Hypercholesterolemic Animals Research Articles

Salix alba attenuated oxidative stress in the heart and kidney of hypercholesterolemic rabbits.

Oxidative stress plays a critical role in the development of hypercholesterolemia-induced complications. This study evaluated the effects of aspirin and Salix alba hydroethanolic extract on oxidative stress in the heart and kidney of hypercholesterolemic rabbits. The antioxidant activity, as well as total phenolic and salicin content of S. alba (Sa) extract were assessed by DPPH radical scavenging activity, Folin-Ciocalteu and HPLC methods, respectively. Animals were divided into two groups of control (fed with normal chow), and HD (fed with high cholesterol diet for 6 weeks). Then, hypercholesterolemic animals allocated to the following treatment groups: CHO (received HD), Sa extract (HD plus extract 60 and 120 mg/kg), and aspirin (HD plus aspirin 120 mg/kg) and received the treatments on a daily basis for 6 weeks. MDA, GSH, and nitrite concentrations as well as the activities of SOD and CAT were evaluated in cardiac and kidney tissues. The scavenging activity, total phenolic content and salicin were 19.1µg/ml (IC50), 153.75 ± 3.6 mg of gallic acid/g, and 18.03 µg/mg, respectively. In comparison to CHO group, MDA levels were diminished in Sa and ASA groups but GSH levels were improved. NO metabolites increased in the heart of Sa 120 mg/kg group and in the kidney of all Sa and ASA treated groups. SOD activity increased only in the heart of Sa groups and in the kidney of Sa and ASA groups. CAT activity increased in the heart and kidney tissues of all Sa and ASA treated groups. The results showed S. alba extract improved redox homeostasis in heart and kidney tissues of hypercholesterolemic rabbits. The extract antioxidant property may be related to its phenolic content.

Abstract 184: Adenylate Cyclase Type 9 Promotes Atherosclerosis in Mice

Polymorphisms in the ADCY9 gene, coding for adenylate cyclase type 9, determine atherosclerotic cardiovascular responses to the CETP inhibitor dalcetrapib in patients. ADCY9 is broadly expressed and involved in various immune cell functions and inflammatory responses. Our objective is to determine the role of ADCY9 in the development of atherosclerosis in the absence of CETP. We used 8-12 week-old wild-type (WT, n=25) or Adcy9 -inactivated ( Adcy9 Gt , n=21) male mice. To induce hypercholesterolemia and atherosclerosis, mice were infected with an adeno-associated virus coding for a gain-of-function mutant of Pcsk9 ( Pcsk9 D377Y ) and were fed an atherogenic high-cholesterol diet for 16 weeks in absence or presence of dalcetrapib treatment (200 mg/kg/day). Percent atherosclerotic lesion area (PALA) in the whole aorta was quantified using en face Oil Red O plaque staining. We used VCAM-1 immunofluorescence staining (n=6 per group) in atherosclerotic lesions of the aortic root to quantify inflammation. We also measured aortic root accumulation of macrophages and vascular smooth muscle cells by immunofluorescence imaging of CD68 and smooth muscle actin (SMA), respectively, in plaque lesions. We also quantified blood leukocytes in normocholesterolemic WT and Adcy9 Gt mice by flow cytometry analysis of CD45 + cells. In hypercholesterolemic animals, Adcy9 Gt mice showed a 60% decrease in atherosclerotic lesions (PALA: 2.7±0.5%) compared to WT mice (6.5±0.7%, P<0.01). Dalcetrapib treatment, in these mice without CETP, did not modify significantly the reduction (63%) of PALA in Adcy9 Gt mice (2.9±0.4%) compared to WT (7.6±1.6%, P<0.01). Macrophage content was reduced by 55% from 17.8±2.8% in WT to 7.2%±1.9% in Adcy9 Gt mice (P<0.05), while SMA staining was similar. VCAM-1 expression also tended to be decreased, from 5.7±3.3% in WT to 2.0±0.4% in Adcy9 Gt mice (P=0.0598). CD45 + blood leukocytes were reduced by 35.4% in Adcy9 Gt compared to WT normocholesterolemic mice (P<0.01). Adcy9 inactivation in mice (without CETP) results in large reductions of atherosclerosis and plaque macrophage and in decreased VCAM-1 expression. These results support the ADCY9 genotype-dependent clinical effects of dalcetrapib.

β-caryophyllene reduces atherogenic index and coronary risk index in hypercholesterolemic rats: The involvement of cardiac oxidative damage

Hypercholesterolemia and cardiac oxidative damage have been implicated in the pathophysiology of atherosclerosis. In earlier studies, treatment using natural phytocannabinoid β-caryophyllene caused a hypolipemic effect, as well as ameliorated hepatic oxidative damage. In this regard, the present study aimed to investigate whether β-caryophyllene treatment was able to protect the cardiac tissue against hypercholesterolemic atherosclerosis, and to investigate the involvement of antioxidant mechanisms in this effect using a model of hypercholesterolemia induced by Triton WR-1339. The hypercholesterolemic animals exhibited a significant increase in the cholesterol (TC), triglycerides (TG) and free fatty acids (FFA) contents in cardiac tissue, as well as showed significant increase on atherogenic index (AI) and coronary risk index (CRI). Moreover, cardiac levels of reactive oxygen species (ROS) and thiobarbituric acid reactive substances (TBARS) were increased in hypercholesterolemic animals, while the glutathione reduced (GSH) levels and glutathione peroxidase (GPx) activity were decreased. β-caryophyllene treatment reduced the cardiac lipid content, as well as decreased the AI and CRI. Moreover, the treatment was able to improve the antioxidant/oxidant status in heart tissue of hypercholesterolemic animals. In summary, β-caryophyllene possesses antioxidant properties, preventing lipidic oxidative damage and ameliorating the GPx activity, an important enzyme linked to the prevention of atherosclerosis. Thus, this compound can be used as an attempt to prevent or reduce atherosclerosis in hypercholesterolemic rats.

Hypercholesterolemia downregulates autophagy in the rat heart

BackgroundWe have previously shown that efficiency of ischemic conditioning is diminished in hypercholesterolemia and that autophagy is necessary for cardioprotection. However, it is unknown whether isolated hypercholesterolemia disturbs autophagy or the mammalian target of rapamycin (mTOR) pathways. Therefore, we investigated whether isolated hypercholesterolemia modulates cardiac autophagy-related pathways or programmed cell death mechanisms such as apoptosis and necroptosis in rat heart.MethodsMale Wistar rats were fed either normal chow (NORM; n = 9) or with 2% cholesterol and 0.25% cholic acid-enriched diet (CHOL; n = 9) for 12 weeks. CHOL rats exhibited a 41% increase in plasma total cholesterol level over that of NORM rats (4.09 mmol/L vs. 2.89 mmol/L) at the end of diet period. Animals were sacrificed, hearts were excised and briefly washed out. Left ventricles were snap-frozen for determination of markers of autophagy, mTOR pathway, apoptosis, and necroptosis by Western blot.ResultsIsolated hypercholesterolemia was associated with a significant reduction in expression of cardiac autophagy markers such as LC3-II, Beclin-1, Rubicon and RAB7 as compared to controls. Phosphorylation of ribosomal S6, a surrogate marker for mTOR activity, was increased in CHOL samples. Cleaved caspase-3, a marker of apoptosis, increased in CHOL hearts, while no difference in the expression of necroptotic marker RIP1, RIP3 and MLKL was detected between treatments.ConclusionsThis is the first comprehensive analysis of autophagy and programmed cell death pathways of apoptosis and necroptosis in hearts of hypercholesterolemic rats. Our data show that isolated hypercholesterolemia suppresses basal cardiac autophagy and that the decrease in autophagy may be a result of an activated mTOR pathway. Reduced autophagy was accompanied by increased apoptosis, while cardiac necroptosis was not modulated by isolated hypercholesterolemia. Decreased basal autophagy and elevated apoptosis may be responsible for the loss of cardioprotection reported in hypercholesterolemic animals.

Cholesterol contributes to dopamine-neuronal loss in MPTP mouse model of Parkinson’s disease: Involvement of mitochondrial dysfunctions and oxidative stress

Hypercholesterolemia is a known contributor to the pathogenesis of Alzheimer’s disease while its role in the occurrence of Parkinson’s disease (PD) is only conjecture and far from conclusive. Altered antioxidant homeostasis and mitochondrial functions are the key mechanisms in loss of dopaminergic neurons in the substantia nigra (SN) region of the midbrain in PD. Hypercholesterolemia is reported to cause oxidative stress and mitochondrial dysfunctions in the cortex and hippocampus regions of the brain in rodents. However, the impact of hypercholesterolemia on the midbrain dopaminergic neurons in animal models of PD remains elusive. We tested the hypothesis that hypercholesterolemia in MPTP model of PD would potentiate dopaminergic neuron loss in SN by disrupting mitochondrial functions and antioxidant homeostasis. It is evident from the present study that hypercholesterolemia in naïve animals caused dopamine neuronal loss in SN with subsequent reduction in striatal dopamine levels producing motor impairment. Moreover, in the MPTP model of PD, hypercholesterolemia exacerbated MPTP-induced reduction of striatal dopamine as well as dopaminergic neurons in SN with motor behavioral depreciation. Activity of mitochondrial complexes, mainly complex-I and III, was impaired severely in the nigrostriatal pathway of hypercholesterolemic animals treated with MPTP. Hypercholesterolemia caused oxidative stress in the nigrostriatal pathway with increased generation of hydroxyl radicals and enhanced activity of antioxidant enzymes, which were further aggravated in the hypercholesterolemic mice with Parkinsonism. In conclusion, our findings provide evidence of increased vulnerability of the midbrain dopaminergic neurons in PD with hypercholesterolemia.

Anti‐hypercholesterolemic influence of the spice cardamom (Elettaria cardamomum) in experimental rats

Cardamom (Elettaria cardamomum) is an aromatic seed spice grown extensively in India and used as a flavoring in sweets. In this study, the anti-hypercholesterolemic effect of cardamom was evaluated in Wistar rats by inducing hypercholesterolemia with a high-cholesterol diet for 8 weeks. Dietary interventions were made with (a) cardamom powder (50 g kg-1 ), (b) cardamom oil (3 g kg-1 , equivalent to 50 g kg-1 cardamom) and (c) de-oiled cardamom powder (50 g kg-1 ). A significant reduction in blood total cholesterol (31%) and low-density lipoprotein cholesterol (44%) was observed by oral administration of cardamom oil in hypercholesterolemic rats, accompanied by a marked decrease in serum triglycerides by 42%. The cholesterol content of cardiac muscle was beneficially lowered by 39% with administration of cardamom oil in hypercholesterolemic rats. Liver triglycerides were reduced by 33%. Incorporation of cardamom oil/powder in the diet did not alter feed consumption by rats. Compromised activities of hepatic antioxidant enzymes in the hypercholesterolemic situation were generally countered by dietary cardamom. Treatment with de-oiled cardamom as well as cardamom oil countered the diminished activity of catalase in hypercholesterolemic animals. Cardamom also enhanced the activity of heart superoxide dismutase in the hypercholesterolemic situation. The concentration of ascorbic acid in serum was significantly increased by dietary cardamom or its fractions in the hypercholesterolemic situation. This animal study has established the potential of cardamom oil in restoring the alteration in lipid homeostasis in conditions of hypercholesterolemia. The significant reduction in atherogenicity index by dietary intervention with cardamom powder and cardamom oil indicates the potential cardioprotective effect of cardamom. © 2016 Society of Chemical Industry.

Regular treadmill exercise inhibits mitochondrial accumulation of cholesterol and oxysterols during myocardial ischemia-reperfusion in wild-type and ob/ob mice

Mitochondria play a central role in the irreversible damages induced to the heart by a prolonged period of ischemia followed by reperfusion. We previously demonstrated that (1) myocardial ischemia-reperfusion induces mitochondrial accumulation of cholesterol and oxysterols that are deleterious for the organelle; (2) inhibition of cholesterol and oxysterol accumulation prevents mitochondrial injury at reperfusion; (3) exercise is cardioprotective and remains efficient in the presence of co-morbidities such as obesity. The aim of this study was to investigate whether regular exercise limits mitochondrial cholesterol and oxysterol accumulation in wild-type and obese mice.Wild-type C57BL/6J and obese (ob/ob) mice were assigned to sedentary conditions or regular treadmill exercise and submitted to 30min of coronary artery occlusion followed by 15min of reperfusion. Regular exercise improved oxidative phosphorylation, restored the antioxidant capacity of the heart by increasing the expression of SOD1 and catalase and reduced the mitochondrial generation of oxysterols in wild-type as well as in ob/ob mice. In wild-type animals, exercise limited the production of oxysterols. In ob/ob mice, despite hypercholesterolemia, chronic exercise abolished the mitochondrial accumulation of cholesterol and concomitantly reduced the generation of 7α-hydroxycholesterol, 7-ketocholesterol and cholesterol-5α,6α-epoxide.In conclusion, regular exercise prevents the mitochondrial accumulation of cholesterol and oxysterols which occurs during early reperfusion of an ischemic myocardium in mice. This effect is observed in normo and hypercholesterolemic animals. It may be partly responsible for the antioxidant properties of regular exercise and contribute to its cardioprotective effect in obese conditions.

The Effects of Cinnamomum zeylanicum on Lipid Profiles and Histology Via Up-Regulation of LDL Receptor Gene Expression in Hamsters Fed a High Cholesterol Diet

Background: Recently, medicinal plants have become the focus of more attention due to their potentially effective roles in the prevention and treatment of many diseases. Objectives: The aim of this research was to examine the effects of Cinnamomum zeylanicum (CZ) on lipid profile and histological changes due to LDL receptor (LDL-R) gene expression in hamsters fed a high cholesterol diet. Methods: Thirty-two male hamsters were allocated into four groups (eight in each group under four weeks of treatment) as follows: group ND were fed a standard normal diet; group HCD were fed a normal diet supplemented with high cholesterol; group HCD + CZ2 were fed a high cholesterol diet (HCD) along with 2% CZ; and group HCD + CZ8 were fed an HCD diet along with 8% CZ. After the treatment process, blood samples were taken from all of studied animals, and sera were prepared for lipid profile assays. Liver LDL-R gene expression was assayed using the real-time polymerase chain reaction (PCR) method. Liver histological changes were determined using the hematoxylin and eosin staining method. Results: A significant reduction was observed in serum triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), very-low-density lipoprotein cholesterol (VLDL-c), aspartate transaminase (AST), and alanine transaminase (ALT) levels in the HCD + CZ8 group, while serum high density lipoprotein cholesterol (HDL-c) levels increased when compared with the HCD group (P < 0.001). The HCD group demonstrated decreased LDL-R gene expression in the animals’ livers, whereas treatment with CZ up-regulated its expression. The scores for hepatic steatosis in the HCD + CZ8 group were diminished significantly. Conclusions: The administration of CZ improved dyslipidemia in hypercholesterolemic animals, probably by increasing LDL-R gene expression in the liver; consequently, it can be concluded that CZ can reverse hepatic steatosis. Therefore, CZ was determined as having a protective role against hypercholesterolemia.

The Effects of Cinnamomum zeylanicum on Lipid Profiles and Histology Via Up-Regulation of LDL Receptor Gene Expression in Hamsters Fed a High Cholesterol Diet

Background: Recently, medicinal plants have become the focus of more attention due to their potentially effective roles in the prevention and treatment of many diseases. Objectives: The aim of this research was to examine the effects of Cinnamomum zeylanicum (CZ) on lipid profile and histological changes due to LDL receptor (LDL-R) gene expression in hamsters fed a high cholesterol diet. Methods: Thirty-two male hamsters were allocated into four groups (eight in each group under four weeks of treatment) as follows: group ND were fed a standard normal diet; group HCD were fed a normal diet supplemented with high cholesterol; group HCD + CZ2 were fed a high cholesterol diet (HCD) along with 2% CZ; and group HCD + CZ8 were fed an HCD diet along with 8% CZ. After the treatment process, blood samples were taken from all of studied animals, and sera were prepared for lipid profile assays. Liver LDL-R gene expression was assayed using the real-time polymerase chain reaction (PCR) method. Liver histological changes were determined using the hematoxylin and eosin staining method. Results: A significant reduction was observed in serum triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), very-low-density lipoprotein cholesterol (VLDL-c), aspartate transaminase (AST), and alanine transaminase (ALT) levels in the HCD + CZ8 group, while serum high density lipoprotein cholesterol (HDL-c) levels increased when compared with the HCD group (P < 0.001). The HCD group demonstrated decreased LDL-R gene expression in the animals’ livers, whereas treatment with CZ up-regulated its expression. The scores for hepatic steatosis in the HCD + CZ8 group were diminished significantly. Conclusions: The administration of CZ improved dyslipidemia in hypercholesterolemic animals, probably by increasing LDL-R gene expression in the liver; consequently, it can be concluded that CZ can reverse hepatic steatosis. Therefore, CZ was determined as having a protective role against hypercholesterolemia.

Effect of pathological conditions on peritoneal macrophage glycosaminoglycans: Impact on cytoadherence

Glycosaminoglycans (GAGs) have a plethora of functions to play. They are widely present in extracellular matrix, cell surface and inside the cell. During pathological conditions remodeling of GAGs leads to modifications in their structure and functions. In the present work, peritoneal macrophages were isolated from normal, diabetic, and diet-induced hypercholesterolemic rats and evaluated in terms of GAGs and cytoadherence to various extracellular matrix (ECM) components. Peritoneal macrophages are known to play important roles in the control of infection and inflammation. Isolated GAGs were characterized as belonging to heparan sulfate/heparin class. There were quantitative changes in sulfated GAGs in diabetic and hypercholesterolemic groups when compared to normal rats. Dose-dependent changes in cytoadherence were observed only with respect to fibronectin in LPS-activated macrophages from diabetic animals but not with laminin and type IV collagen when compared to macrophages from normal rats. Cytoadherence was significantly decreased on treatment with heparinase indicating that cytoadherence was at least partly mediated by heparan sulfate/heparin class of GAGs. Global disaccharide composition analysis showed that GAGs from macrophages of diabetic animals had higher sulfation ratio when compared to that of control and hypercholesterolemic animals.

Study of oxidative and inflammatory parameters in LDLr-KO mice treated with a hypercholesterolemic diet: Comparison between the use of Campomanesia xanthocarpa and acetylsalicylic acid

Background: Atherosclerosis is an inflammatory disease that affects the arterial wall leading to myocardial, cerebral, and peripheral ischemic syndromes. The use of low doses of aspirin inhibits platelet aggregation and inflammation and prevents cardiovascular mortality. However, ASA may produce hemorrhagic events. Thus, several studies have sought new natural compounds to suppress platelet aggregation without causing serious adverse effects. Purpose: In this sense, this study aims to compare the effects of Campomanesia xanthocarpa plant extract with those of acetylsalicylic acid (ASA) on inflammatory parameters observed in homozygous mice knockout for the low-density lipoprotein receptor (LDLr-KO) treated with a hypercholesterolemic diet. Material and Methods: In this study, 28 male LDLr-KO mice were divided into three groups and fed a hypercholesterolemic diet for 4 weeks. Thereafter, the animals that received the hypercholesterolemic diet were treated for 5 days with (1) distilled water, (2) C. xanthocarpa extract, or (3) acetylsalicylic acid. The levels of inflammatory markers were assessed in the blood samples. The gastric tolerability of the animals after oral administration of the treatments was assessed through quantification of the lesions in the gastric mucosa. Results: The levels of proinflammatory cytokines IL-1, IL-6, TNF-α, and INF-γ were reduced to 19.2 ± 3%, 20.4 + 1.3%, 24.7 ± 1.2%, and 20.8 ± 1.7%, respectively, in the group treated with C. xanthocarpa, when compared to control group. Furthermore, treatment with plant extract significantly increased the levels of the anti-inflammatory cytokine IL-10 by 27.3 ± 5.9%, but ASA showed no significant effect on the same cytokines when compared to the control group, with the exception of IL-10, which presented an increase of 8.6 ± 3.5%. Treatments with C. xanthocarpa and ASA also caused significant reductions of 26.4 ± 3% and 38.4± 6% in the serum levels of oxLDL, respectively. However, only treatment with C. xanthocarpa reduced the levels of anti-oxLDL antibodies when compared with the control (25.8 ± 6%). In addition, the analyzed extract did not induce ulcerogenic activity, while ASA induced the formation of lesions. Conclusion: In conclusion, treatment with C. xanthocarpa causes anti-inflammatory activity in hypercholesterolemic animals, with results superior to those obtained with the use of ASA.

Grape Seed Proanthocyanidins Attenuate Anxiety-Like Behavior in an Experimental Model of Dietary-Induced Hypercholesterolemia in Rats.

Grape seed proanthocyanidins have many health-protective effects. The present work aimed to assess their possible anxiolytic effects in dietary-induced hypercholesterolemia in rats. 30 Male Wistar rats were divided into 3 groups (n = 10): control (normal chow), high cholesterol (cholesterol and cholic acid chow) and high cholesterol + grape seed extract (hypercholesterolemic chow + grape seed extract, 100 mg/kg body weight/day). After 4 months, total cholesterol levels and animals' behavior in the open field and elevated plus maze were assessed. High-cholesterol diet elevated cholesterol levels (p < 0.001 vs control group), however, grape seed administration ameliorated this elevation (p < 0.001 vs high-cholesterol untreated group). In the open field, hypercholesterolemic rats showed increased periods of immobility (138 ± 20.3 seconds (s) vs 96.9 ± 14.5 in control rats p < 0.001) and time latency to enter field center (109 ± 18.3 s compared to 40.8 ± 10.5 s in the control group p < 0.001). Both parameters were reduced by grape seed treatment (p < 0.01, p < 0.001 vs the untreated hypercholesterolemic group, respectively). Elevated plus maze testing demonstrated higher closed-arm entries (5.5 ± 1.1 in hypercholesterolemic animals vs 3 ± 1.1 in the control group p < 0.001) and lower percentage of time spent in open arms (19.7 ± 3.5 % vs 35.8 ± 4.8 % in control rats p < 0.001). Grape seed extract significantly enhanced the percentage of time spent in open arms (p < 0.001 compared to hypercholesterolemic rats). The present results highlight the possible anxiolytic effect of grape seed proanthocyanidins in dietary-induced hypercholesterolemia.

Hypocholesterolemic effects of Balangu (Lallemantia royleana) seeds in the rabbits fed on a cholesterol-containing diet.

Lallemantia royleana (Benth. in Wall.) Benth. (Lamiaceae) is a medicinal plant used in Iranian traditional and folklore medicine in the treatment of various nervous, hepatic, and renal diseases. In the present study, whole seeds of the herb were prepared and evaluated for hypolipidemic activities using an animal model. Animals were fed normal diets or diets supplemented with cholesterol (0.5%) for 12 weeks to evoke hypercholesterolemia. Moreover, hypercholesterolemic animals were treated with different doses of whole seeds of Balangu (0, 5, 10, and 20%) for 12 weeks. Results showed that the serum total cholesterol and triglyceride decreased in all groups treated with Balangu seeds p<0.05. Changes in the distribution of cholesterol in low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) were found. LDL-C and HDL-C decreased significantly in all of the groups treated with whole seeds of the herb with respect to hypercholesterolemic group p<0.05. Our results showed that L. royleana seeds decreased the serum cholesterol and triglyceride levels in hypercholesterolemic animals but led to the increase of atherogenic index in all treated groups.

A study on the effects of the hydroalcholic extract of the aerial parts of Alhagi camelorum on prolactin and pituitary-gonadal activity in rats with hypercholesterolemia.

Although endocrine disorders are not a common cause of infertility, in some cases, testing thyroid function, and hypothalamus - pituitary - gonadal axis can determine the cause of infertility. We aimed to investigate the effect of the aerial parts of Alhagi camelorum extract on prolactin, cortisol and pituitary - gonadal axis activities in rats with hypercholesterolemia. In this study, 35 male wistar rats in 5 groups (n = 7) were assigned as: control group with normal diet, the sham group with fat diet and three experimental groups of hypercholesterolaemic animals which received Alhagi camelorum extract at a minimum dose of 100 mg/kg, average dose of 200 ml/kg and maximum dose of 300 mg/kg over a period of 21 days. At the end of the period, blood samples were collected from all groups and blood factors were then measured and analyzed. In the sham group compared to the control, cholesterol levels increased and FSH levels decreased, whereas cholesterol levels reduced in the experimental groups. Alhagi camelorum extract also reduced testosterone level and increased prolactin and gonadotropins. Alhagi camelorum extract at low and average doses reduced cortisol, testosterone and cholesterol and increased gonadotropins. So it can cause reproductive disorders in male rats. The extract at maximum dose can increase cortisol and prolactin. As these two hormones work together to produce milk, this plant can help to boost breastfeeding.

Elsibucol inhibits atherosclerosis following arterial injury: Multifunctional effects on cholesterol levels, oxidative stress and inflammation

Background: Elsibucol is a metabolically stable derivative of probucol with antioxidant, anti-inflammatory and antiproliferative properties. Here we investigated the effect of elsibucol on the development of atherosclerosis following arterial injury in hypercholesterolemic rabbits. Methods and results: New Zealand White rabbits were fed a high cholesterol diet that was supplemented or not with 0.5% elsibucol, 1% elsibucol or 1% probucol. An angioplasty of the iliac artery was performed after 3 weeks of diet. We found that treatment with elsibucol significantly decreases blood total cholesterol, LDLc and triglyceride levels. This is associated with a significant 46% reduction of neointimal hyperplasia following arterial injury. Interestingly, the effect of elsibucol on cholesterol levels and neointimal formation appears to be more pronounced than that of probucol. In vitro, elsibucol reduces vascular smooth muscle cell proliferation without affecting cell viability. In vivo, treatment with elsibucol is associated with a significant reduction of cellular proliferation (PCNA immunostaining), oxidative stress (nitrotyrosine immunostaining), VCAM-1 expression and macrophage infiltration in injured arteries. Despite its potent effect on neointimal hyperplasia, elsibucol does not prevent endothelial healing (Evans blue staining) following arterial injury. Conclusions: In hypercholesterolemic animals, elsibucol inhibits atherosclerosis and preserves endothelial healing following arterial injury. The mechanisms involved include lowering of blood cholesterol levels together with a reduction of oxidative stress and inflammation in injured arteries.

A novel posttranscriptional mechanism for dietary cholesterol-mediated suppression of liver LDL receptor expression

It is well-established that over-accumulation of dietary cholesterol in the liver inhibits sterol-regulatory element binding protein (SREBP)-mediated LDL receptor (LDLR) gene transcription leading to a reduced hepatic LDLR mRNA level in hypercholesterolemic animals. However, it is unknown whether elevated cholesterol levels can elicit a cellular response to increase LDLR mRNA turnover to further repress LDLR expression in liver tissue. In the current study, we examined the effect of a high cholesterol diet on the hepatic expression of LDLR mRNA binding proteins in three different animal models and in cultured hepatic cells. Our results demonstrate that high cholesterol feeding specifically elevates the hepatic expression of LDLR mRNA decay promoting factor heterogeneous nuclear ribonucleoprotein (HNRNP)D without affecting expressions of other LDLR mRNA binding proteins in vivo and in vitro. Employing the approach of adenovirus-mediated gene knockdown, we further show that depletion of HNRNPD in the liver results in a marked reduction of serum LDL-cholesterol and a substantial increase in liver LDLR expression in hyperlipidemic mice. Additional studies of gene knockdown in albumin-luciferase-untranslated region (UTR) transgenic mice provide strong evidence supporting the essential role of 3'UTR in HNRNPD-mediated LDLR mRNA degradation in liver tissue. Altogether, this work identifies a novel posttranscriptional regulatory mechanism by which dietary cholesterol inhibits liver LDLR expression via inducing HNRNPD to accelerate LDLR mRNA degradation.

Hypercholesterolemia Induces Angiogenesis and Accelerates Growth of Breast Tumors in Vivo

Obesity and metabolic syndrome are linked to an increased prevalence of breast cancer among postmenopausal women. A common feature of obesity, metabolic syndrome, and a Western diet rich in saturated fat is a high level of circulating cholesterol. Epidemiological reports investigating the relationship between high circulating cholesterol levels, cholesterol-lowering drugs, and breast cancer are conflicting. Here, we modeled this complex condition in a well-controlled, preclinical animal model using innovative isocaloric diets. Female severe combined immunodeficient mice were fed a low-fat/no-cholesterol diet and then randomized to four isocaloric diet groups: low-fat/no-cholesterol diet, with or without ezetimibe (cholesterol-lowering drug), and high-fat/high-cholesterol diet, with or without ezetimibe. Mice were implanted orthotopically with MDA-MB-231 cells. Breast tumors from animals fed the high-fat/high-cholesterol diet exhibited the fastest progression. Significant differences in serum cholesterol level between groups were achieved and maintained throughout the study; however, no differences were observed in intratumoral cholesterol levels. To determine the mechanism of cholesterol-induced tumor progression, we analyzed tumor proliferation, apoptosis, and angiogenesis and found a significantly greater percentage of proliferating cells from mice fed the high-fat/high-cholesterol diet. Tumors from hypercholesterolemic animals displayed significantly less apoptosis compared with the other groups. Tumors from high-fat/high-cholesterol mice had significantly higher microvessel density compared with tumors from the other groups. These results demonstrate that hypercholesterolemia induces angiogenesis and accelerates breast tumor growth in vivo.

The protective effect of Na+/Ca2+ exchange blocker kb-r7943 on myocardial ischemia-reperfusion injury in hypercholesterolemic rat.

KB-R7943 reduces lethal reperfusion injury under normal conditions, but its effectiveness under certain pathological states is in dispute. In the present study, we sought to determine the effect of KB-R7943 in hyperlipidemic animals and assess if the K ATP (+) are involved in the protective mechanisms. In group 1 (G1), isolated rat hearts underwent 25 min global ischemia (GI) and 120 min reperfusion (R). In group 2 (G2), G1 was repeated but the animals were subjected to a 1.5 % cholesterol-enriched diet during 6 weeks (hypercholesterolemic animals). In group 3 (G3), G2 was repeated but 1 μM KB-R7943 was added to the perfusate for 10 min from the start of reperfusion. In group 4 (G4), G3 was repeated, and glibenclamide (K ATP (+) , blocker, 0.3 μM) was administered. The infarct size was measured by triphenyltetrazolium. The infarct size was 35 ± 5.0 % in G1 and 46 ± 8.7 % in G2 (P < 0.05); KB-R7943 reduced the infarct size (28.6 ± 3.3 % in G3 vs. G2, P < 0.05). In addition, KB-R7943 attenuated apoptotic cell (G3 vs. G2, P < 0.05), but glibenclamide abolished the effect reached by KB-R7943. Thus, diet-induced hypercholesterolemia enhances myocardial injury; KB-R7943 reduces infarct size and apoptosis in hyperlipidemic animals through the activation of K(+)ATP channels.

Effect of Bunium persicum aqueous extract plus endurance exercise on cardiorespiratory capacity and serum lipid profile.

We examined the effects of endurance exercise in the presence of Bunium persicum extract administration on lipid profile and cardiorespiratory capacity in hypercholesterolemic male mice. Materials and Methods : Forty male hypercholesterolemic mice were divided into four groups: Vehicle, Endurance exercise (EE), Bunium persicum extract (BPE), and EE + BPE. The exercise protocol was performed at a speed of 18 m/min, 40 min/day, and 5 days/week for 6 weeks. The BPE was administered orally by a dose of 20 mg/Kg/day. The results indicated that the 6-week endurance training accompanied by Bunium Persicum extract administration increased cardiorespiratory capacity significantly (601±39 vs. 293±20 meters, p<0.001). Total cholesterol level was significantly reduced in EE + BPE compared with Vehicle and EE groups (p<0.05). LDL-c was lower in EE + BPE compared with the Vehicle (p<0.01). HDL-c in BPE and EE + BPE groups was significantly higher than Vehicle (p<0.001 and p<0.05, respectively). Serum triglyceride level was significantly (p<0.05) lower in BPE than the other three groups. Body weight changes were not significantly different between groups. The results suggested that Bunium persicum extract is very useful in improvement of lipid profile in hypercholesterolemic animals. Supplementation of the extract to exercise significantly increased the cardiorespiratory capacity.

&lt;b&gt;Evaluation of the protective effect of guava fruits and leaves on oxidative stress &lt;/b&gt; - doi: 10.4025/actascibiolsci.v36i1.19839

Oxidative stress is an imbalance between reactive oxygen species and antioxidant capacity of action. Thus, research, alternative to mitigate the damaging effects of oxidative stress, improving the body´s antioxidant capacity, prevented the disease and its complicatons. The leaves and fruits of guava are rich in the antioxidants. This work aimed to study the effect of flour and ethanolic/acetone extracts leaves and fruits of guava on lipid oxidation in rats with hypercholesterolemic. The flour and extracts decreased leves of triglycerides and non – HDL cholesterol and increased in the HDL. Cholesterol levels decreased only leaves and fruits. The activity of GPx decreased in samples serum in all treatments and the SOD only the extracts were effective. There was no difference in levels the MDA in relation hypercholesterolemic control. For the samples of liver, there was no difference in activity SOD. In relation of activity GPx, only the flour was effective. There were differences in levels the MDA of the hypercholesterolemic animals treated with flour and extracts with the animals of the hypercholesterolemic control.