The interaction effects of risk factors for hypertension in adults: a cross-sectional survey in Guilin, China.

BACKGROUND: The prevalence of hypertension in adults is increasing each year and has become a main public health issue worldwide. We must consider the impact of both individual factors and interactions among these factors on hypertension in adults. This study was designed to elucidate the clinical and metabolic characteristics of the prevalence of hypertension in adults and to explore the risk factors and interactions among these factors in adults with hypertension. METHODS: We used overall random sampling to conduct a cross-sectional survey of 6660 individuals undergoing a health check from July to November 2012, the subjects were aged 20 to 89 years, including 3480 men and 3180 women. The survey content included a questionnaire, anthropometry, laboratory measurements, and liver Doppler ultrasonography. The clinical and metabolic characteristics were compared between the cases (adult hypertensive patients) and the controls (normotensives). The classification tree model and the non-conditional logistic regression were used to analyze the interactions of risk factors for hypertension in adults. RESULTS: In total, 1623 adult hypertensive patients (940 men and 683 women) were detected. The results showed that adult hypertensive patients were older and had higher levels of systolic blood pressure, diastolic blood pressure, body mass index, fasting plasma glucose, uric acid, triglycerides, total cholesterol, low-density lipoprotein cholesterol, and prevalence of non-alcoholic fatty liver disease (P < 0.001). The classification tree model comprising 5 layers, 39 nodes, and 20 terminal nodes showed that two variables, age and BMI, were closely related to hypertension in adults. The area under the receiver operating characteristic curve for classification tree model was 81.6 % (95 % CI: 80.6 % ~ 82.5 %). Both univariate and multivariate logistic regression analyses revealed that advanced age and high BMI had a significant positive interaction in terms of hypertension in adults. After controlling for confounding factors, the percentage of attributed interaction was 47.62 %. CONCLUSIONS: This study showed that age, BMI, UA, TG, and TC were closely associated with the risk of hypertension in adults, and the positive interaction effect between advanced age and high BMI was an important risk factor for the prevalence of hypertension in adults.

The Role of Non-coding RNAs in Diabetic Nephropathy-Related Oxidative Stress.

Diabetic nephropathy (DN) is one of the main complications of diabetes and the main cause of diabetic end-stage renal disease, which is often fatal. DN is usually characterized by progressive renal interstitial fibrosis, which is closely related to the excessive accumulation of extracellular matrix and oxidative stress. Non-coding RNAs (ncRNAs) are RNA molecules expressed in eukaryotic cells that are not translated into proteins. They are widely involved in the regulation of biological processes, such as, chromatin remodeling, transcription, post-transcriptional modification, and signal transduction. Recent studies have shown that ncRNAs play an important role in the occurrence and development of DN and participate in the regulation of oxidative stress in DN. This review clarifies the functions and mechanisms of ncRNAs in DN-related oxidative stress, providing valuable insights into the prevention, early diagnosis, and molecular therapeutic targets of DN.

Atorvastatin Regulates MALAT1/miR-200c/NRF2 Activity to Protect Against Podocyte Pyroptosis Induced by High Glucose.

BACKGROUND: Diabetic nephropathy (DN) is one of the main complications of diabetes mellitus (DM), which leads to the long-term loss of kidney functions. Long noncoding RNAs (LncRNAs) can alleviate DN by interacting with microRNAs (miRNAs). In this work, we aimed to explore the effects of the MALAT1/miR-200c/NRF2 regulatory axis on the pyroptosis and oxidative stress (Oxidative stress, OS) of renal podocytes in high glucose (HG) environment and whether the lipid-lowering drug atorvastatin (AT) can relieve renal OS through this approach. METHODS: MPC-5, a mouse podocyte cell line, was induced by HG as a cell model. The protein expressions of caspase-1, GSDMD, NLRP3, NRF2, etc. were detected by Western blotting and immunofluorescence, and the mRNA level of caspase-1, GSDMD, NLRP3, NRF2, MALAT1, miR-200c was tested by qRT-PCR. The cell pyroptosis of podocytes treated with AT was verified by CCK-8 or flow cytometry. The levels of Malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) were measured by spectrophotometer, respectively. RESULTS: The caspase-1 was upregulated in time-dependent manner and got the peak at 48 h and 30 mmol/L respectively in MPC-5 cells treated with HG. Further, the expression of GSDMD, MALAT1 and miR-200c were increased, while the level of NRF2, HO-1, OS-related indicators, were decreased simultaneously. Knockdown the MALAT1 protected MPC-5 cells from pyroptosis and OS induced by HG. However, overexpressing miR-200c in control-group cells increased pyroptosis and upregulated the OS level with HG culture medium. Further, atorvastatin protected MPC-5 cells from cell pyroptosis and downregulated the level of renal OS via attenuating the expression of MALAT1 and miR-200c. CONCLUSION: Atorvastatin protects podocyte cells via MALAT1/miR-200c/NRF2 signal pathway from pyroptosis and OS induced by HG.

Atorvastatin prevents glomerular extracellular matrix formation by interfering with the PKC signaling pathway.

Platelet-activating factor (PAF) promotes glomerular extracellular matrix (ECM) deposition, primarily through activation of the protein kinase C (PKC) pathway. The present study was designed to investigate whether atorvastatin, which mediates a protective effect against glomerular ECM deposition and diabetic neuropathy, may interfere with the PKC­transforming growth factor­ß1 (TGF­ß1) pathway in a model of human mesangial cells (HMCs) exposed to a high glucose (HG) and lysophosphatidylcholine (LPC) environment. HMCs were divided into three treatment groups: Control, high glucose and lysophosphatidylcholine (HG+LPC), and HG+LPC+atorvastatin. Cells were cultured for 24 h. The levels of the ECM­associated molecules collagen IV (Col IV) and fibronectin (Fn) in the supernatant were detected using an ELISA kit. PKC­ß1, TGF­ß1 and PAF­receptor gene expression was detected by reverse transcription­quantitative polymerase chain reaction. PKC­ß1 and TGF­ß1 protein expression was detected by western blotting, and the subcellular localization of PKC­ß1 was assessed using immunofluorescence. The results indicated that atorvastatin may reduce the secretion of ECM components (Fn and Col IV) in HMCs in a HG and LPC environment, by inhibiting the increase in PAF secretion and the activation of the PKC­TGF­ß1 signaling pathway.

High glucose/lysophosphatidylcholine levels stimulate extracellular matrix deposition in diabetic nephropathy via platelet­activating factor receptor.

Platelet-activating factor (PAF), protein kinase C (PKC)ßI, transforming growth factor (TGF)­ß1 and aberrant extracellular matrix (ECM) deposition have been associated with diabetic nephropathy (DN). However, the mechanistic basis underlying this association remains to be elucidated. The present study investigated the association among the aforementioned factors in a DN model consisting of human mesangial cells (HMCs) exposed to high glucose (HG) and lysophosphatidylcholine (LPC) treatments. HMCs were divided into the following treatment groups: Control; PAF; PAF+PKCßI inhibitor LY333531; HG + LPC; PAF + HG + LPC; and PAF + HG + LPC + LY333531. Cells were cultured for 24 h, and PKCßI and TGF­ß1 expression was determined using the reverse transcription­quantitative polymerase chain reaction and western blotting. The expression levels of the ECM­associated molecules collagen IV and fibronectin in the supernatant were detected using ELISA analysis. Subcellular localization of PKCßI was assessed using immunocytochemistry. PKCßI and TGF­ß1 expression was increased in the PAF + HG + LPC group compared with the other groups (P<0.05); however, this effect was abolished in the presence of LY333531 (P<0.05). Supernatant fibronectin and collagen IV levels were increased in the PAF + HG + LPC group compared with the others (P<0.05); this was reversed by treatment with LY333531 (P<0.05). In cells treated with PAF, HG and LPC, PKCßI was translocated from the cytosol to the nucleus, an effect which was blocked when PKCßI expression was inhibited (P<0.05). The findings of the present study demonstrated that PAF stimulated ECM deposition in HMCs via activation of the PKC­TGF­ß1 axis in a DN model.

LncRNAs: key players and novel insights into diabetes mellitus.

Long non-coding RNAs (LncRNAs) are a class of endogenous RNA molecules, which have a transcribing length of over 200 nt, lack a complete functional open reading frame (ORF), and rarely encode a functional short peptide. Recent studies have revealed that disruption of LncRNAs levels correlates with several human diseases, including diabetes mellitus (DM), a complex multifactorial metabolic disorder affecting more than 400 million people worldwide. LncRNAs are emerging as pivotal regulators in various biological processes, in the progression of DM and its associated complications, involving pancreatic ß-cell disorder, insulin resistance, and epigenetic regulation, etc. Further investigation into the mechanisms of action of LncRNAs in DM will be of great value in the thorough understanding of pathogenesis. However, prior to successful application of LncRNAs, further search for molecular biomarkers and drug targets to provide a new strategy for DM prevention, early diagnosis, and therapy is warranted.

CD4+ T cells and the Th1/Th2 imbalance are implicated in the pathogenesis of Graves' ophthalmopathy.

Graves' ophthalmopathy (GO) is considered to be an organ-specific autoimmune disease. However, the pathogenesis of GO is incompletely understood at the present time. To clarify the immunological differences between newly diagnosed GO and Graves' disease (GD) without ophthalmopathy or healthy controls (HC), we examined T-cell profile and the Th1/Th2 profile cell balance in GO (n=20), GD (n=20) and HC (n=20) using flow cytometry. We also assessed the influence of methimazole on the immunocyte profiles in patients with GO and GD and analyzed the relationship of the immunologic changes with CAS, FT3, FT4, TRAb, TMA and TGA among the three investigated groups. We report in this study that: 1) The percentage of CD4+ T cells and the ratio of CD4+/CD8+ cells were higher, but the population of CD8+ T cells was lower in both GO and GD than those of HC (P<0.05); 2) The percentage of CD8-/IFNgamma+ T cells (Th1) and the ratio of CD8-/IFNgamma+ to CD8-/IL-4+ T cells (Th1/Th2) in GO were considerably higher as compared to those in GD and HC (P<0.05). On the contrary, the population of Th1 cells, as well as the ratio of Th1/Th2 cells, was lower in GD than that of GO and HC (P<0.05); 3) There were no significant differences in T-cell profile and the Th1/Th2 cell balance in either GO or GD patients before and after methimazole treatment; 4) There was a positive correlation of Th1 cell percentage and the Th1/Th2 cell ratio with the clinical activity score (CAS) in GO (P<0.05), whereas CAS in GO had no correlation with the T-cell profile, the percentage of Th2 cells, and TRAb (P>0.05); 5) T-cell subset and the ratio of Th1/Th2 cells did not correlate significantly with FT3, FT4, TRAb, TMA, or TGA in GO and GD (P>0.05). Finally, 6) there were no statistical differences in TRAb, TMA, and TGA between early GO and GD without ophthalmopathy (P>0.05). Collectively, these results indicate that the balance of Th1/Th2 in GO shifts to Th1 dominance and that the cellular immune responses mediated by the Th1-type CD4+ cells might play a dominant role in the pathogenesis of GO, and thus suggest that the Th1 cell percentage and the ratio of Th1/Th2 cell subsets may be potentially utilized as clinical parameters for disease activity, for monitoring the effectiveness of immunosuppressive treatment, or for developing immunospecific forms of therapy for Graves' ophthalmopathy.

The role of p38MAPK signal pathway in the neuroprotective mechanism of limb postconditioning against rat cerebral ischemia/reperfusion injury.

It has been reported that remote ischemic postconditioning was able to protect from a harmful ischemia occurring in brain. In the present study, we investigated the role of p38 MAPK signal pathway in the process of neuroprotection and anti-apoptosis following remote limb ischemic postconditioning on rat focal cerebral ischemia/reperfusion (I/R) model. Male Sprague-Dawley rats were divided randomly into four groups: the sham-operated group, I/R group, limb ischemic postconditioning (LPostC) group, and LPostC+SB203580 (p38 MAPK inhibitor) group. Focal ischemia was induced by transient middle cerebral artery occlusion. Limb ischemic postconditioning was implemented by brief cycles of femoral artery occlusion. At 24h after modeling, we analyzed the neurological deficit score, assessed the cerebral tissue morphology by H-E staining, and evaluated neuronal apoptosis by TUNEL staining. The protein expression levels of p-p38 or p-ATF2 (phospho-activating transcription factor 2) in the penumbra region were detected by western blotting or immunohistochemical staining. Our findings revealed that LPostC relieved cerebral ischemia/reperfusion injury by decreasing neurological score, improving neuronal morphological changes in the ischemic penumbra area, and reducing neuronal apoptosis. In addition, LPostC or LPostC+SB203580 attenuated the increase in p-p38 and p-ATF2 levels in ischemia/reperfusion brain tissue. These results indicate that the protective effects of LPostC against cerebral I/R injury may be related to the attenuation of neuronal apoptosis and the suppression of p38 MAPK-ATF2 pathway.

Renoprotective effect of atorvastatin on STZ-diabetic rats through attenuating kidney-associated dysmetabolism.

Atorvastatin (AT) has been alternatively used for managing diabetic complications in clinic. However, AT-related therapeutic potentiality remains relatively unexplored, especially in diabetic nephropathy. This study aimed to investigate the underlying potentiality that AT exerted on anti-diabetic nephropathy role against streptozotocin (STZ)-induced kidney injury in rats. STZ-diabetic rats were intragastrically administered with AT (10, 20 mg/kg/d) for consecutive 8 weeks. The effects of AT on body weight, levels of blood glucose, lipometabolism, redox state, cellular metabolism, regulator factor and kidney morphological changes were monitored by routine measurement, biochemistry assay, PT-PCR analysis, ultrastructural and pathological observations, respectively. Compared with the diabetic nephropathy rats, AT elevated the body weight of diabetic nephropathy rats (P<0.01), effectively reduced the blood glucose level (P<0.01), increased the levels of insulin and high-density lipoprotein cholesterol (HDL-C) in plasma (P<0.01), and decreased the 24 h urine protein content and serum concentrations of low-density lipoprotein cholesterol (LDL-C) (P<0.01). Meanwhile, increase in kidney tissue, the intrarenal activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were enhanced, while the malonaldehyde (MDA) content was reduced (P<0.01). In addition, the expression of transforming growth factor beta 1 (TGF-ß1) mRNA in kidney tissue was notably down-regulated (P<0.01). Furthermore, AT contributed to alleviating STZ-induced nephritic damages in rats. These results demonstrate that atorvastatin exerts the effective protective role against kidney injuries of STZ-induced diabetic nephropathy rat, which the underlying mechanisms are associated with ameliorating glyco, lipometabolism, enhancing antioxidant ability, and mitigating renal damage.