Mito-Tempo alleviates ox-LDL-provoked foam cell formation by regulating Nrf2/NLRP3 signaling.

Our previous studies have demonstrated that Mito-Tempol (also known as 4-hydroxy-Tempo), a mitochondrial reactive oxygen species scavenger, alleviates oxidized low-density lipoprotein (ox-LDL)-triggered foam cell formation. Given the effect of oxidative stress on activating the NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome, which promotes foam cell formation, we aimed to explore whether Mito-Tempo inhibits ox-LDL-triggered foam cell formation by regulating NLRP3 inflammasome. The results revealed that Mito-Tempo re-activated Nrf2 and alleviated macrophage foam cell formation induced by ox-LDL, whereas the effects were reversed by ML385 (a specific Nrf2 inhibitor). Mito-Tempo restored the expression and nuclear translocation of Nrf2 by decreasing ox-LDL-induced ubiquitination. Furthermore, Mito-Tempo suppressed ox-LDL-triggered NLRP3 inflammasome activation and subsequent pyroptosis, whereas the changes were blocked by ML385. Mito-Tempo decreased lipoprotein uptake by inhibiting CD36 expression and suppressed foam cell formation by regulating the NLRP3 inflammasome. Taken together, Mito-Tempo exhibits potent anti-atherosclerotic effects by regulating Nrf2/NLRP3 signaling.

Gut microbiota as a promising therapeutic target for age-related sarcopenia.

Sarcopenia is characterized by a progressive loss of skeletal muscle mass and function with aging. Recently, sarcopenia has been shown to be closely related with gut microbiota. Strategies such as probiotics and fecal microbiota transplantation have shown potential to ameliorate the muscle loss. This review will focus on the age-related sarcopenia, in particular on the relationship between gut microbiota and age-related sarcopenia, how gut microbiota is engaged in sarcopenia, and the potential role of gut microbiota in the treatment of age-related sarcopenia.

Appraisal of Non-Cardiovascular Safety for Sodium-Glucose Co-Transporter 2 Inhibitors: A Systematic Review and Meta-Analysis of Placebo-Controlled Randomized Clinical Trials.

Background: Whereas the cardiovascular safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors has been well reported, there is limited data from controlled clinical trials regarding the non-cardiovascular safety. This was the focus of our study. Methods and Findings: We systematically searched MEDLINE, EMBASE, and Cochrane Library (5th Sep 2018) for randomized controlled trials (RCTs) that reported safety data for SGLT2 inhibitors and placebo. Relative risks (RRs) and their 95% confidence intervals (CIs) were pooled using random-effects models. Seventy RCTs (83 studies enrolling 36,958 patients in 78 publications) were identified. SGLT2 inhibitors were associated with a lower risk of serious adverse events (RR 0.90, 95% CI 0.86 to 0.94, P < 0.001), death (RR 0.78, 95% CI 0.64 to 0.94, P < 0.05), gastroenteritis (RR 0.38, 95% CI 0.20 to 0.72, P < 0.05), arthralgia (RR 0.72, 95% CI 0.54 to 0.96, P < 0.05), hypertension (RR 0.61, 95% CI 0.50 to 0.75, P < 0.001), and edema/peripheral edema (RR 0.49, 95% CI 0.33 to 0.72, P < 0.001) compared to placebo. SGLT2 inhibitors were associated with higher risk of infections compared to placebo (RR 1.27, 95% CI 1.17 to 1.37, P < 0.001), especially for genital mycotic infection (GMI) (RR 3.71, 95% CI 3.19 to 4.32, P < 0.001). Other significant effects were observed for osmotic diuresis-related AEs (RR 2.73, 95% CI 2.20 to 3.40, P < 0.001), volume-related AEs (RR 1.26, 95% CI 1.08 to 1.46, P < 0.05), renal-related AEs (RR 1.36, 95% CI 1.02 to 1.80, P < 0.05), hypoglycemia (RR 1.18, 95% CI 1.10 to 1.26, P < 0.001), and increased blood ketone bodies (RR 2.00, 95% CI 1.01 to 3.97, P < 0.05). Subgroup and sensitivity analyses strengthened the robustness of primary results. Conclusion: Results from RCTs confirmed lower risk of death, serious adverse events, hypertension, and edema associated with type 2 diabetes mellitus (T2DM) patients treated with SGLT2 inhibitors when compared with placebo. The use of SGLT2 inhibitors were associated with higher risk of infection, osmotic diuresis, volume depletion effects, renal related AEs, and higher blood ketone bodies when compared with placebo.

Young patient with arterial thrombosis and skin changes as the onset manifestations: POEMS syndrome.

POEMS syndrome is a rare multi-systemic disease characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes. Arterial thrombosis is a distinctively unusual feature in patients with POEMS syndrome. We report a 33-year-old man with intermittent amaurosis of left eye and skin changes as the onset manifestations, who was finally confirmed as having POEMS syndrome. Most notably, this was a young man without high risk factors of arterial thrombosis and no monoclonal protein was detected until the repeated measurement later. This case evokes the need to consider the diagnosis of POEMS syndrome for young patients with symptoms of arterial thrombosis but no high risk factors of thrombosis.

Association of Sst I polymorphism in apolipoprotein C3 gene with hypertriglyceridaemia in coronary atherosclerotic heart disease and type II diabetes mellitus in Chinese population.

Several independent population studies have reported that the apolipoprotein C3 (APOC3) Sst I polymorphism in apolipoprotein (apo) A1 /C3/A4/A5 gene cluster is associated with Hypertriglyceridaemia (HTG). HTG is a known risk factor for coronary atherosclerotic heart disease(CHD)and type II diabetes mellitus (non-insulin-dependent diabetes, NIDDM). The aim of this study is to investigate the association between the APOC3 gene Sst I polymorphism and the hypertriglyceridaemia in CHD and NIDDM in Chinese population. The genotype and allele frequencies of APOC3 Sst I polymorphism (S1/S2) were analyzed by PCR-restriction fragment length polymorphism in 267 CHD patients, 246 NIDDM patients and 491 unrelated healthy control individuals. The frequencies of minor allele 52 in CHD group, NIDDM group and control group were 0.301, 0.307 and 0.286, respectively. Compared with controls, there was no significant difference in distribution of genotype and allele frequencies of Sst I polymorphic site in CHD patients and NIDDM patients, respectively. However, the frequency of S1 S2 genotype in the HTG subgroup was significantly higher than that of the normal triglyceridaemia subgroup (NTG) in CHD patients (0.542 > 0.357, chi2 = 8.77, P = 0.0124). In NIDDM patients, the frequency of S2 S2 genotype in the HTG subgroup was significantly high, compared with that in the NTG subgroup (0.200 > 0.055, chi2 = 20.21, P = 0.0000), and there was significantly difference in the distribution of allele frequencies in subgroups of NTG and HTG (chi2 = 19.86, P = 0.0000). The level of triglyceride (TG) in S1 S2 genotype patients of CHD group were higher than that of S1 S1 genotype patients (P = 0.036). In NIDDM and controls groups, S2 S2 genotype individuals exhibited a significant increase in plasma TG concentrations, respectively compared with S1 S1 and S1 S2 genotype individuals of each group (P < 0.01). The minor allele S2, which was associated with both CHD with HTG and NIDDM with HTG and may contribute to the susceptibility of hypertriglyceridemia in CHD and NIDDM patients, may be one of the genetic predispositions to both CHD with HTG and NIDDM with HTG in Chinese population.

Insulin resistance caused by lipotoxicity is related to oxidative stress and endoplasmic reticulum stress in LPL gene knockout heterozygous mice.

OBJECTIVE: To investigate the correlation of hypertriglyceridemia with abnormal glucose metabolism and insulin resistance. METHODS: Lipid and glucose metabolism, whole-body and tissue-specific insulin sensitivity, genes and proteins related with oxidative stress and endoplasmic reticulum (ER) stress were compared between LPL+/- and control mice at different weeks of age. RESULTS: 16-50-week LPL+/- mice had increased body weight compared with their respective controls. Fat mass in visceral adipose tissue (VAT) of 16 and 28-week LPL+/- mice were twice more than their control littermates, and 50-week LPL+/- mice showed the same trend of increase. Plasma lipids were higher in 16-50-week LPL+/- mice. 28- and 50-week LPL+/- mice had elevated tissue lipid accumulation (liver, skeletal muscle, pancreas) and impaired glucose tolerance, while 16-week LPL+/- mice showed no differences. Homeostasis model assessment of insulin resistance for 28 and 50-week LPL+/- mice were twofold greater, whereas that for 16-week LPL+/- mice had no change. Insulin-stimulated phosphorylated Akt (Ser473) in VAT of 28-week LPL+/- mice decreased by 80.6% (p = 0.001), and that in liver and skeletal muscle decreased by 62.4% (P < 0.001) and 51.8% (p = 0.005) respectively. Then we found that plasma malondialdehyde and reactive oxygen species levels in liver and skeletal muscle of LPL+/- mice were elevated. Increased ER stress biomarkers were also detected in liver and VAT of 28-week LPL+/- mice. CONCLUSIONS: Systemic LPL deletion results in impaired glucose tolerance, whole-body and tissue-specific insulin resistance, which is associated with tissue lipid deposition in various insulin target tissues. Furthermore, the activation of oxidative stress and ER stress may play an important role in the development of tissue-specific and systemic insulin resistance.

[Atherogenic index of plasma is associated with carotid intima-media thickness in patients with type 2 diabetes mellitus].

OBJECTIVE: To investigate the relationship of atherogenic index of plasma (AIP), an indirect indicator of LDL particle size, to carotid intima-media thickness (IMT) in patients with type 2 diabetes mellitus (T2DM) among Chinese Han nationality population. METHODS: One hundred and seventy-nine type 2 diabetic patients and 87 healthy subjects from a population of Chinese Han nationality were included. The AIP is the logarithmically transformed ratio of TG/HDL-c, which may serve as a surrogate method for assessing LDL particle size. The carotid IMT, as a surrogate continuous variable for macroangiopathy, was measured by B-mode ultrasonography in type 2 diabetic patients. The patients with T2DM were divided into three subgroups according to the IMT: IMT < or = 0.65 mm, 0.65 mm < IMT < or = 1.1 mm and IMT > 1.1 mm. The Student-t test, one-way analysis of variance, univariate and multivariate analyses were implemented. RESULTS: (1) In T2DM group the values of triglyeeride (TG) and AIP were significantly higher than those in control group respectively, and the HDL-c value of T2DM group was significantly lower than that of control group. (2) There was significant difference in the age, body mass index (BMI), waist-hip ratio (WHR), the duration of DM, triglyceride (TG), total cholesterol (TC), LDL-c, HDL-c, HbAlc, TG/HDL-c and AIP among the three subgroups; the HDL-c value was inversely related to the IMT of T2DM, and all the other risk factors were positively related to the IMT of T2DM. (3) Multivariate analysis by linear regression showed that the value of AIP was an important risk factor in the pathogenesis and progress of IMT in patients with T2DM. CONCLUSION: AIP value, an indirect indicator of LDL particle size, is an important risk factor in pathogenesis and progress of IMT in patients with T2DM.