Integrated analysis of mRNA-m6A-protein profiles reveals novel insights into the mechanisms for cadmium-induced urothelial transformation.

Objective: This study aimed to investigate the mechanisms underlying Cd-induced urothelial transformation, using multi-omics analyses (transcriptome, epitranscriptome, and proteome).Methods: Transcriptomics analysis was performed to estimate the expression of genes, methylated RNA immunoprecipitation sequencing analysis was used to detect m6A modification, while proteomics analysis was used to identify differentially expressed proteins. Differentially expressed genes (DEGs) were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis.Results: A total of 9491 DEGs, 711 differentially expressed proteins, and 633 differentially m6A modified genes between Cd-transformed cells and control cells were identified. The regulation of most genes varied at different omics layers. The three omics data shared 57 genes, and these genes were enriched in response to DNA damage stimulus and cell proliferation. Interestingly, 13 genes, most of which are related to the onset or progression of cancer, were shared by the m6A and proteomics data, but not the transcriptome data. This suggested that m6A modification is crucial for post-transcriptional regulation related to Cd2+-induced malignant transformation.Conclusion: Our multi-omics analysis provided a comprehensive reference map of gene activity and revealed m6A signalling pathways crucial for Cd2+ carcinogenesis.

Associations of body mass index with mortality in heart failure with preserved ejection fraction patients with ischemic versus non-ischemic etiology.

Background: Obesity could paradoxically improve prognosis in patients with heart failure (HF), termed the "obesity paradox." Whether HF etiology could modify the "obesity paradox" is still controversial. In the present study, we aimed to assess the relationship between obesity and death in patients with heart failure with preserved ejection fraction (HFpEF) with non-ischemic versus ischemic etiologies. Methods: We analyzed 3,360 HFpEF patients from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial. Cox regression models were used to assess the association of obesity assessed by body mass index (BMI) with short-term and long-term death risk. Results: Overweight and obesity were associated with a lower risk of long-term all-cause death in patients with non-ischemic HFpEF, even in those with class III obesity (adjusted HR: 0.61, 95% CI 0.38-0.97). However, in the ischemic subgroup, as obesity advanced, this paradoxical relationship was gradually attenuated and disappeared in class III obesity (adjusted HR: 0.93, 95% CI 0.56-1.57). Restricted cubic spline analyses confirmed the differential relationship of baseline BMI with risk of long-term death with a BMI higher than 30 kg/m2 in non-ischemic versus ischemic HFpEF. In the short-term follow-up, the beneficial effects of overweight and obesity on survival were consistently observed in all the BMI categories, with the nadirs of all-cause death risk at class III obesity category both in non-ischemic and ischemic subgroups. Conclusion: "Obesity paradox" was evident both in non-ischemic and ischemic HFpEF during short-term follow-up, even in those with class III obesity. However, the beneficial effect of class III obesity disappeared during long-term follow-up in ischemic HFpEF. Clinical Trial Registration: [https://clinicaltrials.gov], identifier [NCT00094302].

Effectiveness and Safety of DOACs vs. Warfarin in Patients With Atrial Fibrillation and Frailty: A Systematic Review and Meta-Analysis.

Background: Patients with atrial fibrillation (AF) and frailty are a considerable group in clinical practice. However, existing studies provide insufficient evidence of anticoagulation strategies for these patients. Therefore, we conducted a meta-analysis to determine the effectiveness and safety outcomes of direct oral anticoagulants (DOACs) for these patients. Methods: Randomized controlled trials or observational studies reporting the data about the DOACs and warfarin therapy among frail AF patients were included. The search was performed in the PubMed and Embase databases up to March 2022. Frailty was defined using the most widely used claims-based frailty index or the cumulative deficit model-based frailty index. Results: A total of 4 studies involving 835,520 patients were included. Compared with warfarin, DOACs therapy reduced the risks of stroke or systemic embolism (HR = 0.79, 95%CI: 0.69-0.90), ischemic stroke (HR = 0.79, 95%CI: 0.71-0.87), hemorrhagic stroke (HR = 0.52, 95%CI: 0.35-0.76), and all-cause death (HR = 0.90, 95%CI: 0.84-0.96). In safety outcomes, DOACs was significantly associated with reduced risks of major bleeding (HR = 0.79, 95%CI: 0.64-0.97) and intracranial hemorrhage (HR = 0.58, 95%CI: 0.52-0.65) compared to warfarin, but there were no statistically differences in gastrointestinal bleeding (HR = 0.97, 95%CI: 0.73-1.29). Conclusions: DOACs exerted superior effectiveness and safety outcome than warfarin in AF patients with frailty.

AMPK activation enhances PPARα activity to inhibit cardiac hypertrophy via ERK1/2 MAPK signaling pathway.

Activation of adenosine monophosphate-activated protein kinase (AMPK) has been shown to inhibit cardiac hypertrophy through peroxisome proliferators-activated receptor-α (PPARα) signaling pathway, but the detailed mechanism remains unclear. A rat model of cardiac hypertrophy created by transaortic constriction (TAC) was used to investigate the mechanism involved in regulation of PPARα activity by AMPK. It was observed that treatment with AICAR (5-aminoimidazole 1 carboxamide ribonucleoside), an AMPK activator, significantly inhibited cardiac hypertrophy in vivo and in vitro. Phosphorylated extracellular signal regulated protein kinase (phospho-ERK1/2) and phospho-p38 mitogen-activated protein kinase (MAPK) protein levels were significantly up-regulated, while PPARα protein level was down-regulated in TAC rats. AICAR treatment reversed the changes of PPARα and phospho-ERK1/2, but increased phospho-p38 MAPK protein level in TAC rats. Similar changes of PPARα and phospho-ERK1/2 protein levels were observed in the hypertrophied cardiomyocytes induced by phenylephrine treatment. Epidermal growth factor (EGF, ERK1/2 activator), but not SB203580 (p38 inhibitor) blocked the up-regulation of PPARα protein level induced by AICAR. Luciferase assay showed that AICAR increased PPARα transcriptional activity which was abrogated by EGF, but not by SB203580. These results demonstrate that AMPK activation enhances the activity of PPARα to inhibit cardiac hypertrophy through ERK1/2, but not p38 MAPK, signaling pathway.

Diagnostic Accuracy of the HAS-BLED Bleeding Score in VKA- or DOAC-Treated Patients With Atrial Fibrillation: A Systematic Review and Meta-Analysis.

Background: Several bleeding risk assessment models have been developed in atrial fibrillation (AF) patients with oral anticoagulants, but the most appropriate tool for predicting bleeding remains uncertain. Therefore, we aimed to assess the diagnostic accuracy of the Hypertension, Abnormal liver/renal function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly, Drugs/alcohol concomitantly (HAS-BLED) score compared with other risk scores in anticoagulated patients with AF. Methods: We comprehensively searched the PubMed and Embase databases until July 2021 to identify relevant pieces of literature. The predictive abilities of risk scores were fully assessed by the C-statistic, net reclassification improvement (NRI) and integrated discrimination improvement (IDI) values, calibration data, and decision curve analyses. Results: A total of 39 studies met the inclusion criteria. The C-statistic of the HAS-BLED score for predicting major bleeding was 0.63 (0.61-0.65) in anticoagulated patients regardless of vitamin k antagonists [0.63 (0.61-0.65)] and direct oral anticoagulants [0.63 (0.59-0.67)]. The HAS-BLED had the similar C-statistic to the Hepatic or renal disease, Ethanol abuse, Malignancy, Older, Reduced platelet count or function, Re-bleeding risk, Hypertension (uncontrolled), Anemia, Genetic factors, Excessive fall risk, Stroke (HEMORR2HAGES), the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA), the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT), the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF), or the Age, Biomarkers, Clinical History (ABC) scores, but significantly higher C-statistic than the Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke/transient ischemic attack history (CHADS2) or the Congestive heart failure/left ventricular ejection fraction ≤ 40%, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke/transient ischemic attack/thromboembolism history, Vascular disease, Age 65-74 years, Sex (female) (CHA2DS2-VASc) scores. NRI and IDI values suggested that the HAS-BLED score performed better than the CHADS2 or the CHA2DS2-VASc scores and had similar or superior predictive ability compared with the HEMORR2HAGES, the ATRIA, the ORBIT, or the GARFIELD-AF scores. Calibration and decision curve analyses of the HAS-BLED score compared with other scores required further assessment due to the limited evidence. Conclusion: The HAS-BLED score has moderate predictive abilities for bleeding risks in patients with AF regardless of type of oral anticoagulants. Current evidence support that the HAS-BLED score is at least non-inferior to the HEMORR2HAGES, the ATRIA, the ORBIT, the GARFIELD-AF, the CHADS2, the CHA2DS2-VASc, or the ABC scores.

Meta-analysis of type 1 diabetes mellitus and risk of cardiovascular disease.

BACKGROUND: Individuals with diabetes have a high risk of cardiovascular disease (CVD). However, the association between type 1 diabetes mellitus (T1DM) and the risk of CVD has not been well addressed. This meta-analysis aimed to investigate the association between T1DM and CVD. METHODS: We searched the PubMed and EMBASE for studies that examined the association between T1DM and CVD until October 2020. We calculated the pooled risk ratios (RRs) with confidence intervals (CIs) from individual studies based on a random-effects model. RESULTS: We included 10 observational studies involving 166,027 patients with T1DM, and individuals were matched controls from the general population. Among T1DM patients, the RR of CVD was 5.09 (95% CI, 3.72-6.96), of coronary heart disease (CHD) was 9.38 (95% CI, 5.56-15.82), and of myocardial infarction was 6.37 (95% CI, 3.81-10.66). The RR of heart failure was 4.29 (95% CI, 3.54-5.19), of atrial fibrillation was 1.36 (95% CI, 1.17-1.59), and of stroke was 4.08 (95% CI, 3.42-4.86). Moreover, there was an increased RR among females for CHD, CVD, myocardial infarction, and stroke associated with T1DM. CONCLUSIONS: This study suggests that T1DM is associated with an increased risk of several types of CVD. However, the possible mechanisms for the increased risk of CVD remain unclear.

Lycopene protects against pressure overload-induced cardiac hypertrophy by attenuating oxidative stress.

Oxidative stress is considered an important pathogenic process of cardiac hypertrophy. Lycopene is a kind of carotenoid antioxidant that protects the cardiovascular system, so we hypothesized that lycopene might inhibit cardiac hypertrophy by attenuating oxidative stress. Phenylephrine and pressure overload were used to set up the hypertrophic models in vitro and in vivo respectively. Our data revealed that treatment with lycopene can significantly block pressure overload-induced cardiac hypertrophy in in vitro and in vivo studies. Further studies demonstrated that lycopene can reverse the increase in reactive oxygen species (ROS) generation during the process of hypertrophy and can retard the activation of ROS-dependent pro-hypertrophic MAPK and Akt signaling pathways. In addition, protective effects of lycopene on the permeability transition pore opening in neonatal cardiomyocytes were observed. Moreover, we demonstrated that lycopene restored impaired antioxidant response element (ARE) activity and activated ARE-driven expression of antioxidant genes. Consequently, our findings indicated that lycopene inhibited cardiac hypertrophy by suppressing ROS-dependent mechanisms.

Curcumin suppresses cell growth and invasion and induces apoptosis by down-regulation of Skp2 pathway in glioma cells.

Studies have demonstrated that curcumin exerts its tumor suppressor function in a variety of human cancers including glioma. However, the exact underlying molecular mechanisms remain obscure. Emerging evidence has revealed that Skp2 (S-phase kinase associated protein 2) plays an oncogenic role in tumorigenesis. Therefore, we aim to determine whether curcumin suppresses the Skp2 expression, leading to the inhibition of cell growth, invasion, induction of apoptosis, and cell cycle arrest. To this end, we conducted multiple methods such as MTT assay, Flow cytometry, Wound healing assay, invasion assay, RT-PCR, Western blotting, and transfection to explore the functions and molecular insights of curcumin in glioma cells. We found that curcumin significantly inhibited cell growth, suppressed cell migration and invasion, induced apoptosis and cell cycle arrest in glioma cells. Furthermore, we observed that overexpression of Skp2 promoted cell growth, migration, and invasion, whereas depletion of Skp2 suppressed cell growth, migration, and invasion and triggered apoptosis in glioma cells. Mechanistically, we defined that curcumin markedly down-regulated Skp2 expression and subsequently up-regulated p57 expression. Moreover, our results demonstrated that curcumin exerts its antitumor activity through inhibition of Skp2 pathway. Collectively, our findings suggest that targeting Skp2 by curcumin could be a promising therapeutic approach for glioma prevention and therapy.