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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 -
Current Diabetes Reviews May 2024The link between Type 2 Diabetes (T2DM) and Parkinson's Disease (PD) dates back to the early 1960s, and ongoing research is exploring this association. PD is linked to...
The link between Type 2 Diabetes (T2DM) and Parkinson's Disease (PD) dates back to the early 1960s, and ongoing research is exploring this association. PD is linked to dysregulation of dopaminergic pathways, neuroinflammation, decreased PPAR-γ coactivator 1-α, increased phosphoprotein enriched in diabetes, and accelerated α-Syn amyloid fibril production caused by T2DM. This study aims to comprehensively evaluate the T2DM-PD association and risk factors for PD in T2DM individuals. The study reviews existing literature using reputable sources like Scopus, ScienceDirect, and PubMed, revealing a significant association between T2DM and worsened PD symptoms. Genetic profiles of T2DM-PD individuals show similarities, and potential risk factors include insulin-resistance and dysbiosis of the gut-brain microbiome. Anti-diabetic drugs exhibit neuroprotective effects in PD, and nanoscale delivery systems like exosomes, micelles, and liposomes show promise in enhancing drug efficacy by crossing the Blood-Brain Barrier (BBB). Brain targeting for PD uses exosomes, micelles, liposomes, dendrimers, solid lipid nanoparticles, nano-sized polymers, and niosomes to improve medication and gene therapy efficacy. Surface modification of nanocarriers with bioactive compounds (such as angiopep, lactoferrin, and OX26) enhances α-Syn conjugation and BBB permeability. Natural exosomes, though limited, hold potential for investigating DM-PD pathways in clinical research. The study delves into the underlying mechanisms of T2DM and PD and explores current therapeutic approaches in the field of nano-based targeted drug delivery. Emphasis is placed on resolved and ongoing issues in understanding and managing both conditions.
PubMed: 38747222
DOI: 10.2174/0115733998291968240429111357 -
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 -
Neuropharmacology Aug 2024Neuropathic pain (NP) is usually treated with analgesics and symptomatic therapy with poor efficacy and numerous side effects, highlighting the urgent need for effective...
Neuropathic pain (NP) is usually treated with analgesics and symptomatic therapy with poor efficacy and numerous side effects, highlighting the urgent need for effective treatment strategies. Recent studies have reported an important role for peroxisome proliferator-activated receptor alpha (PPARα) in regulating metabolism as well as inflammatory responses. Through pain behavioral assessment, we found that activation of PPARα prevented chronic constriction injury (CCI)-induced mechanical allodynia and thermal hyperalgesia. In addition, PPARα ameliorated inflammatory cell infiltration at the injury site and decreased microglial activation, NOD-like receptor protein 3 (NLRP3) inflammasome production, and spinal dendritic spine density, as well as improved serum and spinal cord metabolic levels in mice. Administration of PPARα antagonists eliminates the analgesic effect of PPARα agonists. PPARα relieves NP by inhibiting neuroinflammation and functional synaptic plasticity as well as modulating metabolic mechanisms, suggesting that PPARα may be a potential molecular target for NP alleviation. However, the effects of PPARα on neuroinflammation and synaptic plasticity should be further explored.
Topics: Animals; PPAR alpha; Neuralgia; Male; Mice; Spinal Cord; Mice, Inbred C57BL; Hyperalgesia; Metabolomics; Microglia; NLR Family, Pyrin Domain-Containing 3 Protein; Neuroinflammatory Diseases; Dendritic Spines; Inflammasomes
PubMed: 38744401
DOI: 10.1016/j.neuropharm.2024.109988 -
Pakistan Journal of Pharmaceutical... Jan 2024Vanadyl sulfate (VS), is a component of some food supplements and experimental drugs. This study was carried out to present a novel method for induction of Type 2...
Vanadyl sulfate (VS), is a component of some food supplements and experimental drugs. This study was carried out to present a novel method for induction of Type 2 diabetes in rats, then for the first time in literature, for evaluating the effect of VS on metabolic parameters and gene expression, simultaneously. 40 male wistar rats were distributed between the four groups, equally. High fat diet and fructose were used for diabetes induction. Diabetic rats treated by two different dose of VS for 12 weeks. Metabolic profiles were evaluated by commercial available kits and gene expression were assayed by real time-PCR. Compared to controls, in non-treated diabetic rats, weight, glucose, triglyceride, total cholesterol, insulin and insulin resistance were increased significantly (p-value <0.05) that indicated induction of type 2 diabetes. Further, the results showed that VS significantly reduced weight, insulin secretion, Tumor Necrosis Factor-alpha (TNF-α) genes expression, lipid profiles except HDL that we couldn't find any significant change and increased Peroxisome Proliferator-Activated Receptor- gamma (PPAR-γ) gene expression in VS-treated diabetic animals in comparison with the non-treated diabetics. Our study demonstrated that vanadyl supplementation in diabetic rats had advantageous effects on metabolic profiles and related gene expression.
Topics: Animals; Male; Rats, Wistar; Tumor Necrosis Factor-alpha; PPAR gamma; Diabetes Mellitus, Type 2; Diabetes Mellitus, Experimental; Blood Glucose; Vanadium Compounds; Insulin Resistance; Rats; Insulin; Hypoglycemic Agents; Diet, High-Fat; Gene Expression Regulation
PubMed: 38741403
DOI: No ID Found -
Food & Function Jun 2024The structural characteristics of fucoidans exhibit species and regional diversity. Previous studies have demonstrated that - and -derived fucoidans have type I and type... (Comparative Study)
Comparative Study
The structural characteristics of fucoidans exhibit species and regional diversity. Previous studies have demonstrated that - and -derived fucoidans have type I and type II fucosyl chains, respectively. These chemical differences may contribute to distinct hypolipidemic effects and mechanisms of action. Chemical analysis demonstrated that the percentage contents of sulfate, glucuronic acid, and galactose were higher in -derived fucoidans than those of -derived fucoidans. In hyperlipidemic apolipoprotein E-deficient mice, both - and -derived fucoidans significantly decreased the plasma and hepatic levels of total cholesterol and triglyceride, leading to the reduction of atherosclerotic plaques. Western blotting experiments demonstrated that these fucoidans significantly enhanced the expression and levels of scavenger receptor B type 1, cholesterol 7 alpha-hydroxylase A1, and peroxisome proliferator-activated receptor (PPAR)-α, contributing to circulating lipoprotein clearance and fatty acid degradation, respectively. Differentially, -derived fucoidan significantly increased the LXR/ATP-binding cassette G8 signaling pathway in the small intestine, as revealed by real-time quantitative PCR, which may lead to further cholesterol and other lipid excretion. Collectively, these data are useful for understanding the hypolipidemic mechanisms of action of seaweed-derived fucoidans, and their potential application for the prevention and/or treatment of atherosclerotic cardiovascular diseases.
Topics: Animals; Laminaria; Ascophyllum; Mice; Polysaccharides; Hypolipidemic Agents; Apolipoproteins E; Male; Mice, Inbred C57BL; Triglycerides; Cholesterol; Mice, Knockout; PPAR alpha; Hyperlipidemias; Plant Extracts; Liver; Humans; Edible Seaweeds
PubMed: 38738998
DOI: 10.1039/d3fo05521c -
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 -
Toxicology Letters Jun 2024The activation of pregnane X receptor (PXR) or peroxisome proliferator-activated receptor α (PPARα) can induce liver enlargement. Recently, we reported that PXR or...
The activation of pregnane X receptor (PXR) or peroxisome proliferator-activated receptor α (PPARα) can induce liver enlargement. Recently, we reported that PXR or PPARα activation-induced hepatomegaly depends on yes-associated protein (YAP) signaling and is characterized by hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. However, it remains unclear whether PXR or PPARα activation-induced hepatomegaly can be reversed after the withdrawal of their agonists. In this study, we investigated the regression of enlarged liver to normal size following the withdrawal of PCN or WY-14643 (typical agonists of mouse PXR or PPARα) in C57BL/6 mice. The immunohistochemistry analysis of CTNNB1 and KI67 showed a reversal of hepatocyte size and a decrease in hepatocyte proliferation after the withdrawal of agonists. In details, the expression of PXR or PPARα downstream proteins (CYP3A11, CYP2B10, ACOX1, and CYP4A) and the expression of proliferation-related proteins (CCNA1, CCND1, and PCNA) returned to the normal levels. Furthermore, YAP and its downstream proteins (CTGF, CYR61, and ANKRD1) also restored to the normal states, which was consistent with the change in liver size. These findings demonstrate the reversibility of PXR or PPARα activation-induced hepatomegaly and provide new data for the safety of PXR and PPARα as drug targets.
Topics: Animals; PPAR alpha; Hepatomegaly; Pregnane X Receptor; YAP-Signaling Proteins; Mice, Inbred C57BL; Pyrimidines; Hepatocytes; Male; Liver; Cell Proliferation; beta Catenin; Signal Transduction; Adaptor Proteins, Signal Transducing; Cell Cycle Proteins; Cytochrome P-450 CYP4A; Cytochrome P450 Family 4; Mice; Phosphoproteins; Ki-67 Antigen; Membrane Proteins; Steroid Hydroxylases; Cytochrome P450 Family 2; Cytochrome P-450 CYP3A; Aryl Hydrocarbon Hydroxylases
PubMed: 38734220
DOI: 10.1016/j.toxlet.2024.05.006 -
Translational Research : the Journal of... Sep 2024Peptide drug discovery for the treatment of chronic kidney disease (CKD) has attracted much attention in recent years due to the urge to find novel drugs and mechanisms...
Peptide drug discovery for the treatment of chronic kidney disease (CKD) has attracted much attention in recent years due to the urge to find novel drugs and mechanisms to delay the progression of the disease. In this study, we identified a novel short peptide (named YR-7, primary sequence 'YEVEDYR') from the natural Fibroin protein, and demonstrated that it significantly alleviated pathological renal changes in ADR-induced nephropathy. PANX1 was identified as the most notably upregulated component by RNA-sequencing. Further analysis showed that YR-7 alleviated the accumulation of lipid droplets via regulation of the lipid metabolism-related proteins PPAR α and PANK1. Using chemical proteomics, fluorescence polarization, microscale thermophoresis, surface plasmon resonance, and molecular docking, YR-7 was proven to directly bind to β-barrel domains of TGM2 protein to inhibit lipid accumulation. TGM2 knockdown in vivo increased the protein levels of PPAR α and PANK1 while decreased the levels of fibrotic-related proteins to alleviate nephropathy. In vitro, overexpression TGM2 reversed the protective effects of YR-7. Co-immunoprecipitation indicated that TGM2 interacted with PANX1 to promote lipid deposition, and pharmacological inhibition or knockdown of PANX1 decreased the levels of PPAR α and PANK1 induced by ADR. Taken together, our findings revealed that TGM2-PANX1 interaction in promoting lipid deposition may be a new signaling in promoting ADR-induced nephropathy. And a novel natural peptide could ameliorate renal fibrosis through TGM2-PANX1-PPAR α/PANK1 pathway, which highlight the potential of it in the treatment of CKD.
Topics: Animals; PPAR alpha; Protein Glutamine gamma Glutamyltransferase 2; Lipid Metabolism; Male; Doxorubicin; Fibroins; Signal Transduction; Kidney Diseases; Peptides; Rats; Nerve Tissue Proteins; Rats, Sprague-Dawley
PubMed: 38734063
DOI: 10.1016/j.trsl.2024.05.006