-
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 -
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 -
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 -
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 -
RSC Advances May 2024A new series of 2-imino or 2-oxo-2-chromene-6-sulfonamide derivatives 2-9 with potential anti-diabetic activity were designed and synthesized. The new 6-sulfonamide...
A new series of 2-imino or 2-oxo-2-chromene-6-sulfonamide derivatives 2-9 with potential anti-diabetic activity were designed and synthesized. The new 6-sulfonamide chromenes were synthesized by reacting 3-formyl-4-hydroxybenzenesulfonyl chloride with activated methylene derivatives in the presence of ammonium acetate as a catalyst. The structure of the products was confirmed by spectroscopic analysis. All the designed derivatives 2-9 were evaluated for their activity against α-amylase and exhibited inhibitory percentage values higher than 93% at 100 μg mL. Additionally, the IC values represented a variable degree of activity with two derivatives 2 and 9 exhibiting the most promising derivative results with IC values of 1.76 ± 0.01 and 1.08 ± 0.02 μM, respectively, compared to Acarbose (IC = 0.43 ± 0.01 μM). Additionally, these derivatives showed potency against the α-glucosidase enzyme with IC values of 0.548 ± 0.02 and 2.44 ± 0.09 μg mL, compared to Acarbose (0.604 ± 0.02 μg mL). Moreover, the PPAR-γ transactivation assay revealed that chromene-6-sulfonamide derivatives 2 and 9 exhibited potential PPAR-γ activity with IC values of 3.152 ± 0.03 and 3.706 ± 0.32 μg mL, respectively, compared to Pioglitazone (4.884 ± 0.29 μg mL). This indicates that these derivatives have insulin sensitivity and glucose metabolism activity. The ADMET prediction showed that these derivatives have an acceptable range of oral bioavailability, drug-likeness, and a safe toxicity profile, including being non-cytotoxic, non-mutagenic, non-immunotoxic, and non-carcinogenic. Finally, computational docking analysis demonstrated the ability of these derivatives to interact with α-amylase, α-glucosidase, and PPAR-γ enzymes, with confirmed successful placement due to good binding energy values and various interactions within the pocket.
PubMed: 38746843
DOI: 10.1039/d4ra02143f -
Journal of Advanced Research May 2024Depression is a debilitating and poorly understood mental disorder. There is an urgency to explore new potential biological mechanisms of depression and the gut...
INTRODUCTION
Depression is a debilitating and poorly understood mental disorder. There is an urgency to explore new potential biological mechanisms of depression and the gut microbiota is a promising research area.
OBJECTIVES
Our study was aim to understand regional heterogeneity and potential molecular mechanisms underlying depression induced by dysbiosis of mucus-associated microbiota.
METHODS
Here, we only selected female macaques because they are more likely to form a natural social hierarchy in a harem-like environment. Because high-ranking macaques rarely displayed depressive-like behaviors, we selected seven monkeys from high-ranking individuals as control group (HC) and the same number of low-ranking ones as depressive-like group (DL), which displayed significant depressive-like behaviors. Then, we collected mucus from the duodenum, jejunum, ileum, cecum and colon of DL and HC monkeys for shotgun metagenomic sequencing, to profile the biogeography of mucus-associated microbiota along duodenum to colon.
RESULTS
Compared with HC, DL macaques displayed noticeable depressive-like behaviors such as longer duration of huddle and sit alone behaviors (negative emotion behaviors), and fewer duration of locomotion, amicable and ingestion activities (positive emotion behaviors). Moreover, the alpha diversity index (Chao) could predict aforementioned depressive-like behaviors along duodenum to colon. Further, we identified that genus Pseudomonas was consistently decreased in DL group throughout the entire intestinal tract except for the jejunum. Specifically, there were 10, 18 and 28 decreased Pseudomonas spp. identified in ileum, cecum and colon, respectively. Moreover, a bacterial module mainly composed of Pseudomonas spp. was positively associated with three positive emotion behaviors. Functionally, Pseudomonaswas mainly involved in microbiota derived lipid metabolisms such as PPAR signaling pathway, cholesterol metabolism, and fat digestion and absorption.
CONCLUSION
Different regions of intestinal mucus-associated microbiota revealed that depletion of genus Pseudomonas is associated with depressive-like behaviors in female macaques, which might induce depressive phenotypes through regulating lipid metabolism.
PubMed: 38735389
DOI: 10.1016/j.jare.2024.05.013 -
Nutrients Apr 2024Prenatal alcohol exposure (AE) affects cognitive development. However, it is unclear whether prenatal AE influences the metabolic health of offspring and whether...
Prenatal Choline Supplementation Improves Glucose Tolerance and Reduces Liver Fat Accumulation in Mouse Offspring Exposed to Ethanol during the Prenatal and Postnatal Periods.
Prenatal alcohol exposure (AE) affects cognitive development. However, it is unclear whether prenatal AE influences the metabolic health of offspring and whether postnatal AE exacerbates metabolic deterioration resulting from prenatal AE. Choline is a semi-essential nutrient that has been demonstrated to mitigate the cognitive impairment of prenatal AE. This study investigated how maternal choline supplementation (CS) may modify the metabolic health of offspring with prenatal and postnatal AE (AE/AE). C57BL/6J female mice were fed either a Lieber-DeCarli diet with 1.4% ethanol between embryonic day (E) 9.5 and E17.5 or a control diet. Choline was supplemented with 4 × concentrations versus the control throughout pregnancy. At postnatal week 7, offspring mice were exposed to 1.4% ethanol for females and 3.9% ethanol for males for 4 weeks. AE/AE increased hepatic triglyceride accumulation in male offspring only, which was normalized by prenatal CS. Prenatal CS also improved glucose tolerance compared to AE/AE animals. AE/AE suppressed hepatic gene expression of peroxisome proliferator activated receptor alpha () and low-density lipoprotein receptor (), which regulate fatty acid catabolism and cholesterol reuptake, respectively, in male offspring. However, these changes were not rectified by prenatal CS. In conclusion, AE/AE led to an increased risk of steatosis and was partially prevented by prenatal CS in male mice.
Topics: Animals; Female; Pregnancy; Choline; Ethanol; Male; Dietary Supplements; Liver; Prenatal Exposure Delayed Effects; Mice, Inbred C57BL; Mice; Fatty Liver; Triglycerides; PPAR alpha; Receptors, LDL; Glucose Intolerance; Lipid Metabolism
PubMed: 38732511
DOI: 10.3390/nu16091264 -
Nutrients Apr 2024Isoeugenol (IEG), a natural component of clove oil, possesses antioxidant, anti-inflammatory, and antibacterial properties. However, the effects of IEG on adipogenesis...
Isoeugenol (IEG), a natural component of clove oil, possesses antioxidant, anti-inflammatory, and antibacterial properties. However, the effects of IEG on adipogenesis have not yet been elucidated. Here, we showed that IEG blocks adipogenesis in 3T3-L1 cells at an early stage. IEG inhibits lipid accumulation in adipocytes in a concentration-dependent manner and reduces the expression of mature adipocyte-related factors including PPARγ, C/EBPα, and FABP4. IEG treatment at different stages of adipogenesis showed that IEG inhibited adipocyte differentiation by suppressing the early stage, as confirmed by lipid accumulation and adipocyte-related biomarkers. The early stage stimulates growth-arrested preadipocytes to enter mitotic clonal expansion (MCE) and initiates their differentiation into adipocytes by regulating cell cycle-related factors. IEG arrested 3T3-L1 preadipocytes in the G/G phase of the cell cycle and attenuated cell cycle-related factors including cyclinD1, CDK6, CDK2, and cyclinB1 during the MCE stage. Furthermore, IEG suppresses reactive oxygen species (ROS) production during MCE and inhibits ROS-related antioxidant enzymes, including superoxide dismutase1 (SOD1) and catalase. The expression of cell proliferation-related biomarkers, including pAKT and pERK1/2, was attenuated by the IEG treatment of 3T3-L1 preadipocytes. These findings suggest that it is a potential therapeutic agent for the treatment of obesity.
Topics: Animals; Adipogenesis; 3T3-L1 Cells; Mice; Adipocytes; Mitosis; Eugenol; Reactive Oxygen Species; Cell Differentiation; PPAR gamma; Cell Proliferation; Fatty Acid-Binding Proteins; Lipid Metabolism; CCAAT-Enhancer-Binding Protein-alpha; Antioxidants
PubMed: 38732509
DOI: 10.3390/nu16091262