Association of lipid-lowering drug targets with risk of cutaneous melanoma: a mendelian randomization study.

BACKGROUND: Melanoma proliferation is partly attributed to dysregulated lipid metabolism. The effectiveness of lipid-lowering drugs in combating cutaneous melanoma (CM) is a subject of ongoing debate in both in vitro and clinical studies. METHOD: This study aims to evaluate the causal relationship between various lipid-lowering drug targets, namely 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR, targeted by statins), Proprotein convertase subtilisin/kexin type 9 (PCSK9, targeted by alirocumab and evolocumab), and Niemann-Pick C1-like 1 (NPC1L1, targeted by ezetimibe), and the outcomes of cutaneous melanoma. To mimic the effects of lipid-lowering drugs, we utilized two genetic tools: analysis of polymorphisms affecting the expression levels of drug target genes, and genetic variations linked to low-density lipoprotein cholesterol levels and drug target genes. These variations were sourced from genome-wide association studies (GWAS). We applied Summary-data-based Mendelian Randomization (SMR) and Inverse Variance Weighted Mendelian Randomization (IVW-MR) to gauge the effectiveness of these drugs. RESULTS: Our findings, with SMR results showing an odds ratio (OR) of 1.44 (95% CI: 1.08-1.92; P = 0.011) and IVW-MR results indicating an OR of 1.56 (95% CI: 1.10-2.23; P = 0.013), demonstrate a positive correlation between PCSK9 expression and increased risk of CM. However, no such correlations were observed in other analyses. CONCLUSION: The study concludes that PCSK9 plays a significant role in the development of CM, and its inhibition is linked to a reduced risk of the disease.

Discovery of Oral AMP-Activated Protein Kinase Activators for Treating Hyperlipidemia.

Activation of AMP-activated protein kinase (AMPK) is proposed to alleviate hyperlipidemia. With cordycepin and N6-(2-hydroxyethyl) adenosine (HEA) as lead compounds, a series of adenosine-based derivatives were designed, synthesized, and evaluated on activation of AMPK. Finally, compound V1 was identified as a potent AMPK activator with the lipid-lowering effect. Molecular docking and circular dichroism indicated that V1 exerted its activity by binding to the γ subunit of AMPK. V1 markedly decreased the serum low-density lipoprotein cholesterol levels in C57BL/6 mice, golden hamsters, and rhesus monkeys. V1 was selected as the clinical compound and concluded Phase 1 clinical trials. A single dose of V1 (2000 mg) increased AMPK activation in human erythrocytes after 5 and 12 h of treatment. RNA sequencing data suggested that V1 downregulated expression of genes involved in regulation of apoptotic process, lipid metabolism, endoplasmic reticulum stress, and inflammatory response in liver by activating AMPK.

Discovery of Highly Potent Solute Carrier 13 Member 5 (SLC13A5) Inhibitors for the Treatment of Hyperlipidemia.

In the face of escalating metabolic disease prevalence, largely driven by modern lifestyle factors, this study addresses the critical need for novel therapeutic approaches. We have identified the sodium-coupled citrate transporter (NaCT or SLC13A5) as a target for intervention. Utilizing rational drug design, we developed a new class of SLC13A5 inhibitors, anchored by the hydroxysuccinic acid scaffold, refining the structure of PF-06649298. Among these, LBA-3 emerged as a standout compound, exhibiting remarkable potency with an IC50 value of 67 nM, significantly improving upon PF-06649298. In vitro assays demonstrated LBA-3's efficacy in reducing triglyceride levels in OPA-induced HepG2 cells. Moreover, LBA-3 displayed superior pharmacokinetic properties and effectively lowered triglyceride and total cholesterol levels in diverse mouse models (PCN-stimulated and starvation-induced), without detectable toxicity. These findings not only spotlight LBA-3 as a promising candidate for hyperlipidemia treatment but also exemplify the potential of targeted molecular design in advancing metabolic disorder therapeutics.

Aqueous extract of fermented Eucommia ulmoides leaves alleviates hyperlipidemia by maintaining gut homeostasis and modulating metabolism in high-fat diet fed rats.

BACKGROUND: As a traditional Chinese medicinal herb, the lipid-lowing biological potential of Eucommia ulmoides leaves (EL) has been demonstrated. After fermentation, the EL have been made into various products with lipid-lowering effects and antioxidant activity. However, the anti-hyperlipidemic mechanism of fermented Eucommia ulmoides leaves (FEL) is unclear now. PURPOSE: To evaluate the effects of FEL on hyperlipidemia and investigate the mechanism based on regulating gut homeostasis and host metabolism. METHODS: Hyperlipidemia animal model in Wistar rats was established after 8 weeks high-fat diet (HFD) fed. The administered doses of aqueous extract of FEL (FELE) were 128, 256 and 512 mg/kg/d, respectively. Serum biochemical parameters detection, histopathological sections analysis, 16S rDNA sequencing of gut microbiota and untargeted fecal metabolomics analysis, were performed to determine the therapeutic effects and predict related pathways of FELE on hyperlipidemia. The changes of proteins and genes elated to lipid were detected by Immunofluorescence (IF) and quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: 56 Components in FELE were identified by UPLC-MS, with organic acids, flavonoids and phenolic acids accounting for the majority. The intervention of FELE significantly reduced the body weight, lipid accumulation and the levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein-cholesterol (LDL-C) in hyperlipidemia rats, while increased the level of High-density lipoprotein-cholesterol (HDL-C). Meanwhile, FELE improved the inflammatory makers and oxidative stress factors, which is tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT). These results demonstrated that FETE can effectively reduce blood lipids and alleviate inflammation and oxidative damage caused by hyperlipidemia. Mechanistically, FELE restore the homeostasis of gut microbiota by reducing the Firmicutes/Bacteroidetes ratio and increasing the abundance of probiotics, especially Lactobacillus, Rombousia, Bacteroides, Roseburia, Clostridia_UCG-014_Unclassified, while modulated metabolism through amino acid, bile acid and lipid-related metabolism pathways. In addition, the Pearson correlation analysis found that the upregulated bilirubin, threonine, dopamine and downregulated lipocholic acid, d-sphingosine were key metabolites after FELE intervention. IF and qRT-PCR analysis showed that FELE upregulated the expression of fatty acid oxidation proteins and genes (PPARα, CPT1A), bile acid synthesis and excretion proteins and genes (LXRα, CYP7A1, FXR), and downregulated the expression of adipogenic gene (SREBP-1c) by regulating gut microbiota to improve metabolism and exert a lipid-lowering effect. CONCLUSION: This work filled the lipid-lowering mechanism gap of FEL. FELE can improve HFD-induced hyperlipidemia by regulating the gut microbiota homeostasis and metabolism. Thus, FEL has the potential to develop into the novel raw material of lipid-lowering drugs.

Response surface methodology optimization of extraction and enrichment conditions of total triterpenoid saponins from Celosiae Semen and evaluation of its lipid-lowering activity.

The saponin-enriched extract from Celosiae Semen is a promising resource owing to its lipid-lowering activity. However, triterpenoid saponins are difficult to extract owing to their high molecular weight and strong water solubility. The aim of this paper was to explore an eco-friendly and effective technology of extraction and enrichment of total triterpenoid saponins to obtain high lipid-lowering fractions. Initially, Box-Behnken design experiments were employed to optimize the heat reflux extraction process on the basic of mono-factor experiments. Afterwards, the crude extract was further purified using D-101 resin, and the purification parameters were investigated based on adsorption/desorption experiments and biological activity assay. Under optimal conditions, the purity of the finally obtained total triterpenoid saponins was increased by 7.28-fold. The lipid-lowering activities of the six main triterpenoid saponins were evaluated in HepG2 cells induced by palmitic acid. The results of Oil Red O staining showed that the compounds all exhibited potential lipid-lowering activity. The structure-activity relationship analysis suggested that the oligosaccharide chain at C-28 played an essential role in their lipid-lowering activity and the substituent group at C-23 site also showed important effects. The optimal extraction and purification methods may facilitate the utilization of Celosiae Semen for the industrial production as a functional food and drug.

Inhibition of tumor migration and invasion by fenofibrate via suppressing epithelial-mesenchymal transition in breast cancers.

The recurrence and metastasis in breast cancer within 3 years after the chemotherapies or surgery leads to poor prognosis with approximately 1-year overall survival. Large-scale scanning research studies have shown that taking lipid-lowering drugs may assist to reduce the risk of death from many cancers, since cholesterol in lipid rafts are essential for maintain integral membrane structure and functional signaling regulation. In this study, we examined five lipid-lowering drugs: swertiamarin, gemfibrozil, clofibrate, bezafibrate, and fenofibrate in triple-negative breast cancer, which is the most migration-prone subtype. Using human and murine triple-negative breast cancer cell lines (Hs 578 t and 4 T1), we found that fenofibrate displays the highest potential in inhibiting the colony formation, wound healing, and transwell migration. We further discovered that fenofibrate reduces the activity of pro-metastatic enzymes, matrix metalloproteinases (MMP)-9 and MMP-2. In addition, epithelial markers including E-cadherin and Zonula occludens-1 are increased, whereas mesenchymal markers including Snail, Twist and α-smooth muscle actin are attenuated. Furthermore, we found that fenofibrate downregulates ubiquitin-dependent GDF-15 degradation, which leads to enhanced GDF-15 expression that inhibits cell migration. Besides, nuclear translocation of FOXO1 is also upregulated by fenofibrate, which may responsible for GDF-15 expression. In summary, fenofibrate with anti-cancer ability hinders TNBC from migration and invasion, and may be beneficial to repurposing use of fenofibrate.

Lipid-lowering drugs and cancer: an updated perspective.

Statins and non-statin medications used for the management of dyslipidemia have been shown to possess antitumor properties. Since the use of these drugs has steadily increased over the past decades, more knowledge is required about their relationship with cancer. Lipid-lowering agents are heterogeneous compounds; therefore, it remains to be revealed whether anticancer potential is a class effect or related to them all. Here, we reviewed the literature on the influence of lipid-lowering medications on various types of cancer during development or metastasis. We also elaborated on the underlying mechanisms associated with the anticancer effects of antihyperlipidemic agents by linking the reported in vivo and in vitro studies.

Advances in Research on Marine-Derived Lipid-Lowering Active Substances and Their Molecular Mechanisms.

Hyperlipidemia (HLP) is a metabolic disorder caused by abnormal lipid metabolism. Recently, the prevalence of HLP caused by poor dietary habits in the population has been increasing year by year. In addition, lipid-lowering drugs currently in clinical use have shown significant improvement in blood lipid levels, but are accompanied by certain side effects. However, bioactive marine substances have been shown to possess a variety of physiological activities such as hypoglycemic, antioxidant, antithrombotic and effects on blood pressure. Therefore, the hypolipidemic efficacy of marine bioactive substances with complex and diverse structures has also attracted attention. This paper focuses on the therapeutic role of marine-derived polysaccharides, unsaturated fatty acids, and bioactive peptides in HLP, and briefly discusses the main mechanisms by which these substances exert their hypolipidemic activity in vivo.

Potential Effect of Baobab's Polyphenols as Antihyperlipidemic Agents: In Silico Study.

Adansonia digitata L. is an African tree commonly called baobab. This tree is effectively used in traditional medicine to treat cardiovascular disorders. Hyperlipidemia is a well-known cardiovascular risk factor associated with the increased incidence of mortality worldwide. This study aimed to demonstrate the mechanism of baobab polyphenols in the activities of hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and pancreatic lipase as lipid metabolic enzymes. Molecular docking and an incentive for drug design showed that all the polyphenols in baobab bound to the proteins with higher affinity and a lower binding energy compared with simvastatin as the positive control (ΔG: from -5.5 kcal/mol to -6.5 kcal/mol). The same polyphenols exhibited a considerable binding affinity to pancreatic lipase (ΔG: from -7.5 kcal/mol to -9.8 kcal/mol) in comparison with the control and HMG-CoA reductase. Quercetin showed the best docking score from the selected Baobab polyphenols (ΔG = -9.8 kcal/mol). The root mean square deviation (RMSD) results indicated that stable epicatechin and quercetin complexes were demonstrated with HMG-CoA reductase, and other less stable complexes were developed using rutin and chlorogenic acid. Moreover, the analysis of the root mean square fluctuation (RMSF) simulation results was consistent with that of the RMSD. The RMSF value for all the baobab polyphenols, including the crystal control ligand, was kept between 0.80 and 8.00 Å, similarly to simvastatin, and less than 4.8 Å for pancreatic lipase. Chlorogenic acid, quercetin, epicatechin, and rutin had negative ΔG binding scores from highest to lowest. The same ligands displayed more negative ΔG binding scores than those observed in HMG-CoA reductase and crystal control ligand (methoxyundecyl phosphinic acid) in their simulation with pancreatic lipase. In conclusion, baobab polyphenols interact with HMG-CoA reductase and pancreatic lipase to inhibit their substrate binding and block their activity.

Antihyperlipidemic mechanisms of a formula containing Curcuma xanthorrhiza, Sechium edule, and Syzigium polyanthum: In silico and in vitro studies.

Herbal medicines are multi-component and can exhibit synergistic effects in the treatment of diseases. Sechium edule, Syzigium polyanthum, and Curcuma xanthorrhiza have been used in traditional medicine to reduce serum lipid levels. However, the molecular mechanism was not described clearly, especially as a mixture. Thus, we performed a network pharmacology study combined with molecular docking to find a rational explanation regarding the molecular mechanisms of this antihyperlipidemic formula. According to the network pharmacology study, we predicted that this extract mixture would act as an antihyperlipidemic agent by modulating several pathways including insulin resistance, endocrine resistance, and AMP-activated protein kinase (AMPK) signaling pathway. Based on the topology parameters, we identified 6 significant targets that play an important role in reducing lipid serum levels: HMG-CoA reductase (HMGCR), peroxisome proliferator-activated receptor alpha (PPARA), RAC-alpha serine/threonine-protein kinase (AKT1), epidermal growth factor receptor (EGFR), matrix metalloproteinase-9 (MMP9), and tumor necrosis factor-alpha (TNF). Meanwhile, 8 compounds: ß-sitosterol, bisdesmethoxycurcumin, cucurbitacin D, cucurbitacin E, myricetin, phloretin, quercitrin, and rutin were the compounds with a high degree, indicating that these compounds have a multitarget effect. Our consensus docking study revealed that HMGCR was the only protein targeted by all potential compounds, and rutin was the compound with the best consensus docking score for almost all targets. The in vitro study revealed that the extract combination could inhibit HMGCR with an IC50 value of 74.26 µg/mL, indicating that HMGCR inhibition is one of its antihyperlipidemic mechanisms.

Oxidized dietary lipids induce vascular inflammation and atherogenesis in post-menopausal rats: estradiol and selected antihyperlipidemic drugs restore vascular health in vivo.

BACKGROUND: Thermoxidation of edible oil through deep fat frying results in the generation of several oxidized products that promote lipid peroxidation and ROS production when eaten. Consumption of thermoxidized oil in post-menopausal conditions where the estrogen level is low contributes to cardiovascular disease. This study evaluates the role of estradiol and antihyperlipidemic agents (AHD) in restoring the vascular health of ovariectomized (OVX) rats fed with thermoxidized palm oil (TPO) and thermoxidized soya oil (TSO) diets. METHOD: A total of 10 groups of rats (n = 6) were set up for the experiment. Group I (normal control) rats were sham handled while other groups were OVX to bring about estrogen deficient post-menopausal state. Group II (OVX only) was not treated and received normal rat chow. Groups III-X were fed with either TPO or TSO diet for 12 weeks and treated with estradiol (ETD) 0.2 mg/kg/day, atorvastatin (ATV) 10 mg/kg/day, and a fixed-dose combination of ezetimibe and ATV (EZE 3 mg/kg/day + ATV 10 mg/kg/day). RESULTS: Pro-atherogenic lipids levels were significantly elevated in untreated TSO and TPO groups compared to OVX and sham, resulting in increased atherogenic and Coronary-risk indices. Treatment with Estradiol and AHDs significantly reduced the total cholesterol, triglycerides, low-density lipoprotein cholesterol as well as AI and CRI compared to untreated TSO and TPO groups, whereas TSO and TPO groups showed significant elevation in these parameters compared to Group I values. Moreover, aortic TNF-α levels were extremely elevated in the untreated TSO and TPO compared to Group I. TNF-α levels were significantly reduced in rats treated with AHDs and ETD. Localized oxidative stress was indicated in the aortic tissues of TSO and TPO-fed OVX rats by increased malondialdehyde and decreased glutathione, catalase, and superoxide dismutase levels. This contributed to a depletion in aortic nitric oxide. AHDs and ETD replenished the nitric oxide levels significantly. Histological evaluation of the aorta of TSO and TPO rats revealed increased peri-adventitia fat, aortic medial hypertrophy, and aortic recanalization. These pathologic changes were less seen in AHDs and ETD rats. CONCLUSION: This study suggests that ETD and AHDs profoundly attenuate oxidized lipid-induced vascular inflammation and atherogenesis through oxidative-stress reduction and inhibition of TNF-α signaling.

Established and Emerging Lipid-Lowering Drugs for Primary and Secondary Cardiovascular Prevention.

Despite treatment with statins, patients with elevated low-density lipoprotein cholesterol (LDL-C) and triglycerides remain at increased risk for adverse cardiovascular events. Consequently, novel pharmaceutical drugs have been developed to control and modify the composition of blood lipids to ultimately prevent fatal cardiovascular events in patients with dyslipidaemia. This article reviews established and emerging lipid-lowering drugs regarding their mechanism of action, development stage, ongoing clinical trials, side effects, effect on blood lipids and reduction in cardiovascular morbidity and mortality. We conducted a keyword search to identify studies on established and emerging lipid modifying drugs. Results were summarized in a narrative overview. Established pharmaceutical treatment options include the Niemann-Pick-C1 like-1 protein (NPC1L1) inhibitor ezetimibe, the protein convertase subtilisin-kexin type 9 (PCSK9) inhibitors alirocumab and evolocumab, fibrates as peroxisome proliferator receptor alpha (PPAR-α) activators, and the omega-3 fatty acid icosapent ethyl. Statins are recommended as the first-line therapy for primary and secondary cardiovascular prevention in patients with hypercholesterinaemia and hypertriglyceridemia. For secondary prevention in hypercholesterinaemia, second-line options such as statin add-on or statin-intolerant treatments are ezetimibe, alirocumab and evolocumab. For secondary prevention in hypertriglyceridemia, second-line options such as statin add-on or statin-intolerant treatments are icosapent ethyl and fenofibrate. Robust data for these add-on therapeutics in primary cardiovascular prevention remains scarce. Recent biotechnological advances have led to the development of innovative small molecules (bempedoic acid, lomitapide, pemafibrate, docosapentaenoic and eicosapentaenoic acid), antibodies (evinacumab), antisense oligonucleotides (mipomersen, volanesorsen, pelcarsen, olezarsen), small interfering RNA (inclisiran, olpasiran), and gene therapies for patients with dyslipidemia. These molecules specifically target new cellular pathways, such as the adenosine triphosphate-citrate lyase (bempedoic acid), PCSK9 (inclisiran), angiopoietin-like 3 (ANGPTL3: evinacumab), microsomal triglyceride transfer protein (MTP: lomitapide), apolipoprotein B-100 (ApoB-100: mipomersen), apolipoprotein C-III (ApoC-III: volanesorsen, olezarsen), and lipoprotein (a) (Lp(a): pelcarsen, olpasiran). The authors are hopeful that the development of new treatment modalities alongside new therapeutic targets will further reduce patients' risk of adverse cardiovascular events. Apart from statins, data on new drugs' use in primary cardiovascular prevention remain scarce. For their swift adoption into clinical routine, these treatments must demonstrate safety and efficacy as well as cost-effectiveness in randomized cardiovascular outcome trials.

Fibrates Affect Levels of Phosphorylated p38 in Intestinal Cells in a Differentiation-Dependent Manner.

Fibrates are widely used hypolipidaemic agents that act as ligands of the peroxisome proliferator-activated receptor α (PPARα). p38 is a protein kinase that is mainly activated by environmental and genotoxic stress. We investigated the effect of the PPARα activators fenofibrate and WY-14643 and the PPARα inhibitor GW6471 on the levels of activated p38 (p-p38) in the colorectal cancer cell lines HT-29 and Caco2 in relation to their differentiation status. Fibrates increased p-p38 in undifferentiated HT-29 cells, whereas in other cases p-p38 expression was decreased. HT-29 cells showed p-p38 predominantly in the cytoplasm, whereas Caco2 cells showed higher nuclear positivity. The effect of fibrates may depend on the differentiation status of the cell, as differentiated HT-29 and undifferentiated Caco2 cells share similar characteristics in terms of villin, CYP2J2, and soluble epoxide hydrolase (sEH) expression. In human colorectal carcinoma, higher levels of p-p38 were detected in the cytoplasm, whereas in normal colonic surface epithelium, p-p38 showed nuclear positivity. The decrease in p-p38 positivity was associated with a decrease in sEH, consistent with in vitro results. In conclusion, fibrates affect the level of p-p38, but its exact role in the process of carcinogenesis remains unclear and further research is needed in this area.

Physicochemical characterization, rheological properties, and hypolipidemic and antioxidant activities of compound polysaccharides in Chinese herbal medicines by fractional precipitation.

This study aimed to investigate the effects of different compound polysaccharides (CPs) extracted from Folium nelumbinis, Fructus crataegi, Fagopyrum tataricum, Lycium barbarum, Semen cassiae, and Poria cocos (w/w, 2:4:2:1:1.5:1) by gradient ethanol precipitation on the physicochemical properties and biological activities. Three CPs (CP50, CP70, and CP80) were obtained and comprised rhamnose, arabinose, xylose, mannose, glucose, and galactose in different proportions. The CPs contained different amounts of total sugar, uronic acid, and proteins. These also exhibited different physical properties, including particle size, molecular weight, microstructure, and apparent viscosity. Scavenging abilities of 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS), 1,1'-diphenyl-2-picrylhydrazyl (DPPH), hydroxyl, and superoxide radicals of CP80 were more potent compared to those of the other two CPs. Furthermore, CP80 significantly increased serum levels of high-density lipoprotein cholesterol (HDL-C) and lipoprotein lipase (LPL), and hepatic lipase (HL) activity in the liver, while decreasing the serum levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C), along with LPS activity. Therefore, CP80 may serve as a natural novel lipid regulator in the field of medicinal and functional food.

Gemfibrozil-Induced Intracellular Triglyceride Increase in SH-SY5Y, HEK and Calu-3 Cells.

Gemfibrozil is a drug that has been used for over 40 years to lower triglycerides in blood. As a ligand for peroxisome proliferative-activated receptor-alpha (PPARα), which is expressed in many tissues, it induces the transcription of numerous genes for carbohydrate and lipid-metabolism. However, nothing is known about how intracellular lipid-homeostasis and, in particular, triglycerides are affected. As triglycerides are stored in lipid-droplets, which are known to be associated with many diseases, such as Alzheimer's disease, cancer, fatty liver disease and type-2 diabetes, treatment with gemfibrozil could adversely affect these diseases. To address the question whether gemfibrozil also affects intracellular lipid-levels, SH-SY5Y, HEK and Calu-3 cells, representing three different metabolically active organs (brain, lung and kidney), were incubated with gemfibrozil and subsequently analyzed semi-quantitatively by mass-spectrometry. Importantly, all cells showed a strong increase in intracellular triglycerides (SH-SY5Y: 170.3%; HEK: 272.1%; Calu-3: 448.1%), suggesting that the decreased triglyceride-levels might be due to an enhanced cellular uptake. Besides the common intracellular triglyceride increase, a cell-line specific alteration in acylcarnitines are found, suggesting that especially in neuronal cell lines gemfibrozil increases the transport of fatty acids to mitochondria and therefore increases the turnover of fatty acids for the benefit of additional energy supply, which could be important in diseases, such as Alzheimer's disease.

Nimbin analogs N5 and N7 regulate the expression of lipid metabolic genes and inhibit lipid accumulation in high-fat diet-induced zebrafish larvae: An antihyperlipidemic study.

BACKGROUND: Excess accumulation of lipids leads to obesity. Triterpenoids are a group of plant compounds which poses various biological activities. The biological activities of Nimbin analogs N5 and N7 were addressed in this study on inhibiting lipid aggregation and underlying the derivatives molecular mechanisms for a therapeutical approach. AIM: This study aims to evaluate the anti-adipogenic activity of semi-natural Nimbin analogs, N5 and N7, on zebrafish larvae induced with oxidative stress due to a high-fat diet (HFD) and adipogenesis using specific fluorescent stains. MATERIALS AND METHODS: Zebrafish at 4 days post fertilized (dpf) larvae were divided into groups for the HFD diet along with exposure to various concentrations of N5 and N7. HFD induced accumulation of neutral lipids and triglycerides (Oil Red O and Nile red staining, respectively) with weight gain, which generated intracellular ROS (DCFH-DA staining) and superoxide anion production (DHE staining) with depleted glutathione levels (NDA staining) were assayed. HFD exposure promoted the accumulation of inflammatory macrophages (Neutral red staining) and impaired glucose metabolism (2NBDG staining). The ability of N5 and N7 to reduce total regulating lipogenic specific genes C/EBP-α, SREBP-1 and FAS were evaluated using relative gene expression. KEY FINDINGS: The Nimbin analogues N5 and N7 suppressed adipogenesis, forming intracellular ROS and superoxide anion while simultaneously restoring glutathione levels. The analogues significantly lowered total TC and TG levels, prevented inflammatory macrophage build-up and boosted glucose absorption. Also, N5 and N7 down-regulate the lipogenic-specific genes. SIGNIFICANCE: Nimbin analogs N5 and N7 enhance lipolysis and inhibit adipogenesis in in-vivo zebrafish larvae model.

Hederagenin Exerts Potential Antilipemic Effect via p38MAPK Pathway in Oleic Acid-induced HepG2 cells and in Hyperlipidemic Rats.

Hederagenin, a natural compound distributed in many medicinal plants, has a variety of pharmacological properties including anti-bacteria, anti-inflammation, anti-oxidation, and anti- apoptosis.. The aim of this study was to evaluate the effects of hederagenin on decreasing blood lipid and anti-oxidative stress in oleic acid-induced HepG2 cells and hyperlipidemic rats, and explore underlying mechanisms. In vitro, TG was used as the index to verify the lipid-lowering effect of hederagenin in oleic acid-induced HepG2 cells. In vivo, TC, TG, LDL-C, and HDL-C were used as direct indicators to study the antilipemic effect of hederagenin in hyperlipidemic rats. MDA, SOD, and GSH-PX were measured to analyze the anti-oxidative effect of hederagenin. The signaling pathways of anti-oxidation were evaluated using Western blot. Our results showed that hederagenin (250µmol/L) increased significantly TG clearance rate. In addition, treatment with hederagenin, XZK and simvastatin reduced effectively TC, TG, LDL-C and MDA content, and increased HDL-C, SOD and GSH-PX in HFD rats. Moreover, the phosphorylation level of p38 MAPK was inhibited after administration of hederagenin, XZK and simvastatin. Our results revealed that hederagenin possessed beneficial potentials for hypolipidemic effects, especially in TG clearance. The mechanism might be associated with inhibition of lipid absorption, reduction of lipid oxidation, and down-regulation of p38MAPK phosphorylation.

Antihyperglycemic, Antihyperlipidemic, and Antioxidant Effects of Salvia tingitana in Streptozotocin-Induced Diabetic Rats.

AIMS: The study aimed to assess the antidiabetic effect of Salvia tingitana (S. tingitana). BACKGROUND: S. tingitana is an aromatic plant that belongs to the Lamiaceae family. Phytochemical analysis of the aerial parts of S. tingitana revealed the existence of terpenoids and flavonoids. In addition, S. tingitana possesses antimicrobial activity. OBJECTIVE: The goal of the study was to obtain information about the antihyperglycemic, antihyperlipidemic, antioxidant abilities of S. tingitana aqueous extract. METHODS: The effect of an acute and sub-chronic administration of S. tingitana aqueous extract (AEST) at the doses of 60 and 80 mg/kg on glucose, lipid profile, and lipoprotein profile was examined in normoglycemic and hyperglycemic rats. Additionally, a preliminary phytochemical screening and the antioxidant activity using DPPH assay were carried out. RESULTS: Rats treated with AEST at a dose of 60 mg/kg showed a significant decrease in the serum glucose levels during the single oral administration at the 4th and 6th hour of treatment in both normal and streptozotocin(STZ)-induced hyperglycemic rats. Interestingly, a dose of 80 mg/kg AEST produced a significant lowering effect on blood glucose levels at the 2nd, 4th, and 6th hour of treatment after a single oral administration in both diabetic and normal rats. Both doses of AEST (60 and 80 mg/kg) revealed a significant amelioration of lipid and lipoprotein profile. In addition, the qualitative and quantitative phytochemical analysis proved the presence of polyphenols compounds, flavonoids, and tannins. Results suggest that S. tingitana contains some secondary metabolites like alkaloids, phenols, flavonoids, and saponins. Importantly, the study revealed that the aqueous extract of S. tingitana has a very interesting antioxidant activity (IC50 = 553.21 µg/ml). CONCLUSION: The study illustrates the beneficial action of the aqueous extract of S. tingitana as an antihyperglycemic and antihyperlipidemic agent.

Bovine Bone Gelatin-Derived Peptides: Food Processing Characteristics and Evaluation of Antihypertensive and Antihyperlipidemic Activities.

This study aimed to evaluate the food processing properties of bovine bone gelatin-derived peptides (BGPs) and their effects and mechanisms on hypertension and hypertension complications in spontaneously hypertensive rats (SHRs). BGPs had good acid, high temperature, and NaCl resistance abilities in vitro. Additionally, Maillard reaction of BGPs with low-dose reducing sugar (≤15%) exhibited a free radical scavenging effect. BGPs significantly reduced the blood pressure, triglyceride levels, and the low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio in SHRs through downregulated angiotensin converting enzyme (ACE), angiotensin II (Ang II), and Ang II type 1 receptor (AT1R) levels and the upregulated Ang II type 2 receptor (AT2R) level. In brief, BGP could alleviate hypertension and dyslipidemia in SHRs by inhibiting ACE/Ang II/AT1R and activating the Ang II/AT2R signaling pathway. Our study suggests that BGP has good food processing properties and could be a potential nutraceutical for antihypertensive and antihyperlipidemic issues.

Insulin sensitizer and antihyperlipidemic effects of Cajanus cajan (L.) millsp. root in methylglyoxal-induced diabetic rats.

Cajanus cajan (L.) Millsp., known as pigeon pea, is one of the major grain legume crops of the tropical world. It recognizes as an ethnomedicine to possess various functions, such as helping in healing wound and cancer therapy. We investigated whether 95% ethanol extracts from C. cajan root (EECR) protect against methylglyoxal (MGO)-induced insulin resistance (IR) and hyperlipidemia in male Wistar rats and explored its possible mechanisms. The hypoglycemic potential of EECR was evaluated using α-amylase, α-glucosidase activities, and advanced glycation end products (AGEs) formation. For in vivo study, the rats were divided into six groups and orally supplemented with MGO except for Group 1 (controls). Group 2 was supplemented with MGO only, Group 3: MGO + metformin, Group 4: MGO + Low dose-EECR (L-EECR; 10 mg/kg bw), Group 5: MGO + Middle dose-EECR (M-EECR; 50 mg/kg bw), and Group 6: MGO + High dose-EECR (H-EECR; 100 mg/kg bw). EECR possessed good inhibition of α-glucosidase, α-amylase activities, and AGEs formation (IC50 = 0.12, 0.32, and 0.50 mg/mL), respectively. MGO significantly increased serum levels of blood glucose (GLU), glycosylated hemoglobin, homeostasis model assessment of IR, AGEs, lipid biochemical values, and atherogenic index, whereas EECR decreased these levels in a dose-dependent manner. EECR can also act as an insulin sensitizer, which significantly decreased (47%, P < 0.05) the blood GLU levels after intraperitoneal injection of insulin in the insulin tolerance tests. The hypoglycemic and antihyperlipidemic mechanisms of EECR are likely through several possible pathways including the inhibition of carbohydrate-hydrolyzing enzymes (α-glucosidase and α-amylase) and the enhancement of MGO-trapping effects on inhibition of AGEs formation.