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Med (New York, N.Y.) May 2024The study by Hirschfield et al. demonstrated safety profile and clinically significant effectiveness of the peroxisome proliferator-activated receptor delta (PPARδ)...
The study by Hirschfield et al. demonstrated safety profile and clinically significant effectiveness of the peroxisome proliferator-activated receptor delta (PPARδ) agonist seladelpar in patients with primary biliary cholangitis, highlighting its plausible use as a second-line treatment to reduce disease activity and pruritus.
Topics: Humans; Pruritus; Liver Cirrhosis, Biliary; PPAR delta
PubMed: 38733969
DOI: 10.1016/j.medj.2024.03.019 -
Phytomedicine : International Journal... Jul 2024Exercise is an effective strategy to prevent sarcopenia, but high physical inactivity in the elderly requires alternative therapeutic approaches. Exercise mimetics are...
BACKGROUND
Exercise is an effective strategy to prevent sarcopenia, but high physical inactivity in the elderly requires alternative therapeutic approaches. Exercise mimetics are therapeutic compounds that simulate the beneficial effects of exercise on skeletal muscles. However, the toxicity and adverse effects of exercise mimetics raise serious concerns.
PURPOSE
We aimed to search novel plant-based alternatives to activate exercise induced-signaling.
METHODS
We used open databases and luciferase assays to identify plant-derived alternatives to activate exercise-induced signaling and compared its efficacy to mild intensity continuous training (MICT) in aged C57BL/6 mice. The nineteen-month-old mice were either fed an experimental diet supplemented with the isolated alternative or subjected to MICT for up to 21 mo of age.
RESULTS
Our analysis revealed that Chrysanthemum zawadskii Herbich var latillobum (Maxim.) Kitamura (CZH), a medicinal plant rich in linarin, is a novel activator of peroxisome proliferator-activated receptor δ (PPARδ) and estrogen-related receptor γ (ERRγ), key regulators of exercise-induced positive effects on muscles. CZH supplementation ameliorated the loss of muscle function and mass, and increased PPARδ and ERRγ expression in mouse muscles. CZH also improved mitochondrial functions and proteostasis in aged mice, similar to MICT. Furthermore, CZH and linarin induced the activation of Sestrin 1, a key mediator of exercise benefits, in muscle. Silencing Sestrin 1 negated the increase in myogenesis and mitochondrial respiration by CZH and linarin in primary myoblasts from old mice.
CONCLUSION
Our findings suggest the potential of CZH as a novel plant-derived alternative to activate exercise-induced signaling for preventing sarcopenia in sedentary older adults. This could offer a safer therapeutic option for sarcopenia treatment.
Topics: Animals; Chrysanthemum; Mice, Inbred C57BL; Signal Transduction; Sarcopenia; Mice; Muscle, Skeletal; Physical Conditioning, Animal; Male; PPAR delta; Plant Extracts; Receptors, Estrogen; Humans; Aging; Glycosides
PubMed: 38728922
DOI: 10.1016/j.phymed.2024.155695 -
Cancer Letters Jun 2024Dysfunctional bone marrow (BM) endothelial progenitor cells (EPCs) with high levels of reactive oxygen species (ROS) are responsible for defective hematopoiesis in poor...
Dysfunctional bone marrow (BM) endothelial progenitor cells (EPCs) with high levels of reactive oxygen species (ROS) are responsible for defective hematopoiesis in poor graft function (PGF) patients with acute leukemia or myelodysplastic neoplasms post-allotransplant. However, the underlying mechanism by which BM EPCs regulate their intracellular ROS levels and the capacity to support hematopoiesis have not been well clarified. Herein, we demonstrated decreased levels of peroxisome proliferator-activated receptor delta (PPARδ), a lipid-activated nuclear receptor, in BM EPCs of PGF patients compared with those with good graft function (GGF). In vitro assays further identified that PPARδ knockdown contributed to reduced and dysfunctional BM EPCs, characterized by the impaired ability to support hematopoiesis, which were restored by PPARδ overexpression. Moreover, GW501516, an agonist of PPARδ, repaired the damaged BM EPCs triggered by 5-fluorouracil (5FU) in vitro and in vivo. Clinically, activation of PPARδ by GW501516 benefited the damaged BM EPCs from PGF patients or acute leukemia patients in complete remission (CR) post-chemotherapy. Mechanistically, we found that increased expression of NADPH oxidases (NOXs), the main ROS-generating enzymes, may lead to elevated ROS level in BM EPCs, and insufficient PPARδ may trigger BM EPC damage via ROS/p53 pathway. Collectively, we found that defective PPARδ contributes to BM EPC dysfunction, whereas activation of PPARδ in BM EPCs improves their hematopoiesis-supporting ability after myelosuppressive therapy, which may provide a potential therapeutic target not only for patients with leukemia but also for those with other cancers.
Topics: Adult; Animals; Female; Humans; Male; Mice; Middle Aged; Young Adult; Bone Marrow Cells; Endothelial Progenitor Cells; Fluorouracil; Hematopoiesis; Mice, Inbred C57BL; Myelodysplastic Syndromes; NADPH Oxidases; PPAR delta; Reactive Oxygen Species; Thiazoles; Tumor Suppressor Protein p53
PubMed: 38704134
DOI: 10.1016/j.canlet.2024.216937 -
Diabetes Research and Clinical Practice Jun 2024Type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD), mainly related to nutrition and lack of physical activity, are both very... (Review)
Review
Type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD), mainly related to nutrition and lack of physical activity, are both very common conditions, share several disease pathways and clinical manifestations, and increasingly co-occur with disease progression. Insulin resistance is an upstream node in the biology of both conditions and triggers liver parenchymal injury, inflammation and fibrosis. Peroxisome proliferator-activated receptor (PPAR) nuclear transcription factors are master regulators of energy homeostasis - insulin signaling in liver, adipose and skeletal muscle tissue - and affect immune and fibrogenesis pathways. Among distinct yet overlapping effects, PPARα regulates lipid metabolism and energy expenditure, PPARβ/δ has anti-inflammatory effects and increases glucose uptake by skeletal muscle, while PPARγ improves insulin sensitivity and exerts direct antifibrotic effects on hepatic stellate cells. Together PPARs thus represent pharmacological targets across the entire biology of MASH. Single PPAR agonists are approved for hypertriglyceridemia (PPARα) and T2D (PPARγ), but these, as well as dual PPAR agonists, have shown mixed results as anti-MASH treatments in clinical trials. Agonists of all three PPAR isoforms have the potential to improve the full disease spectrum from insulin resistance to fibrosis, and correspondingly to improve cardiometabolic and hepatic health, as has been shown (phase II data) with the pan-PPAR agonist lanifibranor.
Topics: Humans; Diabetes Mellitus, Type 2; Peroxisome Proliferator-Activated Receptors; Fatty Liver; Insulin Resistance; PPAR alpha; PPAR gamma; Animals
PubMed: 38697298
DOI: 10.1016/j.diabres.2024.111688 -
Food & Function May 2024Ginsenoside Rk1, one kind of ginsenoside, is a minor ginsenoside found in and used as traditional Chinese medicine for centuries. It exhibits anti-tumor and...
Ginsenoside Rk1, one kind of ginsenoside, is a minor ginsenoside found in and used as traditional Chinese medicine for centuries. It exhibits anti-tumor and anti-aggregation effects. However, little research has been done on its effect on endothelial function. This study investigated whether ginsenoside Rk1 improved endothelial dysfunction in diabetes and the underlying mechanisms and . Male C57BL/6 mice were fed with a 12 week high-fat diet (60% kcal % fat), whereas treatment groups were orally administered with ginsenoside Rk1 (10 and 20 mg per kg per day) in the last 4 weeks. Aortas isolated from C57BL/6 mice were induced by high glucose (HG; 30 mM) and co-treated with or without ginsenoside Rk1 (1 and 10 μM) for 48 h . Moreover, primary rat aortic endothelial cells (RAECs) were cultured and stimulated by HG (44 mM) to mimic hyperglycemia, with or without the co-treatment of ginsenoside Rk1 (10 μM) for 48 h. Endothelium-dependent relaxations of mouse aortas were damaged with elevated oxidative stress and downregulation of three isoforms of peroxisome proliferator-activated receptors (PPARs), PPAR-α, PPAR-β/δ, and PPAR-γ, as well as endothelial nitric oxide synthase (eNOS) phosphorylation due to HG or high-fat diet stimulation, which also existed in RAECs. However, after the treatment with ginsenoside Rk1, these impairments were all ameliorated significantly. Moreover, the vaso-protective and anti-oxidative effects of ginsenoside Rk1 were abolished by PPAR antagonists (GSK0660, GW9662 or GW6471). In conclusion, this study reveals that ginsenoside Rk1 ameliorates endothelial dysfunction and suppresses oxidative stress in diabetic vasculature through activating the PPAR/eNOS pathway.
Topics: Ginsenosides; Animals; Male; Mice, Inbred C57BL; Mice; Rats; Peroxisome Proliferator-Activated Receptors; Endothelium, Vascular; Oxidative Stress; Endothelial Cells; Aorta; Nitric Oxide Synthase Type III; Panax; Diet, High-Fat
PubMed: 38690748
DOI: 10.1039/d3fo05222b -
Shock (Augusta, Ga.) May 2024
Topics: Shock, Hemorrhagic; PPAR gamma; Animals; Prostaglandin D2; Ligands
PubMed: 38686834
DOI: 10.1097/SHK.0000000000002341 -
Bioorganic & Medicinal Chemistry Letters Jul 2024We have previously reported the total synthesis and structure-activity relationships (SAR) of 2-prenylated benzopyrans with PPAR agonist activity. Herein, we have...
We have previously reported the total synthesis and structure-activity relationships (SAR) of 2-prenylated benzopyrans with PPAR agonist activity. Herein, we have described the synthesis and PPAR activity of 2-prenylated benzopyrans and 2-prenylated quinolines. The benzopyran nucleus was generated via enamine-catalyzed Kabbe condensation, and the quinoline nucleus via Friedländer condensation. Results demonstrated that both benzopyran (5a) and quinoline (4b) derivatives bearing a γ,δ-unsaturated ester displayed a pan-PPAR agonism. They were full PPARα agonists, but showed different preferences for PPARγ and PPARβ/δ activation. It was noteworthy that quinoline 4b displayed full hPPARα activation (2-fold than WY-14,643), weak PPARβ/δ and partial PPARγ activation. In addition, quinoline 4b showed anti-inflammatory effects on macrophages by reducing LPS-induced expression of both MCP-1 and IL-6. Therefore, 4b emerges as a first-in-class promising hit compound for the development of potential therapeutics aimed at treating metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD), and its associated cardiovascular comorbidities.
Topics: Metabolic Syndrome; Quinolines; Structure-Activity Relationship; Humans; Peroxisome Proliferator-Activated Receptors; Molecular Structure; Lipopolysaccharides; Anti-Inflammatory Agents; Macrophages; Dose-Response Relationship, Drug; Benzopyrans; Animals; Mice
PubMed: 38677560
DOI: 10.1016/j.bmcl.2024.129770 -
Diabetes Jul 2024Forkhead box O1 (FOXO1) regulates muscle growth, but the metabolic role of FOXO1 in skeletal muscle and its mechanisms remain unclear. To explore the metabolic role of...
Forkhead box O1 (FOXO1) regulates muscle growth, but the metabolic role of FOXO1 in skeletal muscle and its mechanisms remain unclear. To explore the metabolic role of FOXO1 in skeletal muscle, we generated skeletal muscle-specific Foxo1 inducible knockout (mFOXO1 iKO) mice and fed them a high-fat diet to induce obesity. We measured insulin sensitivity, fatty acid oxidation, mitochondrial function, and exercise capacity in obese mFOXO1 iKO mice and assessed the correlation between FOXO1 and mitochondria-related protein in the skeletal muscle of patients with diabetes. Obese mFOXO1 iKO mice exhibited improved mitochondrial respiratory capacity, which was followed by attenuated insulin resistance, enhanced fatty acid oxidation, and improved skeletal muscle exercise capacity. Transcriptional inhibition of FOXO1 in peroxisome proliferator-activated receptor δ (PPARδ) expression was confirmed in skeletal muscle, and deletion of PPARδ abolished the beneficial effects of FOXO1 deficiency. FOXO1 protein levels were higher in the skeletal muscle of patients with diabetes and negatively correlated with PPARδ and electron transport chain protein levels. These findings highlight FOXO1 as a new repressor in PPARδ gene expression in skeletal muscle and suggest that FOXO1 links insulin resistance and mitochondrial dysfunction in skeletal muscle via PPARδ.
Topics: Animals; Insulin Resistance; Forkhead Box Protein O1; PPAR delta; Mice; Muscle, Skeletal; Mice, Knockout; Humans; Male; Mitochondria, Muscle; Diet, High-Fat; Obesity; Mitochondria
PubMed: 38656552
DOI: 10.2337/db23-0432 -
Journal of Medicinal Food Jun 2024To probe the functions of (AG) extract containing various caffeoylquinic acids on dyslipidemia, obesity, and skeletal muscle-related diseases focused on the roles of...
To probe the functions of (AG) extract containing various caffeoylquinic acids on dyslipidemia, obesity, and skeletal muscle-related diseases focused on the roles of skeletal muscle, we measured the levels of biomarkers involved in oxidative phosphorylation and type change of skeletal muscle in CC cells and skeletal muscle tissues from apolipoprotein E knockout (ApoE KO) mice. After AG extract treatment in cell and animal experiments, western blotting, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA) were used to estimate the levels of proteins that participated in skeletal muscle type change and oxidative phosphorylation. AG extract elevated protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), phosphorylated 5'-AMP-activated protein kinase (p-AMPK), peroxisome proliferator-activated receptor beta/delta (PPARβ/δ), myoblast determination protein 1 (MyoD), and myoglobin in skeletal muscle tissues. Furthermore, it elevated the ATP concentration. However, protein expression of myostatin was decreased by AG treatment. In CC cells, increments of MyoD, myoglobin, myosin, ATP-producing pathway, and differentiation degree by AG were dependent on PPARβ/δ and caffeoylquinic acids. AG extract can contribute to the amelioration of skeletal muscle inactivity and sarcopenia through myogenesis in skeletal muscle tissues from ApoE KO mice, and function of AG extract may be dependent on PPARβ/δ, and the main functional constituents of AG are trans-5--caffeoylquinic acid and 3,5--dicaffeoylquinic acid. In addition, in skeletal muscle, AG has potent efficacies against dyslipidemia and obesity through the increase of the type 1 muscle fiber content to produce more ATP by oxidative phosphorylation in skeletal muscle tissues from ApoE KO mice.
Topics: Animals; Mice; Quinic Acid; Plant Extracts; PPAR-beta; Muscle, Skeletal; Mice, Knockout; Muscle Development; PPAR delta; Male; Apolipoproteins E; Humans; MyoD Protein; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Mice, Inbred C57BL; AMP-Activated Protein Kinases
PubMed: 38651680
DOI: 10.1089/jmf.2024.k.0027 -
Clinics and Research in Hepatology and... Jun 2024Various liver diseases pose great threats to humans. Although the etiologies of these liver diseases are quite diverse, they share similar pathologic phenotypes and... (Review)
Review
Various liver diseases pose great threats to humans. Although the etiologies of these liver diseases are quite diverse, they share similar pathologic phenotypes and molecular mechanisms such as oxidative stress, lipid and glucose metabolism disturbance, hepatic Kupffer cell (KC) proinflammatory polarization and inflammation, insulin resistance, and hepatic stellate cell (HSC) activation and proliferation. Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is expressed in various types of liver cells with relatively higher expression in KCs and HSCs. Accumulating evidence has revealed the versatile functions of PPARβ/δ such as controlling lipid homeostasis, inhibiting inflammation, regulating glucose metabolism, and restoring insulin sensitivity, suggesting that PPARβ/δ may serve as a potential molecular drug target for various liver diseases. This article aims to provide a concise review of the structure, expression pattern and biological functions of PPARβ/δ in the liver and its roles in various liver diseases, and to discuss potential future research perspectives.
Topics: Humans; PPAR-beta; PPAR delta; Liver Diseases; Molecular Targeted Therapy; Insulin Resistance
PubMed: 38641250
DOI: 10.1016/j.clinre.2024.102343