Long noncoding RNA PVT1 regulates the proliferation and apoptosis of ARPE-19 cells in vitro via the miR-1301-3p/KLF7 axis.

Diabetic retinopathy (DR) as a frequent diabetic microvascular complication shows signs in one-third of diabetic patients. Long non-coding RNAs (lncRNAs) have drawn increasing attention because of their regulatory roles in DR. LncRNA plasmacytoma variant translocation 1 (PVT1) is documented to be upregulated in diabetes-related diseases, while its effects in DR remains unexplored. ARPE-19 cells under the treatment of high-glucose (HG) were used as DR cell models. The gene expression in ARPE-19 cells was examined using RT-qPCR. The viability and apoptosis of ARPE-19 cells were determined by MTT and TUNEL assays. The levels of inflammation-associated proteins or mRNA were measured using western blot. Luciferase reporter assay and RNA pull down assay were conducted for the exploration of the underlying mechanism of PVT1. PVT1 was revealed to be upregulated in DR cell models. Silencing of PVT1 promoted the viability and inhibited apoptosis of HG-stimulated ARPE-19 cells. The results revealed that PVT1 can bind with miR-1301-3p. PVT1 negatively modulated miR-1301-3p expression. Additionally, KLF7 was targeted by miR-1301-3p. PVT1 upregulated KLF7 expression by binding with miR-1301-3p. The silenced PVT1-mediated influence on cell viability and cell apoptosis was rescued by overexpression of KLF7. PVT1 suppresses proliferation and promotes apoptosis of ARPE-19 cells treated with HG in vitro by binding with miR-1301-3p to upregulate KLF7.

NORAD lentivirus shRNA mitigates fibrosis and inflammatory responses in diabetic cardiomyopathy via the ceRNA network of NORAD/miR-125a-3p/Fyn.

OBJECTIVE: Diabetic cardiomyopathy (DCM) is a serious complication of diabetes, but its pathogenesis is still unclear. This study investigated the mechanism of long noncoding RNA (lncRNA) NORAD in DCM. METHODS: Male leptin receptor-deficient (db/db) mice and leptin control mice (db/ +) were procured. DCM model was established by subcutaneous injection of angiotensin II (ATII) in db/db mice. NORAD lentivirus shRNA or Adv-miR-125a-3p was administered to analyze cardiac function, fibrosis, serum biochemical indexes, inflammation and fibrosis. Primary cardiomyocytes were extracted and transfected with miR-125a-3p mimic. The competing endogenous RNA (ceRNA) network of NORAD/miR-125a-3p/Fyn was verified. The levels of fibrosis- and inflammation-related factors were measured. RESULTS: In db/db mice treated with ATII, the body weight and serum biochemical indexes were increased, while the cardiac function was decreased, and inflammatory cell infiltration and fibrosis were induced. NORAD was upregulated in diabetic and DCM mice. The 4-week intravenous injection of NORAD lentivirus shRNA reduced body weight and serum biochemical indexes, improved cardiac function, and attenuated inflammation and fibrosis in DCM mice. NORAD acted as a sponge to adsorb miR-125a-3p, and miR-125a-3p targeted Fyn. Intravenous injection of miR-125a-3p adenovirus improved cardiac function and fibrosis and reduced inflammatory responses in DCM mice. Co-overexpression of miR-125-3p and Fyn partly reversed the improving effect of miR-125-3p overexpression on cardiac fibrosis in DCM mice. CONCLUSION: NORAD lentivirus shRNA improved cardiac function and fibrosis and reduced inflammatory responses in DCM mice via the ceRNA network of NORAD/miR-125a-3p/Fyn. These findings provide a valuable and promising therapeutic target for the treatment of DCM.

Niclosamide and its derivative DK-520 inhibit RANKL-induced osteoclastogenesis.

Niclosamide is a potent inhibitor of osteoclastogenesis and bone remodeling. DK-520 is an acyl derivative of Niclosamide and significantly increased both the plasma concentration and the duration of exposure of Niclosamide when dosed orally. However, at present the effect of DK-520 on osteoclastogenesis has not been reported. Here, we investigated whether DK-520 can regulate receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis of bone marrow macrophages (BMMs) in vitro. Following induction of BMMs with RANKL for three days, we detected differentiated osteoclasts with typical morphology and high levels of tartrate-resistant acid phosphatase (TRAP), RANKL, and cathepsin K (CTSK) expression. Treatment with either Niclosamide or DK-520 did not affect the viability of osteoclast precursors (OCPs), but significantly inhibited RANKL-induced transdifferentiation of macrophages into OCPs, particularly in the early stage of osteoclastogenesis. Both Niclosamide and DK-520 significantly decreased the relative levels of transcription factor PU.1 mRNA transcripts and dendritic cell-specific transmembrane protein (DC-STAMP), but not v-ATPasev0 d2 protein expression in OCPs. In addition, the inhibitory effect of DK-520 on osteoclastogenesis is realized through impairment of the NF-kB (nuclear factor-κB) and MAPK (mitogen-activated protein kinase) signaling pathways. These results demonstrate that DK-520, like Niclosamide, effectively inhibits the early stage of osteoclastogenesis. The findings presented here, together with its increased oral plasma concentrations and bioavailability, suggest that DK-520 may be a promising drug candidate for treatment of osteoclast-related diseases.

Sex differences in the association between marital status and the risk of cardiovascular, cancer, and all-cause mortality: a systematic review and meta-analysis of 7,881,040 individuals.

Purpose: To ascertain whether sex differences exist in the relationship between marital status and cardiovascular diseases (CVD), coronary heart disease (CHD), cancer and all-cause mortality in the general population and to explore the potential effect of age, location, the duration of follow-up and publication years on these outcomes. Methods: A systematic search was performed in PubMed and EMBASE from inception through to April 2018 and review of references to obtain sex-specific relative risks and their 95% confidence intervals. These were used to derive the women-to-men ratio of RRs (RRR) and 95% CI for each study. RRs and RRRs for each outcome were then pooled using random effects inverse-variance weighted meta-analysis. Results: Twenty-one studies with 7,891,623 individuals and 1,888,752 deaths were included in the meta-analysis. Compared with married individuals, being unmarried was significantly associated with all-cause, cancer, CVD and coronary heart disease mortalities for both sexes. However, the association with CVD and all-cause mortality was stronger in men. Being divorced/separated was associated with a higher risk of all-cause mortality in men and a stronger risk of cancer and CVD mortality. The pooled ratio for women versus men showed 31 and 9% greater risk of stroke mortality and all-cause mortality associated with never married in men than in women. Conclusions: Being unmarried conferred higher risk of stroke and all-cause mortality for men than women. Moreover, divorced/separated men had higher risk of cancer mortality and CVD mortality. Further studies are warranted to clarify the biological, behavioral, and/or social mechanisms involved in sex differences by these associations.

Sex differences in the association between diabetes and risk of cardiovascular disease, cancer, and all-cause and cause-specific mortality: a systematic review and meta-analysis of 5,162,654 participants.

BACKGROUND: Studies have suggested sex differences in the mortality rate associated with diabetes. We conducted a meta-analysis to estimate the relative effect of diabetes on the risk of all-cause, cancer, cardiovascular disease (CVD), infectious disease, and respiratory disease mortality in women compared with men. METHODS: Studies published from their inception to April 1, 2018, identified through a systematic search of PubMed and EMBASE and review of references. We used the sex-specific RRs to derive the women-to-men ratio of RRs (RRR) and 95% CIs from each study. Subsequently, the RRR for each outcome was pooled with random-effects meta-analysis weighted by the inverse of the variances of the log RRRs. RESULTS: Forty-nine studies with 86 prospective cohorts met the inclusion criteria and were eligible for analysis. The pooled women-to-men RRR showed a 13% greater risk of all-cause mortality associated with diabetes in women than in men (RRR 1.13, 95% CI 1.07 to 1.19; P < 0.001). The pooled multiple-adjusted RRR indicated a 30% significantly greater excess risk of CVD mortality in women with diabetes compared with men (RRR 1.30, 95% CI 1.13 to 1.49; P < 0.001). Compared with men with diabetes, women with diabetes had a 58% greater risk of coronary heart disease (CHD) mortality, but only an 8% greater risk of stroke mortality (RRRCHD 1.58, 95% CI 1.32 to 1.90; P < 0.001; RRRstroke 1.08, 95% CI 1.01 to 1.15; P < 0.001). However, no sex differences were observed in pooled results of populations with or without diabetes for all-cancer (RRR 1.02, 95% CI 0.98 to 1.06; P = 0.21), infectious (RRR 1.13, 95% CI 0.90 to 1.38; P = 0.33), and respiratory mortality (RRR 1.08, 95% CI 0.95 to 1.23; P = 0.26). CONCLUSIONS: Compared with men with the same condition, women with diabetes have a 58% and 13% greater risk of CHD and all-cause mortality, respectively, although there was a significant heterogeneity between studies. This points to an urgent need to develop sex- and gender-specific risk assessment strategies and therapeutic interventions that target diabetes management in the context of CHD prevention.

The prevalence of thyroid nodules in northwest China and its correlation with metabolic parameters and uric acid.

This study aimed to estimate the prevalence of thyroid nodules (TN) and investigate its correlation with metabolic parameters, especially uric acid (UA) in northwest Chinese population. We conducted a large cross-sectional survey with 67,781 residents (33,020 men, 34,761 women), aged from 18 to 86 years in Shanxi, China, from January 2012 to December 2014. A thyroid ultrasound examination was performed with number and size of nodules being recorded. Metabolic parameters including body mass index (BMI), blood pressure (BP), triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), fasting glucose (FG), and uric acid (UA) were also examined. Our study revealed that approximately 30.7% of men and 39.9% of women in Northwest China had TN, about half of which were multi-nodularity and a quarter of their TN larger than 1 cm. The prevalence of TN increased with aging and increasing BMI, and metabolic disorders, which also related to the increased incident of multi-nodularity and larger TN. Serum UA appeared to be a protective factor for TN in men older than 30 years, but a risk factor in both men younger than 30 years and women older than 30 years. This phenomenon needs to be further investigated.