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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 -
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 -
Biomedicine & Pharmacotherapy =... May 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.
PubMed: 38824834
DOI: 10.1016/j.biopha.2024.116854 -
Biomedicine & Pharmacotherapy =... May 2024Hyperglycemic stress can directly lead to neuronal damage. The mechanosensitive ion channel PIEZO1 can be activated in response to hyperglycemia, but its role in...
Hyperglycemic stress can directly lead to neuronal damage. The mechanosensitive ion channel PIEZO1 can be activated in response to hyperglycemia, but its role in hyperglycemic neurotoxicity is unclear. The role of PIEZO1 in hyperglycemic neurotoxicity was explored by constructing a hyperglycemic mouse model and a high-glucose HT22 cell model. The results showed that PIEZO1 was significantly upregulated in response to high glucose stress. In vitro experiments have shown that high glucose stress induces changes in neuronal cell morphology and membrane tension, a key mechanism for PIEZO1 activation. In addition, high glucose stress upregulates serum/glucocorticoid-regulated kinase-1 (SGK1) and activates PIEZO1 through the Ca pool and store-operated calcium entry (SOCE). PIEZO1-mediated Ca influx further enhances SGK1 and SOCE, inducing intracellular Ca peaks in neurons. PIEZO1 mediated intracellular Ca elevation leads to calcium/calmodulin-dependent protein kinase 2α (CaMK2α) overactivation, which promotes oxidative stress and apoptosis signalling through p-CaMK2α/ERK/CREB and ox-CaMK2α/MAPK p38/NFκB p65 pathways, subsequently inducing synaptic damage and cognitive impairment in mice. The intron miR-107 of pantothenic kinase 1 (PANK1) is highly expressed in the brain and has been found to target PIEZO1 and SGK1. The PANK1 receptor is activated by peroxisome proliferator-activated receptor α (PPARα), an activator known to upregulate miR-107 levels in the brain. The clinically used lipid-lowering drug bezafibrate, a known PPARα activator, may upregulate miR-107 through the PPARɑ/PANK1 pathway, thereby inhibiting PIEZO1 and improving hyperglycemia-induced neuronal cell damage. This study provides a new idea for the pathogenesis and drug treatment of hyperglycemic neurotoxicity and diabetes-related cognitive dysfunction.
PubMed: 38815290
DOI: 10.1016/j.biopha.2024.116837 -
Animal Nutrition (Zhongguo Xu Mu Shou... Jun 2024The intake of high-fat diets (HFD) has been shown to diminish the muscle quality of aquatic animals. Sanguinarine, as an excellent additive, exhibits the capability to...
The intake of high-fat diets (HFD) has been shown to diminish the muscle quality of aquatic animals. Sanguinarine, as an excellent additive, exhibits the capability to reduce fat deposition and alleviate inflammation. However, its role in the muscle quality reduction caused by HFD remains unclear. An eight-week trial was conducted to investigate the impacts of dietary supplementation of sanguinarine at 1200 μg/kg (HFDS; crude fat = 10%) on the muscle quality of grass carp () in comparison to a basic diet (CON, crude fat = 5%). Each group had 3 replicates, with 40 fish per replicate. This experiment employed one-way ANOVA and Duncan's multiple comparisons of the means. The results showed that the HFD exhibited lower growth performance, reduced protein deposition, myofiber diameter, and muscle hardness, coupled with higher levels of fat deposition and inflammation when compared with the CON. However, HFDS improved growth performance ( < 0.05), fat metabolism ( ( = 0.001), ( 0.001, ( < 0.001), and ( = 0.001) expression exhibited a significant elevation), protein deposition (the protein and mRNA levels of AKT ( = 0.004), PI3K ( = 0.027), TOR ( = 0.005), and P70S6K ( = 0.007) demonstrated a marked increase), myofiber diameter, muscle hardness, and the total content of eicosapentaenoic acid and docosahexaenoic acid. Furthermore, the HFDS reduced oxidative damage caused by fat deposition by significantly downregulating ( < 0.001), ( < 0.001), ( < 0.001), ( = 0.003), and ( < 0.001) expression and markedly upregulated ( < 0.001), ( < 0.001), ( < 0.001), ( < 0.001), and ( = 0.003) expression. The findings from this study suggest that sanguinarine has the potential to alleviate the adverse effects of HFD on growth and muscle quality, providing a theoretical foundation for its practical implementation.
PubMed: 38800733
DOI: 10.1016/j.aninu.2024.04.001 -
Nutrients May 2024Metabolic syndrome is a global health problem. The use of functional foods as dietary components has been increasing. One food of interest is forest onion extract (FOE)....
Novel Functional Food Properties of Forest Onion ( Merr.) Phytochemicals for Treating Metabolic Syndrome: New Insights from a Combined Computational and In Vitro Approach.
Metabolic syndrome is a global health problem. The use of functional foods as dietary components has been increasing. One food of interest is forest onion extract (FOE). This study aimed to investigate the effect of FOE on lipid and glucose metabolism in silico and in vitro using the 3T3-L1 mouse cell line. This was a comprehensive study that used a multi-modal computational network pharmacology analysis and molecular docking in silico and 3T3-L1 mouse cells in vitro. The phytochemical components of FOE were analyzed using untargeted ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS). Next, an in silico analysis was performed to determine FOE's bioactive compounds, and a toxicity analysis, protein target identification, network pharmacology, and molecular docking were carried out. FOE's effect on pancreatic lipase, α-glucosidase, and α-amylase inhibition was determined. Finally, we determined its effect on lipid accumulation and MAPK8, PPARG, HMGCR, CPT-1, and GLP1 expression in the preadipocyte 3T3-L1 mouse cell line. We showed that the potential metabolites targeted glucose and lipid metabolism in silico and that FOE inhibited pancreatic lipase levels, α-glucosidase, and α-amylase in vitro. Furthermore, FOE significantly ( < 0.05) inhibits targeted protein expressions of MAPK8, PPARG, HMGCR, CPT-1, and GLP-1 in vitro in 3T3-L1 mouse cells in a dose-dependent manner. FOE contains several metabolites that reduce pancreatic lipase levels, α-glucosidase, α-amylase, and targeted proteins associated with lipid and glucose metabolism in vitro.
Topics: Animals; Mice; Metabolic Syndrome; Onions; 3T3-L1 Cells; Phytochemicals; Plant Extracts; Molecular Docking Simulation; Lipid Metabolism; Functional Food; Lipase; alpha-Amylases; Glucose; Network Pharmacology; PPAR gamma; Tandem Mass Spectrometry; alpha-Glucosidases; Computer Simulation
PubMed: 38794679
DOI: 10.3390/nu16101441 -
International Journal of Molecular... May 2024Microglia are key players in the brain's innate immune response, contributing to homeostatic and reparative functions but also to inflammatory and underlying mechanisms... (Review)
Review
Microglia are key players in the brain's innate immune response, contributing to homeostatic and reparative functions but also to inflammatory and underlying mechanisms of neurodegeneration. Targeting microglia and modulating their function may have therapeutic potential for mitigating neuroinflammation and neurodegeneration. The anti-inflammatory properties of essential oils suggest that some of their components may be useful in regulating microglial function and microglial-associated neuroinflammation. This study, starting from the ethnopharmacological premises of the therapeutic benefits of aromatic plants, assessed the evidence for the essential oil modulation of microglia, investigating their potential pharmacological mechanisms. Current knowledge of the phytoconstituents, safety of essential oil components, and anti-inflammatory and potential neuroprotective effects were reviewed. This review encompasses essential oils of spp., spp., , , spp., and others as well as some of their components including 1,8-cineole, -caryophyllene, -patchoulene, carvacrol, -ionone, eugenol, geraniol, menthol, linalool, thymol, -asarone, and -thujone. Essential oils that target PPAR/PI3K-Akt/MAPK signalling pathways could supplement other approaches to modulate microglial-associated inflammation to treat neurodegenerative diseases, particularly in cases where reactive microglia play a part in the pathophysiological mechanisms underlying neurodegeneration.
Topics: Oils, Volatile; Microglia; Neuroprotective Agents; Humans; Anti-Inflammatory Agents; Animals
PubMed: 38791205
DOI: 10.3390/ijms25105168 -
Scientific Reports May 2024The E3 ubiquitin-ligase UHRF1 is an epigenetic regulator coordinating DNA methylation and histone modifications. However, little is known about how it regulates...
The E3 ubiquitin-ligase UHRF1 is an epigenetic regulator coordinating DNA methylation and histone modifications. However, little is known about how it regulates adipogenesis or metabolism. In this study, we discovered that UHRF1 is a key regulatory factor for adipogenesis, and we identified the altered molecular pathways that UHRF1 targets. Using CRISPR/Cas9-based knockout strategies, we discovered the whole transcriptomic changes upon UHRF1 deletion. Bioinformatics analyses revealed that key adipogenesis regulators such PPAR-γ and C/EBP-α were suppressed, whereas TGF-β signaling and fibrosis markers were upregulated in UHRF1-depleted differentiating adipocytes. Furthermore, UHRF1-depleted cells showed upregulated expression and secretion of TGF-β1, as well as the glycoprotein GPNMB. Treating differentiating preadipocytes with recombinant GPNMB led to an increase in TGF-β protein and secretion levels, which was accompanied by an increase in secretion of fibrosis markers such as MMP13 and a reduction in adipogenic conversion potential. Conversely, UHRF1 overexpression studies in human cells demonstrated downregulated levels of GPNMB and TGF-β, and enhanced adipogenic potential. In conclusion, our data show that UHRF1 positively regulates 3T3-L1 adipogenesis and limits fibrosis by suppressing GPNMB and TGF-β signaling cascade, highlighting the potential relevance of UHRF1 and its targets to the clinical management of obesity and linked metabolic disorders.
Topics: Animals; Humans; Mice; 3T3-L1 Cells; Adipocytes; Adipogenesis; CCAAT-Enhancer-Binding Proteins; Cell Differentiation; Eye Proteins; Fibrosis; Membrane Glycoproteins; Signal Transduction; Transforming Growth Factor beta; Ubiquitin-Protein Ligases
PubMed: 38789534
DOI: 10.1038/s41598-024-62508-y -
Cells May 2024Peroxisome proliferator-activated receptor alpha (PPARA) is a ligand-activated transcription factor that is a key mediator of lipid metabolism and metabolic stress in...
Peroxisome proliferator-activated receptor alpha (PPARA) is a ligand-activated transcription factor that is a key mediator of lipid metabolism and metabolic stress in the liver. Accumulating evidence shows that PPARA regulates the expression of various protein coding and non-coding genes that modulate metabolic stress in the liver. CBFA2/RUNX1 partner transcriptional co-repressor 3 (CBFA2T3) is a DNA-binding transcription factor that belongs to the myeloid translocation gene family. Many studies have shown that CBFA2T3 is associated with acute myeloid leukemia. Especially, CBFA2T3-GLIS2 fusion is a chimeric oncogene associated with a poor survival rate in pediatric acute megakaryocytic leukemia. A previous study identified that PPARA activation promoted induction in liver and that may have a modulatory role in metabolic stress. However, the effect of CBFA2T3 gene expression on metabolic stress is not understood. In this study, the PPARA ligand WY14643 activated expression in mouse liver. Glucose tolerance test and insulin tolerance test data showed that insulin resistance is increased in mice compared to mice. Hepatic CBFA2T3 modulates heat shock protein family A member 1b and carbonic anhydrase 5a expression. Histology analysis revealed lipid droplet and lipid accumulation in the liver of fasting mice but not mice. The expression of lipid accumulation-related genes, such as , , and , was increased in the liver of fasting mice. Especially, basal expression levels of mRNA were elevated in the liver of mice compared to mice. Much higher induction of mRNA was seen in the liver of mice after WY14643 administration. These results indicate that hepatic CBFA2T3 is a PPARA-sensitive gene that may modulate metabolic stress in mouse liver.
Topics: Animals; Lipid Metabolism; Liver; Mice; Fasting; PPAR alpha; Male; Mice, Inbred C57BL; Insulin Resistance; Mice, Knockout; Pyrimidines
PubMed: 38786053
DOI: 10.3390/cells13100831 -
PloS One 2024Cofactors interacting with PPARγ can regulate adipogenesis and adipocyte metabolism by modulating the transcriptional activity and selectivity of PPARγ signaling....
Cofactors interacting with PPARγ can regulate adipogenesis and adipocyte metabolism by modulating the transcriptional activity and selectivity of PPARγ signaling. ZFP407 was previously demonstrated to regulate PPARγ target genes such as GLUT4, and its overexpression improved glucose homeostasis in mice. Here, using a series of molecular assays, including protein-interaction studies, mutagenesis, and ChIP-seq, ZFP407 was found to interact with the PPARγ/RXRα protein complex in the nucleus of adipocytes. Consistent with this observation, ZFP407 ChIP-seq peaks significantly overlapped with PPARγ ChIP-seq peaks, with more than half of ZFP407 peaks overlapping with PPARγ peaks. Transcription factor binding motifs enriched in these overlapping sites included CTCF, RARα/RXRγ, TP73, and ELK1, which regulate cellular development and function within adipocytes. Site-directed mutagenesis of frequent PPARγ phosphorylation or SUMOylation sites did not prevent its regulation by ZFP407, while mutagenesis of ZFP407 domains potentially necessary for RXR and PPARγ binding abrogated any impact of ZFP407 on PPARγ activity. These data suggest that ZFP407 controls the activity of PPARγ, but does so independently of post-translational modifications, likely by direct binding, establishing ZFP407 as a newly identified PPARγ cofactor. In addition, ZFP407 ChIP-seq analyses identified regions that did not overlap with PPARγ peaks. These non-overlapping peaks were significantly enriched for the transcription factor binding motifs of TBX19, PAX8, HSF4, and ZKSCAN3, which may contribute to the PPARγ-independent functions of ZFP407 in adipocytes and other cell types.
Topics: Animals; Humans; Mice; 3T3-L1 Cells; Adipocytes; Binding Sites; DNA-Binding Proteins; Phosphorylation; PPAR gamma; Protein Binding; Retinoid X Receptor alpha; Signal Transduction; Sumoylation; Transcription Factors
PubMed: 38781157
DOI: 10.1371/journal.pone.0294003