HBP participants followed for a median of 6.2 years, VPA was not associated with a reduction in all-cause mortality compared to participants without VPA in multivariate Cox survival analysis. MPA was linked to lower all-cause mortality at durations of 0-150 min/week (HR, 0.72; 95% CI 0.58-0.88), 150-300 min/week (HR, 0.71; 95% CI 0.52-0.96), and > 300 min/week (HR, 0.61; 95% CI 0.49-0.77) compared to no MPA. Sedentary behavior of 6-8 h/day (HR, 1.35; 95% CI 1.15-1.59) and > 8 h/day (HR, 1.55; 95% CI 1.34-1.79) were associated with increased mortality risk versus < 6 h/day. Further research is needed to explore whether VPA can improve outcomes for HBP individuals and to determine the optimal duration of VPA.MPA is linked to lower mortality risk, indicating its potential as the best physical activity intensity for HBP individuals.

SIRT1 safeguards adipogenic differentiation by orchestrating anti-oxidative responses and suppressing cellular senescence.

Adipose tissue is an important endocrine organ that regulates metabolism, immune response and aging in mammals. Healthy adipocytes promote tissue homeostasis and longevity. SIRT1, a conserved NAD+-dependent deacetylase, negatively regulates adipogenic differentiation by deacetylating and inhibiting PPAR-γ. However, knocking out SIRT1 in mesenchymal stem cells (MSCs) in mice not only causes defects in osteogenesis, but also results in the loss of adipose tissues, suggesting that SIRT1 is also important for adipogenic differentiation.Here, we report that severe impairment of SIRT1 function in MSCs caused significant defects and cellular senescence during adipogenic differentiation. These were observed only when inhibiting SIRT1 during adipogenesis, not when SIRT1 inhibition was imposed before or after adipogenic differentiation. Cells generate high levels of reactive oxygen species (ROS) during adipogenic differentiation. Inhibiting SIRT1 during differentiation resulted in impaired oxidative stress response. Increased oxidative stress with H2O2 or SOD2 knockdown phenocopied SIRT1 inhibition. Consistent with these observations, we found increased p16 levels and senescence associated ß-galactosidase activities in the inguinal adipose tissue of MSC-specific SIRT1 knockout mice. Furthermore, previously identified SIRT1 targets involved in oxidative stress response, FOXO3 and SUV39H1 were both required for healthy adipocyte formation during differentiation. Finally, senescent adipocytes produced by SIRT1 inhibition showed decreased Akt phosphorylation in response to insulin, a lack of response to adipocytes browning signals, and increased survival for cancer cells under chemotherapy drug treatments. These findings suggest a novel safeguard function for SIRT1 in regulating MSC adipogenic differentiation, distinct from its roles in suppressing adipogenic differentiation.

Rapamycin suppresses inflammation and increases the interaction between p65 and IκBα in rapamycin-induced fatty livers.

Rapamycin treatment significantly increases lifespan and ameliorates several aging-related diseases in mice, making it a potential anti-aging drug. However, there are several obvious side effects of rapamycin, which may limit the broad applications of this drug. Lipid metabolism disorders such as fatty liver and hyperlipidemia are some of those unwanted side effects. Fatty liver is characterized as ectopic lipid accumulation in livers, which is usually accompanied by increased inflammation levels. Rapamycin is also a well-known anti-inflammation chemical. How rapamycin affects the inflammation level in rapamycin-induced fatty liver remains poorly understood. Here, we show that eight-day rapamycin treatment induced fatty liver and increased liver free fatty acid levels in mice, while the expression levels of inflammatory markers are even lower than those in the control mice. Mechanistically, the upstream of the pro-inflammatory pathway was activated in rapamycin-induced fatty livers, however, there is no increased NFκB nuclear translocation probably because the interaction between p65 and IκBα was enhanced by rapamycin treatment. The lipolysis pathway in the liver is also suppressed by rapamycin. Liver cirrhosis is an adverse consequence of fatty liver, while prolonged rapamycin treatment did not increase liver cirrhosis markers. Our results indicate that although fatty livers are induced by rapamycin, the fatty livers are not accompanied by increased inflammation levels, implying that rapamycin-induced fatty livers might not be as harmful as other types of fatty livers, such as high-fat diet and alcohol-induced fatty livers.

Silencing of TLR4 Inhibits Atrial Fibrosis and Susceptibility to Atrial Fibrillation via Downregulation of NLRP3-TGF-ß in Spontaneously Hypertensive Rats.

Introduction: This study was aimed at exploring whether silencing of TLR4 could inhibit atrial fibrosis and susceptibility to atrial fibrillation (AF) by regulating NLRP3-TGF-ß in hypertensive rats. Methods: Spontaneously hypertensive rats (SHRs) were transfected with either a virus containing TLR4-shRNA to downregulate TLR4 or an empty virus (vehicle) at the age of 14 weeks. Fibrosis of left atrium and susceptibility to AF were detected, and expression of NLRP3-TGF-ß in left atrial tissue at 22 weeks of age was measured. Primary cardiac fibroblasts were transfected with TLR4-shRNA or scrambled vehicle and stimulated with angiotensin (Ang) II. Proliferation of cardiac fibroblasts and expression of NLRP3-TGF-ß were detected. Results: Silencing of TLR4 reduced left atrial fibrosis and susceptibility to AF in SHRs and downregulated expression of NLRP3, TGF-ß, and collagen I. In vitro, TLR4 silencing reduced proliferation of cardiac fibroblasts induced by Ang II as well as expression of NLRP3, TGF-ß, and collagen I. Conclusion: Silencing of TLR4 can downregulate NLRP3-TGF-ß to reduce atrial fibrosis and susceptibility to AF in SHRs.

Vincristine attenuates cardiac fibrosis through the inhibition of NLRP3 inflammasome activation.

Vincristine (VCR) is widely used in cancer therapies, although its benefits on cardiac fibrosis remain unknown. Here, we investigated VCR's efficacy on cardiac fibrosis and elucidated the underlying mechanism of action. Network pharmacology was employed to predict the mechanism of VCR action on cardiac fibrosis. We induced cardiac fibrosis in adult male Sprague-Dawley (SD) rats via isoproterenol (ISO) injection, followed by treatment with VCR or vehicle. After 10 days of treatment, VCR-treated rats exhibited a significantly lower heart/body weight ratio relative to those treated with the vehicle. Moreover, cardiac fibrosis was alleviated in VCR-treated rats relative to vehicle-treated rats. The results revealed the down-regulation of mature caspase-1, interleukin (IL)-1ß, and IL-18 in VCR-treated rats relative to vehicle-treated rats. We also observed less colocalization between the nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) and apoptosis-associated speck-like protein containing a CARD (ASC) in VCR-treated rats compared with vehicle-treated rats. We then cultured neonatal rat cardiac fibroblasts (NRCFs) and exposed them to lipopolysaccharide (LPS) and adenosine triphosphate (ATP) in the presence or absence of VCR. The results indicated that VCR mediated the down-regulation of caspase-1, IL-1ß, and IL-18 and the colocalization of NLRP3 and ASC in LPS+ATP-stimulated cardiac fibroblasts (CFs). We found evidence that VCR attenuates cardiac fibrosis by directly suppressing the activation of the NLRP3 inflammasome. These findings provide novel insights into VCR's mechanism of action in alleviating cardiac fibrosis.

A Novel Gene Signature to Predict Survival Time and Incident Ventricular Arrhythmias in Patients with Dilated Cardiomyopathy.

The mortality in nonischaemic dilated cardiomyopathy (NIDCM) patients is still at a high level; sudden death in NIDCM can be caused by ventricular tachycardia. It is necessary to explore the pathogenesis of ventricular arrhythmias (VA) in NIDCM. Differentially expressed genes (DEGs) were identified by comparing the gene expression of NIDCM patients with or without VA in the gene expression profile of GSE135055. A total of 228 DEGs were obtained, and 3 genes were screened out to be significantly related to the survival time of NIDCM patients. We established a prediction model on two-gene (TOMM22, PPP2R5A) signature for the survival time of NIDCM patients. The area under the curve (AUC) was 0.75 calculated by the ROC curve analysis. These risk genes are probably new targets for exploring the pathogenesis of NIDCM with VA; the prediction model for survival time and incident ventricular arrhythmias is useful in clinical decision making for individual treatment.

In Silico Prediction of Molecular Targets of Astragaloside IV for Alleviation of COVID-19 Hyperinflammation by Systems Network Pharmacology and Bioinformatic Gene Expression Analysis.

INTRODUCTION: The overproduction of cytokines and chemokines caused by excessive and uncontrolled inflammation contributes to the development of COVID-19. Astragaloside IV is considered as an anti-inflammatory and antioxidant agent. This study aimed at undertaking a network pharmacology approach and bioinformatics analysis to uncover the pharmacological mechanisms of Astragaloside IV on COVID-19. METHODS: Potential targets of Astragaloside IV were screened from public databases. Differentially expressed genes (DEGs) in SARS-CoV-2 were screened using bioinformatics analysis on the Gene Expression Omnibus (GEO) datasets GSE147507. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were subsequently performed. The overlapping genes, GO terms and KEGG pathways between Astragaloside IV targets and SARS-CoV-2 DEGs were confirmed, and the location of overlapping targets in the key pathways was queried using KEGG Mapper. RESULTS: A total of 425 potential targets of Astragaloside IV were screened. Besides, a total of 546 DEGs were identified between SARS-CoV-2 infected samples and control samples, including 380 up-regulated and 166 down-regulated genes. There was a significant overlap in GO terms and KEGG pathways between Astragaloside IV targets and SARS-CoV-2 DEGs. The shared genes included MMP13, NLRP3, TRIM21, GBP1, ADORA2A, PTAFR, TNF, MLNR, IL1B, NFKBIA, ADRB2, and IL6. CONCLUSIONS: This study is the first to propose Astragaloside IV as a new drug candidate for alleviating hyper-inflammation in COVID-19 patients. Besides, the key targets and pathways may reveal the main pharmacological mechanism of Astragaloside IV in the treatment of COVID-19.