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Phytomedicine : International Journal... Jul 2024Metabolic and alcohol-associated liver disease (MetALD) shows a high prevalence rate in liver patients, but there is currently no effective treatment for MetALD. As a...
BACKGROUND
Metabolic and alcohol-associated liver disease (MetALD) shows a high prevalence rate in liver patients, but there is currently no effective treatment for MetALD. As a typical edible traditional Chinese medicinal herb, the anti-inflammatory, antioxidant, and hepatoprotective properties of water extract of Chrysanthemum morifolium Ramat. (WECM) has been demonstrated. However, its therapeutic effect on MetALD and the associated mechanisms remain unclear.
PURPOSE
To investigate the underlying mechanisms of WECM against MetALD.
METHODS
We constructed a MetALD rat model following a high-fat & high-sucrose plus alcohol diet (HFHSAD). MetALD rats were treated with WECM at 2.1, 4.2, and 8.4 g/kg/d for six weeks. Efficacy was determined, and pathways associated with WECM against MetALD were predicted through serum and hepatic biochemical marker measurement, histopathological section analysis, 16S rDNA sequencing of the gut microbiota and untargeted serum metabolomics analyses. Changes in genes and proteins in the peroxisome proliferator-activated receptor alpha (PPARα) and gamma (PPARγ) signaling pathways were detected by RT‒PCR and Western blotting.
RESULTS
WECM treatment significantly attenuated hepatic steatosis, hyperlipidemia and markers of liver injury in MetALD rats. Moreover, WECM improved vascular endothelial function, hypertension, and systematic oxidative stress. Mechanistically, WECM treatment altered the overall structure of the gut microbiota through maintaining Firmicutes/Bacteroidota ratio and reducing harmful bacterial abundances such as Clostridium, Faecalibaculum, and Herminiimonas. Notably, WECM promoted 15-deoxy-△-prostaglandin J2 (15d-PGJ2) release and further activated the PPARγ to reduce serum TNF-α, IL-1β, and IL-6 levels. Additionally, WECM upregulated PPARα and downregulated the levels of CD36 and FABP4 to improve lipid metabolism.
CONCLUSION
Our findings provide the first evidence that WECM treatment significantly improved hepatic steatosis, oxidative stress and inflammation in MetALD rats by regulating the gut microbiota and activating the 15d-PGJ2/PPARγ and PPARα signaling pathway.
Topics: Chrysanthemum; Animals; Gastrointestinal Microbiome; PPAR gamma; PPAR alpha; Male; Liver Diseases, Alcoholic; Rats, Sprague-Dawley; Diet, High-Fat; Rats; Liver; Plant Extracts; Disease Models, Animal; Signal Transduction; Drugs, Chinese Herbal; Oxidative Stress
PubMed: 38820659
DOI: 10.1016/j.phymed.2024.155774 -
Loss of NAT10 alleviates maternal high-fat diet-induced hepatic steatosis in male offspring of mice.Obesity (Silver Spring, Md.) Jul 2024Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming an escalating health problem in pediatric populations. This study aimed to investigate the...
OBJECTIVE
Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming an escalating health problem in pediatric populations. This study aimed to investigate the role of N-acetyltransferase 10 (NAT10) in maternal high-fat diet (HFD)-induced MASLD in offspring at early life.
METHODS
We generated male hepatocyte-specific NAT10 knockout (Nat10) mice and mated them with female Nat10 mice under chow or HFD feeding. Body weight, liver histopathology, and expression of lipid metabolism-associated genes (Srebp1c, Fasn, Pparα, Cd36, Fatp2, Mttp, and Apob) were assessed in male offspring at weaning. Lipid uptake assays were performed both in vivo and in vitro. The mRNA stability assessment and RNA immunoprecipitation were performed to determine NAT10-regulated target genes.
RESULTS
NAT10 deletion in hepatocytes of male offspring alleviated perinatal lipid accumulation induced by maternal HFD, decreasing expression levels of Srebp1c, Fasn, Cd36, Fatp2, Mttp, and Apob while enhancing Pparα expression. Furthermore, Nat10 male mice exhibited reduced lipid uptake. In vitro, NAT10 promoted lipid uptake by enhancing the mRNA stability of CD36 and FATP2. RNA immunoprecipitation assays exhibited direct interactions between NAT10 and CD36/FATP2 mRNA.
CONCLUSIONS
NAT10 deletion in offspring hepatocytes ameliorates maternal HFD-induced hepatic steatosis through decreasing mRNA stability of CD36 and FATP2, highlighting NAT10 as a potential therapeutic target for pediatric MASLD.
Topics: Animals; Diet, High-Fat; Male; Female; Mice; Mice, Knockout; Lipid Metabolism; Pregnancy; Liver; Hepatocytes; Fatty Liver; Acetyltransferases; CD36 Antigens; Sterol Regulatory Element Binding Protein 1; Prenatal Exposure Delayed Effects; PPAR alpha; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease
PubMed: 38816990
DOI: 10.1002/oby.24041 -
International Immunopharmacology Jul 2024Chlorpyrifos (CPF) is a widely used organophosphate insecticide in agriculture and homes. Exposure to organophosphates is associated with neurotoxicity. Fluoxetine (FLX)...
Chlorpyrifos (CPF) is a widely used organophosphate insecticide in agriculture and homes. Exposure to organophosphates is associated with neurotoxicity. Fluoxetine (FLX) is a selective serotonin reuptake inhibitor (SSRI) that is widely prescribed for depression and anxiety disorders. Studies have shown that FLX has neuroprotective, anti-inflammatory, antioxidant, and antiapoptotic effects. The molecular mechanisms underlying FLX are not fully understood. This work aimed to investigate the potential neuroprotective effect of FLX on CPF-induced neurotoxicity and the underlying molecular mechanisms involved. Thirty-two rats were randomly divided into four groups: (I) the vehicle control group; (II) the FLX-treated group (10 mg/kg/day for 28 days, p.o); (III) the CPF-treated group (10 mg/kg for 28 days); and (IV) the FLX+CPF group. FLX attenuated CPF-induced neuronal injury, as evidenced by a significant decrease in Aβ and p-Tau levels and attenuation of cerebral and hippocampal histological abrasion injury induced by CPF. FLX ameliorated neuronal oxidative stress, effectively reduced MDA production, and restored SOD and GSH levels through the coactivation of the PPARγ and SIRT1 proteins. FLX counteracted the neuronal inflammation induced by CPF by decreasing MPO, NO, TNF-α, IL-1β, and IL-6 levels by suppressing NF-κB and JAK1/STAT3 activation. The antioxidant and anti-inflammatory properties of FLX help to prevent CPF-induced neuronal intoxication.
Topics: Animals; STAT3 Transcription Factor; Sirtuin 1; NF-kappa B; PPAR gamma; Janus Kinase 1; Male; Fluoxetine; Signal Transduction; Chlorpyrifos; Rats; Neuroprotective Agents; Neurons; Oxidative Stress; Insecticides; Anti-Inflammatory Agents; Rats, Sprague-Dawley; Hippocampus; Neurotoxicity Syndromes
PubMed: 38815349
DOI: 10.1016/j.intimp.2024.112335 -
Biomedicine & Pharmacotherapy =... Jul 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.
Topics: Animals; Ion Channels; Mice; Hyperglycemia; Male; Bezafibrate; Neurons; Protein Serine-Threonine Kinases; Mice, Inbred C57BL; Oxidative Stress; Calcium; Cell Line; Immediate-Early Proteins; MicroRNAs; Glucose; Apoptosis; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Disease Models, Animal; Signal Transduction; Up-Regulation
PubMed: 38815290
DOI: 10.1016/j.biopha.2024.116837 -
Archiv Der Pharmazie May 2024A series of benzoxazole-based amides and sulfonamides were synthesized and evaluated for their human peroxisome proliferator-activated receptor (PPAR)α and PPARγ...
A series of benzoxazole-based amides and sulfonamides were synthesized and evaluated for their human peroxisome proliferator-activated receptor (PPAR)α and PPARγ activity. All tested compounds showed a dual antagonist profile on both PPAR subtypes; based on transactivation results, seven compounds were selected to test their in vitro antiproliferative activity in a panel of eight cancer cell lines with different expression rates of PPARα and PPARγ. 3f was identified as the most cytotoxic compound, with higher potency in the colorectal cancer cell lines HT-29 and HCT116. Compound 3f induced a concentration-dependent activation of caspases and cell-cycle arrest in both colorectal cancer models. Docking experiments were also performed to shed light on the putative binding mode of this novel class of dual PPARα/γ antagonists.
PubMed: 38807029
DOI: 10.1002/ardp.202400086 -
The Science of the Total Environment Aug 2024Residual pollutants in discharged and reused water pose both direct and indirect human exposure. However, health effects caused by whole effluent remain largely unknown...
Residual pollutants in discharged and reused water pose both direct and indirect human exposure. However, health effects caused by whole effluent remain largely unknown due to the lack of human relevant model for toxicity test. Effluents from four secondary wastewater treatment plants (SWTPs), a tertiary wastewater treatment plant (TWTP) and a constructed wetland (CW) were evaluated for the integrated toxicity of the organic extractions. Multiple-endpoint human mesenchymal stem cells (MSCs) assay was used as an in vitro model relevant to human health. The effluents caused cytotoxicity, oxidative stress and genotoxicity in MSCs. The osteogenic and neurogenic differentiation were inhibited and the adipogenic differentiation were stimulated by some of the effluent extractions. The SWTP, TWTP and CW treatments reduced integrated biomarker response (IBR) by 26.3 %, 17.5 % and 33.3 % respectively, where the IBR values of final CW (8.3) and TWTP (8.2) effluents were relatively lower than SWTPs (9.1). Among multiple biomarkers, the inhibition of osteogenesis was the least reduced by wastewater treatment. Besides, ozone disinfection in tertiary treatment increased cytotoxicity and differentiation effects suggesting the generation of toxic products. The mRNA expressions of estrogen receptor alpha (ERα) and peroxisome proliferator-activated receptor gamma (PPARγ) were significantly upregulated by effluents. The inhibitory effects of effluents on neural differentiation were mitigated after antagonizing ERα and PPARγ in the cells. It is suggested that ERα and PPARγ agonists in effluents were largely accountable for the impairment of stem cell differentiation. Besides, the concentrations of n-CH, o-cresol, fluorene and phenanthrene in the effluents were significantly correlated with the intergrated stem cell toxicity. The present study provided toxicological evidence for the relation between water contamination and human health, with an insight into the key toxicity drivers. The necessity for deep water treatment and the potential means were suggested for improving water quality.
Topics: Humans; Wetlands; PPAR gamma; Water Pollutants, Chemical; Wastewater; Estrogen Receptor alpha; Waste Disposal, Fluid; Mesenchymal Stem Cells; Cell Differentiation
PubMed: 38802024
DOI: 10.1016/j.scitotenv.2024.173419 -
Psychopharmacology May 2024Peroxisome proliferator-activated receptors (PPARs) are transcription factors that regulate various physiological processes such as inflammation, lipid metabolism, and... (Review)
Review
RATIONALE
Peroxisome proliferator-activated receptors (PPARs) are transcription factors that regulate various physiological processes such as inflammation, lipid metabolism, and glucose homeostasis. Recent studies suggest that targeting PPARs could be beneficial in treating neuropsychiatric disorders by modulating neuronal function and signaling pathways in the brain. PPAR-α, PPAR-δ, and PPAR-γ have been found to play important roles in cognitive function, neuroinflammation, and neuroprotection. Dysregulation of PPARs has been associated with neuropsychiatric disorders like bipolar disorder, schizophrenia, major depression disorder, and autism spectrum disorder. The limitations and side effects of current treatments have prompted research to target PPARs as a promising novel therapeutic strategy. Preclinical and clinical studies have shown the potential of PPAR agonists and antagonists to improve symptoms associated with these disorders.
OBJECTIVE
This review aims to provide an overview of the current understanding of PPARs in neuropsychiatric disorders, their potential as therapeutic targets, and the challenges and future directions for developing PPAR-based therapies.
METHODS
An extensive literature review of various search engines like PubMed, Medline, Bentham, Scopus, and EMBASE (Elsevier) databases was carried out with the keywords "PPAR, Neuropsychiatric disorders, Oxidative stress, Inflammation, Bipolar Disorder, Schizophrenia, Major depression disorder, Autism spectrum disorder, molecular pathway".
RESULT & CONCLUSION
Although PPARs present a hopeful direction for innovative therapeutic approaches in neuropsychiatric conditions, additional research is required to address obstacles and convert this potential into clinically viable and individualized treatments.
PubMed: 38801530
DOI: 10.1007/s00213-024-06617-6 -
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 -
International Journal of Biological... Jun 2024This study evaluated the regulatory effects of Astragalus membranaceus polysaccharides (AMP) on lipid metabolism disorders induced by a high-fat diet (HFD) in spotted...
This study evaluated the regulatory effects of Astragalus membranaceus polysaccharides (AMP) on lipid metabolism disorders induced by a high-fat diet (HFD) in spotted sea bass (Lateolabrax maculatus). Compared with the normal diets (10 % lipids), diets containing 15 % lipid levels were used as the high-fat diet (HFD). Three levels of the AMP (0.06 %, 0.08 %, 0.10 %) were added in the HFD and used as experimental diets. A total of 375 spotted sea bass (average weight 3.00 ± 0.01 g) were divided into 15 tanks and deemed as 5 groups, with each tank containing 25 fish. Fish in each group were fed with different diets for 56 days. After feeding, the HFD induced lipid metabolism disorders in fish, as evidenced by elevated serum lipids, malonaldehyde levels, and more severe liver damage. The AMP alleviated the HFD-induced liver damage, as evidenced by the reduced severity of liver histological lesions and malonaldehyde levels. The low-density lipoprotein cholesterol was reduced, and the expression of FAS and PPAR-α were down and up-regulated, respectively. However, the AMP had a limited ability to affect the serum lipids and abdominal fat percentage. These results reveal the potential of the AMP used in aquaculture to regulate lipid metabolism disorders induced by the HFD.
Topics: Animals; Bass; Diet, High-Fat; Polysaccharides; Astragalus propinquus; Lipid Metabolism; Lipid Metabolism Disorders; Liver; PPAR alpha; Lipids
PubMed: 38795881
DOI: 10.1016/j.ijbiomac.2024.132584 -
European Journal of Pharmacology Aug 2024Migraine, a debilitating neurological condition, significantly affects patients' quality of life. Fenofibrate, a peroxisome proliferator-activated receptor alpha...
Migraine, a debilitating neurological condition, significantly affects patients' quality of life. Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPAR-α) agonist approved for managing dyslipidemia, has shown promise in treating neurological disorders. Therefore, this study aims to investigate the protective effects of fenofibrate against nitroglycerin (NTG)-induced chronic migraine in rats. Migraine was induced in rats by administering five intermittent doses of NTG (10 mg/kg, i. p.) on days 1, 3, 5, 7, and 9. Rats were treated with either topiramate (80 mg/kg/day, p. o.), a standard drug, or fenofibrate (100 mg/kg/day, p. o.) from day 1-10. Fenofibrate significantly improved mechanical and thermal hypersensitivity, photophobia, and head grooming compared to topiramate. These effects were associated with reduced serum levels of nitric oxide (NO), calcitonin gene-related peptide (CGRP), and pituitary adenylate cyclase-activating polypeptide (PACAP). Furthermore, fenofibrate down-regulated c-Fos expression in the medulla and medullary pro-inflammatory cytokine contents. Additionally, fenofibrate attenuated NTG-induced histopathological changes in the trigeminal ganglia and trigeminal nucleus caudalis. These effects were associated with the inhibition of CGRP/p-CREB/purinergic 2X receptor 3 (P2X3) and nerve growth factor (NGF)/protein kinase C (PKC)/acid-sensing ion channel 3 (ASIC3) signaling pathways. This study demonstrates that fenofibrate attenuated NTG-induced migraine-like signs in rats. These effects were partially mediated through the inhibition of CGRP/p-CREB/P2X3 and NGF/PKC/ASIC3 signaling pathways. The present study supports the idea that fenofibrate could be an effective candidate for treating migraine headache without significant adverse effects. Future studies should explore its clinical applicability.
Topics: Animals; Nitroglycerin; Calcitonin Gene-Related Peptide; Signal Transduction; Migraine Disorders; Male; Fenofibrate; Rats; Cyclic AMP Response Element-Binding Protein; Protein Kinase C; Receptors, Purinergic P2X3; Nerve Growth Factor; Nitric Oxide; Rats, Sprague-Dawley; Behavior, Animal
PubMed: 38795754
DOI: 10.1016/j.ejphar.2024.176667