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Pakistan Journal of Pharmaceutical... Mar 2024Heart failure is a condition in which the heart's one or both ventricles are unable to either receive an adequate amount of blood or eject an adequate amount of blood....
Heart failure is a condition in which the heart's one or both ventricles are unable to either receive an adequate amount of blood or eject an adequate amount of blood. Diabetes is considered one of the major risk factors for cardiovascular diseases. The current research is designed to evaluate the cardioprotective effects of dapagliflozin in streptozotocin and isoproterenol-induced comorbid rats. The COX-2, TNF-α, NF-КB, NLRP3, PPAR-γ, CKMB, TROP-I, AR, GP and SGLT were docked against dapagliflozin, propranolol and metformin. Dapagliflozin restored adequate blood flow and halted myofibril damage. Moreover, it's evident from this study that dapagliflozin significantly decreased serum concentration of various blood markers, decreased relative growth rate and QT interval prolongation, as compared to the negative control group. However, it improved the ventricular ejection fraction in rats of the treatment group. The GST, GSH and CAT levels were increased, as compared to normal. On the contrary, a decrease in LPO concentrations was observed. Evaluation of the coronal section of heart tissues showed the anti-inflammatory expressions evaluated through H & E staining and immunohistochemical techniques and with ELISA and PCR. In a nutshell, dapagliflozin reverses myocardial necrosis and apoptosis.
Topics: Animals; Glucosides; Isoproterenol; Heart Failure; Benzhydryl Compounds; NLR Family, Pyrin Domain-Containing 3 Protein; PPAR gamma; Rats; Streptozocin; Signal Transduction; Male; Rats, Wistar; Diabetes Mellitus, Experimental; Cardiotonic Agents; Apoptosis; Sodium-Glucose Transporter 2 Inhibitors; Myocardium
PubMed: 38767101
DOI: No ID Found -
Molecular Metabolism Jul 2024The prevalence of metabolic diseases is increasing globally at an alarming rate; thus, it is essential that effective, accessible, low-cost therapeutics are developed....
OBJECTIVE
The prevalence of metabolic diseases is increasing globally at an alarming rate; thus, it is essential that effective, accessible, low-cost therapeutics are developed. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that tightly regulate glucose homeostasis and lipid metabolism and are important drug targets for the treatment of type 2 diabetes and dyslipidemia. We previously identified LDT409, a fatty acid-like compound derived from cashew nut shell liquid, as a novel pan-active PPARα/γ/δ compound. Herein, we aimed to assess the efficacy of LDT409 in vivo and investigate the molecular mechanisms governing the actions of the fatty acid mimetic LDT409 in diet-induced obese mice.
METHODS
C57Bl/6 mice (6-11-month-old) were fed a chow or high fat diet (HFD) for 4 weeks; mice thereafter received once daily intraperitoneal injections of vehicle, 10 mg/kg Rosiglitazone, 40 mg/kg WY14643, or 40 mg/kg LDT409 for 18 days while continuing the HFD. During treatments, body weight, food intake, glucose and insulin tolerance, energy expenditure, and intestinal lipid absorption were measured. On day 18 of treatment, tissues and plasma were collected for histological, molecular, and biochemical analysis.
RESULTS
We found that treatment with LDT409 was effective at reversing HFD-induced obesity and associated metabolic abnormalities in mice. LDT409 lowered food intake and hyperlipidemia, while improving insulin tolerance. Despite being a substrate of both PPARα and PPARγ, LDT409 was crucial for promoting hepatic fatty acid oxidation and reducing hepatic steatosis in HFD-fed mice. We also highlighted a role for LDT409 in white and brown adipocytes in vitro and in vivo where it decreased fat accumulation, increased lipolysis, induced browning of WAT, and upregulated thermogenic gene Ucp1. Remarkably, LDT409 reversed HFD-induced weight gain back to chow-fed control levels. We determined that the LDT409-induced weight-loss was associated with a combination of increased energy expenditure (detectable before weight loss was apparent), decreased food intake, increased systemic fat utilization, and increased fecal lipid excretion in HFD-fed mice.
CONCLUSIONS
Collectively, LDT409 represents a fatty acid mimetic that generates a uniquely favorable metabolic response for the treatment of multiple abnormalities including obesity, dyslipidemia, metabolic dysfunction-associated steatotic liver disease, and diabetes. LDT409 is derived from a highly abundant natural product-based starting material and its development could be pursued as a therapeutic solution to the global metabolic health crisis.
Topics: Animals; Mice; Mice, Inbred C57BL; Obesity; Diet, High-Fat; Male; Fatty Acids; Fatty Liver; PPAR alpha; Lipid Metabolism; Peroxisome Proliferator-Activated Receptors; Liver; Non-alcoholic Fatty Liver Disease
PubMed: 38763495
DOI: 10.1016/j.molmet.2024.101958 -
Free Radical Biology & Medicine Aug 2024Androgen receptor (AR)-targeting therapy induces oxidative stress in prostate cancer. However, the mechanism of oxidative stress induction by AR-targeting therapy...
Oxidative stress in peroxisomes induced by androgen receptor inhibition through peroxisome proliferator-activated receptor promotes enzalutamide resistance in prostate cancer.
Androgen receptor (AR)-targeting therapy induces oxidative stress in prostate cancer. However, the mechanism of oxidative stress induction by AR-targeting therapy remains unclear. This study investigated the mechanism of oxidative stress induction by AR-targeting therapy, with the aim to develop novel therapeutics targeting oxidative stress induced by AR-targeting therapy. Intracellular reactive oxygen species (ROS) was examined by fluorescence microscopy and flow cytometry analysis. The effects of silencing gene expression and small molecule inhibitors on gene expression and cytotoxic effects were examined by quantitative real-time PCR and cell proliferation assay. ROS induced by androgen depletion co-localized with peroxisomes in prostate cancer cells. Among peroxisome-related genes, PPARA was commonly induced by AR inhibition and involved in ROS production via PKC signaling. Inhibition of PPARα by specific siRNA and a small molecule inhibitor suppressed cell proliferation and increased cellular sensitivity to the antiandrogen enzalutamide in prostate cancer cells. This study revealed a novel pathway by which AR inhibition induced intracellular ROS mainly in peroxisomes through PPARα activation in prostate cancer. This pathway is a promising target for the development of novel therapeutics for prostate cancer in combination with AR-targeting therapy such as antiandrogen enzalutamide.
Topics: Male; Humans; Phenylthiohydantoin; Nitriles; Peroxisomes; Oxidative Stress; Drug Resistance, Neoplasm; Benzamides; Receptors, Androgen; Reactive Oxygen Species; PPAR alpha; Cell Proliferation; Prostatic Neoplasms; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Signal Transduction; Androgen Receptor Antagonists; RNA, Small Interfering
PubMed: 38762061
DOI: 10.1016/j.freeradbiomed.2024.05.030 -
Neurochemistry International Jul 2024Neuroinflammation stands as a critical player in the pathogenesis of diverse neurological disorders, with microglial cells playing a central role in orchestrating the...
Neuroinflammation stands as a critical player in the pathogenesis of diverse neurological disorders, with microglial cells playing a central role in orchestrating the inflammatory landscape within the central nervous system. Cannabidiol (CBD) has gained attention for its potential to elicit anti-inflammatory responses in microglia, offering promising perspectives for conditions associated with neuroinflammation. Here we investigated whether the NLRP3 inflammasome and inducible nitric oxide synthase (iNOS) are involved in the protective effects of CBD, and if their modulation is dependent on cannabinoid receptor 2 (CB2) and PPARγ signalling pathways. We found that treatment with CBD attenuated pro-inflammatory markers in lipopolysaccharide (LPS)-challenged BV2 microglia in a CB2- and PPARγ-dependent manner. At a molecular level, CBD inhibited the LPS-induced pro-inflammatory responses by suppressing iNOS and NLRP3/Caspase-1-dependent signalling cascades, resulting in reduced nitric oxide (NO), interleukin-1β (IL-1β), and tumour necrosis factor-alpha (TNF-α) concentrations. Notably, the protective effects of CBD on NLRP3 expression, Caspase-1 activity, and IL-1β concentration were partially hindered by the antagonism of both CB2 receptors and PPARγ, while iNOS expression and NO secretion were dependent exclusively on PPARγ activation, with no CB2 involvement. Interestingly, CBD exhibited a protective effect against TNF-α increase, regardless of CB2 or PPARγ activation. Altogether, these findings indicate that CB2 receptors and PPARγ mediate the anti-inflammatory effects of CBD on the NLRP3 inflammasome complex, iNOS activity and, ultimately, on microglial phenotype. Our results highlight the specific components responsible for the potential therapeutic applications of CBD on neuroinflammatory conditions.
Topics: PPAR gamma; Animals; Microglia; NLR Family, Pyrin Domain-Containing 3 Protein; Cannabidiol; Nitric Oxide Synthase Type II; Lipopolysaccharides; Mice; Receptor, Cannabinoid, CB2; Inflammasomes; Inflammation; Cell Line; Anti-Inflammatory Agents
PubMed: 38761855
DOI: 10.1016/j.neuint.2024.105769 -
Senolytic combination of dasatinib and quercetin attenuates renal damage in diabetic kidney disease.Phytomedicine : International Journal... Jul 2024Senolytic combination of dasatinib and quercetin (DQ) is the most studied senolytics drugs used to treat various age-related diseases. However, its protective activity...
BACKGROUND
Senolytic combination of dasatinib and quercetin (DQ) is the most studied senolytics drugs used to treat various age-related diseases. However, its protective activity against diabetic kidney disease (DKD) and underlying mechanisms are uncertain.
PURPOSE
To investigate the functions and potential mechanisms of the senolytics DQ on DKD.
METHODS
Diabetic db/db mice were administrated DQ or transfected with over-expressed PPARα or shPPARα vector. The positive control group was administered irbesartan. Renal function and fibrotic changes in kidney tissue were tested. Single-cell RNA-seq (scRNA-seq) was conducted to analyze the differential transcriptome between the diabetic and control mice. Molecular docking simulation was used to assess the combination of DQ and potential factors. Moreover, tubular epithelial cells under high-glucose (HG) conditions were incubated with DQ and transfected with or without over-expressed PPARα/siPPARα vector.
RESULTS
DQ significantly improved renal function, histopathological and fibrotic changes, alleviated lipid deposition, and increased ATP levels in mice with DKD. DQ reduced multiple fatty acid oxidation (FAO) pathway-related proteins and up-regulated PPARα in db/db mice. Overexpression of PPARα upregulated the expression of PPARα-targeting downstream FAO pathway-related proteins, restored renal function, and inhibited renal fibrosis in vitro and in vivo. Moreover, molecular docking and dynamics simulation analyses indicated the nephroprotective effect of DQ via binding to PPARα. Knockdown of PPARα reversed the effect of DQ on the FAO pathway and impaired the protective effect of DQ during DKD.
CONCLUSION
For the first time, DQ was found to exert a renal protective effect by binding to PPARα and attenuating renal damage through the promotion of FAO in DKD.
Topics: Animals; Diabetic Nephropathies; Quercetin; PPAR alpha; Mice; Dasatinib; Molecular Docking Simulation; Male; Kidney; Mice, Inbred C57BL; Diabetes Mellitus, Experimental
PubMed: 38761776
DOI: 10.1016/j.phymed.2024.155705 -
BioFactors (Oxford, England) May 2024Foam cell formation plays a pivotal role in atherosclerosis-associated cardiovascular diseases. Bioactive peptides generated from marine sources have been found to...
Foam cell formation plays a pivotal role in atherosclerosis-associated cardiovascular diseases. Bioactive peptides generated from marine sources have been found to provide multifunctional health advantages. In the present study, we investigated the anti-atherosclerotic effects of LLRLTDL (Bu1) and GYALPCDCL (Bu2) peptides, isolated from ark shell protein hydrolysates by assessing their inhibitory effect on oxidized LDL (oxLDL)-induced foam cell formation. The two peptides showed a promising anti-atherosclerotic effect by inhibiting foam cell formation, which was evidenced by inhibiting lipid accumulation in oxLDL-treated RAW264.7 macrophages and oxLDL-treated primary human aortic smooth muscle cells (HASMC). Two peptides effectively reduced total cholesterol, free cholesterol, cholesterol ester, and triglyceride levels by upregulating cholesterol efflux and downregulating cholesterol influx. Expression of cholesterol influx-related proteins such as SR-A1 and CD36 were reduced, whereas cholesterol efflux-related proteins such as ATP-binding cassette transporter ABCA-1 and ABCG-1 were highly expressed. In addition, Bu1 and Bu2 peptides increased PPAR-γ and LXR-α expression. However, PPAR-γ siRNA transfection reversed the foam cell formation inhibitory activity of Bu1 and Bu2 peptides. Furthermore, the synergistic effect of Bu1 and Bu2 peptides on foam cell formation inhibition was observed with PPAR-γ agonist thiazolidinediones, indicating that PPAR-γ signaling pathway plays a key role in foam cell formation of macrophages. Beyond their impact on foam cell formation, Bu1 and Bu2 peptides demonstrated anti-inflammatory potential by inhibiting the generation of pro-inflammatory cytokines and nitric oxide and NF-κB nuclear activation. Taken together, these results suggest that Bu1 and Bu2 peptides may be useful for atherosclerosis and associated anti-inflammatory therapies.
PubMed: 38760074
DOI: 10.1002/biof.2075 -
BMC Nutrition May 2024The present study was designed to investigate the influence of different dietary lipids (sheep's fat, olive oil, coconut oil, and corn oil) on specific biomarkers...
BACKGROUND
The present study was designed to investigate the influence of different dietary lipids (sheep's fat, olive oil, coconut oil, and corn oil) on specific biomarkers associated with metabolic syndrome in both healthy and diabetic rats.
METHODS
The study designed for 45 days, utilized a male diabetic wistar rat (body weight, 180-220 g) model induced by streptozotocin (45 mg/kg bw). The rats were divided into two sections: five non-diabetic and five diabetic groups, each containing six rats. The first group in each section serving as the control, received a standard diet. Both non-diabetic or diabetic groups, were provided with a standard diet enriched with 15% sheep fat, 15% coconut oil, 15% olive oil, and 15% corn oil, respectively for a duration of 45 days.
RESULTS
Post-supplementation, both healthy and diabetic control rats exhibited a higher food intake compared to rats supplemented with lipid diet; notably food intake was higher in diabetic control than healthy control. However, rats fed with coconut oil, olive oil and sheep fat showed weight gain at the end of the experiment, in both healthy and diabetic groups. Coconut oil supplementation significantly (p ≤ 0.05) increased HDL-C and total cholesterol level in diabetic groups compared to healthy group, it was confirmed by an increased PPAR-α and ABCA-1 protein level. Olive oil significantly decreased triglyceride, total cholesterol, and LDL-C levels in diabetic rats when compared to sheep fat or coconut oil. Corn oil significantly decreased fasting glucose, total cholesterol and LDL-C levels compared to all other groups. Corn and olive oil supplemented normal groups, found with significant increase in hepatic glucose-lipid oxidative metabolism associated protein, like FGF-21, MSH, ABCA-1, PPAR-γ and decreased lipogenesis proteins like, SREBP and PPAR-α levels. In contrast, sheep grease and coconut oil increased SREBP and PPAR-α expression in both normal and diabetic groups. Most notably, normal and diabetic groups pretreated with sheep grease resulted in increased inflammatory (MCP-1, IL-1β, TLR-4, TNF-α), and oxidative stress markers (LPO, GSH, GPx, SOD and CAT) linked with metabolic complications.
CONCLUSION
The combination or alternative use of olive oil and corn oil in daily diet may play a significant role in preventing proinflammatory condition associated with insulin resistance and cardiovascular diseases.
PubMed: 38755663
DOI: 10.1186/s40795-024-00881-7 -
ACS Pharmacology & Translational Science May 2024A main hepatic consequence of obesity is metabolic-associated fatty liver disease (MAFLD), currently treated by improving eating habits and administrating fibrates yet...
A main hepatic consequence of obesity is metabolic-associated fatty liver disease (MAFLD), currently treated by improving eating habits and administrating fibrates yet often yielding suboptimal outcomes. Searching for a new therapeutic approach, we aimed to evaluate the efficacy of hydroxytyrosol linoleoyl ether (HTLE), a dual Ppar-α agonist/Cb1 antagonist with inherent antioxidant properties, as an antisteatotic agent. Using lean and obese Zucker rats, they were administrated daily doses of HTLE (3 mg/kg) over a 15-day period, evaluating its safety profile, pharmacokinetics, impact on body weight, hepatic fat content, expression of key enzymes involved in lipogenesis/fatty acid oxidation, and antioxidant capacity. HTLE decreased the body weight and food intake in both rat genotypes. Biochemical analysis demonstrated a favorable safety profile for HTLE along with decreased concentrations of urea, total cholesterol, and aspartate aminotransferase AST transaminases in plasma. Notably, HTLE exhibited potent antisteatotic effects in obese rats, evidenced by a decrease in liver fat content and downregulation of lipogenesis-related enzymes, alongside increased expression of proteins controlling lipid oxidation. Moreover, HTLE successfully counteracted the redox imbalance associated with MAFLD in obese rats, attenuating lipid peroxidation and replenishing both glutathione levels and the overall antioxidant. Our findings highlight the effectiveness of triple-action strategies in managing MAFLD effectively. Based on our results in the Zucker rat model, HTLE emerges as a promising candidate with triple functionality as an anorexigenic, antisteatotic, and antioxidant agent, offering potential relief from MAFLD symptoms associated with obesity while exhibiting minimal side effects. In conclusion, our study positions HTLE as a highly promising compound for therapeutic intervention in MAFLD treatment, warranting further exploration in clinical trials.
PubMed: 38751648
DOI: 10.1021/acsptsci.4c00105 -
Scientific Reports May 2024Xanthine oxidoreductase (XOR) contributes to reactive oxygen species production. We investigated the cytoprotective mechanisms of XOR inhibition against high glucose...
Xanthine oxidoreductase (XOR) contributes to reactive oxygen species production. We investigated the cytoprotective mechanisms of XOR inhibition against high glucose (HG)-induced glomerular endothelial injury, which involves activation of the AMP-activated protein kinase (AMPK). Human glomerular endothelial cells (GECs) exposed to HG were subjected to febuxostat treatment for 48 h and the expressions of AMPK and its associated signaling pathways were evaluated. HG-treated GECs were increased xanthine oxidase/xanthine dehydrogenase levels and decreased intracellular AMP/ATP ratio, and these effects were reversed by febuxostat treatment. Febuxostat enhanced the phosphorylation of AMPK, the activation of peroxisome proliferator-activated receptor (PPAR)-gamma coactivator (PGC)-1α and PPAR-α and suppressed the phosphorylation of forkhead box O (FoxO)3a in HG-treated GECs. Febuxostat also decreased nicotinamide adenine dinucleotide phosphate oxidase (Nox)1, Nox2, and Nox4 expressions; enhanced superoxide dismutase activity; and decreased malondialdehyde levels in HG-treated GECs. The knockdown of AMPK inhibited PGC-1α-FoxO3a signaling and negated the antioxidant effects of febuxostat in HG-treated GECs. Despite febuxostat administration, the knockdown of hypoxanthine phosphoribosyl transferase 1 (HPRT1) also inhibited AMPK-PGC-1α-FoxO3a in HG-treated GECs. XOR inhibition alleviates oxidative stress by activating AMPK-PGC-1α-FoxO3a signaling through the HPRT1-dependent purine salvage pathway in GECs exposed to HG conditions.
Topics: Humans; Glucose; Xanthine Dehydrogenase; Endothelial Cells; AMP-Activated Protein Kinases; Purines; Signal Transduction; Febuxostat; Kidney Glomerulus; Oxidative Stress; Reactive Oxygen Species
PubMed: 38750091
DOI: 10.1038/s41598-024-61436-1 -
Poultry Science Jul 2024Little information is available on the effect of Hericium erinaceus polysaccharides (HEP) on laying hens, especially on improving liver and ovarian health and function....
Little information is available on the effect of Hericium erinaceus polysaccharides (HEP) on laying hens, especially on improving liver and ovarian health and function. Therefore, this study was conducted to investigate the impacts of HEP on liver and ovarian function to delay the decline in the laying performance of aged hens. A total of 360 fifty-eight-wk-old laying hens were randomly allocated to 4 treatments, with 6 replicates of 15 birds each. After 2 wk of adaptation, the birds were fed basal diet (CON) or basal diets supplemented with 250, 500, and 750 mg/kg of HEP (HEP250, HEP500, and HEP 750, respectively) for 12 wk. The results showed that, compared with CON, hens fed HEP had significantly increased laying performance (P < 0.05) and promoted follicle development, as evidenced by the increased numbers of hierarchical follicles, small follicles, and total follicles (P < 0.05). Birds fed 500 mg/kg of HEP improved the liver function by increasing T-AOC activity (P < 0.05) and decreasing hepatic oxidative stress and inflammatory responses (inflammatory cell infiltration) caused by aging. The lipid metabolism was improved, and yolk precursor synthesis was promoted in the liver of HEP-treated laying hens by upregulating the mRNA expression of FAS, MTTP, PPAR-α, APOVLDL-Ⅱ, and VTG-Ⅱ (P < 0.05). In addition, HEP significantly decreased ovarian inflammation by regulating the mRNA levels of NF-κB, IL-1β, IL-6, and TNF-α (P < 0.05). As a result, the contents of E, LH, and FSH in serum and the gene expression of ERα of the liver and FSHR of the ovary increased in HEP-treated hens (P < 0.05). In conclusion, dietary HEP supplementation exhibited potential hepatic and ovarian protective effects, thereby increasing the laying performance of aged hens by enhancing reproductive hormone secretion hormone secretion and promoting yolk precursor synthesis and follicle development via the liver-blood-ovary axis. The optimal supplementation level of HEP in aged hens was 500 mg/kg.
Topics: Animals; Chickens; Female; Liver; Animal Feed; Diet; Ovarian Follicle; Dietary Supplements; Egg Yolk; Random Allocation; Ovary; Dose-Response Relationship, Drug; Fungal Polysaccharides; Polysaccharides; Reproduction
PubMed: 38749108
DOI: 10.1016/j.psj.2024.103810