Lead effect on the oxidation resistance of erythrocyte membrane in rat triton-induced hyperlipidemia

The anemia observed in severe chronic lead poisoning is in part attributable to alterations in the erythrocyte physicochemical properties. Since they are partly related to the membrane lipid composition, the aim of the present study was to determine the effects of a triton-induced hyperlipidemia on the resistance to oxidation of erythrocyte membranes in lead-treated Wistar rats. Our results showed that triton administration to lead-treated rats induced an increase in erythrocyte choline phospholipid levels together with a significant decrease in the erythrocyte membrane lipid resistance to oxidation. These results led us to suggest that anemia in lead poisoning is linked to interactions between lead present in the membrane and plasma phospholipids. Their increase in rat hyperlipidemia induced by triton resulted in a decrease in the membrane resistance to oxidation and finally in an erythrocyte fragility leading to their destruction.     

Inositol‐requiring enzyme‐1 regulates phosphoinositide signaling lipids and macrophage growth

The ER‐bound kinase/endoribonuclease (RNase), inositol‐requiring enzyme‐1 (IRE1), regulates the phylogenetically most conserved arm of the unfolded protein response (UPR). However, the complex biology and pathology regulated by mammalian IRE1 cannot be fully explained by IRE1’s one known, specific RNA target, X box‐binding protein‐1 (XBP1) or the RNA substrates of IRE1‐dependent RNA degradation (RIDD) activity. Investigating other specific substrates of IRE1 kinase and RNase activities may illuminate how it performs these diverse functions in mammalian cells. We report that macrophage IRE1 plays an unprecedented role in regulating phosphatidylinositide‐derived signaling lipid metabolites and has profound impact on the downstream signaling mediated by the mammalian target of rapamycin (mTOR). This cross‐talk between UPR and mTOR pathways occurs through the unconventional maturation of microRNA (miR) 2137 by IRE1’s RNase activity. Furthermore, phosphatidylinositol (3,4,5) phosphate (PI(3,4,5)P₃) 5‐phosphatase‐2 (INPPL1) is a direct target of miR‐2137, which controls PI(3,4,5)P₃ levels in macrophages. The modulation of cellular PI(3,4,5)P₃/PIP₂ ratio and anabolic mTOR signaling by the IRE1‐induced miR‐2137 demonstrates how the ER can provide a critical input into cell growth decisions.     

Treatment of growth hormone attenuates hepatic steatosis in hyperlipidemic mice via downregulation of hepatic CD36 expression

ABSTRACT

The recombinant human growth hormone (GH) has been used for the treatment of growth hormone deficiency (GHD) and diverse short stature state, and its physiological and therapeutic effects are well documented. However, since the effect of GH treatment on metabolic disorders has not been well characterized, we injected GH to Western diet-fed low-density lipoprotein receptor-deficient (Ldlr ^?/?) mice to understand the exact effect of GH on metabolic diseases including atherosclerosis, hepatic steatosis, and obesity. Exogenous GH treatment increased plasma IGF-1 concentration and decreased body weight without affecting serum lipid profiles. GH treatment changed neither atherosclerotic lesion size nor collagen and smooth muscle cells accumulation in the lesion. GH treatment reduced macrophage accumulation in adipose tissue. Importantly, GH treatment attenuated hepatic steatosis and inflammation. The hepatic expression IL-1β mRNA were decreased by GH treatment. The mRNA and protein levels of CD36 were markedly decreased in GH treated mice without significant changes in other molecules related to lipid metabolism. Therefore, the treatment of GH treatment could attenuate hepatic steatosis and inflammation with downregulation of CD36 expression in hyperlipidemic condition.     

Increase of Circulating CD11b+Gr1+ cells and Recruitment into the Synovium in Osteoarthritic Mice with Hyperlipidemia

Although recent studies suggest that hyperlipidemia is a risk factor for osteoarthritis (OA), the link between OA and hyperlipidemia is not fully understood. As the number of activated, circulating myeloid cells is increased during hyperlipidemia, we speculate that myeloid cells contribute to the pathology of OA. Here, we characterized myeloid cells in STR/Ort mice, a murine osteoarthritis model, under hyperlipidemic conditions. Ratios of myeloid cells in bone marrow, the spleen, and peripheral blood were determined by flow cytometry. To examine the influence of the hematopoietic environment, including abnormal stem cells, on the hematopoietic profile of STR/Ort mice, bone marrow transplantations were performed. The relationship between hyperlipidemia and abnormal hematopoiesis was examined by evaluating biochemical parameters and spleen weight of F₂ animals (STR/Ort x C57BL/6J). In STR/Ort mice, the ratio of CD11b⁺Gr1⁺ cells in spleens and peripheral blood was increased, and CD11b⁺Gr1⁺ cells were also present in synovial tissue. Splenomegaly was observed and correlated with the ratio of CD11b⁺Gr1⁺ cells. When bone marrow from GFP-expressing mice was transplanted into STR/Ort mice, no difference in the percentage of CD11b⁺Gr1⁺ cells was observed between transplanted and age-matched STR/Ort mice. Analysis of biochemical parameters in F₂ mice showed that spleen weight correlated with serum total cholesterol. These results suggest that the increase in circulating and splenic CD11b⁺Gr1⁺ cells in STR/Ort mice originates from hypercholesterolemia. Further investigation of the function of CD11b⁺Gr1⁺ cells in synovial tissue may reveal the pathology of OA in STR/Ort mice.     

Discovery of selective farnesoid X receptor agonists for the treatment of hyperlipidemia from traditional Chinese medicine based on virtual screening and in vitro validation

Abstract

Farnesoid X receptor (FXR), a bile acid receptor, has important roles in maintaining bile acid and cholesterol homeostasis, which is an attractive target for hyperlipidemia. Present study aimed to discover potential selective FXR agonists over G-protein coupled bile acid receptor 1 (GPBAR1, TGR5) from traditional Chinese medicine (TCM) by using virtual screening, in vitro studies and molecular dynamics simulation (MD). Ligand-based pharmacophore model for FXR was firstly built to screen FXR agonists from the Traditional Chinese Medicine Database (TCMD). Then, 21 FXR crystal structures were clustered in two types and two representative structures (PDB ID: 3OMM and 3P89) were, respectively, used to carry out molecular docking to refine the screened result. Moreover, the pharmacophore model for GPBAR1 was built to screen selective FXR agonists with no activity on GPBAR1. A set of 24 candidate selective FXR agonists which fitvalue of FXR pharmacophore model and docking score of 3OMM and 3P89 were in the top 100 and cannot match the pharmacophore model for GPBAR1 were obtained. By the lipid-lowering activity test in HepG2 cell lines, Arctigenin was identified to be potential selective FXR agonist with the activity of 20?μmol·L^?1. After down-regulating FXR, Arctigenin could increase the mRNA of FXR while exerted no effect on the mRNA of GPBAR1. MD was further used to interpret the mechanism of Arctigenin with the representative structures. This research provided a new screening procedure for finding selective candidate compounds and appropriate docking models of a target by considering the structure diversity of PDB structures, which was applied to discovery novel selective FXR agonists to treat hyperlipidemia.

Communicated by Ramaswamy H. Sarma     

A meta‐analysis of cardio‐metabolic abnormalities in drug naïve,first‐episode and multi‐episode patients with schizophrenia versus general population controls

A meta‐analysis was conducted to explore the risk for cardio‐metabolic abnormalities in drug naïve, first‐episode and multi‐episode patients with schizophrenia and age‐ and gender‐ or cohort‐matched general population controls. Our literature search generated 203 relevant studies, of which 136 were included. The final dataset comprised 185,606 unique patients with schizophrenia, and 28 studies provided data for age‐ and gender‐matched or cohort‐matched general population controls (n=3,898,739). We found that multi‐episode patients with schizophrenia were at increased risk for abdominal obesity (OR=4.43; CI=2.52‐7.82; p<0.001), hypertension (OR=1.36; CI=1.21‐1.53; p<0.001), low high‐density lipoprotein cholesterol (OR=2.35; CI=1.78‐3.10; p<0.001), hypertriglyceridemia (OR=2.73; CI=1.95‐3.83; p<0.001), metabolic syndrome (OR=2.35; CI=1.68‐3.29; p<0.001), and diabetes (OR=1.99; CI=1.55‐2.54; p<0.001), compared to controls. Multi‐episode patients with schizophrenia were also at increased risk, compared to first‐episode (p<0.001) and drug‐naïve (p<0.001) patients, for the above abnormalities, with the exception of hypertension and diabetes. Our data provide further evidence supporting WPA recommendations on screening, follow‐up, health education and lifestyle changes in people with schizophrenia.     

有氧运动对小鼠高脂血症及脂蛋白代谢的影响

本研究以高胆固醇饮食小鼠为实验对象,观察有氧运动对脂质水平异常的动物个体血脂及脂蛋白代谢的影响。结果显示,经１１周有氧耐力训练后,高脂膳食＋运动组小鼠血浆ＴＧ、ＴＣ及ＬＤＬ－Ｃ水平均显著低于高脂膳食组（Ｐ＜０．０５）,而ＨＤＬ－Ｃ／ＴＣ和ＨＤＬ－Ｃ／ＬＤＬ－Ｃ比值均显著高于高脂膳食组（Ｐ＜０．０５）。表明长期有氧耐力训练能显著改善高胆固醇饮食小鼠血脂及脂蛋白代谢状况。     

Use of random forest in FTIR analysis of LDL cholesterol and tri‐glycerides for hyperlipidemia

A quantitative determination method for the diagnosis of hyperlipidemia was developed using Fourier transform infrared (FTIR) spectroscopy. Random forest (RF) was demonstrated as a potential multivariate algorithm for the FTIR analysis of low‐density lipoprotein cholesterol (LDL‐C) and tri‐glycerides (TG) in human serum samples. The informative wavebands for LDL‐C and TG were selected based on the Gini importance. The selected wavebands were mainly within the fingerprint region. The RF modeling results were better than those derived using PLS in validation process, because the chance for over‐fitting was possibly eliminated in RF algorithm. ARF also demonstrated favorable results in the test process. The prospective model exhibited a higher than 90% true prediction in negative/positive properties for male and female samples. These clinical statistical results indicated the optimization of RF algorithm performed accurately in the FTIR determination of LDL‐C and TG. RF is evaluated as a promising tool for diagnosing and controlling hyperlipidemia in populations. The parameter optimization methodology is useful in the improving model accuracy using FTIR spectroscopic technology. © 2015 American Institute of Chemical Engineers Biotechnol. Prog., 31:1693–1702, 2015     

The Effects of Combined Treatment with Niacin and Chromium on the Renal Tissues of Hyperlipidemic Rats

In this study, 12 months old female Swiss albino rats were used. They were randomly divided into four groups. The animals of group I were fed with pellet chow. Group II were fed with pellet chow and treated with 250 μg/kg CrCl₃.6H₂o and 100 mg/kg niacinfor 45 days. Group III were fed a lipogenic diet consisting of 2% cholesterol, 0.5% cholicacidand 2%sun flower oil added to the pellet chow, andgiven 3%alcoholic water for 60 days. Group IV were fed with the same lipogeni cdiet for 60 day sand treated by gavage technique to rats at a dose of 250 mu/kg CrCl_3.6H₂O and 100 mg/kg niacin for 45 days, 15 days after experimental animals were rendered hyperlipidemic. At the 60th day, renal tissue and blood samples were taken from the animals. The sections were examined under light and electron microscopy. The degenerative changes were much more in the hyperlipidemic rats than the control group. The changes in renal tissue were also observed in hyperlipidemic animals given niacin and chromium. In the hyperlipidemic rats, renal glutathione levels decreased and renal lipid peroxidation levels, and serum urea and creatinine levels were increased. But, renal glutathione levels increased and lipid peroxidation levels and serum urea and creatinine levels decreased in hyperlipidemic rats given niacin and chromium. The purpose of this study was to investigate whether a protective effect of a combination of niacin and chromium is present on the renal tissue of hyperlipidemic rats or not. In conclusion, we can say that niacin and chromium do not have a protective effect on the morphology of the renal tissue of hyperlipidemic rats, except a protective effect on their biochemical parameters.     

Comparison of metabolic risk factors between severely and very severely obese patients

Objective: A prospective clinical intervention study was performed to estimate the metabolic risk factors in patients with very severe obesity (VSO) vs. severe obesity (SO). Research Methods and Procedures: Two hundred twenty‐eight VSO (BMI ≥ 50 kg/m²) and 221 SO patients (BMI = 40 to 49.9 kg/m²) participated in the study (367 women and 82 men). Metabolic measurements included plasma lipids, glucose and insulin, hemoglobin A_1c, leptin, and sex hormones, as well as hepatic steatosis in a subgroup of patients. Subgroups of patients with non–insulin‐dependent diabetes and hyperlipidemia (HLP) were examined. Results: The most unexpected result of our study was that VSO men showed significantly better lipid profiles than SO men. Furthermore, 18% of VSO men had no metabolic aberrations, whereas all SO men did. The advantageous metabolic status of VSO men was associated with sex hormone changes that favor gynoid fat distribution. The beneficial metabolic situation with VSO seems to be sex specific for men. Discussion: This study shows that the metabolic situation in VSO is not more severe than in the less obese cohort. These findings distinctly differ from the positive associations that have previously been reported between BMI, lipids, and other metabolic indices among individuals whose BMI is <40 kg/m².