ABSTRACT
BACKGROUND: Hyperlipidemia is one of the main causes of aggravated hepatic ischemia-reperfusion injury (IRI). Simvastatin (SIM), a lipid-lowering drug, has been shown to effectively alleviate IRI caused by hyperlipidemia. However, the regulatory mechanism by which SIM alleviates hyperlipidemia-induced hepatic IRI is still not clear. This study aims to explore the potential mechanisms of SIM in inhibiting hyperlipidemia-induced hepatic IRI, providing new therapeutic strategies for the alleviation of hepatic IRI. METHODS: An animal model of hyperlipidemia was induced by feeding mice a high-fat diet for 8 weeks. Subsequently, a hepatic IRI animal model of hyperlipidemia was established by occluding the hepatic artery and portal vein for one hour, followed by reperfusion for 6 or 12 h. Enzyme linked immunosorbent assay, Western blotting, hematoxylin-eosin (H&E) staining, immunohistochemistry, immunofluorescence, and Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling assay, were used to evaluate liver injury, neutrophil extracellular traps (NETs) formation, and related molecular mechanisms. RESULTS: Hepatic IRI was accelerated by hyperlipidemia, which enhanced the expression of oxidized low-density lipoprotein (oxLDL) and Macrophage-1antigen (Mac-1), leading to the promotion of NETs formation and apoptosis of liver cells. The administration of simvastatin reduced the levels of oxLDL and Mac-1, decreased the formation of NETs, and alleviated hepatic IRI induced by hyperlipidemia. CONCLUSIONS: Simvastatin reduced hyperlipidemia-induced hepatic IRI by inhibiting the formation of NETs through the regulation of the oxLDL/Mac-1 pathway.
Subject(s)
Diet, High-Fat , Extracellular Traps , Hyperlipidemias , Liver , Reperfusion Injury , Simvastatin , Animals , Simvastatin/pharmacology , Simvastatin/therapeutic use , Reperfusion Injury/prevention & control , Reperfusion Injury/pathology , Reperfusion Injury/drug therapy , Reperfusion Injury/metabolism , Mice , Extracellular Traps/drug effects , Extracellular Traps/metabolism , Male , Diet, High-Fat/adverse effects , Liver/pathology , Liver/drug effects , Liver/metabolism , Hyperlipidemias/drug therapy , Hyperlipidemias/metabolism , Hyperlipidemias/pathology , Hyperlipidemias/complications , Mice, Inbred C57BL , Disease Models, Animal , Lipoproteins, LDL/metabolism , Signal Transduction/drug effects , Apoptosis/drug effectsABSTRACT
Dysregulation of the hematopoietic niche during hyperlipidemia facilitates pathologic leukocyte production, driving atherogenesis. Although definitive hematopoiesis occurs primarily in the bone marrow, during atherosclerosis this also occurs in the spleen. Cells of the bone marrow niche, particularly endothelial cells, have been studied in atherosclerosis, although little is known about how splenic endothelial cells respond to the atherogenic environment. Here we show unique dysregulated pathways in splenic compared to bone marrow endothelial cells during atherosclerosis, including perturbations of lipid metabolism and endocytic trafficking pathways. As part of this response, we identify the mixed lineage kinase domain-like (MLKL) protein as a repressor of splenic, but not bone marrow, myelopoiesis. Silencing MLKL in splenic endothelial cells results in inefficient endosomal trafficking and lipid accumulation, ultimately promoting the production of myeloid cells that participate in plaque development. These studies identify endocytic trafficking by MLKL as a key mechanism of splenic endothelial cell maintenance, splenic hematopoiesis and, subsequently, atherosclerosis.
Subject(s)
Atherosclerosis , Endothelial Cells , Hyperlipidemias , Protein Kinases , Spleen , Spleen/pathology , Spleen/metabolism , Protein Kinases/metabolism , Protein Kinases/genetics , Endothelial Cells/metabolism , Endothelial Cells/pathology , Animals , Atherosclerosis/pathology , Atherosclerosis/metabolism , Hyperlipidemias/metabolism , Hyperlipidemias/pathology , Mice, Inbred C57BL , Disease Models, Animal , Male , Myelopoiesis , Humans , Cells, Cultured , Lipid Metabolism , Mice , Plaque, Atherosclerotic/pathology , Plaque, Atherosclerotic/metabolism , Mice, Knockout, ApoE , Endocytosis/physiology , Endosomes/metabolism , Stem Cell Niche/physiologyABSTRACT
Introduction: The development of cognitive dysfunction is not necessarily associated with diet-induced obesity. We hypothesized that cognitive dysfunction might require additional vascular damage, for example, in atherosclerotic mice. Methods: We induced atherosclerosis in male C57BL/6N mice by injecting AAV-PCSK9DY (2x1011 VG) and feeding them a cholesterol-rich Western diet. After 3 months, mice were examined for cognition using Barnes maze procedure and for cerebral blood flow. Cerebral vascular morphology was examined by immunehistology. Results: In AAV-PCSK9DY-treated mice, plaque burden, plasma cholesterol, and triglycerides are elevated. RNAseq analyses followed by KEGG annotation show increased expression of genes linked to inflammatory processes in the aortas of these mice. In AAV-PCSK9DY-treated mice learning was delayed and long-term memory impaired. Blood flow was reduced in the cingulate cortex (-17%), caudate putamen (-15%), and hippocampus (-10%). Immunohistological studies also show an increased incidence of string vessels and pericytes (CD31/Col IV staining) in the hippocampus accompanied by patchy blood-brain barrier leaks (IgG staining) and increased macrophage infiltrations (CD68 staining). Discussion: We conclude that the hyperlipidemic PCSK9DY mouse model can serve as an appropriate approach to induce microvascular dysfunction that leads to reduced blood flow in the hippocampus, which could explain the cognitive dysfunction in these mice.
Subject(s)
Atherosclerosis , Hyperlipidemias , Male , Mice , Animals , Proprotein Convertase 9/genetics , Incidence , Mice, Inbred C57BL , Hyperlipidemias/pathology , Atherosclerosis/metabolism , Cholesterol , Cerebrovascular Circulation/physiologyABSTRACT
BACKGROUND: Chronic interstitial fibrosis is the primary barrier against the long-term survival of transplanted kidneys. Extending the lifespan of allografts is vital for ensuring the long-term health of patients undergoing kidney transplants. However, few targets and their clinical applications have been identified. Moreover, whether dyslipidemia facilitates fibrosis in renal allograft remains unclear. METHODS: Blood samples were collected from patients who underwent kidney transplantation. Correlation analyses were conducted between the Banff score and body mass index, and serum levels of triacylglycerol, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. A rat model of renal transplantation was treated with the lipid-lowering drug, fenofibrate, and kidney fibrosis levels were determined by histochemical staining. Targeted metabolomic detection was conducted in blood samples from patients who underwent kidney transplantation and were divided into fibrotic and non-fibrotic groups. Rats undergoing renal transplantation were fed either an n-3 or n-6 polyunsaturated fatty acid (PUFA)-enriched diet. Immunohistochemical and Masson's trichrome staining were used to determine the degree of fibrosis. RESULTS: Hyperlipidemia was associated with fibrosis development. Treatment with fenofibrate contributed to improve fibrosis in a rat model of renal transplantation. Moreover, n-3 PUFAs from fibrotic group showed significant downregulation compared to patients without fibrotic renal allografts, and n-3 PUFAs-enriched diet contributed to delayed fibrosis in a rat model of renal transplantation. CONCLUSIONS: This study suggests that hyperlipidemia facilitates fibrosis of renal allografts. Importantly, a new therapeutic approach was provided that may delay chronic interstitial fibrosis in transplanted kidneys by augmenting the n-3 PUFA content in the diet.
Subject(s)
Fatty Acids, Omega-3 , Fenofibrate , Hyperlipidemias , Kidney Transplantation , Humans , Rats , Animals , Kidney Transplantation/adverse effects , Fenofibrate/pharmacology , Kidney/pathology , Fibrosis , Allografts , Hyperlipidemias/pathology , CholesterolABSTRACT
Myocardial infarction (MI) is a leading cause of death. Lipid-lowering interventions have been shown to decrease coronary events and mortality of MI and heart failure. In this investigation, we assessed the anti-hyperlipidemic effects of ß-caryophyllene in isoproterenol-induced myocardial infarcted rats. ß-Caryophyllene (20 mg/kg body weight) pre-and co-treatment was given to rats orally, daily, for 3 weeks. Isoproterenol (100 mg/kg body weight) was administered to rats to induce MI. The levels of serum cardiac troponins T and I, serum and heart total cholesterol, triglycerides, free fatty acids, and the levels of serum low-density and very low-density lipoprotein-cholesterols were augmented, and the level of serum high-density lipoprotein-cholesterol was lessened in myocardial infarcted rats. Further, the activity/levels of liver 3-hydroxy-3-methylglutaryl-coenzyme A reductase and plasma thiobarbituric acid reactive substances were amplified and the activity/levels of heart glutathione -S- transferase, vitamin C, and vitamin E were lessened by isoproterenol. A down-regulated expression of liver sterol regulatory element-binding protein-2 and liver low-density lipoprotein-receptor genes was observed by a reverse transcription-polymerase chain reaction study. Moreover, histopathology of Sudan III staining revealed an accumulation of fats in the heart of isoproterenol-induced rats. Nevertheless, ß-caryophyllene pre-and co-treatment blocked alterations in all the parameters examined in isoproterenol-induced rats and inhibited the risk of MI. Moreover, the in vitro study revealed the potent free radical scavenging and antioxidant effects of ß-caryophyllene. ß-Caryophyllene's antioxidant and anti-hyperlipidemic properties are the possible mechanisms for the observed protective effects in this investigation.
Subject(s)
Hyperlipidemias , Myocardial Infarction , Rats , Animals , Isoproterenol/pharmacology , Reactive Oxygen Species , Rats, Wistar , Hyperlipidemias/pathology , Myocardial Infarction/chemically induced , Myocardial Infarction/drug therapy , Antioxidants/adverse effects , Myocardium/metabolism , Cholesterol/adverse effects , Lipoproteins, LDL/adverse effects , Body WeightABSTRACT
This study examined the mechanism underlying the protective effect of royal jelly (RJ) against high-fat-diet (HFD)-mediated non-alcoholic liver disease (NAFLD) in rats. Adult male rats were divided into five groups (n = 8 each): control fed a standard diet, control + RJ (300 mg/kg), HFD, HFD + RJ (300 mg/kg), and HFD + RJ + CC (0.2 mg/kg). The treatment with RJ reduced weight gain, increased fat pads, and attenuated fasting hyperglycemia, hyperinsulinemia, and glucose tolerance in the HFD-fed rats. It also reduced the serum levels of liver function enzymes, interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and leptin but significantly increased the serum levels of adiponectin. In addition, and with no effect on lipid excretion in stool, RJ significantly decreased the hepatic mRNA expression of SREBP1, serum, hepatic cholesterol, and triglycerides but increased hepatic mRNA levels of PPARα. Furthermore, RJ reduced the hepatic levels of TNF-α, IL-6, and malondialdehyde (MDA) in the livers of these rats. Of note, with no effect on the mRNA levels of AMPK, RJ stimulated the phosphorylation of AMPK and increased the levels of superoxide dismutase (SOD) and total glutathione (GSH) in the livers of the control and HFD-fed rats. In conclusion, RJ attenuates NAFLD via its antioxidant potential and adiponectin-independent activation of liver AMPK.
Subject(s)
Hyperglycemia , Hyperlipidemias , Non-alcoholic Fatty Liver Disease , Rats , Male , Animals , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/prevention & control , AMP-Activated Protein Kinases/metabolism , Hyperlipidemias/drug therapy , Hyperlipidemias/etiology , Hyperlipidemias/pathology , Tumor Necrosis Factor-alpha/pharmacology , Adiponectin/metabolism , Interleukin-6/genetics , Liver/metabolism , Diet, High-Fat/adverse effects , Hyperglycemia/drug therapy , Hyperglycemia/pathology , RNA, Messenger/metabolismABSTRACT
OBJECTIVE: Hypercholesterolemia (HC) is a devastating metabolic disorder that has a negative effect on the kidneys' functional and structural modalities via oxidative stress and inflammation. The aim of this paper is to elaborate on the role of the flavonoid apigenin (Apg), considering its antioxidant, anti-inflammatory, and antiapoptotic capabilities, in alleviating hypercholesterolemic-induced kidney injury. MATERIALS AND METHODS: Twenty-four adult Wister male rats were allocated into four equal groups and treated for eight consecutive weeks: a control group, supplemented with a normal pellet diet (NPD); the Apg group, supplemented with NPD and Apg (50 mg/Kg); the HC group, fed with NPD enriched with 4% cholesterol and 2% sodium cholate; and the HC/Apg group, concomitantly rendered hypercholesterolemic and gavaged with Apg. At the end of the experiment, serum samples were collected to measure renal function parameters, lipid profile, MDA, and GPX-1. Thereafter, the kidneys were processed for histological study and homogenized to assess IL-1ß, IL-10, and the gene expression of kidney injury molecule-1 (KIM-1), fibronectin 1 (Fn1), and NF-E2-related factor 2 (Nrf2) via RT-qPCR. RESULTS: HC disturbed the renal function, lipid profile, and serum redox balance. In addition, HC elicited a proinflammatory/anti-inflammatory imbalance, upregulating KIM-1 and Fn1 and downregulating the Nrf2 gene expression of the kidney tissue. Moreover, HC induced marked histopathological changes in the kidney cytoarchitecture. Efficaciously, upon concomitant Apg supplementation with a high-cholesterol diet, most functional, histological, and biomolecular impairments of the kidney were comparatively restored in the HC/Apg group. CONCLUSIONS: Apg mitigated HC-induced kidney injury via modulating the KIM-1, Fn1, and Nrf2 signaling pathways, a promising effect that may be useful as an adjunct to antihypercholesterolemic medications to treat the devastating renal complications of HC.
Subject(s)
Hypercholesterolemia , Hyperlipidemias , Animals , Male , Rats , Anti-Inflammatory Agents/pharmacology , Apigenin/metabolism , Apigenin/pharmacology , Fibronectins/metabolism , Hyperlipidemias/pathology , Kidney/metabolism , Lipids , NF-E2-Related Factor 2/metabolism , Oxidative Stress , Rats, Wistar , Signal TransductionABSTRACT
Vascular calcification, a prevalent pathological alteration in metabolic syndromes, is tightly related with cardiometabolic risk events. Ferroptosis, a newly iron-dependent programmed cell death, induced by palmitic acid (PA), the major saturated free fatty acid in hyperlipidemia, is a vital mechanism of vascular calcification. Recent studies reported that ferroptosis is a distinctive type of cell death dependent on autophagy, with the lipotoxicity of PA on cell viability being closely linked with autophagy. Oleoylethanolamide (OEA), an endogenous bioactive mediator of lipid homeostasis, exerts vascular protection against intimal calcification, atherosclerosis; however, its beneficial effect on vascular smooth muscle cell (VSMC)-associated medial calcification has not been investigated. Our aim was to characterize the effect of OEA on vascular calcification and ferroptosis of VSMCs under hyperlipidaemia/PA exposure. In vivo, vascular calcification model was induced in rats by high-fat diet and vitamin D3 plus nicotine; in vitro, VSMCs ferroptosis was induced by PA or plus ß-glycerophosphate mimicking vascular calcification. The calcium deposition in hyperlipidaemia-mediated rat thoracic aortas, the PA-induced ferroptosis and subsequent calcium deposition in VSMCs, were suppressed by OEA treatment. Additionally, CGAS-STING1-induced ferritinophagy, the main molecular mechanism of PA-triggered ferroptosis of VSMCs, was activated by mitochondrial DNA damage; however, early administration of OEA alleviated these phenomena. Intriguingly, overexpression of peroxisome proliferator activated receptor alpha (PPARα) contributed to a decrease in PA-induced ferroptosis, whereas PPARÉ knockdown inhibited the OEA-mediated anti-ferroptotic effects. Collectively, our study demonstrated that OEA serves as a prospective candidate for the prevention and treatment of vascular calcification in metabolic abnormality syndromes.
Subject(s)
Ferroptosis , Hyperlipidemias , Vascular Calcification , Rats , Animals , PPAR alpha/genetics , PPAR alpha/metabolism , DNA, Mitochondrial/metabolism , Calcium/metabolism , Hyperlipidemias/drug therapy , Hyperlipidemias/metabolism , Hyperlipidemias/pathology , Vascular Calcification/drug therapy , Vascular Calcification/prevention & control , Vascular Calcification/genetics , Fatty Acids/metabolism , Palmitic Acid/pharmacology , Autophagy , Myocytes, Smooth MuscleABSTRACT
BACKGROUND: Green algae contain many polysaccharides. However, there is no information on whether Chaetomorpha linum polysaccharides (CLP) can modulate lipid and glucose metabolism. MATERIAL AND METHODS: CLP were extracted from chlorella and their components were characterized. Male C57BL/6 mice were randomized and provided with control chow as the control, or high fat diet (HFD) to induce nonalcoholic fatty liver disease (NAFLD). NAFLD mice were treated orally with water as the HFD group or with 50 or 150 mg/kg CLP daily for 10 weeks. The impact of CLP treatment on lipid and glucose metabolism and the PPARα signaling was examined by histology, Western blotting and biochemistry. RESULTS: CLP mainly contained arabinogalactan sulfate. Compared with the control, HFD feeding increased body weights, lipid droplet liver deposition and induced hyperlipidemia, liver functional impairment and glucose intolerance in mice. Treatment with CLP, particularly with a higher dose of CLP, limited the HFD-increased body weights and liver lipid droplet deposition, mitigated the HFD-induced hyperlipidemia and improved liver function and glucose tolerance in mice. Mechanistically, feeding with HFD dramatically decreased the expression of liver PPARα, CPT-1, and MCAD, but treatment with CLP enhanced their expression in a trend of dose-dependent in mice. CONCLUSIONS: These findings indicated that CLP treatment alleviated the gain in body weights, NAFLD, and glucose intolerance in mice after HFD feeding by enhancing the PPARα/CPT-1/MCAD signaling.
Subject(s)
Chlorella , Flax , Glucose Intolerance , Hyperlipidemias , Non-alcoholic Fatty Liver Disease , Mice , Male , Animals , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/metabolism , PPAR alpha/genetics , PPAR alpha/metabolism , Glucose Intolerance/pathology , Mice, Inbred C57BL , Diet, High-Fat/adverse effects , Liver/metabolism , Carnitine O-Palmitoyltransferase/metabolism , Hyperlipidemias/pathology , Weight Gain , Glucose/metabolism , Polysaccharides/pharmacology , Polysaccharides/therapeutic use , Lipids/therapeutic use , Lipid MetabolismABSTRACT
A 75-year-old man was admitted to our hospital with acute onset of marked jaundice, elevated liver enzymes, and hyperlipidemia. He had been taking clopidogrel and pemafibrate for 3 months. He tested negative for autoantibodies and hepatitis-causing viruses. Gadoxetate-enhanced magnetic resonance imaging showed diffusely hypointense liver parenchyma in the hepatobiliary phase, with no appreciable excretion of gadoxetate into the biliary system. Histological examination of a liver specimen revealed disappearance of the bile ducts in the portal area and decreased expression of organic transporting polypeptide 1B3 on immunostaining. The patient was diagnosed with drug-induced vanishing bile duct syndrome and treated with ursodeoxycholic acid. The signs of liver dysfunction shown on blood chemistry tests improved spontaneously. After the acute hepatitis and lipid abnormalities had improved, repeat liver biopsy and gadoxetate-enhanced magnetic resonance imaging revealed improvement of the vanishing bile duct syndrome and recovery of the expression of organic transporting polypeptide 1B3. The reduction of OATP1B3 expression might be involved in the development of vanishing bile duct syndrome.
Subject(s)
Bile Duct Diseases , Cholestasis , Hyperlipidemias , Liver Diseases , Aged , Bile Duct Diseases/chemically induced , Bile Duct Diseases/complications , Bile Duct Diseases/pathology , Bile Ducts/pathology , Bile Ducts, Intrahepatic/pathology , Cholestasis/etiology , Humans , Hyperlipidemias/complications , Hyperlipidemias/pathology , Liver Diseases/complications , MaleABSTRACT
Background: Intracranial atherosclerosis (ICAS) is one of the most common causes of ischemic stroke, but there are few animal models that can recapitulate its pathological features. In this study, we examined ICAS pathological features and anatomic distributions using three types of hyperlipidemic rabbit models. We also investigated the effect of different lipoprotein profiles and hypertension on ICAS. Materials and Methods: We examined Watanabe heritable hyperlipidemic (WHHL) rabbits, apoE knockout (KO) rabbits and wild-type rabbits (WT) fed a cholesterol diet, in addition to WT rabbits fed a standard diet as a control. The whole brain was dissected and embedded in paraffin. Serial sections were stained with either hematoxylin/eosin or elastica van Gieson, or immunohistochemically stained with monoclonal antibodies against macrophages and smooth muscle cells. We investigated (1) the presence of cerebral atherosclerosis; (2) the lesion locations in the cerebral arteries; (3) the degree of lumen stenosis; (4) pathological features and cellular components of the lesions in these rabbits; and (5) whether hypertension affects ICAS. Results: ICAS was detected in apoE and WHHL rabbits, but not in WT rabbits. Compared with apoE KO rabbits, WHHL rabbits had greater ICAS. The lesions of cerebral atherosclerosis were mainly distributed at the bifurcations of the posterior cerebral artery, basilar artery and vertebral artery, and they were basically characterized by smooth muscle cells and extracellular matrix with few macrophages. The extent of the ICAS in WHHL rabbits was significantly increased by hypertension. Conclusions: ICAS was detected in WHHL and apoE KO rabbits, and occurred in specific locations in the cerebral arteries. Hypertension promotes the development of ICAS in the setting of hypercholesterolemia.
Subject(s)
Hypercholesterolemia , Hyperlipidemias , Hypertension , Intracranial Arteriosclerosis , Animals , Apolipoproteins E/genetics , Hypercholesterolemia/complications , Hyperlipidemias/pathology , Intracranial Arteriosclerosis/complications , RabbitsABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Zexie Tang (ZXT), only two consists with Alismatis Rhizoma (AR) and Atractylodes macrocephala Rhizoma (AM), a classical Chinese medicine formula from Synopsis of the Golden Chamber with a history of 2000 years. Clinical observation in recent years has found that ZXT has excellent lipid-lowering effect. AIM OF THE STUDY: To explore the potential mechanism of ZXT ameliorates hyperlipidemia based on FKBP38/mTOR/SREBPs pathway. MATERIALS AND METHODS: WD-induced hyperlipidemia mice and oleic acid induced cell lipid accumulation model were used to investigate pharmacodynamic. The effect of ZXT on the transcriptional activity of SREBPs was detected by reporter gene assay. Proteins and downstream genes of mTOR/SREBPs pathway were detected in vivo and in vitro. Combined with network pharmacology and HPLC-Q-TOF/MS, the active ingredients were screened and identified. The interaction between active compounds of ZXT and FKBP38 protein were analyzed by docking analysis. RESULTS: ZXT decreased TC, TG and LDL-c levels in blood of WD-induced hyperlipidemia mouse model, and improved insulin resistance in vivo. ZXT also reduced TC, TG and lipid accumulation in cells line, and inhibited SREBPs luciferase activity, protein and its target genes expression such as FASN, HMGCR, etc. Meanwhile, ZXT inhibited protein expression levels of p-mTOR, p-S6K, etc in vitro and in vivo. Combined with network pharmacology and HPLC-Q-TOF/MS, 16 active ingredients were screened and identified. Docking results showed that active compounds of ZXT binding to FKBP38 and formed hydrogen bond. CONCLUSION: Our findings highlighted that ZXT ameliorates hyperlipidemia, in which FKBP/mTOR/SREBPs pathway might be the potential regulatory mechanism.
Subject(s)
Hyperlipidemias/pathology , Lipids/blood , Plant Extracts/pharmacology , Sterol Regulatory Element Binding Proteins/drug effects , TOR Serine-Threonine Kinases/drug effects , Tacrolimus Binding Proteins/drug effects , Alismatales , Animals , Atractylodes , Disease Models, Animal , Dose-Response Relationship, Drug , Male , Mice , Mice, Inbred C57BL , Molecular Docking Simulation , Network PharmacologyABSTRACT
The present research work was proposed to discover the beneficial roles of ponicidin against the streptozotocin (STZ)-induced diabetic nephropathy (DN) in rats via modulating the oxidative stress and inflammation. The DN was initiated to the Wistar rats via administering 45 mg/kg of STZ and then diabetic animals were supplemented with 50 mg/kg of ponicidin and 150 mg/kg of metformin (standard drug) for 8 weeks. The body weight and food intake of animals were checked every week. The glucose, insulin, and homeostasis model assessment- insulin resistance (HOMA-IR) levels in the serum were assessed using kits. The levels of reactive oxygen species (ROS) accumulation, oxidative stress and antioxidant markers, and pro-inflammatory cytokines were examined using assay kits. The levels of lipid profiles and renal function markers were investigated using respective kits. The renal tissues were analyzed microscopically to detect the histological alterations. The ponicidin treatment effectively decreased the body weight, food intake, HOMA-IR, and HbAlc levels in the DN animals. The levels of ROS and MDA were decreased and superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) activities were improved by the ponicidin. The ponicidin also reduced the blood urea nitrogen (BUN), creatinine, lactate dehydrogenase (LDH), and kidney injury molecule (KIM-1) levels. The levels of low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), free fatty acid (FFA), and total cholesterol (TC) were decreased and the high-density lipoprotein (HDL) level was improved by the ponicidin treatment to the DN rats. The tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), nuclear factor-kappa B (NF-κB), and IL-6 levels were appreciably attenuated by the ponicidin. The ponicidin also ameliorated the DM-provoked histological alterations in the renal tissues. In conclusion, this study work evidenced that ponicidin has the therapeutic action in ameliorating the development of DN via averting oxidative stress, inflammation, and renal injury. It could be a promising therapeutic agent to treat DN in the future.
Subject(s)
Diabetes Mellitus , Diabetic Nephropathies , Hyperlipidemias , Insulin Resistance , Animals , Antioxidants/therapeutic use , Biomarkers/metabolism , Body Weight , Diabetes Mellitus/metabolism , Diabetic Nephropathies/drug therapy , Diterpenes , Female , Humans , Hyperlipidemias/metabolism , Hyperlipidemias/pathology , Inflammation/metabolism , Kidney , Male , Oxidative Stress , Rats , Rats, Wistar , Reactive Oxygen Species/metabolism , Streptozocin/pharmacologyABSTRACT
The inverse relationship between HDL-C (high-density lipoprotein cholesterol) and cardiovascular disease is well established. However, it is consensus that the cholesterol content present in HDL does not capture its complexity, and other metrics need to be explored. HDL is a heterogeneous, protein-enriched particle with functions going beyond lipid metabolism. In this way, its protein content seems to be attractive to investigate its behavior in the face of pathologies. Many of the proteins with important function in HDL are in low abundance (<1% of total proteins), which makes their detection challenging. Quantitative proteomics allows detecting proteins with high precision and robustness in complex matrix. However, quantitative proteomics is still poorly explored in the context of HDL. In this sense, in the second chapter of this thesis, the analytical performance of two quantitative methodologies was carefully investigated. These methods achieved adequate linearity and high precision using labeled peptides in a pool HDL, in addition to comparable ability to differentiate proteins from HDL subclasses of healthy subjects. Another bottleneck that waits for a solution in proteomics is the lack of standardization in data processing and analysis after mass spectrometry acquisition. In addition, interest in the cardioprotective properties of omega-3 is growing, but little is known about its effects on the HDL proteome. Thus, in the third chapter of this thesis, we compared five protein quantification strategies using Skyline and MaxDIA software platforms in order to investigate the HDL proteome from mice submitted to a high-fat diet supplemented or not with omega-3. MaxDIA with label-free quantification (MaxLFQ) achieved high precision to show that polyunsaturated fatty acids remodel the HDL proteome to a less inflammatory profile. Therefore, the two studies presented in this thesis begin to open new paths for a deeper and more reliable understanding of HDL, both at the level of protein quantification by mass spectrometry and after data acquisition
A inversa relação entre HDL-C (do inglês, high-density lipoprotein cholesterol) e doenças cardiovasculares é bem estabelecida. No entanto, é consenso que o conteúdo de colesterol presente na HDL não captura sua complexidade, e outras métricas precisam ser exploradas. A HDL é uma partícula heterogênea, enriquecida em proteínas, com funções que vão além do metabolismo de lipídeos. Dessa forma, seu conteúdo proteico parece ser mais atrativo para exprimir seu comportamento frente às patologias. Muitas das proteínas com função importante estão em baixa abundância (<1% do total de proteínas), o que torna a detecção desafiadora. Métodos quantitativos de proteômica permitem detectar proteínas com alta precisão e robustez em matrizes complexas. No entanto, a proteômica quantitativa ainda é pouco explorada no contexto da HDL. Nesse sentido, no segundo capítulo dessa tese, a performance analítica de dois métodos quantitativos foi criteriosamente investigada, os quais alcançaram adequada linearidade e alta precisão usando peptídeos marcados em um pool de HDL, além de comparável habilidade em diferenciar as proteínas das subclasses da HDL de indivíduos saudáveis. Outro gargalo que aguarda por solução em proteômica é a falta de padronização no processamento e análise de dados após a aquisição por espectrometria de massas. Além disso, é crescente o interesse das propriedades cardioprotetivas do ômega-3, porém pouco se conhece sobre seus efeitos no proteoma da HDL. Então, no terceiro capítulo dessa tese, comparamos cinco estratégias de quantificação de proteínas utilizando os softwares Skyline e MaxDIA com o intuito de comparar o proteoma da HDL de camundongos submetidos a uma dieta hiperlipídica suplementados ou não com ômega-3. MaxDIA com quantificação label-free (MaxLFQ) apresentou alta precisão para mostrar que o ômega-3 remodela o proteoma da HDL para um perfil menos inflamatório. Portanto, os dois estudos apresentados nessa tesa começam a abrir novos caminhos para o entendimento mais profundo e confiável da HDL tanto por meio da quantificação das proteínas por espectrometria de massas quanto após à aquisição dos dados
Subject(s)
Proteomics/instrumentation , Hyperlipidemias/pathology , Cholesterol, HDL/analysis , Mass Spectrometry/methods , Cardiovascular Diseases/pathology , Diet/classification , Diet, High-Fat/adverse effectsABSTRACT
Polygonum cuspidatum (PC) has been reported to exert a potent antihyperlipidemic effect. However, its mechanisms of action and active ingredients remain elusive and require further research. In this study, we first conducted in vivo experiments to validate that Polygonum cuspidatum extract (PCE) could ameliorate the blood lipid level in hyperlipidemia model rats. Then, ultrahigh performance liquid chromatography coupled with Q-Exactive MS/MS (UPLC-QE-MS/MS) was applied to verify its 12 main active ingredients. The pharmacophore matching model was employed to predict the target point of the active ingredient, and 27 overlapping genes were identified via database and literature mining. String online database and Cytoscape software were utilized to construct a Protein-Protein Interaction (PPI) network, followed by function annotation analysis and pathway enrichment analysis. The results showed that the PI3K/AKT signaling pathway and its downstream FOXO3/ERα factors were significantly enriched. Furthermore, in vitro experiments were performed to determine the lipid content and oxidative stress (OS) indicators in OA-induced HepG2 cells, and immunofluorescence and western blotting analysis were carried out to analyze the effects of PCE on related proteins. Our experimental results show that the mechanism of antihyperlipidemic action of PCE is related to the activation of the PI3K/AKT signaling pathway and its downstream FOXO3/ERα factors, and polydatin and resveratrol are the main active ingredients in PCE that exert antihyperlipidemic effects.
Subject(s)
Fallopia japonica/chemistry , Forkhead Box Protein O3/metabolism , Hyperlipidemias/drug therapy , Hypolipidemic Agents/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Plant Extracts/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Animals , Female , Forkhead Box Protein O3/genetics , Gene Expression Regulation , Hep G2 Cells , Humans , Hyperlipidemias/etiology , Hyperlipidemias/metabolism , Hyperlipidemias/pathology , Oxidative Stress , Phosphatidylinositol 3-Kinases/genetics , Protein Interaction Maps , Proto-Oncogene Proteins c-akt/genetics , Rats , Rats, Wistar , Signal TransductionABSTRACT
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. Therapeutic activity of icariin, a major bioactive component of Epimedii Herba, in NAFLD is still unknown. Herein, the C57BL/6J mice were fed with a high-fat diet for 16 weeks to establish a NAFLD model. Mice were assigned to five groups: control group, NAFLD group, and icariin treatment groups. Effects of icariin on blood indices, glucose tolerance, insulin sensitivity, histopathological morphology, cell apoptosis, lipid accumulation, and AMPK signaling were analyzed. In addition, another cohort of mice were assigned to five groups: control group, NAFLD group, dorsomorphin treatment group, icariin treatment group, and dorsomorphin + icariin treatment group. Expression of proteins in liver tissues associated with AMPK signaling, and levels of ALT and AST were evaluated. Icariin attenuated the NAFLD-induced increase of the TG, TC, LDL-C, ALT, AST levels. HDL-C levels were affected neither by NAFLD nor by icariin. Furthermore, icariin treatment (100-200 mg/kg) counteracted the NAFLD-reduced glucose tolerance and insulin sensitivity and modulated histopathological changes, cell apoptosis, and lipid accumulation in liver tissues. Additionally, icariin mitigated the NAFLD-induced up-regulation of the cleaved caspase 3/9, SREBP-1c, and DGAT-2 levels, and enhanced the expression level of CPT-1, p-ACC/ACC, AMPKα1, PGC-1α, and GLUT4. Effects of icariin on the AMPK signaling and levels of AST and ALT could be reversed by AMPK inhibitor, dorsomorphin. This paper investigates the glucose-reducing and lipid-lowering effects of icariin in NAFLD. Moreover, icariin might function through activating the AMPKα1/PGC-1α/GLTU4 pathway.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Flavonoids/toxicity , Glucose Transporter Type 4/metabolism , Hyperlipidemias , Liver , Non-alcoholic Fatty Liver Disease , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Animals , Hyperlipidemias/chemically induced , Hyperlipidemias/metabolism , Hyperlipidemias/pathology , Liver/metabolism , Liver/pathology , Male , Mice , Non-alcoholic Fatty Liver Disease/chemically induced , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/geneticsABSTRACT
Loquat (Eriobotrya japonica Lindl.), a subtropical fruit tree native to Asia, is not only known to be nutritive but also beneficial for the treatment of diabetes in the south of China. To expand its development, this study was undertaken concerning the potential therapeutic role of total sesquiterpene glycosides (TSGs) from loquat leaves in insulin resistance (IR), the major causative factor of type 2 diabetes mellitus (T2DM). Male C57BL/6 mice were fed on high-fat diet (HFD) to induce IR and then were given TSG by oral administration at 25 and 100 mg/kg/day, respectively. TSG notably improved metabolic parameters including body weight, serum glucose, and insulin levels and prevented hepatic injury. Moreover, inflammatory response and oxidative stress were found to be remarkably alleviated in IR mice with TSG supplement. Further research in liver of IR mice demonstrated that TSG repaired the signalings of insulin receptor substrate-1 (IRS-1)/glucose transporter member 4 (GLUT4) and AMP-activated protein kinase (AMPK), which improved glucose and lipid metabolism and prevented lipid accumulation in liver. It was also observed that TSG suppressed the expression of transient receptor potential vanilloid 1 (TRPV1), whereas the signaling pathway of sirtuin-6 (SIRT6)/nuclear factor erythroid 2-related factor 2 (Nrf2) was significantly promoted. Based on the results, the current study demonstrated that TSG from loquat leaves potentially ameliorated IR in vivo by enhancing IRS-1/GLUT4 signaling and AMPK activation and modulating TRPV1 and SIRT6/Nrf2 signaling pathways.
Subject(s)
Diet, High-Fat , Eriobotrya/chemistry , Gene Expression Regulation/drug effects , Glycosides/pharmacokinetics , Hyperglycemia/prevention & control , Hyperlipidemias/prevention & control , Insulin Resistance , Animals , Glucose Transporter Type 4/genetics , Glucose Transporter Type 4/metabolism , Hyperglycemia/etiology , Hyperglycemia/metabolism , Hyperglycemia/pathology , Hyperlipidemias/etiology , Hyperlipidemias/metabolism , Hyperlipidemias/pathology , Insulin Receptor Substrate Proteins/genetics , Insulin Receptor Substrate Proteins/metabolism , Male , Mice , Mice, Inbred C57BL , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Plant Extracts/pharmacology , Plant Leaves , Sesquiterpenes/pharmacology , Sirtuins/genetics , Sirtuins/metabolism , TRPV Cation Channels/genetics , TRPV Cation Channels/metabolismABSTRACT
Obesity is a major global health problem and is associated with a significant risk of renal function decline. Obesity-related nephropathy, as one of the complications of obesity, is characterized by a structural and functional damage of the kidney and represents one of the important contributors to the morbidity and mortality worldwide. Despite increasing data linking hyperlipidemia and lipotoxicity to kidney injury, the apprehension of molecular mechanisms leading to a development of kidney damage is scarce. MicroRNAs (miRNAs) are endogenously produced small noncoding RNA molecules with an important function in post-transcriptional regulation of gene expression. miRNAs have been demonstrated to be important regulators of a vast array of physiological and pathological processes in many organs, kidney being one of them. In this review, we present an overview of miRNAs, focusing on their functional role in the pathogenesis of obesity-associated renal pathologies. We explain novel findings regarding miRNA-mediated signaling in obesity-related nephropathies and highlight advantages and future perspectives of the therapeutic application of miRNAs in renal diseases.
Subject(s)
Acute Kidney Injury/pathology , Kidney Diseases/genetics , Kidney Diseases/pathology , MicroRNAs/genetics , Obesity/pathology , Animals , Diabetic Nephropathies/genetics , Diabetic Nephropathies/pathology , Gene Expression Regulation/genetics , Humans , Hyperlipidemias/genetics , Hyperlipidemias/pathology , Kidney/pathology , Mice , Signal Transduction/geneticsABSTRACT
Hyperlipidemia is a potent risk factor for the development of cardiovascular diseases. The reverse cholesterol transport (RCT) process has been shown to alleviate hyperlipidemia and protect against cardiovascular diseases. Recently, rosmarinic acid was reported to exhibit lipid-lowering effects. However, the underlying mechanism is still unclear. This study aims to investigate whether rosmarinic acid lowers lipids by modulating the RCT process in high-fat diet (HFD)-induced hyperlipidemic C57BL/6J mice. Our results indicated that rosmarinic acid treatment significantly decreased body weight, blood glucose, and plasma total cholesterol and triglyceride levels in HFD-fed mice. Rosmarinic acid increased the expression levels of cholesterol uptake-associated receptors in liver tissues, including scavenger receptor B type 1 (SR-B1) and low-density lipoprotein receptor (LDL-R). Furthermore, rosmarinic acid treatment notably increased the expression of cholesterol excretion molecules, ATP-binding cassette G5 (ABCG5) and G8 (ABCG8) transporters, and cholesterol 7 alpha-hydroxylase A1 (CYP7A1) as well as markedly reduced cholesterol and triglyceride levels in liver tissues. In addition, rosmarinic acid facilitated fatty acid oxidation through AMP-activated protein kinase (AMPK)-mediated carnitine palmitoyltransferase 1A (CPT1A) induction. In conclusion, rosmarinic acid exhibited a lipid-lowering effect by modulating the expression of RCT-related proteins and lipid metabolism-associated molecules, confirming its potential for the prevention or treatment of hyperlipidemia-derived diseases.
Subject(s)
Cardiovascular Diseases/drug therapy , Cinnamates/pharmacology , Depsides/pharmacology , Hyperlipidemias/drug therapy , Receptors, LDL/genetics , Scavenger Receptors, Class B/genetics , AMP-Activated Protein Kinase Kinases/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 5/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 8/genetics , Animals , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/pathology , Cardiovascular Diseases/prevention & control , Carnitine O-Palmitoyltransferase/genetics , Cholesterol/genetics , Cholesterol/metabolism , Cholesterol 7-alpha-Hydroxylase/genetics , Diet, High-Fat/adverse effects , Disease Models, Animal , Gene Expression Regulation/drug effects , Humans , Hyperlipidemias/metabolism , Hyperlipidemias/pathology , Hyperlipidemias/prevention & control , Lipid Metabolism/drug effects , Lipoproteins/genetics , Liver/drug effects , Liver/metabolism , Male , Mice , Rosmarinic AcidABSTRACT
The aim of the study was to assess the predictors of major adverse cardiovascular events (MACE) in patients with systemic sclerosis (SSc) without pulmonary arterial hypertension. The study comprised 68 patients with SSc who were followed up for the median time of 99 (96; 107) months. The main exclusion criteria involved tricuspid regurgitation maximal velocity > 2.8 m/s and structural heart disease. At baseline the patients underwent clinical assessment of cardiovascular risk factors, 6-min walk test, transthoracic echocardiography and biomarker testing, including growth differentiation factor 15 (GDF-15). The primary composite endpoint was onset of MACE defined as death, myocardial infarction, myocardial revascularization and hospitalization for heart failure. The follow-up consisted of outpatient visits at 1 year intervals and telephone interview every 6 months. The baseline analysis revealed that chronic kidney disease (HR 28.13, 95%CI 4.84-163.38), lung fibrosis on high resolution computed tomography (HR 4.36, 95%CI 1.04-18.26) and GDF-15 concentration (unit HR 1.0006, 95%CI 1.0002-1.0010) were independent predictors of MACE occurrence. CHLD (Chronic kidney disease, Hypertension, hyperLipidaemia, Diabetes mellitus) score was formulated which assigned 1 point for the presence of arterial hypertension, hyperlipidaemia, diabetes mellitus and chronic kidney disease. After inclusion of CHLD score in Cox proportional model, it remained the only independent predictor of MACE onset (unit HR per 1 point 3.46; 95%CI 2.06-5.82, p < 0.0001). Joint assessment of traditional risk factors in the form of CHLD score may serve as a reliable predictor of long-term outcome in patients with SSc without pulmonary arterial hypertension.