Hypercholesterolemic Diet Research Articles

Intratumoral Restoration of miR-137 Plus Cholesterol Favors Homeostasis of the miR-137/Coactivator p160/AR Axis and Negatively Modulates Tumor Progression in Advanced Prostate Cancer.

MicroRNAs (miRNAs) have gained a prominent role as biomarkers in prostate cancer (PCa). Our study aimed to evaluate the potential suppressive effect of miR-137 in a model of advanced PCa with and without diet-induced hypercholesterolemia. In vitro, PC-3 cells were treated with 50 pmol of mimic miR-137 for 24 h, and gene and protein expression levels of SRC-1, SRC-2, SRC-3, and AR were evaluated by qPCR and immunofluorescence. We also assessed migration rate, invasion, colony-forming ability, and flow cytometry assays (apoptosis and cell cycle) after 24 h of miRNA treatment. For in vivo experiments, 16 male NOD/SCID mice were used to evaluate the effect of restoring miR-137 expression together with cholesterol. The animals were fed a standard (SD) or hypercholesterolemic (HCOL) diet for 21 days. After this, we xenografted PC-3 LUC-MC6 cells into their subcutaneous tissue. Tumor volume and bioluminescence intensity were measured weekly. After the tumors reached 50 mm3, we started intratumor treatments with a miR-137 mimic, at a dose of 6 μg weekly for four weeks. Ultimately, the animals were killed, and the xenografts were resected and analyzed for gene and protein expression. The animals' serum was collected to evaluate the lipid profile. The in vitro results showed that miR-137 could inhibit the transcription and translation of the p160 family, SRC-1, SRC-2, and SRC-3, and indirectly reduce the expression of AR. After these analyses, it was determined that increased miR-137 inhibits cell migration and invasion and impacts reduced proliferation and increased apoptosis rates. The in vivo results demonstrated that tumor growth was arrested after the intratumoral restoration of miR-137, and proliferation levels were reduced in the SD and HCOL groups. Interestingly, the tumor growth retention response was more significant in the HCOL group. We conclude that miR-137 is a potential therapeutic miRNA that, in association with androgen precursors, can restore and reinstate the AR-mediated axis of transcription and transactivation of androgenic pathway homeostasis. Further studies involving the miR-137/coregulator/AR/cholesterol axis should be conducted to evaluate this miR in a clinical context.

MYD88 and Proinflammatory Chemokines in Aortic Atheromatosis: Exploring Novel Statin Effects.

Atherosclerosis is driven by a diverse range of cellular and molecular processes. In the present study, we sought to better understand how statins mitigate proatherogenic inflammation. 48 male New Zealand rabbits were divided into eight groups, each including 6 animals. The control groups received normal chow for 90 and 120 days. Three groups underwent a hypercholesterolemic diet (HCD) for 30, 60, and 90 days. Another three groups underwent HCD for 3 months, followed by normal chow for one month, with or without rosuvastatin or fluvastatin. The cytokine and chemokine expressions were assessed in the samples of thoracic and abdominal aorta. Rosuvastatin significantly reduced MYD88, CCL4, CCL20, CCR2, TNF-α, IFN-β, IL-1b, IL-2, IL-4, IL-8, and IL-10, both in the thoracic and abdominal aorta. Fluvastatin also downregulated MYD88, CCR2, IFN-β, IFN-γ, IL-1b, IL-2, IL-4, and IL-10 in both aortic segments. Rosuvastatin curtailed the expression of CCL4, IFN-β, IL-2, IL-4, and IL-10 more effectively than fluvastatin in both types of tissue. MYD88, TNF-α, IL-1b, and IL-8 showed a stronger downregulation with rosuvastatin compared to fluvastatin only in the thoracic aorta. The CCL20 and CCR2 levels reduced more extensively with rosuvastatin treatment only in abdominal aortic tissue. In conclusion, statin therapy can halt proatherogenic inflammation in hyperlipidemic animals. Rosuvastatin may be more effective in downregulating MYD88 in atherosclerotic thoracic aortas.

Role of mitochondrial dynamics in abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is an asymptomatic pathology representing 75% of aortic aneurysms and occurring mainly in men over 65 years old, with a high mortality rate (80%) due to aortic rupture. Currently, only surgical management are used, and no pharmacological treatment exists. A potential therapeutic track would be the regulation of mitochondrial functions, already involved in neurological, ophthalmic, and cardiac pathologies. However, mitochondrial dynamics regulation, especially important within smooth muscle cells, is still untapped in abdominal aortic aneurysm. Our aim is to understand the role of mitochondrial dynamics in abdominal aortic aneurysm. We used a murine model of 6 months old of hypertensive Ldlr-/- male mice (angiotensin II, 1 mg/kg/day) associated with an hypercholesterolemic diet (HCD) for 28 days. Moreover, 6 months old Opa1+/- hypertensive male mice were used to study aortic remodeling. Aortic samples were studied by histomorphometric analyzes, RT-qPCR and Western blot. Ldlr-/- mice suffering from an abdominal aortic aneurysm showed a significant increase in mitochondrial fission (FIS1, DRP1) and mitophagy (PARKIN, PINK1). In addition, our results demonstrated strong pathological adventitial remodeling in supra-renal abdominal aorta in Opa1+/- hypertensive mice with a significant increase of Mmp2/Timp2 ratio in gene expression involved in aneurysm remodeling. Those results were associated with a significant decrease in smooth muscle cell contraction gene expression, inducing phenotypic cell switch, and pathological arterial remodeling. Mitochondrial dynamics dysfunction associated with hypertensive stress are involved in abdominal aortic aneurysm development.

Influence of Georgian Saperavi Grapevine Shoots Extract on Lipid Profile in Diet-Induced Hypercholesterolemia in Rats

Hypercholesterolemia raises the risk of cardiovascular diseases (CVD), the leading cause of morbidity and mortality worldwide. Numerous clinical trials of lipid-lowering diets and medicines have been established for proper lipid profile regulation to reduce the significant level of pathological conditions of cardiovascular origin. Winemaking is a well-developed part of Georgian agriculture. Besides usual products such as grapes and wine, it is characterized by a significant amount of waste products like leaves and shoots, which can be used as a source of bio-active ingredients, namely polyphenols, which are wellknown to have hypocholesterolemia effects. Therefore, the decision was made to use polyphenols derived from wasted shoots and assess their potential protective and treating effect on lipid profile in the Vivo model of dietary-induced hyperlipidemia. During previous studies, 14 individual polyphenols were extracted and detected from Georgian grapevine shoots, and current research demonstrates the cholesterol-lowering effects of this polyphenol-rich extract in laboratory rats. Study results demonstrated the positive protective effect of Georgian Vitis Vinifera (Saperavi) polyphenols on the lipid profile of rats. Along with relatively low values of total cholesterol (5.47%), LDL (16%), and TG (9.9%), better results for HDL value were observed for the group receiving Saperavi shoots extract, than the group receiving only a hypercholesterolemia diet. Compared with a 10 mg/kg Atorvastatin daily dose, Saperavi shoots extract showed a smoother reduction of serum cholesterol; however, the normal range was reached. These findings support the potential of using currently wasted Georgian grapevine shoots as a source of biologically active ingredients. Based on the study results, Saperavi shoot extract can be considered a cost-effective candidate for phytomedicine supplementing and treating cardiovascular diseases associated with lipid profile disorders.

Dietary Grape Seed Tannins Affect Lipoproteins, Lipoprotein Lipases and Tissue Lipids in Rats Fed Hypercholesterolemic Diets , ,

The effects of monomeric and polymeric grape seed tannins on rat plasma lipoproteins, lipoprotein lipase, hepatic lipase and aortic and hepatic lipid concentration were studied. Male Sprague-Dawley rats received either a normal diet (with no added cholesterol and no tannins), a control diet (hypercholesterolemic diet) or hypercholesterolemic diets supplemented with 2% tannin monomers or 2% polymers 3 or 9 wk. Plasma total cholesterol, triacylglycerol, LDL cholesterol and VLDL concentrations were significantly higher and the HDL cholesterol concentration lower in controls and in rats fed the diet supplemented with monomers compared with rats fed polymeric tannins at both time points. Lipoprotein lipase and hepatic lipase activities were significantly higher in control and in monomer-fed groups than in the polymer-fed group. Hepatic and aortic cholesterol and triacylglycerol concentrations were significantly higher in control rats and those fed monomers than in the polymer-fed group. Moreover, plasma HDL cholesterol and hepatic lipase activity were closely associated with low aortic cholesterol and triacylglycerol in rats fed polymeric tannins. These rats also exhibited greater fecal excretion of cholesterol and especially bile acids than the control or monomer-fed groups. Thus dietary grape seed tannins have a pronounced anti-hypercholesterolemic effect by enhancing reverse cholesterol transport and also by reducing intestinal cholesterol absorption and increasing bile acid excretion.

Plasma Total and Lipoprotein Cholesterol, Liver Cholesterol and Fecal Cholesterol Excretion in Hamsters Fed Fiber Diets

The effect of dietary fibers on plasma lipids, liver cholesterol and fecal cholesterol excretion was investigated in hamsters. Male 9- to 11-wk-old Golden-Syrian hamsters (n = 155) were fed a purified hypercholesterolemic diet (0.1% cholesterol, 10% fat) for 5 wk to elevate plasma lipid concentrations. Sixteen animals with elevated plasma total cholesterol were randomly assigned to each treatment group: control, oat bran, guar gum, cellulose, xylan and terminal groups. After 4 wk of fiber diet consumption, the plasma total cholesterol concentrations were significantly decreased in the oat bran, guar gum and xylan groups (16, 12 and 15%, respectively) (P < 0.05). Plasma HDL cholesterol concentration was significantly decreased only in the guar gum group (12%) (P < 0.05). The combined plasma VLDL+LDL cholesterol concentrations were significantly lowered by the oat bran, xylan and cellulose diets (38, 34 and 40%, respectively) (P < 0.05). After 4 wk of control diet consumption, the liver cholesterol concentration quadrupled to 10.6 mumol cholesterol/g liver (P < 0.05). After 4 wk of consumption of the treatment diets, liver cholesterol was further increased (P < 0.05) only in the cellulose group, to 14.5 mumol cholesterol/g liver. The total fecal cholesterol excretion was the highest (P < 0.05) in the oat bran group. In the present study, oat bran, guar gum and xylan were effective hypocholesterolemic agents in hamsters.

Secoisolariciresinol diglucoside and anethole ameliorate lipid abnormalities, oxidative injury, hypercholesterolemia, heart, and liver conditions.

Fennel seeds and flaxseed have been traditionally used against many medical ailments due to their medicinal characteristics. The aim of the study was to investigate the health properties of secoisolariciresinol diglucoside (SDG) and anethole from flaxseed and fennel seeds in rats fed with high-fat diet. Histopathological changes in the heart and liver were also examined. Sixty rats were divided into two main groups. Group I (10 rats) was used as a negative control group and fed on the basal diet only. Group II (50 rats) was fed a hypercholesterolemic diet but not given any drugs during the trial for 2 weeks. This group was further divided into five subgroups (10 rats each). One of them was fed on the basal diet and used as a positive control group. However, the other four subgroups were fed on basal diets and anethole (20 mg/kg/day, orally), SDG (20 mg/kg/day, orally), a mixture of anethole + SDG (10 + 10 mg/kg/day, orally), and atorvastatin (10 mg/kg/day, orally) for 6 weeks. Compared to control, treatment with a combination of anethole + SDG showed a significant (p ≤ .05) improvement in serum levels of triglyceride (TG) (137.88 ± 1.61 mg/dL), total cholesterol-(TC) (180.12 ± 8.99 mg/dL), LDL-C (46.40 ± 6.67 mg/dL), VLDL-C (11.81 ± 1.07 mg/dL), aspartate aminotransferase (AST) (75.97 ± 6.92 U/L), alanine aminotransferase (ALT) (34.83 ± 2.17 U/L), alkaline phosphatase (ALP) (130.65 ± 1.05 U/L), and malondialdehyde (MDA) (30.12 ± 1.89 mmol/g), and improved activities of catalase (70.99 ± 3.29 U/g) and superoxide dismutase (SOD) (35.13 ± 2.53 U/dL) enzymes while SDG and anethole group had relatively less impact. Atorvastatin also improved serum levels of triglyceride, total cholesterol, LDL-C, and VLDL-C significantly and rose serum high-density lipoprotein cholesterol (HDL-C) levels considerably meanwhile it had a minor but negative impact on AST, ALT, and ALP, and negligible impact on activities of MDA, CAT, and SOD enzymes compared to the positive control group. The study revealed that combining anethole and SDG may improve dyslipidemia, improve lipid profile, decrease risks of chronic heart diseases, increase HDL-C, and enhance antioxidant enzymes' activities.

Brazilian green propolis extracts modulate cholesterol homeostasis in a preclinical guinea pig model: an in vitro and in vivo study.

Green propolis produced by Apis melífera bees, having Baccharis dracunculifolia D.C. (Asteraceae) as the primary botanical source, has been used in traditional medicine to treat numerous disorders. However, studies evaluating propolis' potential in treating cardiovascular diseases via its effects on cholesterol metabolism are lacking. Therefore, this study investigated the effects of green propolis extracts on lipid metabolism in hypercholesterolemic guinea pigs. Chemical characterization of ethanolic extracts of green propolis samples was undertaken using HPLC. The in vitro characterization included an evaluation of the antioxidant capacity of the hydroalcoholic extract of green propolis (DPPH and FRAP assays) and its ability to act as an inhibitor of the HMG-CoA reductase enzyme. In vivo, we investigated the effect of the hydroalcoholic extract of green propolis on lipid metabolism in hypercholesterolemic guinea pigs. Results obtained validated previous reports of significant antioxidant activity. HPLC analysis confirmed that coumaric acid, artepillin C, and baccharin were the most common and abundant compounds in green propolis samples among the studied compounds. Furthermore, the compounds in these extracts acted as effective HMG-CoA reductase inhibitors in vitro. In vivo assays demonstrated that a hypercholesterolemic diet significantly reduced serum levels of the HDL cholesterol fraction. Simvastatin and propolis hydroalcoholic extracts promoted a significant increase in HDL cholesterol, suggesting that these extracts can improve the serum lipid profile of hypercholesterolemic guinea pigs. Results obtained in this study provide a perspective on the possible hypocholesterolemic effect of green propolis, suggesting that it can improve the serum lipid profile in hypercholesterolemic guinea pigs.

The gut microbiome dysbiosis is recovered by restoring anormal diet in hypercholesterolemic pigs.

Gut microbiota is thought to modulate cardiovascular risk. However, the effect of cardiovascular primary prevention strategies on gut microbiota remains largely unknown. This study investigates the impact of diet and rosuvastatin interventions on gut microbiota composition in hypercholesterolemic pigs and associated potential changes in host metabolic pathways. Diet-induced hypercholesterolemic pigs (n=32) were randomly distributed to receive one of the following 30-day interventions: (I) continued hypercholesterolemic diet (HCD; n=9), (II) normocholesterolemic diet (NCD; n=8), (III) continued HCD plus 40 mg rosuvastatin/daily (n=7), or (IV) NCD plus 40 mg rosuvastatin/daily (n=8). Faeces were collected at study endpoint for characterisation of the gut microbiome and metabolic profile prediction (PICRUSt2). TMAO levels and biochemical parameters were determined. Principal coordinate analyses (beta-diversity) showed clear differences in the microbiota of NCD vs HCD pigs (PERMANOVA, p=.001). NCD-fed animals displayed significantly higher alpha-diversity, which inversely correlated with total cholesterol and LDL-cholesterol levels (p < .0003). NCD and HCD animals differed in the abundance of 12 genera (ANCOM; p=.001 vs HCD), and PICRUSt2 analysis revealed detrimental changes in HCD-related microbiota metabolic capacities. These latter findings were associated with a significant fivefold increase in TMAO levels in HCD-fed pigs (p < .0001 vs NCD). The addition of a 30-day rosuvastatin treatment to either of the diets exerted no effects in microbiota nor lipid profile. In hypercholesterolemic animals, the ingestion of a low-fat diet for 30 days modifies gut microbiota composition in favour of alpha-diversity and towards a healthy metabolic profile, whereas rosuvastatin treatment for this period exerts no effects.

Cholesterol Triggers Nuclear Co-Association of Androgen Receptor, p160 Steroid Coactivators, and p300/CBP-Associated Factor Leading to Androgenic Axis Transactivation in Castration-Resistant Prostate Cancer.

Cholesterol modulates intratumoral androgenic signaling in prostate cancer; however, the molecular mechanisms underlying these changes in castration-resistant prostate cancer (CRPC) are not fully elucidated. Herein, we investigated the effect of cholesterol on androgen receptor (AR) coactivators expression and tumorigenesis in vitro and in vivo. Herein, we monitored the expression of AR coactivators (SRC-1, 2, 3 and PCAF) genes in PC-3 cells exposed to 2µg/mL of cholesterol for 8 hours by qPCR. We also performed cell migration at 0, 8, 24, 48 and 72h and flow cytometry assays (viability, apoptosis, and cell cycle) after a 24h exposure. Immunofluorescence assay was performed to evaluate the protein expression of the AR coactivators. Additionally, in vivo experiments were conducted using 22 male NOD/SCID mice. Mice were fed a standard (Control) or hypercholesterolemic (HCOL) diet for 21 days and then subcutaneously implanted with PC-3 cells. The tumor volume was calculated every two days, and after four weeks, the tumors were resected, weighed, and the serum lipid profile was measured. We also measured the intratumoral lipid profile and AR coactivators gene and protein expression by qPCR and Western Blot, respectively. Intratumor testosterone and dihydrotestosterone (DHT) concentrations were determined using ELISA. Cholesterol up-regulated the gene expression of coactivators SRC-1, SRC-2, SRC-3 and PCAF, increasing AR expression in PC-3 cells. Next, cholesterol-supplemented PC-3 cells exhibited increased cell migration and altered cell cycle phases, leading to changes in proliferation and reduced apoptosis. We found that SRC-1, SRC-2, SRC-3 and PCAF proteins co-localized in the nucleus of cholesterol-supplemented cells and co-associate with AR. In the in vivo model, the hypercholesterolemic (HCOL) group displayed higher serum total and intratumoral cholesterol levels, increased testosterone and dihydrotestosterone concentrations, and up-regulated AR coactivator expression. The tumor volume of the HCOL group was significantly higher than the control group. Our findings revealed that increased nuclear translocation of the coactivators leads to up-regulated AR gene and protein expression, potentially influencing tumor progression. Studies targeting cholesterol-modulated changes in AR coactivator expression may provide insights into the molecular mechanisms associated with the CRPC phenotype.

Mechanosensitive Stem-Cell Genes and Klotho in Atherosclerotic Aortas: Regulating Spatially Deranged Expression Patterns Using Colchicine Regimens.

Inflammatory dysregulation of mechanosensitive developmental genes may be central to atherogenesis. In the present seven-week model, we utilized colchicine regimens to curtail aortic atherogenesis in New Zealand White rabbits. We also explored the effect of colchicine regimens on atheroprotective (<i>Klotho</i>, <i>HOXA5</i>, <i>NOTCH1</i>, and <i>OCT4</i>) and proatherogenic (<i>HIF1a</i>, <i>SOX2</i>, <i>BMP4</i>, and <i>NANOG</i>) genes. The control (n = 6) and group A (n = 6) received standard and cholesterol-enriched chow, respectively. Groups B (n = 8) and C (n = 8) were fed hypercholesterolemic diet and were treated with colchicine plus fenofibrate or N-acetylcysteine (NAC), respectively. Group A developed significantly greater thoracic and abdominal aortic atherosclerosis compared to groups B (<i>p</i> &lt; 0.001) and C (<i>p</i> &lt; 0.001). Combining colchicine with NAC resulted in stronger atheroprotection both in the thoracic and the abdominal aorta. In group A thoracic aortas, <i>Klotho</i> was downregulated compared to controls (95% CI: 1.82-15.76). Both colchicine regimens upregulated <i>Klotho</i> back to baseline levels (<i>p</i> &lt; 0.001). Colchicine/fenofibrate also significantly upregulated thoracic <i>NOTCH1</i> compared to controls (95% CI: -8.09 to -0.48). Colchicine/NAC significantly reduced thoracic <i>NANOG</i> expression compared to hyperlipidemic diet alone (95% CI: 0.37-8.29). In the abdominal aorta, hypercholesterolemic diet resulted in significant downregulation of <i>HOXA5</i> (95% CI: 0.03-2.74) which was reversed with colchicine/NAC back to baseline (95% CI: -1.19 to 1.51). Colchicine/fenofibrate downregulated <i>HIF1a</i> compared to baseline (95% CI: 0.83-6.44). No significant differences were noted in terms of <i>BMP4</i>, <i>SOX2</i>, and <i>OCT4</i>. Overall, the aortic expression pattern of mechanosensitive genes seems to be spatially influenced by a hyperlipidemic diet and can be modified using colchicine-based therapy.

Effect of dried figs (Ficus carica L.) on hypercholesterolemia in rats

This study aimed to evaluate the effect of dried figs with high content of antioxidants namely fig (Ficus carica L) on lowering blood cholesterol in hypercholesterolemic rats. Vitamins A and C, total polyphenols and total flavonoids were determined in figs in fresh fruits and after being dried. All these antioxidants were found in considerable amounts in fig. Thirty male albino rats were divided into six groups 5each, the first group received a standard and served as a negative control, and the second group received a hypercholesterolemic diet and served as a positive control. Group 4 was the protective group that fed on a higher percentage of figs 6% and the other three groups received a hypercholesterolemic diet containing different levels from fig (2, 4 and 6%) for 8 weeks. At the end of this period, blood was withdrawn after overnight fasting and biochemical parameters were analyzed. Serum total cholesterol, serum triacylglycerol (TG), serum low density lipoprotein cholesterol (LDL-C), serum very low density lipoprotein cholesterol (VLDL-C), serum high density lipoprotein cholesterol (HDL-C) and atherogenic index (LDL-C/HDL-C) were estimated. Also, the activity of the liver enzymes ALT and AST were determined. A histopathological examination of the aorta was done.

Hypercholesterolemia-Induced HDL Dysfunction Can Be Reversed: The Impact of Diet and Statin Treatment in a Preclinical Animal Model.

High-density lipoproteins (HDL) undergo adverse remodeling and loss of function in the presence of comorbidities. We assessed the potential of lipid-lowering approaches (diet and rosuvastatin) to rescue hypercholesterolemia-induced HDL dysfunction. Hypercholesterolemia was induced in 32 pigs for 10 days. Then, they randomly received one of the 30-day interventions: (I) hypercholesterolemic (HC) diet; (II) HC diet + rosuvastatin; (III) normocholesterolemic (NC) diet; (IV) NC diet + rosuvastatin. We determined cholesterol efflux capacity (CEC), antioxidant potential, HDL particle number, HDL apolipoprotein content, LDL oxidation, and lipid levels. Hypercholesterolemia time-dependently impaired HDL function (−62% CEC, −11% antioxidant index (AOI); p < 0.01), increased HDL particles numbers 2.8-fold (p < 0.0001), reduced HDL-bound APOM (−23%; p < 0.0001), and increased LDL oxidation 1.7-fold (p < 0.0001). These parameters remained unchanged in animals on HC diet alone up to day 40, while AOI deteriorated up to day 25 (−30%). The switch to NC diet reversed HDL dysfunction, restored apolipoprotein M content and particle numbers, and normalized cholesterol levels at day 40. Rosuvastatin improved HDL, AOI, and apolipoprotein M content. Apolipoprotein A-I and apolipoprotein C-III remained unchanged. Lowering LDL-C levels with a low-fat diet rescues HDL CEC and antioxidant potential, while the addition of rosuvastatin enhances HDL antioxidant capacity in a pig model of hypercholesterolemia. Both strategies restore HDL-bound apolipoprotein M content.

Effects of diagnostic ultrasound with cRGD-microbubbles on simultaneous detection and treatment of atherosclerotic plaque in ApoE-/- mice.

BackgroundAtherosclerotic vulnerable plaque is the leading cause of acute fatal cardiovascular events. Thus, early rapid identification and appropriate treatment of atherosclerotic plaque maybe can prevent fatal cardiovascular events. However, few non–invasive molecular imaging techniques are currently available for the simultaneous detection and targeted treatment of atherosclerotic plaques. We hypothesized that diagnostic ultrasound (DU) combined with cyclic Arg-Gly-Asp-modified microbubbles (MBR) could provide targeted imaging and dissolution of activated platelets to identify advanced atherosclerotic plaques and improve plaque instability.MethodsThree mouse models, apolipoprotein E-deficient mice on a hypercholesterolemic diet (HCD) or normal chow diet and wild-type mice on an HCD were used. The most appropriate ultrasonic mechanical index (MI) was determined based on the expression of GP IIb/IIIa in sham, DU alone and DUMBR-treated groups at MI values of 0.5, 1.5, and 1.9. The video intensity (VI) values, activated platelets and plaque instability were analyzed by ultrasound molecular imaging, scanning electron microscopy and histopathological methods.ResultsWe found that the VI values of ultrasound molecular imaging of MBR were positively correlated with plaque GP IIb/IIIa expression, vulnerability index and necrotic center / fiber cap ratio. 24 h after treatment at different MIs, compared with those of the other groups, both the VI values and GP IIb/IIIa expression were significantly reduced in MI 1.5 and MI 1.9 DUMBR-treated groups. The plaque vulnerability index and necrotic center / fiber cap ratio were significantly decreased in MI 1.5-treated group, which may be due to targeted dissolution of activated platelets, with a reduction in von Willebrand factor expression.ConclusionDUMBR targeting GP IIb/IIIa receptors could rapidly detect advanced atherosclerotic plaques and simultaneously give targeted therapy by dissolving activated and aggregated platelets. This technology may represent a novel approach for the simultaneous identification and treatment of atherosclerotic plaques.

Phytochemical characterization of Morus nigra fruit ultrasound-assisted ethanolic extract for its cardioprotective potential.

The current work investigated the phytochemical profile of ultrasound-assisted ethanolic extract of Morus nigra (M.nigra) fruit. FTIR analysis of M.nigra fruit extract revealed the presence of alcohols (O-H), alkanes (C-H stretch), alkenes (C=C), and alkynes (C≡C). The HPLC analysis quantified the quercetin, gallic acid, vanillic acid, chlorogenic acid, syringic acid, cinnamic acid, sinapic acid, and kaempferol. Furthermore, the cardioprotective activity of ethanolic extract of M.nigra fruit was investigated. Cholesterol supplementation (2%) in the daily diet and exposure to cigarette smoke (2 cigarettes twice a day) were to induce hypertension in rats. The experimental animals were categorized into four groups: G0 (negative control), G1 (positive control), G2 (standard drug), and G3 (M.nigra fruit). The fruit extract administration at 300 mg/kg BW/day orally for 2 months significantly (p < .001) enhanced the activities of serum and cardiac tissue antioxidants in hypertensive rats. Meanwhile, the fruit extract reduced the elevated serum lipid profile while significantly increasing the high-density lipoproteins in G3 than G1 and G2. The increase in blood pressure, liver transaminases, and serum lactate dehydrogenase also reduced significantly in M.nigra fruit extract-treated rats. Histopathological findings revealed mild normalization of cardiac myocytes with central nuclei, branching, and cross-striations. Consequently, the M.nigra fruit extract exerted the cardioprotective potential via increasing the antioxidant enzymes and reducing the lipids, lactate dehydrogenase, liver transaminases, and blood pressure. The therapeutic potential of M.nigra fruit can be due to flavonols and phenolic acids. PRACTICAL APPLICATIONS: The present work quantified the Morus nigra fruit phytochemicals and its significant role in reducing lipid markers and blood pressure and improving antioxidant status in rats fed a hypercholesterolemic diet and exposed to cigarette smoke. Conclusively, the inclusion of M.nigra fruit in daily diet could improve the cardiac health of the individuals. Furthermore, the therapeutic potential of M.nigra fruit and its isolated constituents in modulating the gene expression against cardiac problems can explore after clinical trials and standardization in higher animals.

Hepatic Alarmins and Mitochondrial Dysfunction under Residual Hyperlipidemic Stress Lead to Irreversible NAFLD.

Nonalcoholic fatty liver disease (NAFLD) includes a range of progressive disorders generated by excess lipid accumulation in the liver leading to hepatic steatosis and eventually fibrosis. We aimed to identify by high performance mass spectrometry-based proteomics the main signaling pathways and liver proteome changes induced by hypercholesterolemia in a rabbit atherosclerotic model that induced high accumulation of lipids in the liver. The effect of combined lipid-lowering drugs (statins and anti-PCSK9 monoclonal antibody) were used after the interruption of the hypercholesterolemic diet to identify also the potential mediators, such as alarmins, responsible for the irreversible NAFLD build up under the hyperlipidemic sustained stress. Proteomic analysis revealed a number of proteins whose abundance was altered. They were components of metabolic pathways including fatty-acid degradation, glycolysis/gluconeogenesis, and nonalcoholic fatty liver disease. Mitochondrial dysfunction indicated alteration at the mitochondrial respiratory chain level and down-regulation of NADH: ubiquinone oxidoreductase. The expression of a majority of cytochromes (P4502E1, b5, and c) were up-regulated by lipid-lowering treatment. Long-term hyperlipidemic stress, even with a low-fat diet and lipid-lowering treatment, was accompanied by alarmin release (annexins, galectins, HSPs, HMGB1, S100 proteins, calreticulin, and fibronectin) that generated local inflammation and induced liver steatosis and aggressive fibrosis (by high abundance of galectin 3, fibronectin, and calreticulin). The novel findings of this study were related to the residual effects of hyperlipidemic stress with consistent, combined lipid-lowering treatment with statin and inhibitor of PCSK9.

The Effectiveness of Green Grape Extract (Vitis vinifera) on Decreasing White Rat (Rattus novergicus) Triglycerides Levels

Background: Grapes (Vitis vinifera) are a source of antioxidants with high content of polyphenols and anthocyanins. Grape skin is rich in flavonoids. Anthocyanins and flavonoids have the effect of lowering blood triglyceride levels. Purposes: This study aimed to determine the effect of using green grape extract (GGE) in lowering triglyceride levels in the blood. Methods: Five groups of white male rats (Rattus novergicus) were divided into a negative control group (KN), positive control (KP), rats with a GGE dose of 100 mg/200g BW as P1, rats with a GGE dose of 250mg/200g BW as P2, and rats with GGE dose of 500 mg/200g BW as P3. Each group was given a hypercholesterolemic diet for five weeks. Groups P1, P2, and P3 were given GGE according to their respective doses for 14 days, then measured triglyceride levels in the blood. Results: The results showed that GGE 500mg/200g BW significantly reduced triglyceride levels in all treated mice. Conclusion: These results indicate that GGE has a great potential to treat dyslipidemia by lowering triglyceride levels in the blood.

Carvone’s Hypoglycemic and Hypolipidemic Potent Activity Via Regulation Insulin-Induced Genes in Diabetic Hyperlipidemic Rats

Carvone is a monoterpene and component of many essential oils from medicinal plants. Our research intended to evaluate the therapeutic efficacy of carvone in the handling of diabetes and hyperlipidemia in alloxan-induced type 2 diabetics. Alloxan (120 mg/kg) was administered intraperitoneally to male albino rats to induce diabetes as a single dose after diabetes, followed by two weeks of feeding the hypercholesterolemic atherogenic diet to develop hyperlipidemia. For one month, carvone (50 mg/kg) was administered orally to diabetic hyperlipidemic rats. Metformin, a common oral hypoglycemic medication, and atorvastatin, a standard oral hypolipidemic drug, were used to compare the findings. Our findings showed a reduction in blood glucose levels, low-density lipoprotein, cholesterol, and triglyceride. Upon administration of carvone, the encoded proteins (Insulin-induced gene-1and insulin-induced gene-2) were evaluated, which prevent Sterol regulatory-element binding proteins from being proteolytically activated. These transcription factors promote cholesterol and fatty acid production in the liver and other tissues. Histopathological alterations in pancreatic tissue were among the biomarkers chosen for hypoglycemic and hypolipidemic examinations. These findings suggested that carvone may be hypoglycemic and hypolipidemic potent activity by regulating insulin-induced genes.

Brazilian Green Propolis Modulates Cholesterol Homeostasis in a Preclinical Guinea Pig Model

This study investigates the effect of the hydroalcoholic extract of Brazilian green propolis on lipid metabolism in hypercholesterolemic guinea pigs. This product has been considered an important source of bioactive compounds with potential health benefits. Thirty‐six guinea pigs, Cavia porcellus (male), 90 days old, weight of 400 g, were divided into six groups of six animals each and fed a standard AIN‐93 M diet (C), hypercholesterolemic diet (H), hypercholesterolemic diet + hydroalcoholic extract (75 mg/kg body weight [HEtOH1]; 150 mg/kg body weight [HEtOH2], and 300 mg/kg body weight [HEtOH3]), or hypercholesterolemic diet + simvastatin (1.5 mg/kg body weight) (HS) for 10 weeks. The group‐specific diet and water were provided ad libitum throughout the experimental period. Blood and liver tissue samples were collected for biochemical analysis and histopathology. Statistical analysis was performed using GraphPad Prism software version 5.0. The experimental protocol for the use of animals was approved by the Ethics Committee on Animal Use of the University of São Paulo (N°18.1.999.60.0). Animals in the H groups had a lower food intake than in the C group. Fecal excretion was regulated by the administration of extracts, being higher in these groups when compared to H and HS groups. Liver weights were influenced by the diet and administration of the hydroalcoholic extract of green propolis. Hypercholesterolemic diets determined an increase of about 2 times in the relative weight of this organ when compared to the C group, being more expressive in the groups of animals that received the hydroalcoholic extract. A significant increase in serum levels of total and non‐HDL cholesterol was observed in H group, concomitant with a reduction in the concentration of cholesterol‐HDL when compared to group C. However, these high levels of total cholesterol were reduced when simvastatin and extracts were administered with the hypercholesterolemic diet. The same was observed for the non‐HDL cholesterol fraction, where administration with simvastatin and extracts significantly reduced the concentration of these fractions, especially in HS and HEtOH3 groups when compared to group H. Analysis of the HDL fraction demonstrates that the animals submitted to the hypercholesterolemic diet had the lowest levels for this parameter when compared to the groups that received the control diet and/or extracts and simvastatin. There was a significant reduction in serum triacylglycerol levels in the HEtOH2 and HEtOH3 groups. However, a change in liver metabolism was observed, favoring the deposition of lipids in the liver, a different profile from what was observed when administering simvastatin. C group presented a histological aspect compatible with the normality of the organ. The H and HS groups presented moderate to severe fat degeneration, with a slight degeneration in the HS group when compared to the H group. A profile similar to that of the HS group was observed in the HEtOH2 group. Our results suggest that the Brazilian green propolis extract induces positive effects on dyslipidemia.

Cilostazol attenuates cardiac oxidative stress and inflammation in hypercholesterolemic rats.

Atherosclerosis is a multifactorial chronic disease associated with pro-inflammatory and pro-oxidative cardiovascular states. Cilostazol, a selective phosphodiesterase 3 inhibitor (PDE3), is clinically used in the treatment of intermittent claudication and secondary prevention of cerebral infarction. The aim of this study was to evaluate the cardioprotective effects of cilostazol and the molecular mechanisms involved in hypercholesterolemic rats. Male Wistar rats were divided into four groups: control group (C) and control + cilostazol group (C+CILO), that were fed a standard chow diet, and hypercholesterolemic diet group (HCD) and HCD + cilostazol (HCD+CILO) that were fed a hypercholesterolemic diet. Cilostazol treatment started after 30 days for C+CILO and HCD+CILO groups. Animals were administered cilostazol once a day for 15 days. Subsequently, serum and left ventricles were extracted for evaluation of lipid profile, inflammatory, and oxidative biomarkers. The HCD group displayed increased serum lipid levels, inflammatory cytokines production, and cardiac NF-kB protein expression and decreased cardiac Nrf2-mediated antioxidant activity. Conversely, the cilostazol treatment improved all these cardiac deleterious effects, inhibiting NF-kB activation and subsequently decreasing inflammatory mediators, reestablishing the antioxidant properties through Nrf2-mediated pathway, including increased SOD, GPx, and catalase expression. Taken together, our results indicated that cilostazol protects hypercholesterolemia-induced cardiac damage by molecular mechanisms targeting the crosstalk between Nrf2 induction and NF-kB inhibition in the heart.