It is widely believed that high density lipoproteincholesterol (HDL-C) functions to transport cholesterol from peripheral cells to the liver by reverse cholesterol transport (RCT), a pathway that may protect against atherosclerosis by clearing excess cholesterol from arterial cells. A cellular ATP binding cassette transporter called ABCA1 mediates the first step of RCT. NO-1886 has been proven to be highly effective at increasing HDL-C and reducing atherosclerosis. However, the mechanism of atherosclerosis inhibition for NO-1886 is not fully understood. In this study, the effects of NO-1886 on ABCA1 were investigated in high-fat/highsucrose/high-cholesterol-fed Chinese Bama minipigs. Administration of NO-1886 (0.1 g/kg body weight/day) in the diet for 5 months significantly reduced atherosclerosis lesions and significantly increased plasma HDL-C and apolipoprotein A-I levels. The mRNA and protein levels of ABCA1 in the liver, retroperitoneal adipose tissue, and aorta were increased by NO-1886 as well. Multivariate linear regression analysis showed that the levels of LPL in plasma and the levels of ABCA1 in aorta were independently associated with the atherosclerotic lesion area. In addition, NO-1886 upregulated liver X receptor a and affected the expression of scavenger receptor class B type I in the liver. These results demonstrate that the mechanism of atherosclerosis inhibition for NO-1886 is associated with its effect on ABCA1. (1) reported that a novel compound, NO-1886, possesses a potent LPL-enhancing activity. Administration of NO-1886 increased LPL activity in the postheparin plasma, adipose tissue, and myocardium in rats, with a concomitant reduction in plasma triglyceride (TG) level and increase of high density lipoprotein-cholesterol (HDL-C) level (2). LPL hydrolyzes chylomicron and VLDL to remnants and LDL, whereas cholesterol, apolipoproteins, and surface phospholipids released from TGrich lipoproteins fuse with smaller HDL particles, forming mature cholesterol-rich HDL particles. A negative relationship has been observed between the HDL-C concentration and the extent of atherosclerosis in many studies (3-5). One explanation for this protective effect of HDL against atherosclerosis is reverse cholesterol transport (RCT), the process by which cholesterol is removed from extrahepatic tissues and returned to the liver for conversion into bile acids and excretion into bile.The first crucial step in the RCT pathway is the movement of excess cellular cholesterol and phospholipid from cell membranes to nascent HDL particles (6, 7). ABCA1 plays a key role in this step. Subsequently, HDL particles act in conjunction with the cholesterol-esterifying enzyme, lecithin:cholesterol acyltransferase. Cholesteryl ester accumulating in HDL then is involved in a number of different fates: uptake in the liver in HDL containing apolipo-
To develop a minipig model of type 2 diabetes that simulates the common manifestations of the metabolic abnormalities and resembles
Background The association of asthma to the risk of mortality among coronavirus disease 2019 (COVID-19) patients is not clear. Objective The purpose of this study was to investigate the association between asthma and the risk of mortality among COVID-19 patients. Methods Systematic searches were performed through electronic databases including PubMed, EMBASE and Web of Science to identify the potential articles reporting adjusted effect estimates on the association of asthma with fatal COVID-19. A random-effects model was conducted to estimate the pooled effects. Sensitivity analysis, subgroup analysis, meta-regression, Begg’s test and Egger’s test were also performed. Results The overall results based on sixty-two studies with 2,457,205 cases reporting adjusted effect estimates demonstrated that COVID-19 patients with asthma had a significantly reduced risk of mortality compared with those without (15 cohort studies-829,670 patients, pooled hazard ratio (HR) = 0.88, 95% confidence interval (CI) [0.82-0.95], I 2 = 65.9%, P < 0.001; 34 cohort studies-1,008,015 patients, pooled odds ratio (OR) = 0.88, 95% CI [0.82-0.94], I 2 = 39.4%, P = 0.011; 11 cross-sectional studies-1,134,738 patients, pooled OR = 0.87, 95% CI [0.78-0.97], I 2 = 41.1%, P = 0.075). Subgroup analysis based on the types of adjusted factors indicated that COVID-19 patients with asthma had a significantly reduced risk of mortality among studies adjusting for demographic, clinical and epidemiologic variables (pooled OR = 0.87, 95% CI [0.83-0.92], I 2 = 36.3%, P = 0.013; pooled HR = 0.90, 95% CI [0.83-0.97], I 2 = 69.2%, P < 0.001), but not among studies only adjusting for demographic variables (pooled OR = 0.88, 95% CI [0.70-1.12], I 2 = 40.5%, P = 0.097; pooled HR = 0.82, 95% CI [0.64-1.06], I 2 = 0%, P = 0.495). Sensitivity analysis proved that our results were stable and robust. Both Begg’s test and Egger’s test indicated that potential publication bias did not exist. Conclusion Our data based on adjusted effect estimates indicated that asthma was significantly related to a reduced risk for COVID-19 mortality.
Insulin resistance and dyslipidemia are both considered to be risk factors for metabolic syndrome. Low levels of IGF1 are associated with insulin resistance. Elevation of low-density lipoprotein cholesterol (LDL-C) concomitant with depression of high-density lipoprotein cholesterol (HDL-C) increase the risk of obesity and type 2 diabetes mellitus (T2DM). Liver secretes IGF1 and catabolizes cholesterol regulated by the rate-limiting enzyme of bile acid synthesis from cholesterol 7a-hydroxylase (CYP7A1). NO-1886, a chemically synthesized lipoprotein lipase activator, suppresses diet-induced insulin resistance with the improvement of HDL-C. The goal of the present study is to evaluate whether NO-1886 upregulates IGF1 and CYP7A1 to benefit glucose and cholesterol metabolism. By using human hepatoma cell lines (HepG2 cells) as an in vitro model, we found that NO-1886 promoted IGF1 secretion and CYP7A1 expression through the activation of signal transducer and activator of transcription 5 (STAT5). Pretreatment of cells with AG 490, the inhibitor of STAT pathway, completely abolished NO-1886-induced IGF1 secretion and CYP7A1 expression. Studies performed in Chinese Bama minipigs pointed out an augmentation of plasma IGF1 elicited by a single dose administration of NO-1886. Long-term supplementation with NO-1886 recovered hyperinsulinemia and low plasma levels of IGF1 suppressed LDL-C and facilitated reverse cholesterol transport by decreasing hepatic cholesterol accumulation through increasing CYP7A1 expression in high-fat/high-sucrose/high-cholesterol diet minipigs. These findings indicate that NO-1886 upregulates IGF1 secretion and CYP7A1 expression to improve insulin resistance and hepatic cholesterol accumulation, which may represent an alternative therapeutic avenue of NO-1886 for T2DM and metabolic syndrome.
Introduction Smoking can cause muco-ciliary clearing dysfunction and poor pulmonary immunity, leading to more severe infection. We performed this study to explore the association between smoking and mortality of coronavirus disease 2019 (COVID-19) patients utilizing a quantitative meta-analysis on the basis of adjusted effect estimates. Methods We conducted a systematic search of the online databases including PubMed, Web of Science, Scopus and Embase. Only articles reporting adjusted effect estimates on the association between smoking and the risk of mortality among COVID-19 patients in English were included. Newcastle-Ottawa scale (NOS) was fitted to assess the risk of bias. A random-effects model was applied to calculate the pooled effect with the corresponding 95% confidence interval (CI). Results A total of 73 articles with 863,313 COVID-19 patients were included in this meta-analysis. Our results indicated that smoking was significantly associated with an increased risk for death in patients with COVID-19 (pooled relative risk = 1.19, 95% CI = 1.12-1.27). Sensitivity analysis indicated that our results were stable and robust. Conclusion Smoking was independently associated with an increased risk for mortality in COVID-19 patients.
Lack of significant association between dyslipidemia and COVID-19 mortality Recently, Aung et al. reported that distribution frequency of angiotensin converting enzyme (ACE) insertion/insertion (II) genotype had a significant impact on coronavirus disease 2019 (COVID-19) mortality. 1 Dyslipidemia is one of the most comorbidities among COVID-19 patients, however, the conclusions from published articles on the relationship between dyslipidemia and COVID-19 mortality are still controversial. For instance, several studies found that there was a significant relationship between dyslipidemia and an increased risk for mortality among COVID-19 patients, 2-4 while other studies reported that dyslipidemia was not significantly associated with COVID-19 mortality. 5 , 6 Therefore, there is an urgent need to address the relationship between dyslipidemia and COVID-19 mortality by a quantitative meta-analysis. It has been reported that demographical characteristics (age and gender) and certain comorbidities (diabetes mellitus, cardiovascular disease, hypertension, chronic kidney disease and autoimmune diseases, etc.) are well-known modulators that affect the clinical outcomes of COVID-19 patients, 7-9 suggesting that these factors might modulate the relationship between dyslipidemia and COVID-19 mortality. Thus, in this current meta-analysis, risk factors-adjusted effect estimates rather than crude effect estimates were utilized to calculate the pooled effect sizes. We did this systematic meta-analysis in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). All potentially eligible articles published between January 1, 2020 and February 26, 2021 were identify in the online databases (PubMed, Web of Science and EMBASE) with the following keywords: "SARS-CoV-2" or "severe acute respiratory syndrome coronavirus 2" or "COVID-19" or "coronavirus disease 2019" or "2019-nCoV" or "2019 novel coronavirus" and "dyslipidemia" or "hyperlipidemia" or "low-density lipoprotein" or "high-density lipoprotein" or "triglycerides" or "total cholesterol". Reference lists of eligible articles were also searched to look for additional studies. The exposure group was defined as COVID-19 patients with dyslipidemia and the control group was defined as COVID-19 patients without dyslipidemia. The outcome of interest was mortality, which was defined as mortality, death, died, nonsurvivor, fatality or deceased. All peer-reviewed articles published in English language reporting the risk factors-adjusted effect estimate on the relationship between dyslipidemia and COVID-19 mortality were eligibly selected. Accordingly, we excluded preprints, case reports, review papers, corrections, comments, animal studies and in vitro studies, studies reporting crude effect estimate, studies without sufficient data and studies reporting clinical outcomes as severe/critical illness, intensive care unit admission, invasive mechanical ventilation/intubation or composite outcomes rather than mortality. Essential info...
To investigate the effects of recombinant human adiponectin on the metabolism of diabetic swine induced by feeding a high-fat/high-sucrose diet (HFSD), diabetic animal models were constructed by feeding swine with HFSD for 6 months. The effects of recombinant adiponectin were assessed by detecting the change of plasma glucose levels by commercially available enzymatic method test kits and evaluating the insulin sensitivity by oral glucose tolerance test (OGTT). About 1.5 g purified recombinant adiponectin was produced using a 15-liter fermenter. A single injection of purified recombinant human adiponectin to diabetic swine led to a 2- to 3-fold elevation in circulating adiponectin, which triggered a transient decrease in basal glucose level (P<0.05). This effect on glucose was not associated with an increase in insulin level. Moreover, after adiponectin injection, swine also showed improved insulin sensitivity compared with the control (P<0.05). Adiponectin might have the potential to be a glucose-lowering agent for metabolic disease. Adiponectin as a potent insulin enhancer linking adipose tissue and glucose metabolism could be useful to treat insulin resistance.
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