Increased Plasma Lipid Research Articles

Atorvastatin exerts inhibitory effect on endothelial senescence in hyperlipidemic rats through a mechanism involving down-regulation of miR-21-5p/203a-3p

Statins are reported to exert benefits on endothelial function through a mechanism involving in prevention of endothelial senescence. This study aims to explore whether atorvastatin exerts inhibitory effect on endothelial senescence in hyperlipidemic rats or ox-LDL-treated HUVECs through a mechanism involving suppress of miR-21-5p/203a-3p expression and their downstream pathway. The rats were fed with high-fat diet to establish a hyperlipidemic model, which showed an increase in plasma lipids and endothelial senescence, accompanied by the elevation in plasma levels of miR-21-5p/203a-3p, down-regulation of Drp1 and up-regulation of p53 in the aorta of hyperlipidemic rats; these phenomena were reversed by atorvastatin. Next, HUVECs were incubated with ox-LDL to establish a senescent model in vitro. Consistent with the finding in vivo, atorvastatin treatment decreased the level of miR-21-5p and miR-203a-3p in the ox-LDL-treated HUVECs, restored Drp1 expression and mitochondrial function, as well as suppressed p53 and p16 expression and endothelial senescence. Based on these observations, we conclude that atorvastatin exerts inhibitory effect on endothelial senescence in hyperlipidemic rats through a mechanism involving down-regulation of miR-21-5p/203a-3p, which leads to the restoration of Drp1 level and recovery of mitochondrial function. Our findings highlight a novel non-lipid effect for atorvastatin besides its function in modulation of lipids.

Riesgo cardiovascular

ConceptArteriosclerosis is a systemic, progressive and silent disease that is associated with potentially modifiable life habits and conditions, which are known as cardiovascular risk factors (CRFs). ClassificationWe have identified 6 main CRFs: nicotine addiction, obesity, diabetes, physical inactivity, increased blood pressure and increased plasma lipid concentrations. However, the role of other variables (genetic and molecular) is being investigated to explain why some patients develop cardiovascular disease despite having the abovementioned CRFs under control. EpidemiologyCardiovascular morbidity and mortality is increasing due to the increase in diabetes and obesity and to the scarce implementation of control measures for this pandemic. Prognostic factorsIt is important to learn to estimate the overall cardiovascular risk. The most widely used model for this calculation is the Systematic Coronary Risk Evaluation (SCORE). Prevention strategiesOnce the cardiovascular risk has been established, the therapeutic objectives need to be established to control all CRFs synergistically and appropriately. Patients with a higher risk should undergo earlier and more intensive interventions; however, we should also proceed to detect subclinical atherosclerosis with noninvasive techniques in individuals with vascular risk near the decision threshold.

Correlation between NADPH oxidase-mediated oxidative stress and dysfunction of endothelial progenitor cell in hyperlipidemic patients.

Background/AimsNADPH (nicotinamide adenine dinucleotide phosphate) oxidase (NOX)-mediated oxidative stress plays a key role in promotion of oxidative injury in the cardiovascular system. The aim of this study is to evaluate the status of NOX in endothelial progenitor cells (EPCs) of hyperlipidemic patients and to assess the correlation between NOX activity and the functions EPCs.MethodsA total of 30 hyperlipidemic patients were enrolled for this study and 30 age-matched volunteers with normal level of plasma lipids served as controls. After the circulating EPCs were isolated, the EPC functions (migration, adhesion and tube formation) were evaluated and the status of NOX (expression and activity) was examined.ResultsCompared to the controls, hyperlipidemic patients showed an increase in plasma lipids and a reduction in EPC functions including the attenuated abilities in adhesion, migration and tube formation, concomitant with an increase in NOX expression (NOX2 and NOX4), NOX activity, and reactive oxygen species production. The data analysis showed negative correlations between NOX activity and EPC functions.ConclusionsThere is a positive correlation between the NOX-mediated oxidative stress and the dysfunctions of circulating EPCs in hyperlipidemic patients, and suppression of NOX might offer a novel strategy to improve EPCs functions in hyperlipidemia.

Increased plasma lipid levels exacerbate muscle pathology in the mdx mouse model of Duchenne muscular dystrophy

BackgroundDuchenne muscular dystrophy (DMD) is caused by loss of dystrophin expression and leads to severe ambulatory and cardiac function decline. However, the dystrophin-deficient mdx murine model of DMD only develops a very mild form of the disease. Our group and others have shown vascular abnormalities in animal models of MD, a likely consequence of the fact that blood vessels express the same dystrophin-associated glycoprotein complex (DGC) proteins as skeletal muscles.MethodsTo test the blood vessel contribution to muscle damage in DMD, mdx4cv mice were given elevated lipid levels via apolipoprotein E (ApoE) gene knockout combined with normal chow or lipid-rich Western diets. Ambulatory function and heart function (via echocardiogram) were assessed at 4 and 7 months of age. After sacrifice, muscle histology and aortic staining were used to assess muscle pathology and atherosclerosis development, respectively. Plasma levels of total cholesterol, high-density lipoprotein (HDL), triglycerides, and creatine kinase (CK) were also measured.ResultsAlthough there was an increase in left ventricular heart volume in mdx-ApoE mice compared to that in mdx mice, parameters of heart function were not affected. Compared with wild-type and ApoE-null, only mdx-ApoE KO mice showed significant ambulatory dysfunction. Despite no significant difference in plasma CK, histological analyses revealed that elevated plasma lipids in chow- and Western diet-fed mdx-ApoE mice was associated with severe exacerbation of muscle pathology compared to mdx mice: significant increase in myofiber damage and fibrofatty replacement in the gastrocnemius and triceps brachii muscles, more reminiscent of human DMD pathology. Finally, although both ApoE and mdx-ApoE groups displayed increased plasma lipids, mdx-ApoE exhibited atherosclerotic plaque deposition equal to or less than that of ApoE mice.ConclusionsSince others have shown that lipid abnormalities correlate with DMD severity, our data suggest that plasma lipids could be primary contributors to human DMD severity and that the notoriously mild phenotype of mdx mice might be attributable in part to their endogenously low plasma lipid profiles. Hence, DMD patients may benefit from lipid-lowering and vascular-targeted therapies.

Investigating The Role of Novel Bioactive Compound from Ficus Virens Ait on Cigarette Smoke Induced Oxidative Stress and Hyperlipidemia in Rats.

The present study is premeditated to extenuate the role of Ficus virens extract and its bioactive compound on cigarette smoke, an important risk factor for CVD, induced oxidative stress and hyperlipidemia. Cigarette smoke (CS) exposure to rats results in significant loss of body weight and increases blood carbon monoxide saturation (carboxyhemoglobin), nicotine, plasma TC, TG, and LDL-C levels but reduced level of antiatherogenic HDL-C. Moreover, owing to substantial oxidative stress generated in rats due to cigarette smoke a significant increase in plasma and erythrocytes lipid peroxidation products were observed which was well correlated with increase in ex-vivo BDC (48%) and MDA (53%) level (p < 0.001). Simultaneous administration of FVBM extract at higher dose (100 mg/rat) and F18 (n-Octadecanyl-O-α-D-glucopyranosyl(6'→1'')-O-α-D-glucopyranoside) compound to CS-exposed rats effectively blocked the increase in plasma lipid and lipoprotein levels (p < 0.001) which was due to the marked suppression in the hepatic HMG-CoA reductase activity (p < 0.001) and significantly inhibit the lipid peroxidation process thus preventing the membrane damage, LDL oxidation, and in turn subsequent atherosclerosis. Thus, the results clearly demonstrated the protective role of FVBM extract and F18 compound in risk factor induced cardiovascular disease.

Ferulic Acid on Glucose Dysregulation, Dyslipidemia, and Inflammation in Diet-Induced Obese Rats: An Integrated Study.

Obesity is considered to be a low-grade chronic inflammatory process, which is associated with cardiovascular and metabolic diseases. An integral evaluation of the effects of ferulic acid on biomarkers of glucose dysregulation, dyslipidemia, inflammation, and antioxidant potential induced by a high-fat diet (HFD) in rats was carried out. Three groups of male Wistar rats (six per group) consumed a basal diet (BD), which was supplemented with either lard at 310 g/kg (HFD) or lard and ferulic acid at 2 g/kg (HFD + FA), ad libitum for eight weeks. Body weight gain, hyperplasia, and hypertrophy in abdominal fat tissues were higher in the HFD group than in the HFD+FA group. The rats fed a HFD + FA significantly inhibited the increase in plasma lipids and glucose, compared with the HFD group. Biomarkers associated with inflammation were found at higher concentrations in the serum of rats fed a HFD than the HFD + FA group. Plasma antioxidant levels were lower in HFD rats compared to rats fed the HFD + FA. These results suggest that ferulic acid improves the obesogenic status induced by HFD, and we elucidated the integral effects of ferulic acid on a biological system.

Obesity: an independent risk factor for oxidative stress

Background: Obesity is increasing in prevalence and presents a serious risk for the development of various disorders like diabetes mellitus, hypertension, heart disease, gall bladder disease and certain forms of cancer. Animal studies have shown that obesity is associated with increased myocardial oxidative stress and increased lipid peroxidation. The objective of this study was to test the hypothesis that obesity per se causes increased plasma lipid peroxidation and decreased erythrocyte cytoprotection.Methods: A prospective randomized study including 300 obese subjects, was conducted in the Department of Medicine and Department of Biochemistry, G. R. Medical College, Gwalior. Age and sex matched 100 subjects having BMI between 19 to 25 kg/m2 were also enrolled. Patients were grouped as Case (n=300) and Control (n=100). Detailed physical examination and laboratory investigations including lipid profile were performed. Venous blood was obtained and used for the estimation of Superoxide dismutase (SOD) and plasma malondialdehyde (MDA). Unpaired t test and analysis of variance (ANOVA) with post-hoc Bonferroni and Tukey test along with Pearson correlation was used to analyze the data using IMB SPSS ver. 20 software. Significance is assessed at 5 % level.Results: Mean age of subjects among Case and Control group was 46.2±2.4 years and 44.5±2.2 years respectively with male predominance in each group. Mean weight, height, BMI, waist, hip, waist to hip ratio, mean blood glucose, total cholesterol, triglyceride, LDL-C, HDL-C and VLDL-C among Cases were91.57±9.8 kg, 161.6±9.3 cm, 36.17± 3.4 kgm2, 114.7±6.2 cm, 114.23±17.12 cm, 0.98±0.22, 87.3±2.6 mg/dl, 196.0±12.6 mg/dl, 253.6±27.3 mg/dl, 135±47.03 mg/dl, 47.1±1.2 mg/dl and 45.8±14.03 mg/dl and among Control group were61±5.2 kg, 163.1±8.7 cm, 21.24±1.88 cm, 21.24±1.88 kg m2, 85.2±1.4 cm, 97.32±9.12 cm, 0.86±0.14, 94.4 ± 3.2 mg/dl, 186.6 ± 6.9 mg/dl, 143.4±15.4 mg/dl, 95.73±27.48 mg/dl, 51.6±1.7 mg/dl and 22.4±10.45mg/dl respectively. Mean MDA level in Case and Control group was 4.68 ± 1.72 and 2.06±0.76 μmol/ml respectively (p&lt; 0.001). Mean SOD level among Case and Control groups was 7.65±1.13 and 12.42±2.18 units/ml respectively (p&lt;0.001). Female obese patients had lower level of SOD. A significant negative correlation of SOD was observed with BMI (n=300, r= -0.045, P&lt;0.001), whereas, MDA was positively correlated with BMI (n=300, r= 0.342, P&lt;0.001).Conclusions: Obesity in humans is an independent risk factor for lipid peroxidation and depletion of cytoprotective enzymes even in the absence of other confounding factors such as diabetes and hyperlipidaemia.

Abstract 591: Absence of Nicotinamide Nucleotide Transhydrogenase Exacerbates Atherosclerosis in Mice

Oxidant stress contributes to endothelial cell injury and inflammation that are hallmarks of early stage atherosclerosis. Emerging evidence implicates mitochondrial reactive oxygen species (ROS) as important contributors to this oxidant stress and differences in mitochondrial function may augment this process. We have shown that variation in mitochondrial function and ROS production associated with ethnicity contributes to endothelial and vascular dysfunction. To model these distinct mitochondrial redox phenotypes we used C57Bl/6N (6N) and C57Bl/6J (6J) mice that also display unique mitochondrial functional properties due to the differential expression nicotinamide nucleotide transhydrogenase (NNT). Mice were treated with adeno-associated virus encoding a gain-of-function form of proprotein convertase subtilisin/kexin type 9 (PCSK9) that leads to hypercholesterolemia, increased LDL levels, and atherosclerosis in mice. PCSK9 treatment and 8 weeks of high fat diet led to increases in plasma lipids in both 6N and 6J mice. However, 6J animals displayed significantly higher levels of fat deposition in the vasculature and increased plaque size in the carotid sinus. 6N mice co-treated with the mitochondria targeted superoxide dismutase mimetic MitoTEMPO for the final 4 weeks of the experiment displayed reduced plasma lipids, but no impact on fat deposition or plaque size was observed. In contrast, MitoTEMPO increased vascular fat deposition and plaque size in 6J mice consistent with a more severe atherosclerotic phenotype. Increased mitochondrial ROS was confirmed by demonstrating elevated vascular superoxide in 6J versus 6N animals and that this difference is exacerbated on high fat diet. MitoTEMPO diminished vascular superoxide production to near baseline levels in both groups, yet increased plaque size and fat deposition in 6J mice suggests a role for hydrogen peroxide in this process. These data indicate that loss of NNT and changes in mitochondrial function increase vascular ROS production and exacerbate lipid deposition and plaque development in the early stages of atherosclerosis.

Abstract 26: Identification of a Novel Gene, DENND5B, Associated With Plasma High Density Lipoprotein Levels and Intestinal Fat Absorption

In an effort to identify novel high density lipoprotein (HDL) receptors expressed by the liver, a bacteriophage library expressing liver cDNA fragments was used to screen for clones that bind to HDL. The gene DENND5B showed significant enrichment for HDL binding over 3 cycles of biopanning, with negative selection against low density lipoprotein binding. Although little is known about the recently described DENN-domain containing family of proteins, some members act as guanine nucleotide exchange factors involved in the activation of Rab proteins and membrane trafficking. To examine the influence of DENND5B on HDL physiology, a DENND5B knockout mouse was generated using a custom zinc finger nuclease. DENND5B -/- mice had decreased plasma total cholesterol (-30.9%, p &lt; 0.0001) and phosphatidylcholine (-31.4%, p &lt; 0.0001). When plasma was analyzed by size-exclusion chromatography, the lipid effects were attributed entirely to decreased HDL. When fed western diet for 4 months, DENND5B -/- mice showed significantly smaller increases in plasma lipids and body weight compared to wild type mice. After sacrifice, DENND5B -/- mice were found to have a distended small intestine that was whitish in color. To evaluate fat absorption, mice were given an oral gavage of vegetable oil (10 uL/gram body weight) and plasma lipids were measured at 0, 2, and 4 hours post-gavage. DENND5B -/- mice had significantly reduced plasma triglyceride (p &lt; 0.05) and free fatty acids (p &lt; 0.01) in response to oil gavage compared to wild type mice. To identify a possible role for this gene in human lipoprotein metabolism, we examined gene expression data from 5,458 participants in the Framingham Heart Study. Consistent with the mouse data, a significant negative relationship exists between DENND5B expression and plasma HDL-C (p = 4.82 x 10 -5 ). In summary, using a phage display screening approach, we have identified a novel gene associated with circulating HDL levels in mice and humans. Additionally, in a homozygous knockout mouse model, a defect in intestinal fat absorption is present. Future studies will be aimed at evaluating the influence of this gene on HDL function, fat absorption, and atherosclerotic disease burden.

MiR-21-5p/203a-3p promote ox-LDL-induced endothelial cell senescence through down-regulation of mitochondrial fission protein Drp1

This study aims to identify both endothelia-specific/enriched and senescence-associated miRNAs as well as their functions. The rats were fed on high-fat diet to establish a hyperlipidemic model, which showed an increase in plasma lipids and acceleration in endothelial senescence and endothelial dysfunction, accompanied by alterations in 7 endothelia-specific/enriched and senescence-associated miRNAs. Among the 7 selected miRNAs, miR-21-5p and miR-203a-3p were significantly up-regulated in a human umbilical vein endothelial cells (HUVECs) senescent model induced by ox-LDL, consistent with their changes in the hyperlipidemic rats. After performing the bioinformatic analysis, dynamin-related protein 1 (Drp1) was predicted to be a potential target for both miR-21-5p and miR-203a-3p. In ox-LDL-induced senescent HUVECs, Drp1 was significantly down-regulated, concomitant with mitochondrial dysfunctions and the activation of AMPK-p53/p16 pathway, while these phenomena were attenuated by miR-21-5p or miR-203a-3p inhibitor. Luciferase reporter gene assay confirmed a direct interaction between miR-21-5p and Drp1 but not between miR-203a-3p and Drp1. Based on these observations, we conclude that miR-21-5p/203a-3p promote ox-LDL-induced endothelial senescence through down-regulation of Drp1 in a direct or indirect way. Our findings highlight the plasma levels of miR-21-5p/203a-3p may serve as novel biomarkers to evaluate the degree of endothelial senescence in hyperlipidemia.

Gene Expression, Oxidative Stress, and Senescence of Primary Coronary Endothelial Cells Exposed to Postprandial Serum of Healthy Adult and Elderly Volunteers after Oven-Cooked Meat Meals.

Epidemiological studies have linked high consumption of meat with major age-related diseases including cardiovascular diseases. Abnormal postprandial increases in plasma lipids after a meat meal have been hypothesized among the pathogenetic mechanisms. However, it is still unknown if the postprandial serum derived after a normal meat meal is able to affect endothelial function, and if the type of meat and the age of the donors are critical factors. Here, we show the effects of postprandial sera derived from healthy adults and elderly volunteers who consumed meat meals on human coronary artery endothelial cell (HCAEC) oxidative stress, gene expression, DNA damage, and cellular senescence. We observed that a single exposure to postprandial serum induces a slight increase in ROS that is associated with modulation of gene expression pathways related to oxidative stress response and metabolism. The postprandial-induced increase in ROS is not associated with a measurable DNA oxidative damage. However, repeated exposure to postprandial serum induces an acceleration of cellular senescence. Taking into account the deleterious role of cellular senescence in age-related vascular diseases, the results suggest a new mechanism by which excessive meat consumption and time spent in postprandial state may affect health status during aging.

Study of prescribing patterns of hypolipidemic agents in a tertiary care teaching hospital in North India

Background: Lipid-lowering agents are now the cornerstone of treatment used to reduce the risk of coronary events. Since there is wide variation in selection and use of these drugs, drug utilization studies help to evaluate and analyze drug therapy from time to time. This in turn can guide physicians prescribing practices and help in minimizing adverse drug reactions. Aims and Objectives: To evaluate the prescribing pattern of hypolipidemic drugs in a tertiary care teaching hospital in Jammu. Materials and Methods: An observational study was carried out in patients attending the departments of cardiology and general medicine for 6 months. Prescription of the patients who were prescribed at least one hypolipidemic drug as monotherapy or in combination was evaluated. Hypolipidemic and other classes of drugs prescribed and the World Health Organization prescribing indicators were analyzed. Monthly cost of the hypolipidemic drugs prescribed was also determined. Results: Nearly, two-third (63.7%) patients with increased plasma lipids and 36.2% patients in spite of having normal lipid profile were prescribed hypolipidemic drugs as well. Hypertension with comorbid conditions (39.63%) was the most common diseases, for which hypolipidemic drugs were prescribed. The average number of drugs per prescription was 6.21 ± 1.6. Atorvastatin was the most common hypolipidemic drug prescribed as monotherapy (59.16%), whereas atorvastatin with ramipril was the most common drugs prescribed as combination therapy (14.69%). Conclusion: This study depicts the widespread use of statins in various disease conditions, both as primary and secondary preventive measures. Such studies should be done to educate the physicians on good prescribing practices and on rational use of hypolipidemic drugs.

Severe Atherosclerosis and Hypercholesterolemia in Mice Lacking Both the Melanocortin Type 4 Receptor and Low Density Lipoprotein Receptor.

Dysfunction of the melanocortin system can result in severe obesity accompanied with dyslipidemia and symptoms of the metabolic syndrome but the effect on vascular atherogenesis is not known. To study the impact of obesity and dyslipidemia on the cardiovascular system, we generated mice double-deficient for the melanocortin type 4 receptor (Mc4rmut mice) and the LDL receptor (Ldlr-/- mice). Mc4rmut mice develop obesity due to hyperphagia. Double-mutant mice (Mc4rmut;Ldlr-/-) exhibited massive increases in body weight, plasma cholesterol and triacylglycerol levels and developed atherosclerosis. Atherosclerotic lesion size was affected throughout the aortic root and brachiocephalic artery not only under semisynthetic, cholesterol-containing diet but also under cholesterol-free standard chow. The Mc4rmut mice developed a hepatic steatosis which contributes to increased plasma cholesterol levels even under cholesterol-free standard chow. Transcripts of cholesterol biosynthesis components and liver cholesterol levels did not significantly differ between wild-type and all mutant mouse strains but RNA sequencing data and biochemical measurements point to an altered bile acid elimination in Mc4rmut;Ldlr-/-. Therefore, the unchanged endogenous cholesterol biosynthesis together with a reduced hepatic VLDL and LDL-cholesterol clearance most likely led to increased plasma lipid levels and consequently to atherosclerosis in this animal model. Our data indicate that dysfunction of the melanocortin-regulated food intake and the resulting obesity significantly add to the proatherogenic lipoprotein profile caused by LDL receptor deficiency and, therefore, can be regarded as relevant risk factor for atherosclerosis.

Dysfunction of endothelial progenitor cells in hyperlipidemic rats involves the increase of NADPH oxidase derived reactive oxygen species production.

NADPH oxidase (NOX) is a major source of reactive oxygen species (ROS) in the body and it plays a key role in mediation of oxidative injury in the cardiovascular system. The purposes of this study are to evaluate the status of NOX in endothelial progenitor cells (EPCs) of hyperlipidemic rats and to determine whether NOX-derived ROS promotes the dysfunction of EPCs. The rats were fed on a high-fat diet for 8 weeks to establish a hyperlipidemic rat model, which showed the increased plasma lipids and the impaired functions of circulating EPCs (including the reduced abilities in migration and adhesion) accompanied by an increase in NOX activity and ROS production. Next, EPCs were isolated from normal rats and they were treated with oxidized low-density lipoprotein (ox-LDL) (100 μg/mL) for 24 h to induce a dysfunctional model in vitro. In agreement with our findings in vivo, ox-LDL treatment increased the dysfunctions of EPCs concomitant with an increase in NOX activity and ROS production; these phenomena were reversed by the NOX inhibitor. Based on these observations, we conclude that NOX-derived ROS involved in the dysfunctions of circulating EPCs in hyperlipidemic rats and inhibition of NOX might provide a novel strategy to improve EPC functions in hyperlipidemia.

Hyperlipidemia impairs erectile function in rats by causing cavernosal fibrosis

Men with hyperlipidemia are more likely to have erectile dysfunction (ED) than those without hyperlipidemia, but the mechanisms are not fully understood. The aim of this study was to investigate the underlying mechanism of ED caused by hyperlipidemia. Fourteen 8-week-old Sprague-Dawley rats were randomly divided into two groups: a control group and a hyperlipidemia group (fed chow containing 4% cholesterol and 1% cholic acid). After 6months, we assessed erectile function by performing cavernous nerve electrostimulation followed by intracavernosal pressure/mean arterial pressure measurements, as well as plasma lipid profile assessment in all rats. A transferase-mediated nick end labeling (TUNEL) assay, immunohistochemical staining and Western blotting were performed to determine the levels of apoptosis, autophagy and fibrosis in the penile tissue. Compared with the control group, the hyperlipidemia group exhibited: (i) increased plasma lipid levels; (ii) decreased erectile function; (iii) a decreased smooth muscle/collagen ratio; (iv) increased fibrosis; (v) increased apoptosis and decreased autophagy. Overall, hyperlipidemia may attenuate erectile function in rats by causing of cavernosal fibrosis.

Bioactivity of Platycerium angolense Flavonoid Fraction on Biochemical Parameters of Acetaminophen-induced Rats

This study evaluated the effect of flavonoid fraction (FF) of Platycerium angolense on acetaminophen-induced liver damage in rat with a view to considering the possibility of utilizing the extracts of the plant for the management and treatment of liver related ailments. Powdered leaves of P. angolense were extracted with methanol 70% (v/v) to yield methanolic extract of P. angolense (MEPA). The MEPA followed successive partitioning with n-hexane, chloroform and ethylacetate. The ethylacetate fraction was termed flavonoid fraction (FF). FF was phytochemically screened and total phenolic and flavonoid contents estimated. Biochemical effects of FF on liver marker enzymes (L-alanine and L-aspartate aminotransferases, gamma glutamyltransferase, acid and alkaline phosphatases); lipid profiles (cholesterol, triglycerides, high density lipoprotein (HDL)-cholesterol, low density lipoprotein (LDL)-cholesterol and very low density lipoprotein (VLDL)-cholesterol) enzymatic and non-enzymatic antioxidants (catalase, superoxide dismutase, peroxidase, glutathione (GSH), lipid peroxidation) and metabolites (total protein, albumin and bilirubin) were evaluated in the plasma and liver homogenates of albino rats. Phytochemical screening of FF tested positive for the presence of flavonoids, saponins, anthraquinones and cardiac glycosides. The total phenolics and flavonoids in FF were (33.58 ± 0.11 mg TAE/g, 50.98 ± 0.89 mg RE/g), respectively. Analyses of plasma and liver homogenates of rats (control and experimental) revealed that acetaminophen caused metabolic dysfunction in acetaminophen-induced rats. Administration of FF reversed the altered biochemical parameters. The study concluded that FF of P. angolense increases plasma lipid profile level, exhibits moderate anti-oxidant activity and elicits hepatoprotective potential. Key words: Hepatotoxicity, Platycerium angolense, acetaminophen, flavonoids, flavonoid fraction.

Hepatic carboxylesterase 3 (Ces3/Tgh) is downregulated in the early stages of liver cancer development in the rat

It is accepted that cancer development is associated with metabolic changes. Previously, we established a model of hepatic preneoplasia in which adult rats were subjected to a 2-phase model of hepatocarcinogenesis (initiated-promoted, IP) for 6weeks until they develop altered hepatic foci (AHF). Here, we found that a whole metabolic shift occurs in order to favor cancer development. IP animals presented with increased plasma lipids due to increased VLDL secretion as well as increased liver lipid accretion due to stimulated transacetylase activity rather than lipogenesis, compared to control rats. We found that carboxylesterase 3/triacylglycerol hydrolase (Ces3/Tgh) presented with a perilobular distribution surrounding lipid droplets in normal livers. However, it is downregulated both at the protein and mRNA level in liver homogenates and is almost undetectable inside the AHF with no changes in the surrounding tissue. Ces3/Tgh expression is regulated by ω-3 fatty acids, thus, supplementation of diet with fish oil, allowed the restoration of Ces3/Tgh expression inside the foci and, more interestingly, led to the decrease in number and volume of the AHF. These studies show a preventive role of Ces3/Tgh in liver cancer development.

Increased maternal consumption of methionine as its hydroxyl analog promoted neonatal intestinal growth without compromising maternal energy homeostasis.

BackgroundTo determine responses of neonatal intestine to maternal increased consumption of DL-methionine (DLM) or DL-2-hydroxy-4-methylthiobutanoic acid (HMTBA), eighteen primiparous sows (Landrace × Yorkshire) were allocated based on body weight and backfat thickness to the control, DLM and HMTBA groups (n = 6), with the nutritional treatments introduced from postpartum d0 to d14.ResultsThe DLM-fed sows showed negative energy balance manifested by lost bodyweight, lower plasma glucose, subdued tricarboxylic acid cycle, and increased plasma lipid metabolites levels. Both villus height and ratio of villus height to crypt depth averaged across the small intestine of piglets were higher in the DLM and HMTBA groups than in the control group. Piglet jejunal oxidized glutathione concentration and ratio of oxidized to reduced glutathione were lower in the HMTBA group than in the DLM and control groups. However, piglet jejunal aminopeptidase A, carnitine transporter 2 and IGF-II precursor mRNA abundances were higher in the DLM group than in the HMTBA and control groups.ConclusionIncreasing maternal consumption of methionine as DLM and HMTBA promoted neonatal intestinal growth by increasing morphological development or up-regulating expression of genes responsible for nutrient metabolism. And increasing maternal consumption of HMTBA promoted neonatal intestinal antioxidant capacity without compromising maternal energy homeostasis during early lactation.

Phosphorylation of Nonmuscle Myosin Light Chain Promotes Endothelial Injury in Hyperlipidemic Rats Through a Mechanism Involving Downregulation of Dimethylarginine Dimethylaminohydrolase 2.

Suppression of dimethylarginine dimethylaminohydrolase (DDAH) activation is related to endothelial dysfunction in hyperlipidemia, and nonmuscle myosin regulatory light chain (nmMLC20) has been show to exert transcriptional function in regulation of gene expression. This study aims to explore whether the suppression of DDAH activation promotes endothelial injury under the condition of hyperlipidemia and whether nmMLC20 can regulate DDAH expression in a phosphorylation-dependent manner. The rats were fed with high-fat diet for 8 weeks to establish a hyperlipidemic model, which showed an increase in plasma lipids and endothelial injury, accompanied by an elevation in myosin light chain kinase (MLCK) activity, phosphorylated nmMLC20 (p-nmMLC20) level, and asymmetric dimethylarginine (ADMA) content as well as a reduction in DDAH2 expression, DDAH activity, and nitric oxide (NO) content. Next, human umbilical vein endothelial cells (HUVECs) were incubated with oxidized low-density lipoprotein (ox-LDL; 100 μg/mL) for 24 hours to establish a cellular injury model in vitro. Consistent with the finding in vivo, ox-LDL induced HUVECs injury (apoptosis and necrosis) concomitant with an increase in MLCK activity, p-nmMLC20 level (in total or nuclear proteins), and ADMA content as well as a reduction in DDAH2 expression, DDAH activity, and NO content; these phenomena were attenuated by MLCK inhibitor. Either in hyperlipidemic rats or in ox-LDL-treated HUVECs, there was not significant change in DDAH1 expression. Based on these observations, we conclude that the suppression of DDAH2 expression might account for, at least partially, the vascular endothelial dysfunction in hyperlipidemia, and nmMLC20 plays a role in suppression of DDAH2 expression in a phosphorylation-dependent manner.

Postprandial lipids accelerate and redirect nitric oxide consumption in plasma

Nitric oxide (NO) and O2 are both three-to four-fold more soluble in biological lipids than in aqueous solutions. Their higher concentration within plasma lipids accelerates NO autoxidation to an extent that may be of importance to overall NO bioactivity. This study was undertaken to test the hypothesis that increased plasma lipids after a high-fat meal appreciably accelerate NO metabolism and alter the byproducts formed. We found that plasma collected from subjects after consumption of a single high-fat meal had a higher capacity for NO consumption and consumed NO more rapidly compared to fasting plasma. This increased NO consumption showed a direct correlation with plasma triglyceride concentrations (p = 0.006). The accelerated NO consumption in postprandial plasma was reversed by removal of the lipids from the plasma, was mimicked by the addition of hydrophobic micelles to aqueous buffer, and could not be explained by the presence of either free hemoglobin or ceruloplasmin. The products of NO consumption were shifted in postprandial plasma, with 55% more nitrite (n = 12, p = 0.002) but 50% less SNO (n = 12, p = 0.03) production compared to matched fasted plasma. Modeling calculations indicated that NO autoxidation was accelerated by about 48-fold in the presence of plasma lipids. We conclude that postprandial triglyceride-rich lipoproteins exert a significant influence on NO metabolism in plasma.