Small RNA modifications in Alzheimer's disease

BACKGROUND: While significant advances have been made in uncovering the aetiology of Alzheimer’s disease and related dementias at the genetic level, molecular events at the epigenetic level remain largely undefined. Emerging evidence indicates that small non-coding RNAs (sncRNAs) and their associated RNA modifications are important regulators of complex physiological and pathological processes, including aging, stress responses, and epigenetic inheritance. However, whether small RNAs and their modifications are altered in dementia is not known. METHODS: We performed LC-MS/MS–based, high-throughput assays of small RNA modifications in post-mortem samples of the prefrontal lobe cortices of Alzheimer’s disease (AD) and control individuals. We noted that some of the AD patients has co-occurring vascular cognitive impairment-related pathology (VaD). FINDINGS: We report altered small RNA modifications in AD samples compared with normal controls. The 15–25-nucleotide (nt) RNA fraction of these samples was enriched for microRNAs, whereas the 30–40-nt RNA fraction was enriched for tRNA-derived small RNAs (tsRNAs), rRNA-derived small RNAs (rsRNAs), and YRNA-derived small RNAs (ysRNAs). Interestingly, most of these altered RNA modifications were detected both in the AD and AD with co-occurring vascular dementia subjects. In addition, sequencing of small RNA in the 30–40-nt fraction from AD cortices revealed reductions in rsRNA-5S, tsRNA-Tyr, and tsRNA-Arg. INTERPRETATION: These data suggest that sncRNAs and their associated modifications are novel signals that may be linked to the pathogenesis and development of Alzheimer’s disease. FUNDING: NIH grants (R01HL122770, R01HL091905, 1P20GM130459, R01HD092431, P50HD098593, GM103440), AHA grant (17IRG33370128), Sigmund Gestetner Foundation Fellowship to P Kehoe

Short-term lifestyle education on obesity reduction in adolescents

BackgroundsObesity is increasing in adolescents in China. However, the awareness of obesity and prevention on related risk factors were not well known. We aim to assess the effectiveness of short-term health education intervention on obesity in Chinese adolescents.MethodsIn this study, 42 primary and secondary schools from Qingdao were randomly divided into the education and control groups. A total of 11,739 adolescents was included in the current study. The logistic regression was employed to assess odds ratio (OR) of education intervention on overweight and obesity prevalence adjusting for covariates.ResultsThe baseline prevalence of overweight and obesity was significantly higher in urban than in rural areas and in boys than in girls. After 1 year lifestyle intervention, the proportion of students with awareness of obesity was higher, meanwhile age-adjusted mean values of weight, body mass index, duration of watching TV and doing homework were lower in education group than control group. The corresponding figures were 43.6 [95% CI (confidence intervals); 43.3–43.9] kg versus 44.3 (95% CI; 44.0–44.6) kg, 18.6 (95% CI; 18.5–18.7) kg/m2 versus 18.9 (95% CI; 18.8–19.1) kg/m2, 1.3 (95% CI; 1.2–1.3) hours/d versus 1.4 (95% CI; 1.3–1.4) hours/d, and 1.5 (95% CI; 1.4–1.5) hours/d versus 1.8 (95% CI, 1.7–1.8) hours/d. The multivariable adjusted OR for combined prevalence of overweight and obesity was 0.85 (95% CI, 0.76–0.96) in education group as compared with control group.ConclusionShort-term health education intervention results in significantly higher reductions in obesity parameters and improvement in awareness in Chinese adolescents

Protective Effects of PARP-1 Knockout on Dyslipidemia-Induced Autonomic and Vascular Dysfunction in ApoE−/− Mice: Effects on eNOS and Oxidative Stress

The aims of this study were to investigate the role of poly(ADP-ribose) polymerase (PARP)-1 in dyslipidemia-associated vascular dysfunction as well as autonomic nervous system dysregulation. Apolipoprotein (ApoE)−/− mice fed a high-fat diet were used as a model of atherosclerosis. Vascular and autonomic functions were measured in conscious mice using telemetry. The study revealed that PARP-1 plays an important role in dyslipidemia-associated vascular and autonomic dysfunction. Inhibition of this enzyme by gene knockout partially restored baroreflex sensitivity in ApoE−/− mice without affecting baseline heart-rate and arterial pressure, and also improved heart-rate responses following selective blockade of the autonomic nervous system. The protective effect of PARP-1 gene deletion against dyslipidemia-induced endothelial dysfunction was associated with preservation of eNOS activity. Dyslipidemia induced PARP-1 activation was accompanied by oxidative tissue damage, as evidenced by increased expression of iNOS and subsequent protein nitration. PARP-1 gene deletion reversed these effects, suggesting that PARP-1 may contribute to vascular and autonomic pathologies by promoting oxidative tissue injury. Further, inhibition of this oxidative damage may account for protective effects of PARP-1 gene deletion on vascular and autonomic functions. This study demonstrates that PARP-1 participates in dyslipidemia-mediated dysregulation of the autonomic nervous system and that PARP-1 gene deletion normalizes autonomic and vascular dysfunctions. Maintenance of eNOS activity may be associated with the protective effect of PARP-1 gene deletion against dyslipidemia-induced endothelial dysfunction

The causal relationship between 41 inflammatory cytokines and hypothyroidism: bidirectional two-sample Mendelian randomization study

ObjectiveInvestigating the association between inflammatory cytokines and hypothyroidism remains challenging due to limitations in traditional observational studies. In this study, we employed Mendelian randomization (MR) to assess the causal relationship between 41 inflammatory cytokines and hypothyroidism.MethodInflammatory cytokines in 30,155 individuals of European ancestry with hypothyroidism and in a GWAS summary containing 8,293 healthy participants were included in the study for bidirectional two-sample MR analysis. We utilized inverse variance weighting (IVW), weighted median (WM), and Mendelian randomization-Egger (MR-Egger) methods. Multiple sensitivity analyses, including MR-Egger intercept test, leave-one-out analysis, funnel plot, scatterplot, and MR-PRESSO, were applied to evaluate assumptions.ResultsWe found evidence of a causal effect of IL-7 and macrophage inflammatory protein-1β (MIP-1β) on the risk of hypothyroidism, and a causal effect of hypothyroidism on several cytokines, including granulocyte colony-stimulating factor (G-CSF), IL-13, IL-16, IL-2rα, IL-6, IL-7, IL-9, interferon-γ-inducible protein 10 (IP10), monokine induced by interferon (IFN)-γ (MIG), macrophage inflammatory protein-1β (MIP-1β), stem cell growth factors-β (SCGF-β), stromal cell derived factor-1α (SDF-1α), and tumor necrosis factor-α (TNF-α).ConclusionOur study suggests that IL-7 and MIP-1β may play a role in the pathogenesis of hypothyroidism, and that hypothyroidism may induce a systemic inflammatory response involving multiple cytokines. These findings may have implications for the prevention and treatment of hypothyroidism and its complications. However, further experimental studies are needed to validate the causal relationships and the potential of these cytokines as drug targets

A genetic study of the NOS3 gene for ischemic stroke in a Chinese population

We recruited 560 unrelated patients with ischemic stroke and 153 unrelated controls to undertake a genetic analysis for association between the NOS3 gene and ischemic stroke. All the subjects were Chinese of Han descent. Because the NOS3 gene spans about 21 kb of DNA and contains 26 exons, we selected a single nucleotide polymorphism (SNP) rs3918181, an A to G base change located in intron 14 of the gene, as a DNA marker. PCR-based restriction fragment length polymorphism analysis was applied to genotype rs3918181 (RsaI site). The chi-square (χ2) goodness-of-fit test showed that the genotypic distributions of the marker were not deviated from Hardy-Weinberg equilibrium in both the patient group (χ2 = 0.166, p = 0.684) and the control group (χ2 = 0.421, p = 0.517). The cocaphase analysis showed allelic association of rs3918181 with ischemic stroke in males (χ2 = 4.04, p = 0.044, OR = 1.43, 95% CI 1.01∼2.02) and frequency of allele A was significantly higher in male patients than male control subjects. The χ2 test revealed genotypic association between rs3918181 and ischemic stroke in males (χ2 = 4.26, df = 1, p = 0.039, OR = 1.61, 95% CI 1.02∼2.53) but not in females. The present work suggests that rs3918181 is associated with ischemic stroke in male patients. This finding gives further evidence in support of the eNOS association with ischemic stroke in the Chinese population

Serum Uric Acid and Long-term Prognosis in Patients with Acute Myocardial Infarction

BackgroundIt is still controversial whether or not serum uric acid, a key risk for coronary heart disease, is significantly associated with prognosis of acute myocardial infarction (AMI) . And there are rare large-scale and multicenter studies on serum uric acid and long prognosis of AMI in China.ObjectiveTo investigate the relationship between serum uric acid and long-term prognosis in AMI patients.MethodsOne thousand and ninety-eight AMI patients from 9 hospitals (Chengdu First People's Hospital, Chengdu Second People's Hospital, the Third People's Hospital of Chengdu, the First Affiliated Hospital of Chengdu Medical College, Dujiangyan Medical Center, Pidu District People's Hospital, Chengdu, Shuangliu District First People's Hospital, Jintang First People's Hospital, the People's Hospital of Pengzhou) in Chengdu during September 2016 to July 2019 were consecutively reSScruited. Baseline data were collected via the electronic medical record system of each hospital by trained professionals, including: (1) demographic data: age, gender, prevalence of smoking; (2) clinical complications and related information: hypertension, diabetes, blood pressure, heart rate, Killip class, AMI type (NSTEMI or STEMI) , prevalence of percutaneous coronary intervention (PCI) ; (3) laboratory parameters: serum SScreatinine (Scr) , uric acid (UA) , triglyceride (TG) , total cholesterol (TC) , low-density lipoprotein cholesterol (LDL-C) , high-density lipoprotein cholesterol (HDL-C) , estimated glomerular filtration rate (eGFR) ; (4) post-discharge medication: aspirin, clopidogrel/tigrelol, statins, Beta-blockers, ACEI/ARB, diuretics. Baseline data were compared between patients with and without major adverse cardiovascular and cerebrovascular events (MACCE) during post-discharge follow-up. Then, prognosis was compared aSScross UA tertile subgroups〔A: UA<420 μmol/L; B: 420 ≤UA<480 μmol/L; C: UA≥480 μmol/L〕 stratified by the diagnostic SScriteria for hyperuricemia in Guideline for the Diagnosis and Management of Hyperuricemia and Gout in China (2019) .ResultsThe median follow-up time for all participants was 14.5 (9.2, 20.7) months. Of all cases, 173 were found with MACCE, and 366 with hyperuricemia. Compared with those without MACCE, patients with MACCE had greater average age, Scr and UA, and heart rate, and higher female ratio, higher prevalence of hypertension, diabetes, use of diuretics, and Killip class≥3, but lower prevalence of PCI treatment (P<0.05) . Subgroup A had much lower incidence of MACCE, all-cause death and cardiac death than subgroup B or C (P<0.01) . Kaplan-Meier survival analysis indicated that the cumulative incidence of MACCE, all-cause death and cardiac death either in subgroup B or C was higher than that in subgroup A (P<0.01) . Cox regression analysis showed that Killip class ≥3〔HR=1.812, 95%CI (1.215, 2.700) 〕, older age〔HR=1.045, 95%CI (1.031, 1.059) 〕 and higher UA level〔 (≥420 μmol/L but<480 μmol/L: HR=1.614, 95%CI (1.062, 2.455) ; ≥480 μmol/L: HR=1.949, 95%CI (1.327, 2.862) 〕 were independent risk factors for long-term MACCE events in patients with AMI (P<0.05) . Serum UA had an AUC (95%CI) of 0.578 (0.548, 0.607) with 0.387 sensitivity, and 0.779 specificity in predicting long-term incidence of MACCE, an AUC (95%CI) of 0.645 (0.616, 0.674) with 0.598 sensitivity, and 0.670 specificity in predicting long-term incidence of all-cause death, and an AUC (95% CI) of 0.653 (0.624, 0.681) with 0.534 sensitivity, and 0.761 specificity in predicting long-term incidence of cardiac death.ConclusionElevated serum UA was associated with higher risk of long-term adverse events in AMI patients. Serum UA may be used as a predictor for long-term MACCE events in such patients

The role of the SGK3/TOPK signaling pathway in the transition from acute kidney injury to chronic kidney disease

Introduction: Profibrotic phenotype of renal tubular epithelial cells (TECs) featured with epithelial to mesenchymal transition (EMT) and profibrotic factors secretion, and aberrant accumulation of CD206+ M2 macrophages are the key points in the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). Nevertheless, the underlying mechanisms involved remain incompletely understood. Serum and glucocorticoid-inducible kinase (SGK) is a serine/threonine protein kinase, required for intestinal nutrient transport and ion channels modulation. T-LAK-cell-originated protein kinase (TOPK) is a member of the mitogen activated protein kinase family, linked to cell cycle regulation. However, little is known about their roles in AKI-CKD transition.Methods: In this study, three models were constructed in C57BL/6 mice: low dose and multiple intraperitoneal injection of cisplatin, 5/6 nephrectomy and unilateral ureteral obstruction model. Rat renal tubular epithelial cells (NRK-52E) were dealt with cisplatin to induce profibrotic phenotype, while a mouse monocytic cell line (RAW264.7) were cultured with cisplatin or TGF-β1 to induce M1 or M2 macrophage polarization respectively. And co-cultured NRK-52E and RAW264.7 through transwell plate to explore the interaction between them. The expression of SGK3 and TOPK phosphorylation were detected by immunohistochemistry, immunofluorescence and western blot analysis.Results:In vivo, the expression of SGK3 and p-TOPK were gradually inhibited in TECs, but enhanced in CD206+ M2 macrophages. In vitro, SGK3 inhibition aggravated epithelial to mesenchymal transition through reducing the phosphorylation state of TOPK, and controlling TGF-β1 synthesis and secretion in TECs. However, SGK3/TOPK axis activation promoted CD206+ M2 macrophage polarization, which caused kidney fibrosis by mediating macrophage to myofibroblast transition (MMT). When co-cultured, the TGF-β1 from profibrotic TECs evoked CD206+ M2 macrophage polarization and MMT, which could be attenuated by SGK3/TOPK axis inhibition in macrophages. Conversely, SGK3/TOPK signaling pathway activation in TECs could reverse CD206+ M2 macrophages aggravated EMT.Discussion: We revealed for the first time that SGK3 regulated TOPK phosphorylation to mediate TECs profibrotic phenotype, macrophage plasticity and the crosstalk between TECs and macrophages during AKI-CKD transition. Our results demonstrated the inverse effect of SGK3/TOPK signaling pathway in profibrotic TECs and CD206+ M2 macrophages polarization during the AKI-CKD transition