Rat Model Of Hypercholesterolemia Research Articles

Rivaroxaban attenuates the cardiovascular PAR1-related inflammation, fibrosis and atherogenicity in experimental hypertensive/ hypercholesterolemia rat model

Rivaroxaban attenuates the cardiovascular PAR1-related inflammation, fibrosis and atherogenicity in experimental hypertensive/ hypercholesterolemia rat model

Integration of network pharmacology, UHPLC-Q exactive orbitrap HRMS technique and metabolomics to elucidate the active ingredients and mechanisms of compound danshen pills in treating hypercholesterolemic rats

Ethnopharmacological relevanceHypercholesterolemia (HLC) was a key risk factor for cardiovascular disease (CVD) characterized by elevated cholesterol levels, particularly LDL. While traditional Chinese medicine preparations Compound Danshen Pills(CDP) has been clinically used for hypercholesterolemia and coronary heart disease, its specific therapeutic effect on HLC remains understudied, necessitating further investigation into its mechanisms. Aim of the studyThe aim of this study was to explore the potential of CDP in treating HLC and elucidate its underlying mechanisms and active components. Materials and methodsA hypercholesterolemic lipemia rat model induced by a high-fat diet was employed. Network pharmacology combined with UHPLC-Q exactive orbitrap HRMS technique was used to predict the active components, targets and mechanisms of CDP for HLC. Histological analysis and serum biochemical assays were used to assess the therapeutic effect of CDP and its main active ingredient Sa B on hypercholesterolemic lipemia rat model. Immunofluorescence assays and western blotting were used to verify the mechanism of CDP and Sa B in the treatment of HLC. Metabolomics approach was used to demonstrate that CDP and Sa B affected the metabolic profile of HLC. ResultsOur findings demonstrated that both CDP and its main active ingredient Sa B significantly ameliorated hypercholesterolemic lipemic lesions, reducing levels of TC, LDL, AST, ALT, and ALP. Histological analysis revealed a decrease in lipid droplet accumulation and collagen fiber deposition in the liver, as well as reduced collagen fiber deposition in the aorta. Network pharmacology predicted potential targets such as PPARα and CYP27A1. Immunofluorescence assays and western blotting confirmed that CDP and Sa B upregulated the expression of Adipor1, PPARα and CYP27A1. Metabolomics analyses further indicated improvements in ABC transporters metabolic pathways, with differential metabolites such as riboflavin, taurine, and choline showed regression in levels after CDP treatment and riboflavin, L-Threonine, Thiamine, L-Leucine, and Adenosine showed improved expression after Sa B treatment. ConclusionCDP and Sa B have been shown to alleviate high-fat diet-induced hypercholesterolemia by activating the PPAR pathway and improving hepatic lipid metabolism. Our study demonstrated, for the first time, the complex mechanism of CDP, Sa B in the treatment of hypercholesterolemia at the protein and metabolic levels and provided a new reference that could elucidate the pharmacological effects of traditional Chinese medicine on hypercholesterolemia from multiple perspectives.

Molecular mechanism study and potential active ingredients prediction of Danhe granules in the treatment of hypercholesterolemia via TICE

AbstractThis study aims to explore the molecular mechanism and potential active ingredients of Danhe granules in improving the blood lipid level of hypercholesterolemia by intestinal TICE (transintestinal cholesterol excretion) through in vivo experimental research, network pharmacology methods, and molecular docking. The diet‐induced hypercholesterolemia rat model evaluated the effects of Danhe granules on fecal cholesterol levels and intestinal TICE‐related protein expression in rats. Based on the experimental results, the network pharmacology method was used to predict the potential active ingredients, and the binding strength between the potential active ingredients and key targets was further confirmed by molecular docking. Danhe granules increased LDLR, ABCG5, ABCB1, and LXRα which can promote the uptake of cholesterol by intestinal cells and the excretion of cholesterol into the intestine, and then reduce the levels of serum LDL‐C and TC and increase the level of fecal TC, so as to achieve the effect of treating hypercholesterolemia. The results of network pharmacology and molecular docking showed that 19 active ingredients had good binding activity with the targets. These may be the active ingredients of Danhe granules for the treatment of hypercholesterolemia. This study revealed the molecular mechanism of Danhe granules in the treatment of hypercholesterolemia via TICE, and preliminarily clarified the potential effective ingredients. It provides new ideas for the treatment of hypercholesterolemia and the development of new drugs.

Polymethoxyflavones in citrus extract has a beneficial effect on hypercholesterolemia rats by promoting liver cholesterol metabolism

Ethnopharmacological relevanceHyperlipidemia is characterized by the disorder of lipid metabolism accompanied by oxidative stress damage, and low-grade inflammation, with the pathway of cholesterol and bile acid metabolic are an important triggering mechanism. Polymethoxyflavones (PMFs) are the active constituents of Aurantii Fructus Immaturus, which have many biological effects, including anti-inflammatory, antioxidant activities, anti-obesity, suppressing adipogenesis in adipocytes, and ameliorate type 2 diabetes, with potential roles for regulation of lipid metabolism. However, its associated mechanisms on hyperlipidemia remain unclear. Aim of the studyThis study aims to identify the anti-hypercholesterolemia effects and mechanisms of PMFs in a hypercholesterolemia model triggered by high-fat compounds in an excessive alcohol diet (HFD). Materials and methodsA hypercholesterolemia rat model was induced by HFD, and PMFs was intragastric administered at 125 and 250 mg/kg daily for 16 weeks. The effects of PMFs on hypercholesterolemia were assessed using serum lipids, inflammatory cytokines, and oxidative stress levels. Hematoxylin & eosin (H&E) and Oil Red O staining were performed to evaluate histopathological changes in the rat liver. The levels of total cholesterol (TC) and total bile acid (TBA) in the liver and feces were determined to evaluate lipid metabolism. RAW264.7 and BRL cells loaded with NBD-cholesterol were used to simulate the reverse cholesterol transport (RCT) process in vitro. The signaling pathway of cholesterol and bile acid metabolic was evaluated by Western Blotting (WB) and qRT-PCR. ResultsLipid metabolism disorders, oxidative stress injury, and low-grade inflammation in model rats were ameliorated by PMFs administration. Numerous vacuoles and lipid droplets in hepatocytes were markedly reduced. In vitro experiments results revealed decreased NBD-cholesterol levels in RAW264.7 cells and increased NBD-cholesterol levels in BRL cells following PMFs intervention. PMFs upregulated the expression of proteins associated with the RCT pathway, such as LXRα, ABCA1, LDLR, and SR-BI, thereby promoting TC entry into the liver. Meanwhile, the expression of proteins associated with cholesterol metabolism and efflux pathways such as CYP7A1, CYP27A1, CYP7B1, ABCG5/8, ABCB1, and BSEP were regulated, thereby promoting cholesterol metabolism. Moreover, PMFs treatment regulated the expression of proteins related to the pathway of enterohepatic circulation of bile acids, such as ASBT, OSTα, NTCP, FXR, FGF15, and FGFR4, thereby maintaining lipid metabolism. ConclusionsPMFs might ameliorate hypercholesterolemia by promoting the entry of cholesterol into the liver through the RCT pathway, followed by excretion via metabolism pathways of cholesterol and bile acid. These findings provide a promising therapeutic potential for PMFs to treat hypercholesterolemia.

Sericin enhances ammonia detoxification by promotes urea cycle enzyme genes and activates hepatic autophagy in relation to CARD-9/MAPK pathway

Urea cycle is an important metabolic process that initiates in liver mitochondria and converts ammonia to urea. The impairment of ammonia detoxification, both primary and secondary causes, lead to hyperammonemia, a life-threatening condition affecting to the brain. Current treatments are not enough effective. In addition, our recent proteomics study in hypercholesterolemic rat model demonstrated that sericin enhances hepatic nitrogenous waste removal through carbamoyl-phosphate synthase 1 (CPS-1), aldehyde dehydrogenase-2 (ALDH-2), and uricase proteins. However, the underlining mechanisms regard to this property is not clarified yet. Therefore, the present study aims to examine the effect of sericin on urea cycle enzyme genes (CPS-1 and ornithine transcarbamylase; OTC) and proteins (mitogen-activated protein kinase; MAPK, caspase recruitment domain-containing protein 9; CARD-9, Microtubule-associated protein light chain 3; LC-3), which relate to urea production and liver homeostasis in hepatic cell line (HepG2) and hypercholesterolemic rat treated with or without sericin. qRT-PCR, immunohistochemistry, and electron microscopy techniques were performed. In vitro study determined that high dose of sericin at 1 mg/ml increased liver detoxification enzyme (Cytochrome P450 1A2; CYP1A2 and ALDH-2) and urea cycle enzyme (CPS-1 and OTC) genes. Both in HepG2 cell and rat liver mitochondria, sericin significantly downregulated CARD-9 (apoptotic protein) expression while upregulated MAPK (hepatic homeostasis protein) and LC-3 (autophagic protein) expressions. Hence, it might be concluded that sericin promotes ammonia detoxification by both increases urea cycle enzyme genes and enhances hepatic autophagy in associated with CARD-9/MAPK pathway (as shown by their own negative relationship). This study presents another beneficial property of sericin to develop an upcoming candidate for ammonia toxicity alleviation and liver function improvement.

Bifidobacterium supplementation attenuates hypercholesterolemia induced gut-brain-testis dysfunction in a rat model

Hypercholesterolemia is the state of high LDL blood cholesterol levels. This may lead to cholesterol accumulation in organs and cause diseases such as male infertility and NAFLD. Recent studies have shown strong correlations between Bifidobacterium strains and plasma cholesterol reduction. Bifidobacterium species are gram positive bacteria known to colonize the human gastrointestinal tract. Studies suggest that Bifidobacterium may reduce serum cholesterol levels by increasing bile salt hydrolase (BSH) activity. BSH increases fecal excretion of bile salt, and to compensate the loss of circulating bile acids, productions of bile acids using cholesterol are promoted. Currently, medications such as statins are commonly used. However, long term consumption could cause adverse effects on male reproductive organs. Bifidobacterium strains are known to regulate the hypothalamus-pituitary-gonadal (HPG) axis by modulating gut microbiota . Gut microbial bacteria such as Bifidobacterium contribute to the host metabolism by enhancing gut barrier integrity, reducing inflammation cytokine expressions, and increasing metabolite productions such as short chain fatty acids (SCFAs). Particularly, SCFAs like butyrate can cross the blood-brain barrier, and consequently affect the HPG axis. This suggests that Bifidobacterium strains may lower serum cholesterol while protecting reproductive organs. Therefore, this study aimed to evaluate and compare the serum cholesterol lowering and HPG axis protecting effects of Bifidobacterium strains with statin in the gut-brain-testis axis of a high cholesterol diet (HCD) induced hypercholesterolemia rat model. 6-week oral gavage of Bifidobacterium strains known to have BSH activity effectively reduced serum total cholesterol and LDL cholesterol levels in rats given HCD for the same period. Moreover, serum inflammatory cytokine IL-1β was reduced by Bifidobacterium treatment. Bifidobacterium also exerted protective effects against intestinal, testicular, and cerebral damage by attenuating disruption of histology and modulating transcript levels of inflammation markers. Notably, Bifidobacterium alleviated the HCD-induced reduction of male sex hormone synthesis markers in the testis, which statin had no effect. Fecal analysis revealed that Bifidobacterium treatment modulates gut microbiota compositions and metabolite levels such as SCFAs. Particularly, 16s rRNA genomic annotation showed that Bifidobacterium strains may have specific functions related to cholesterol reduction. Altogether, Bifidobacterium supplementation may reduce serum cholesterol levels by altering gut microbiota compositions, which affect gut metabolite compositions, inflammatory markers, and sex hormone synthesis markers. In conclusion, Bifidobacterium supplementation is a potential therapeutic approach for hypercholesterolemia-induced intestine, brain, and testis dysfunction. This work was supported by Cellbiotech Co., Ltd. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effect of Vitamin D on YKL-40: Rat Hypercholesterolemia Model.

YKL-40 is considered to be associated with cardiovascular disease (CVD). In this study, the effect of serum 25(OH) vitamin D [25(OH)VitD] differences between groups on YKL-40 was evaluated on a hypercholesterolemia rat model. Thirty-two male rats (wistar albino) were equally divided into 4 groups. The first group was the control group; the second group was high-cholesterol (H-CH) adequate vitamin D (VitD) group (H-AdeVD). The third group was the H-CH deficient VitD group (H-DefVD), and the last group was designed with the H-CH supplement VitD (H-SupVD). The feeding process consisted of 2 stages. At the first stage (5 months), the H-DefVD group was fed on VitD deficient chow, while the other groups (control, H-AdeVD, H-SupVD) were fed on standard chow. At the second stage (3 months), the H-AdeVD and the H-SupVD groups were fed on the H-CH chow, whereas the H-DefVD group was fed on the H-CH-VitD deficient chow. Moreover, the H-SupVD group was given 100 IU/kg/day VitD along with the H-CH chow. Compared with the control group, interleukin-6 (IL-6), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and YKL-40 values in the H-DefVD groups increased significantly (p<0.001, p<0.001, p=0.009, p=0.005; sequentially). It can be concluded that VitD can suppress the YKL-40, thus, it will prevent CVD development in rat. Therefore, further clinical studies related with human will reveal the effect of VitD and YKL-40 on CVD development.

Effect of Linoleic Acid on Cholesterol Levels in a High-Fat Diet-Induced Hypercholesterolemia Rat Model.

Cardiovascular disease is the leading cause of morbidity and mortality worldwide, accounting for almost one-third of all deaths. The risk factors for developing this disease include high levels of serum total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL), alongside low levels of high-density lipoprotein (HDL). Dietary linoleic acid has been suggested to reduce these risk factors. This study aims to determine the effects of linoleic acid on cholesterol levels, liver function tests, and structural changes in liver tissue in comparison with fenofibrate in a hypercholesterolemic rat model. Thirty-six male Sprague Dawley rats (150-180 g) were divided into non-hypercholesterolemic and hypercholesterolemic groups. Hypercholesterolemia was induced in the rats by feeding them with a high-fat diet for two weeks. After two weeks, the non-hypercholesterolemic and hypercholesterolemic rats were equally divided into six groups (n = 6): control non-hypercholesterolemic rats, non-hypercholesterolemic rats treated with fenofibrate (60 mg/kg), non-hypercholesterolemic rats treated with linoleic acid (5 mg/kg), control hypercholesterolemic rats, hypercholesterolemic rats treated with fenofibrate (60 mg/kg), and hypercholesterolemic rats treated with linoleic acid (5 mg/kg). The changes in the rats' body weight, serum lipid profiles, atherogenic indices, and liver function test results were obtained. The rats' liver tissues were stained for histopathological analysis. The linoleic acid-treated hypercholesterolemic rats exhibited significantly reduced serum TC, TG, LDL, aspartate aminotransferase, and alanine aminotransferase levels, as well as increased HDL levels compared with the control hypercholesterolemic rats. These linoleic acid effects were comparable to those in the fenofibrate-treated hypercholesterolemic rats. In conclusion, linoleic acid possesses early anti-hypercholesterolemic properties, which may be due to the reductions in serum cholesterol levels and mild early structural changes in the liver tissues of hypercholesterolemic rats. Therefore, continued studies on linoleic acid in atherosclerotic and/or obese animal models are suggested.

The effect of probiotic on abdominal aortic malondialdehyde of hypercholesterolemic rat model

Background and Aims : A high-fat diet is one of the risk factors for hypercholesterolemia. In the condition of hypercholesterolemia, there will be a metabolic disorder of cholesterol where the body will convert cholesterol into bile acids which in the process will produce free radicals. Probiotics are additional foods that have an antihypercholesterolemic effect. This study aims to determine the effect of probiotic administration on abdominal aortic malondialdehyde (MDA) levels in the hypercholesterolemia rat model induced by shortening.

Impaired endothelial cell proliferative, migratory, and adhesive abilities are associated with the slow endothelialization of polycaprolactone vascular grafts implanted into a hypercholesterolemia rat model

Most small diameter vascular grafts (inner diameter<6 mm) evaluation studies are performed in healthy animals that cannot represent the clinical situation. Herein, an hypercholesterolemia (HC) rat model with thickened intima and elevated expression of pro-inflammatory intercellular adhesion molecular-1 (ICAM-1) in the carotid branch is established. Electrospun polycaprolactone (PCL) vascular grafts (length: 1 cm; inner diameter: 2 mm) are implanted into the HC rat abdominal aortas in an end to end fashion and followed up to 43 days, showing a relative lower patency accompanied by significant neointima hyperplasia, abundant collagen deposition, and slower endothelialization than those implanted into healthy ones. Moreover, the proliferation, migration, and adhesion behavior of endothelial cells (ECs) isolated from the HC aortas are impaired as evaluated under both static and pulsatile flow conditions. DNA microarray studies of the HC aortic endothelium suggest genes involved in EC proliferation (Egr2), apoptosis (Zbtb16 and Mt1), and metabolism (Slc7a11 and Hamp) are down regulated. These results suggest the impaired proliferative, migratory, and adhesive abilities of ECs are associated with the bad performances of grafts in HC rat. Future pre-clinical evaluation of small diameter vascular grafts may concern more disease animal models with clinical complications. Statement of significanceDuring the development of small diameter vascular grafts (D<6 mm), young and healthy animal models from pigs, sheep, dogs, to rabbits and rats are preferred. However, it cannot represent the clinic situation, where most cardiovascular grafting procedures are performed in the elderly and age is the primary risk factor for disease development or death. Herein, the performance of electrospun polycaprolactone (PCL) vascular grafts implanted into hypercholesterolemia (HC) or healthy rats were evaluated. Results suggest the proliferative, migratory, and adhesive abilities of endothelial cells (ECs) are already impaired in HC rats, which contributes to the observed slower endothelialization of implanted PCL grafts. Future pre-clinical evaluation of small diameter vascular grafts may concern more disease animal models with clinical complications.

Effect of activation of liver X receptor alpha on cardiac & hepatic ABCC10 and SLC17A5 drug transporters in hypercholesterolemic rat model

BackgroundLiver x receptor α (LXRα) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. Oxysterols (endogenous oxidized cholesterol derivatives) are the most potent endogenous LXRα-agonist. LXRα has a direct impact on several members of drug transporter superfamilies; ATP-binding cassette (ABC) and solute linked carrier (SLC). ObjectiveThe current study aimed to investigate the effect of LXRα-activation by either endogenous oxysterols or a synthetic LXRα-agonist (LXRa) such as TO901317 on hepatic and cardiac gene expression of ABCC10 and SLC17A5 drug transporters in an experimentally hypercholesterolemic rat model. Methods48 male rats were divided randomly into four groups (n = 12); control group rats received vehicle; hypercholesterolemic group (HCH group) rats received diet contain 2.5% cholesterol &deoxycholic acid for 8 weeks; (LXRa group) rats were fed standard pellet chow for 8 weeks, then a single dose of LXRa was administered (IP) at a dose of 10 mg/kg; (HCH + LXRa group) rats received diet contain 2.5% cholesterol &deoxycholic acid for 8 weeks, then a single dose of LXRa was administered (IP) at a dose of 10 mg/kg. ResultsOur findings revealed that hypercholesterolemia and LXRa significantly activated LXRα to varying degrees in both hepatic and cardiac tissues with subsequent alteration of LXRα and ABCC10 gene expression. Whereas, SLC17A5 gene expression was primarily affected by elevated serum cholesterol level and unmediated via LXRα-activation. ConclusionsAccordingly, it was concluded that ABCC10 is a specific LXRα-target gene and that LXRα autoregulates its own expression in rats.

Pleurotus pulmonarius (FR.) Quél Crude Aqueous Extract Ameliorates Wistar-Kyoto Rat Thoracic Aortic Tissues and Vasodilation Responses

Pleurotus pulmonarius crude aqueous (CA) extract was previously reported to have therapeutic potential, thus its ability to alleviate serum total cholesterol, vasodilation, and improve the aortic tissue structure in hypercholesterolemia rat model was studied. Eight groups of Wistar-Kyoto rats were involved including normal (G1), hypercholesterolemia (G2), treatment (G3 to G5) and prevention (G6 to G8). Two doses of CA; 0.5 g/kg body weight (BW), 2.0 g/kg BW, and simvastatin 10 mg/kg BW were orally fed to the rats (G3 to G8). Treatment groups were induced with hypercholesterolemia and later treated with CA/simvastatin, while prevention groups were given both hypercholesterolemia-diet and CA/simvastatin simultaneously. The thoracic aortic rings (TAR) were subjected to contractility study and histopathology examination. In organ bath analysis, pre-contracted TAR of G1 with phenylephrine (PE) achieved 60% vasodilation response towards acetylcholine (ACh) whereas TAR of G2 unable to respond to ACh. G3 to G5 groups failed to dilate when induced with ACh whereas G6 to G8 groups showed a slight improvement. The repeated precontracted TAR of G1 and G2 significantly dilated with the presence of CA and simvastatin. TAR of G1 achieved 100% vasodilation at 3.0 mg/mL CA and 2.4 mg/mL simvastatin. TAR of G2 achieved 73% vasodilation at 6.0 mg/mL CA whereas 76.8% dilation recorded for simvastatin at 4.8 mg/mL. Histopathological examination found that CA was able to improve the structure of the aortic cells. These observations suggest that CA helps to improve tissue condition and vasodilation of the hypercholesterolemic aorta.

The possible alleviating effect of garlic supplement on the neural retina in a rat model of hypercholesterolemia: a histological and immunohistochemical study.

The purpose of this work was to prove that oxidative stress is the main mechanism responsible for retinal neurodegenerative changes, subsequent apoptosis, and inflammatory cytokine release in rats fed with a high cholesterol diet (HCD) and determine the role of garlic in alleviating these changes. Forty rats were equally divided into four groups: control, garlic-treated (positive control), HCD, and HCD + garlic-treated (HCD + G). By the end of the experiment (24 weeks) blood samples were collected for assessment of serum lipid profile, oxidative stress parameters, and plasma levels of IL-6 and TNF-α. Both eyes of the rats were enucleated; one was used for light microscopic examination and the other for electron microscopic examination. There was a significant increase in the levels of serum lipids, oxidative stress parameters, IL-6 and TNF-α, and area of expression of caspase-3 in the HCD group compared to both the control and HCD + G groups. Histological examination revealed degenerative changes in all layers of the neural retina in the HCD group. Garlic administration resulted in a significant improvement in the biochemical, immunohistochemical, and histological characteristics of hypercholesterolemic rats. These findings support the hypotheses that garlic has strong antioxidant, anti-apoptotic, and anti-inflammatory properties. Garlic ameliorates the neurodegenerative changes in the neural retina of hypercholesteremic rats.

Swimming training on moderate intensity significantly reduces total cholesterol and bodyweight on hypercholesterolemic rat model

It is well established that regular exercise has many positive benefits on health. Exercise at the appropriate intensity and level has been shown to improve lipid profile and reduce the risk of cardiovascular disease. This study investigates the effect of swimming training on total cholesterol levels and body weight in male Wistar rats. Thirty rats weighing 150-200 grams were randomly divided into one control (C) and two treatment groups (ST=swimming training, SED=sedentary activity). Rats in control (C) group were fed a standard diet, while rats in both treatment groups were fed high-fat diet-induced hypercholesterolemia for three weeks. Rats in ST were then swim-trained at moderate intensity for 30 minutes/day, six days a week for three weeks, and rats in SED were left without exercise stimuli. Body weight was measured weekly. At the end of the experimental period, intracardiac blood samples were drawn to measure the total cholesterol level. Findings revealed that rats’ bodyweight (p=0,045) and blood cholesterol (p=0,034) in ST group were significantly lower compared to SED. It indicates that swimming exercise is shown to be effective in weight loss and reducing blood cholesterol level in hypercholesterolemic rats.

Raisins preserve thyroid gland function and structure in an animal model of hypercholesterolemia

Background:Statins are among the first line of pharmacological treatment of lipid disorders and lowering serum cholesterol, but they have many side effects.Aim:The study aim was to evaluate the role of raisins in protecting the thyroid function and structure in a rat model of hypercholesterolemia, through biochemical and histopathological investigation.Materials and Methods:Thirty male rats were randomly divided into three groups (n = 10 each) of albino rats included the control, high cholesterol diet (HCD)-fed for 13 weeks and HCD plus Raisins were included in this study. Blood levels of glucose, insulin, cholesterol, lipids, thyroid-stimulating hormone (TSH), T3, T4, oxidants/anti-oxidants were assessed. Thyroid gland was processed and examined histopathologically using light and electron microscopy.Results:Feeding HCD resulted in hypercholesterolemia in rats after 13 weeks as evidence by lipid profile. Ingestion of raisins along with HCD resulted in a significant (P < 0.001) decrease in the levels of insulin, blood glucose, thyroxine (T4) and malondialdehyde (MDA), while the levels of TSH, T3 and total anti-oxidant capacity significantly (P < 0.001) elevated. Raisins histologically alleviated the HCD-induced structural changes in the thyroid glands that included degenerated mitochondria and increased lipid droplets in the cytoplasm.Conclusions:Simultaneous administration of raisins along with HCD, administrated for a short time, could modulate the negative effect on thyroid gland structure and function.

Diosgenin alleviates hypercholesterolemia via SRB1/CES-1/CYP7A1/FXR pathway in high-fat diet-fed rats

Phytosterol diosgenin (DG) exhibits cholesterol-lowering properties. Few studies focused on the underlying mechanism of DG attenuation of hypercholesterolemia by promoting cholesterol metabolism. To investigate the roles of SRB1/CES-1/CYP7A1/FXR pathways in accelerating cholesterol elimination and alleviating hypercholesterolemia, a rat model of hypercholesterolemia was induced by providing a high-fat diet (HFD). Experimental rat models were randomly divided into a normal control (Con) group, HFD group, low-dose DG (LDG) group (150 mg/kg/d), high-dose DG (HDG) group (300 mg/kg) and Simvastatin (Sim) group (4 mg/kg/d). Body weights, serum and hepatic lipid parameters of rats were tested. The expression levels of scavenger receptor class B type I (SRB1), carboxylesterase-1 (CES-1), cholesterol7α- hydroxylase (CYP7A1), and farnesoid X receptor (FXR) were determined. The results showed that DG reduced weight and lowered lipid levels in HFD-fed rats. Pathological morphology analyses revealed that DG notably improved hepatic steatosis and intestinal structure. Further studies showed the increased hepatic SRB1, CES-1, CYP7A1 and inhibited FXR-mediated signaling in DG-fed rats, which contributing to the decrease of hepatic cholesterol. DG also increased intestinal SRB1 and CES-1, inhibiting cholesterol absorption and promoting RCT. The expression levels of these receptors in the HDG group were higher than LDG and Sim groups. These data suggested that DG accelerated reverse cholesterol transport (RCT) and enhanced cholesterol elimination via SRB1/CES-1/CYP7A1/FXR pathway, and DG might be a new candidate for the alleviation of hypercholesterolemia.

Effect of Lactobacillus plantarum HT121 on serum lipid profile, gut microbiota, and liver transcriptome and metabolomics in a high-cholesterol diet-induced hypercholesterolemia rat model.

The aim of this study was to evaluate effect of Lactobacillus plantarum HT121 on serum lipid profile, gut microbiota, and liver transcriptome and metabolomics. L. plantarum HT121 was selected by screening of acid and bile salt tolerance and cholesterol assimilation assay. Sprague Dawley rats were randomly divided into three groups and fed the respective diets for 7 wk: normal chow diet (NCD), high-cholesterol diet (HCD), and high-cholesterol diet plus L. plantarum HT121 (HT121). After 7 wk, blood lipid profile was measured by enzyme-linked immunosorbent assay, gut microbiota was determined by 16 S rRNA sequencing, gene expression, and bile acids in liver were detected by transcriptome and metabolomics, respectively. L. plantarum HT121 feeding decreased serum triacylglycerols (TGs), total cholesterol (TC), and low-density lipoprotein (LDL), and increased serum high-density lipoprotein levels. HT121 treatment increased the α-diversity in the HT121 group to a level close to that in the NCD group, and restored the genera of Adlercreutzia, Mucispirillum, Ruminococcus, Clostridium, Blautia, Roseburia, and Akkermansia to levels similar to those in the NCD group. Furthermore, the high-cholesterol diet decreased taurocholic acid (TCA) and increased taurochenodeoxycholic acid (TCDCA) and glycocholic acid (GCA) in the liver; all these changes were reversed by HT121 treatment, bringing the levels close to those in the NCD group. Finally, HT121 treatment increased expression of bile secretion-related genes Cyp7 a1 in rat liver, which was positively correlated with TG, Clostridium, and GCA. Spearman's correlation analysis showed that TGs, TC, and LDL were positively correlated with the relative abundance of genera of Blautia, Clostridium, and Roseburia, and levels of bile acid glycocholic acid, and inversely correlated with the relative abundance of Ruminococcus and Mucispirillum. L. plantarum HT121 can improve serum lipid profiles in a high-fat diet-induced rat model, which may be attributed to alteration in gut microbiota and bile acid metabolism.

Combination of Omega 3 and Coenzyme Q10 Exerts Neuroprotective Potential Against Hypercholesterolemia-Induced Alzheimer's-Like Disease in Rats.

Alzheimer's disease (AD) is the most common form of dementia that progressively disrupts neurocognitive function, which has neither cure nor effective treatment. Hypercholesterolemia might be involved in brain alterations that could evolve into AD. The present study aims to evaluate the potential of omega-3, Co-enzyme Q10 (Co-Q10), as well as their combination in ameliorating hypercholesterolemia-initiated AD-like disease. We adapted a hypercholesterolemic (HC) rat model, a model of oxidative stress-mediated neurodegeneration, to study AD-like pathology. Hypercholesterolemia resulted in increased lipid peroxidation coupled with declined nitric oxide production, reduced glutathione levels, and decreased antioxidant activities of glutathione-s-transferase(GST) and glutathione peroxidase (GSH-Px)in the brain. Moreover, hypercholesterolemia resulted in decreased acetylcholine (ACh) levels and increased acetylcholine-esterase (AChE) activity, along with an increment of tumor necrosis factor and amyloid-β 42. Behaviorally, HC-rats demonstrated depressive-like behavior and declined memory. Treatment of HC-rats with omega-3 and Co-Q10 (alone or in combination) alleviated the brain oxidative stress and inflammation, regulated cholinergic functioning, and enhanced the functional outcome. These findings were verified by the histopathological investigation of brain tissues. This neuroprotective potential of omega-3 and Co-Q10 was achieved through anti-oxidative, anti-inflammatory, anti-amyloidogenic, pro-cholinergic, and memory-enhancing activities against HC-induced AD-like disease; suggesting that they may be useful as prophylactic and therapeutic agents against the neurotoxic effects of hypercholesterolemia.

Lactobacillus reuteri A9 and Lactobacillus mucosae A13 isolated from Chinese superlongevity people modulate lipid metabolism in a hypercholesterolemia rat model.

While there is strong evidence showing that many food-borne probiotics regulate cholesterol metabolism, few studies have examined how probiotics of human origin affect cholesterol metabolism. Because people living in so-called 'longevity villages' are unlikely to have hypercholesterolemia, we hypothesized that probiotics isolated from the residents would have cholesterol-reducing effects on rats with hypercholesterolemia. We isolated 16 strains of Lactobacillus from four longevity populations in China. The strains were tested in vitro for bile salt hydrolase (BSH) activity and two isolates, Lactobacillus reuteri A9 and Lactobacillus mucosae A13, were screened out. These two strains were then administered daily for 28 d to rats fed a cholesterol-rich diet. The serum total cholesterol levels in the L. reuteri A9 and L. mucosae A13 groups decreased by 24.3% and 21.6%, respectively. The serum low density lipoprotein cholesterol levels decreased by 23.8% and 25.2%, respectively. The L. reuteri A9 and L. mucosae A13 groups also exhibited upregulated hepatic mRNA expression of Sterol regulatory element-binding protein 2 (Srebp2) by 2.71-fold and 2.54-fold, respectively. The mRNA expression levels of hepatic low-density lipoprotein receptor (Ldlr) in the two groups were significantly up-regulated by 1.28-fold and 2.17-fold, respectively. The composition of gut microbiota was recovered by oral gavage in both experimental groups, and the destroyed diversity of gut microbiota was relieved.

Dietary Ethanolic Extract of Mangosteen pericarp Reduces VCAM-1, Perivascular Adipose Tissue and Aortic Intimal Medial Thickness in Hypercholesterolemic Rat Model.

BACKGROUND:High-fat diet (HFD) is associated with dyslipidemia which is a risk factor for atherosclerosis. Dyslipidemia causes oxidative stress which induces vascular cell adhesion molecule-1 (VCAM-1). Oxidative stress also triggers the thickening of tunica intima-media (IMT) and Perivascular Adipose Tissue (PVAT). Xanthone compound in ethanolic extract of Mangosteen pericarp (EEMP) has an antioxidant property to overcome the oxidative stress.AIM:The objective of this study is to investigate the effect of dietary EEMP administration on the expression of VCAM-1 and thickness of PVAT and IMT in atherosclerotic rat model fed with HFD.METHODS:This experimental laboratory study uses 25 Wistar strain Rattus norvegicus which were divided into 5 study groups. Negative Control group (GT1) was given a normal diet, Positive Control group (GT2) was treated with HFD, and three treatment groups were each treated with HFD with Mangosteen pericarp extract of 200 mg/kg BW (GT3), 400 mg/kg BW (GT4), and 800 mg/kg BW (GT5). Measurements of VCAM-1 expression were performed using immunofluorescence. PVAT and IMT measurements were performed on rat aortic preparations.RESULTS:One-way ANOVA test showed the addition of dietary EEMP significantly (p < 0.05) decreased the expression of VCAM-1 and decreased the thickness of PVAT and IMT in treatment groups as compared with both negative and positive controls. Tukey HSD test showed a dose of 800 mg/kg BW was the most effective dose for decreasing VCAM-1 level, PVAT and IMT.CONCLUSION:Dietary EEMP significantly decreases the expression of VCAM-1, as well as the thickness of PVAT and IMT in Wistar strain Rattus norvegicus treated with HFD.