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European Journal of Medicinal Chemistry Jun 2024New analogs of the PPAR pan agonist AL29-26 encompassed ligand (S)-7 showing potent activation of PPARα and -γ subtypes as a partial agonist. In vitro experiments and...
A chemical modification of a peroxisome proliferator-activated receptor pan agonist produced a shift to a new dual alpha/gamma partial agonist endowed with mitochondrial pyruvate carrier inhibition and antidiabetic properties.
New analogs of the PPAR pan agonist AL29-26 encompassed ligand (S)-7 showing potent activation of PPARα and -γ subtypes as a partial agonist. In vitro experiments and docking studies in the presence of PPAR antagonists were performed to help interpretation of biological data and investigate the main interactions at the binding sites. Further in vitro experiments showed that (S)-7 induced anti-steatotic effects and enhancement of the glucose uptake. This latter effect could be partially ascribed to a significant inhibition of the mitochondrial pyruvate carrier demonstrating that (S)-7 also acted through insulin-independent mechanisms. In vivo experiments showed that this compound reduced blood glucose and lipid levels in a diabetic mice model displaying no toxicity on bone, kidney, and liver. To our knowledge, this is the first example of dual PPARα/γ partial agonist showing these combined effects representing, therefore, the potential lead of new drugs for treatment of dyslipidemic type 2 diabetes.
PubMed: 38865743
DOI: 10.1016/j.ejmech.2024.116567 -
Scientific Reports Jun 2024Diabetic corneal neuropathy (DCN) is a common diabetic ocular complication with limited treatment options. In this study, we investigated the effects of topical and oral...
Diabetic corneal neuropathy (DCN) is a common diabetic ocular complication with limited treatment options. In this study, we investigated the effects of topical and oral fenofibrate, a peroxisome proliferator-activated receptor-α agonist, on the amelioration of DCN using diabetic mice (n = 120). Ocular surface assessments, corneal nerve and cell imaging analysis, tear proteomics and its associated biological pathways, immuno-histochemistry and western blot on PPARα expression, were studied before and 12 weeks after treatment. At 12 weeks, PPARα expression markedly restored after topical and oral fenofibrate. Topical fenofibrate significantly improved corneal nerve fibre density (CNFD) and tortuosity coefficient. Likewise, oral fenofibrate significantly improved CNFD. Both topical and oral forms significantly improved corneal sensitivity. Additionally, topical and oral fenofibrate significantly alleviated diabetic keratopathy, with fenofibrate eye drops demonstrating earlier therapeutic effects. Both topical and oral fenofibrate significantly increased corneal β-III tubulin expression. Topical fenofibrate reduced neuroinflammation by significantly increasing the levels of nerve growth factor and substance P. It also significantly increased β-III-tubulin and reduced CDC42 mRNA expression in trigeminal ganglions. Proteomic analysis showed that neurotrophin signalling and anti-inflammation reactions were significantly up-regulated after fenofibrate treatment, whether applied topically or orally. This study concluded that both topical and oral fenofibrate ameliorate DCN, while topical fenofibrate significantly reduces neuroinflammation.
Topics: Animals; PPAR alpha; Mice; Fenofibrate; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Cornea; Male; Administration, Oral; Administration, Topical; Corneal Diseases; Mice, Inbred C57BL; Proteomics
PubMed: 38862650
DOI: 10.1038/s41598-024-64451-4 -
Biomedicine & Pharmacotherapy =... Jul 2024Non-alcoholic fatty liver disease (NAFLD), particularly advanced non-alcoholic steatohepatitis (NASH), leads to irreversible liver damage. This study investigated the...
Non-alcoholic fatty liver disease (NAFLD), particularly advanced non-alcoholic steatohepatitis (NASH), leads to irreversible liver damage. This study investigated the therapeutic effects and potential mechanism of a novel extract from traditional Chinese medicine Alisma orientale (Sam.) Juzep (AE) on free fatty acid (FFA)-induced HepG2 cell model and high-fat diet (HFD) + carbon tetrachloride (CCl)-induced mouse model of NASH. C57BL/6 J mice were fed a HFD for 10 weeks. Subsequently, the mice were injected with CCl to induce NASH and simultaneously treated with AE at daily doses of 50, 100, and 200 mg/kg for 4 weeks. At the end of the treatment, animals were fasted for 12 h and then sacrificed. Blood samples and liver tissues were collected for analysis. Lipid profiles, oxidative stress, and histopathology were examined. Additionally, a polymerase chain reaction (PCR) array was used to predict the molecular targets and potential mechanisms involved, which were further validated in vivo and in vitro. The results demonstrated that AE reversed liver damage (plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatocyte ballooning, hepatic steatosis, and NAS score), the accumulation of hepatic lipids (TG and TC), and oxidative stress (MDA and GSH). PCR array analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that AE protects against NASH by regulating the adipocytokine signaling pathway and influencing nuclear receptors such as PPARα. Furthermore, AE increased the expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PPARGC1α) and reversed the decreased expression of PPARα in NASH mice. Moreover, in HepG2 cells, AE reduced FFA-induced lipid accumulation and oxidative stress, which was dependent on PPARα up-regulation. Overall, our findings suggest that AE may serve as a potential therapeutic approach for NASH by inhibiting lipid accumulation and reducing oxidative stress specifically through the PPARα pathway.
Topics: Animals; Non-alcoholic Fatty Liver Disease; PPAR alpha; Mice, Inbred C57BL; Signal Transduction; Humans; Alisma; Male; Plant Extracts; Hep G2 Cells; Diet, High-Fat; Mice; Oxidative Stress; Liver; Disease Models, Animal; Carbon Tetrachloride; Lipid Metabolism
PubMed: 38850668
DOI: 10.1016/j.biopha.2024.116908 -
Naunyn-Schmiedeberg's Archives of... Jun 2024Originally sourced from plants, Bergenin has been used as a medicinal compound in traditional medicine for centuries, and anecdotal reports suggest a wide range of... (Review)
Review
Originally sourced from plants, Bergenin has been used as a medicinal compound in traditional medicine for centuries, and anecdotal reports suggest a wide range of therapeutic uses. Naturally-occurring and lab-synthesized Bergenin, as well as some of its related compounds, have been shown in in vivo and in vitro studies to alter activity of several enzymes and proteins critical in cellular functioning, including reelin, GSK-3β, Lingo-1, Ten-4, GP-43, Aβ 1-42, P-tau, SOD1,2, GPx, Glx1, NQO1, HO1, PPAR-ɣ, BDNF, VEGF, and STAT6. Additionally, Bergenin alters levels of several cytokines, such as IL-6, IL-1β, TNF-α, and TGF-β. Behavioral and cellular effects of Bergenin have been shown to involve PI3K/Akt, NF-κB, PKC, Nrf2, and Sirt1/FOXO3a pathways. These pathways, enzymes, and proteins have been shown to be important in normal neurological functioning, and/or dysfunctions in these pathways and proteins have been shown to be important in several neuro-based disorders or diseases, which suggests that Bergenin could be therapeutic in management of neuropsychiatric conditions or neurological disorders. In preclinical studies, Bergenin has been shown to be useful for the management of Alzheimer's disease, Parkinson's disease, anxiety, depression, addiction, epilepsy, insomnia, stroke, and potentially, state control. Our review aims to summarize current evidence supporting the conclusion that Bergenin could play a role in treating various neuro-based disorders and that future studies should be conducted to evaluate the mechanisms by which Bergenin could exert its therapeutic effects.
PubMed: 38850305
DOI: 10.1007/s00210-024-03197-2 -
Endocrine, Metabolic & Immune Disorders... 2024Nitrate, as nitric oxide (NO) donor, has been suggested as a nutrition-based treatment for decreasing the risk of menopause-related obesity. This study aimed to specify...
BACKGROUND AND OBJECTIVE
Nitrate, as nitric oxide (NO) donor, has been suggested as a nutrition-based treatment for decreasing the risk of menopause-related obesity. This study aimed to specify the effects of chronic inorganic nitrate administration on uncoupling protein-1 (UCP-1), peroxisome proliferator-activated-receptor-947; (PPAR-947;) coactivator-1945; (PGC-1945;), and PPAR-947; expression in gonadal adipose tissue (GAT) of ovariectomized (OVX) rats.
METHODS
Female rats were assigned to 3 groups: Control, OVX, and OVX+nitrate (n=7/group), which consumed water containing inorganic nitrate (100 mg/L) for 9 months. At month 9, GAT was used for the measurement of NO metabolites (NOx), mRNA levels of NO synthases (endothelial (eNOS), inducible (iNOS), neuronal (nNOS)), and mRNA and protein levels of UCP-1, PGC-1945;, and PPAR-947;.
RESULTS
OVX rats had lower NOx concentration (45%) and eNOS (38%) and nNOS (30%) expression in GAT that was restored to normal values following nitrate administration. OVX rats had significantly lower mRNA and protein levels of UCP-1 (83% and 30%), PGC-1945; (65% and 39%), and PPAR-947; (66% and 34.5%) in GAT. Chronic inorganic nitrate administration in OVXrats increased mRNA and protein levels of UCP-1 (128% and 34%), PGC-1945; (115% and 43%), and PPAR-947; (236% and 38%), respectively.
CONCLUSION
In OVX rats, chronic nitrate administration increased gene and protein levels of UCP-1, PGC-1945;, and PPAR-947; in GAT, indicating the anti-obesity effects of nitrate are partially mediated by the white adipose tissue (WAT) browning. Moreover, the stimulatory effect of inorganic nitrate on the WAT browning in OVX rats was associated with blunting the OVXinduced NO deficiency in GAT.
Topics: Animals; Female; Ovariectomy; Nitrates; Rats; Uncoupling Protein 1; Rats, Wistar; Adipose Tissue, Brown; Nitric Oxide; Gene Expression Regulation; Transcription Factors; Adipose Tissue; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
PubMed: 38847150
DOI: 10.2174/0118715303239481231030043730 -
Frontiers in Cellular Neuroscience 2024It is important to describe effective and non-toxic therapies for multiple sclerosis (MS), an autoimmune demyelinating disease. Experimental autoimmune encephalomyelitis...
It is important to describe effective and non-toxic therapies for multiple sclerosis (MS), an autoimmune demyelinating disease. Experimental autoimmune encephalomyelitis (EAE) is an immune-mediated inflammatory disease that serves as a model for MS. Earlier we and others have shown that, gemfibrozil, a lipid-lowering drug, exhibits therapeutic efficacy in EAE. However, the underlying mechanism was poorly understood. Although gemfibrozil is a known ligand of peroxisome proliferator-activated receptor α (PPARα), here, we established that oral administration of gemfibrozil preserved the integrity of blood-brain barrier (BBB) and blood-spinal cord barrier (BSB), decreased the infiltration of mononuclear cells into the CNS and inhibited the disease process of EAE in both wild type and PPARα mice. On the other hand, oral gemfibrozil was found ineffective in maintaining the integrity of BBB/BSB, suppressing inflammatory infiltration and reducing the disease process of EAE in mice lacking PPARβ (formerly PPARδ), indicating an important role of PPARβ/δ, but not PPARα, in gemfibrozil-mediated preservation of BBB/BSB and protection of EAE. Regulatory T cells (Tregs) play a critical role in the disease process of EAE/MS and we also demonstrated that oral gemfibrozil protected Tregs in WT and PPARα EAE mice, but not PPARβ EAE mice. Taken together, our findings suggest that gemfibrozil, a known ligand of PPARα, preserves the integrity of BBB/BSB, enriches Tregs, and inhibits the disease process of EAE via PPARβ, but not PPARα.
PubMed: 38835441
DOI: 10.3389/fncel.2024.1375531 -
Tissue Engineering. Part A Jun 2024Xenotransplantation of acellular adipose matrix (AAM) has come to prominence as an intriguing option for soft tissue reconstruction. However, the presence of immunogenic...
Xenotransplantation of acellular adipose matrix (AAM) has come to prominence as an intriguing option for soft tissue reconstruction. However, the presence of immunogenic antigens within AAM can trigger unfavorable immune reactions, leading to inadequate regeneration outcomes. Therefore, the development of advanced technology capable of modulating immune responses is crucial for the therapeutic implementation of AAM xenografts. In this work, an innovative technique is created to bypass the immune system by covering the surface of both AAM and Arg-Gly-Asp (RGD) peptide-modified AAM xenografts with autologous red blood cell (RBC) membrane. The RBC membrane coating remained persistent and exhibited no significant decline even after 21 days. Moreover, it effectively reduced the expression of antigen major histocompatibility complex class 1 (MHC1) on the AAM surface. Following xenogeneic transplantation, the RBC-coated xenografts demonstrated increased expression of the adipogenic factor , , , and and higher numbers of adipocytes. In addition, they exhibited decreased expression of immunological factors, including , , and , and fewer inflammatory cells. These findings indicate that RBC membrane coating successfully suppressed immune responses and promoted increased adipogenesis in AAM xenografts. Therefore, AAM camouflage coating with RBC has a lot of potential as a biomaterial for soft tissue reconstruction in clinical settings.
PubMed: 38832873
DOI: 10.1089/ten.TEA.2023.0354 -
Biomedicine & Pharmacotherapy =... Jul 2024Acute pancreatitis (APS) is a prevalent acute pancreatic inflammation, where oxidative stress, inflammatory signaling pathways, and apoptosis activation contribute to...
BACKGROUND
Acute pancreatitis (APS) is a prevalent acute pancreatic inflammation, where oxidative stress, inflammatory signaling pathways, and apoptosis activation contribute to pancreatic injury.
METHODS
Pinocembrin, the predominant flavonoid in propolis, was explored for its likely shielding effect against APS provoked by two intraperitoneal doses of L-arginine (250 mg / 100 g) in a rat model.
RESULTS
Pinocembrin ameliorated the histological and immunohistochemical changes in pancreatic tissues and lowered the activities of pancreatic amylase and lipase that were markedly elevated with L-arginine administration. Moreover, pinocembrin reinstated the oxidant/antioxidant equilibrium, which was perturbed by L-arginine, and boosted the pancreatic levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Pinocembrin markedly reduced the elevation in serum C-reactive protein (CRP) level induced by L-arginine. Additionally, it decreased the expression of high motility group box protein 1 (HMGB1), toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and NOD-like receptor (NLR) Family Pyrin Domain Containing 3 (NLRP3) inflammasome in the pancreas. Furthermore, it also reduced myeloperoxidase (MPO) activity. Pinocembrin markedly downregulated miR-34a-5p expression and upregulated the protein levels of peroxisome proliferator-activated receptor alpha (PPAR-α) and Sirtuin 1 (SIRT1) and the gene expression level of the inhibitor protein of NF-κB (IκB-α), along with normalizing the Bax/Bcl-2 ratio.
CONCLUSIONS
Pinocembrin notably improved L-arginine-induced APS by its antioxidant, anti-inflammatory, and anti-apoptotic activities. Pinocembrin exhibited a protective role in APS by suppressing inflammatory signaling via the TLR4/NF-κB/NLRP3 pathway and enhancing cytoprotective signaling via the miR-34a-5p/SIRT1/Nrf2/HO-1 pathway.
Topics: Animals; Pancreatitis; Sirtuin 1; NF-kappa B; Toll-Like Receptor 4; Male; NLR Family, Pyrin Domain-Containing 3 Protein; MicroRNAs; Flavanones; Signal Transduction; Rats; Disease Models, Animal; Heme Oxygenase (Decyclizing); NF-E2-Related Factor 2; Rats, Sprague-Dawley; Arginine; Acute Disease; Pancreas; Antioxidants; Oxidative Stress
PubMed: 38824834
DOI: 10.1016/j.biopha.2024.116854 -
Food Research International (Ottawa,... Jul 2024Solanum nigrum L. (SN) berry is an edible berry containing abundant polyphenols and bioactive compounds, which possess antioxidant and antiinflammatory properties....
Solanum nigrum L. (SN) berry is an edible berry containing abundant polyphenols and bioactive compounds, which possess antioxidant and antiinflammatory properties. However, the effects of SN on alcohol-induced biochemical changes in the enterohepatic axis remain unclear. In the current study, a chronic ethanol-fed mice ALD model was used to test the protective mechanisms of SN berries. Microbiota composition was determined via 16S rRNA sequencing, we found that SN berries extract (SNE) improved intestinal imbalance by reducing the Firmicutes to Bacteroides ratio, restoring the abundance of Akkermansia microbiota, and reducing the abundance of Allobaculum and Shigella. SNE restored the intestinal short-chain fatty acids content. In addition, liver transcriptome data analysis revealed that SNE primarily affected the genes involved in lipid metabolism and inflammatory responses. Furthermore, SNE ameliorated hepatic steatosis in alcohol-fed mice by activating AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), peroxisome proliferator-activated receptor α (PPAR-α). SNE reduced the expression of toll-like receptor 4 (TLR4), myeloid differentiation factor-88 (MyD88) nuclear factor kappa-B (NF-κB), which can indicate that SNE mainly adjusted LPS/TLR4/MyD88/NF-κB pathway to reduce liver inflammation. SNE enhanced hepatic antioxidant capacity by regulating NRF2-related protein expression. SNE alleviates alcoholic liver injury by regulating of gut microbiota, lipid metabolism, inflammation, and oxidative stress. This study may provide a reference for the development and utilization of SN resources.
Topics: Animals; Gastrointestinal Microbiome; Oxidative Stress; Lipid Metabolism; Plant Extracts; Mice; Fruit; Solanum nigrum; Male; Liver Diseases, Alcoholic; Mice, Inbred C57BL; Inflammation; Liver; Toll-Like Receptor 4; Disease Models, Animal; PPAR alpha; Antioxidants; Ethanol
PubMed: 38823872
DOI: 10.1016/j.foodres.2024.114489 -
Life Sciences Aug 2024The intricate molecular mechanisms underlying estrogen receptor-positive (ER) breast carcinogenesis and resistance to endocrine therapy remain elusive. In this study, we...
AIMS
The intricate molecular mechanisms underlying estrogen receptor-positive (ER) breast carcinogenesis and resistance to endocrine therapy remain elusive. In this study, we elucidate the pivotal role of GPR81, a G protein-coupled receptor, in ER breast cancer (BC) by demonstrating low expression of GPR81 in tamoxifen (TAM)-resistant ER BC cell lines and tumor samples, along with the underlying molecular mechanisms.
MAIN METHODS
Fatty acid oxidation (FAO) levels and lipid accumulation were explored using MDA and FAβO assay, BODIPY 493/503 staining, and Lipid TOX staining. Autophagy levels were assayed using CYTO-ID detection and Western blotting. The impact of GPR81 on TAM resistance in BC was investigated through CCK8 assay, colony formation assay and a xenograft mice model.
RESULTS
Aberrantly low GPR81 expression in TAM-resistant BC cells disrupts the Rap1 pathway, leading to the upregulation of PPARα and CPT1. This elevation in PPARα/CPT1 enhances FAO, impedes lipid accumulation and lipid droplet (LD) formation, and subsequently inhibits cell autophagy, ultimately promoting TAM-resistant BC cell growth. Moreover, targeting GPR81 and FAO emerges as a promising therapeutic strategy, as the GPR81 agonist and the CPT1 inhibitor etomoxir effectively inhibit ER BC cell and tumor growth in vivo, re-sensitizing TAM-resistant ER cells to TAM treatment.
CONCLUSION
Our data highlight the critical and functionally significant role of GPR81 in promoting ER breast tumorigenesis and resistance to endocrine therapy. GPR81 and FAO levels show potential as diagnostic biomarkers and therapeutic targets in clinical settings for TAM-resistant ER BC.
Topics: Tamoxifen; Humans; Breast Neoplasms; Female; Receptors, G-Protein-Coupled; Animals; Drug Resistance, Neoplasm; Fatty Acids; Mice; PPAR alpha; Oxidation-Reduction; Mice, Nude; Antineoplastic Agents, Hormonal; Cell Line, Tumor; Xenograft Model Antitumor Assays; Autophagy; Mice, Inbred BALB C
PubMed: 38823505
DOI: 10.1016/j.lfs.2024.122763