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Trends in Pharmacological Sciences Jan 2024Peroxisome proliferator-activated receptors [PPARs; PPARα, PPARβ/δ (also known as PPARδ), and PPARγ] widely recognized for their important role in glucose/lipid... (Review)
Review
Peroxisome proliferator-activated receptors [PPARs; PPARα, PPARβ/δ (also known as PPARδ), and PPARγ] widely recognized for their important role in glucose/lipid homeostasis, have recently received significant attention due to their additional anti-inflammatory and neuroprotective effects. Several newly developed PPAR agonists have shown high selectivity for specific PPAR isoforms in vitro and in vivo, offering the potential to achieve desired therapeutic outcomes while reducing the risk of adverse effects. In this review, we discuss the latest preclinical and clinical studies of the activation of PPARs by synthetic, natural, and isoform-specific (full, partial, and dual) agonists for the treatment of neuroinflammatory diseases, including HIV-associated neurocognitive disorders (HAND), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and cerebral ischemia.
Topics: Humans; Peroxisome Proliferator-Activated Receptors; Neuroinflammatory Diseases; PPAR delta; PPAR-beta; PPAR alpha; PPAR gamma; Hypoglycemic Agents
PubMed: 38065777
DOI: 10.1016/j.tips.2023.11.004 -
Antiviral Research Aug 2023Recent evidence suggests that lipids play a crucial role in viral infections beyond their traditional functions of supplying envelope and energy, and creating protected...
Recent evidence suggests that lipids play a crucial role in viral infections beyond their traditional functions of supplying envelope and energy, and creating protected niches for viral replication. In the case of Zika virus (ZIKV), it alters host lipids by enhancing lipogenesis and suppressing β-oxidation to generate viral factories at the endoplasmic reticulum (ER) interface. This discovery prompted us to hypothesize that interference with lipogenesis could serve as a dual antiviral and anti-inflammatory strategy to combat the replication of positive sense single-stranded RNA (ssRNA+) viruses. To test this hypothesis, we examined the impact of inhibiting N-Acylethanolamine acid amidase (NAAA) on ZIKV-infected human Neural Stem Cells. NAAA is responsible for the hydrolysis of palmitoylethanolamide (PEA) in lysosomes and endolysosomes. Inhibition of NAAA results in PEA accumulation, which activates peroxisome proliferator-activated receptor-α (PPAR-α), directing β-oxidation and preventing inflammation. Our findings indicate that inhibiting NAAA through gene-editing or drugs moderately reduces ZIKV replication by approximately one log in Human Neural Stem Cells, while also releasing immature virions that have lost their infectivity. This inhibition impairs furin-mediated prM cleavage, ultimately blocking ZIKV maturation. In summary, our study highlights NAAA as a host target for ZIKV infection.
Topics: Humans; Amidohydrolases; Anti-Inflammatory Agents; Inflammation; Zika Virus; Zika Virus Infection
PubMed: 37414288
DOI: 10.1016/j.antiviral.2023.105664 -
Molecular and Cellular Endocrinology May 2024To evaluate the effects of PPARα and PPARγ activation (alone or in combination) on the gut-liver axis, emphasizing the integrity of the intestinal barrier and hepatic...
AIM
To evaluate the effects of PPARα and PPARγ activation (alone or in combination) on the gut-liver axis, emphasizing the integrity of the intestinal barrier and hepatic steatosis in mice fed a high saturated fat diet.
METHODS
Male C57BL/6J were fed a control diet (C) or a high-fat diet (HF) for ten weeks. Then, a four-week treatment started: HF-α (WY14643), HF-γ (low-dose pioglitazone), and HF-αγ (combination).
RESULTS
The HF caused overweight, insulin resistance, impaired gut-liver axis, and marked hepatic steatosis. Treatments reduced body mass, improved glucose homeostasis, and restored the gut microbiota diversity and intestinal barrier gene expression. Treatments also lowered the plasma lipopolysaccharide concentrations and favored beta-oxidation genes, reducing macrophage infiltration and steatosis in the liver.
CONCLUSION
Treatment with PPAR agonists modulated the gut microbiota and rescued the integrity of the intestinal barrier, alleviating hepatic steatosis. These results show that these agonists can contribute to metabolic-associated fatty liver disease treatment.
Topics: Male; Animals; Mice; Diet, High-Fat; PPAR alpha; Obesity; Mice, Inbred C57BL; Liver; Non-alcoholic Fatty Liver Disease
PubMed: 38373652
DOI: 10.1016/j.mce.2024.112177 -
International Journal of Molecular... Jun 2024Consumption of a high-fat diet (HFD) has been suggested as a contributing factor behind increased intestinal permeability in obesity, leading to increased plasma levels...
Consumption of a high-fat diet (HFD) has been suggested as a contributing factor behind increased intestinal permeability in obesity, leading to increased plasma levels of microbial endotoxins and, thereby, increased systemic inflammation. We and others have shown that HFD can induce jejunal expression of the ketogenic rate-limiting enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS). HMGCS is activated via the free fatty acid binding nuclear receptor PPAR-α, and it is a key enzyme in ketone body synthesis that was earlier believed to be expressed exclusively in the liver. The function of intestinal ketogenesis is unknown but has been described in suckling rats and mice pups, possibly in order to allow large molecules, such as immunoglobulins, to pass over the intestinal barrier. Therefore, we hypothesized that ketone bodies could regulate intestinal barrier function, e.g., via regulation of tight junction proteins. The primary aim was to compare the effects of HFD that can induce intestinal ketogenesis to an equicaloric carbohydrate diet on inflammatory responses, nutrition sensing, and intestinal permeability in human jejunal mucosa. Fifteen healthy volunteers receiving a 2-week HFD diet compared to a high-carbohydrate diet were compared. Blood samples and mixed meal tests were performed at the end of each dietary period to examine inflammation markers and postprandial endotoxemia. Jejunal biopsies were assessed for protein expression using Western blotting, immunohistochemistry, and morphometric characteristics of tight junctions by electron microscopy. Functional analyses of permeability and ketogenesis were performed in Caco-2 cells, mice, and human enteroids. Ussing chambers were used to analyze permeability. CRP and ALP values were within normal ranges and postprandial endotoxemia levels were low and did not differ between the two diets. The PPARα receptor was ketone body-dependently reduced after HFD. None of the tight junction proteins studied, nor the basal electrical parameters, were different between the two diets. However, the ketone body inhibitor hymeglusin increased resistance in mucosal biopsies. In addition, the tight junction protein claudin-3 was increased by ketone inhibition in human enteroids. The ketone body β-Hydroxybutyrate (βHB) did not, however, change the mucosal transition of the large-size molecular FD4-probe or LPS in Caco-2 and mouse experiments. We found that PPARα expression was inhibited by the ketone body βHB. As PPARα regulates HMGCS expression, the ketone bodies thus exert negative feedback signaling on their own production. Furthermore, ketone bodies were involved in the regulation of permeability on intestinal mucosal cells in vitro and ex vivo. We were not, however, able to reproduce these effects on intestinal permeability in vivo in humans when comparing two weeks of high-fat with high-carbohydrate diet in healthy volunteers. Further, neither the expression of inflammation markers nor the aggregate tight junction proteins were changed. Thus, it seems that not only HFD but also other factors are needed to permit increased intestinal permeability in vivo. This indicates that the healthy gut can adapt to extremes of macro-nutrients and increased levels of intestinally produced ketone bodies, at least during a shorter dietary challenge.
Topics: Humans; Permeability; Male; Intestinal Mucosa; Diet, High-Fat; Ketone Bodies; Adult; Jejunum; Hydroxymethylglutaryl-CoA Synthase; Female; Animals; Mice; Claudin-3
PubMed: 38928261
DOI: 10.3390/ijms25126555 -
Hormone and Metabolic Research =... Oct 2023The etiopathogenesis of metabolic syndrome (MetS) has not been fully understood yet, and chronic low-grade inflammation is thought to be associated with the development...
The etiopathogenesis of metabolic syndrome (MetS) has not been fully understood yet, and chronic low-grade inflammation is thought to be associated with the development of complications related to MetS. We aimed to investigate the role of Nuclear factor Kappa B ( NF-κB ), Peroxisome Proliferator-Activated Receptor- α and γ (PPAR-α, and PPAR-γ) which are the main markers of inflammation in older adults with MetS. A total of 269 patients aged≥18, 188 patients with MetS who met the diagnostic criteria of the International Diabetes Federation, and 81 controls who applied to geriatrics and general internal medicine outpatient clinics for various reasons were included in the study. Patients were separated into four groups: young with MetS (< 60, n=76), elderly with MetS (≥60, n=96), young control (< 60, n=31), elderly controls (≥60, n=38). Carotid intima-media thickness (CIMT) and NF-κB , PPAR-α, and PPAR-γ plasma levels were measured in all of the participants. Age and sex distribution were similar between MetS and control groups. C-reactive protein (CRP), NF-κB levels (p=0.001) and CIMT (p<0,001) of MetS group were significantly higher than in the control groups. On the other hand, the PPAR-γ (p=0.008) and PPAR-α (p=0.003) levels were significantly lower in MetS. ROC analysis revealed that the NF-κB, PPAR-α, and PPAR-γ could be used to indicate MetS in younger adults (AUC: 0.735, p<0.000; AUC: 0.653, p=0.003), whereas it could not be an indicator in older adults (AUC: 0.617, p=0.079; AUC:0.530, p=0.613). It seems that these markers have important roles in MetS-related inflammation. In our results, suggest that the indicator feature of NF-κB , PPAR-α and PPAR-γ in recognizing MetS in young individuals is lost in older adults with Mets.
Topics: Aged; Humans; Carotid Intima-Media Thickness; Inflammation; Metabolic Syndrome; NF-kappa B; PPAR alpha; PPAR gamma; Middle Aged
PubMed: 37308136
DOI: 10.1055/a-2109-1958 -
Phytotherapy Research : PTR Nov 2023Cardiovascular diseases are currently the primary cause of mortality in the whole world. Growing evidence indicated that the disturbances in cardiac fatty acid... (Review)
Review
Cardiovascular diseases are currently the primary cause of mortality in the whole world. Growing evidence indicated that the disturbances in cardiac fatty acid metabolism are crucial contributors in the development of cardiovascular diseases. The abnormal cardiac fatty acid metabolism usually leads to energy deficit, oxidative stress, excessive apoptosis, and inflammation. Targeting fatty acid metabolism has been regarded as a novel approach to the treatment of cardiovascular diseases. However, there are currently no specific drugs that regulate fatty acid metabolism to treat cardiovascular diseases. Many traditional Chinese medicines have been widely used to treat cardiovascular diseases in clinics. And modern studies have shown that they exert a cardioprotective effect by regulating the expression of key proteins involved in fatty acid metabolism, such as peroxisome proliferator-activated receptor α and carnitine palmitoyl transferase 1. Hence, we systematically reviewed the relationship between fatty acid metabolism disorders and four types of cardiovascular diseases including heart failure, coronary artery disease, cardiac hypertrophy, and diabetic cardiomyopathy. In addition, 18 extracts and eight monomer components from traditional Chinese medicines showed cardioprotective effects by restoring cardiac fatty acid metabolism. This work aims to provide a reference for the finding of novel cardioprotective agents targeting fatty acid metabolism.
Topics: Humans; Cardiovascular Diseases; Heart; Medicine, Chinese Traditional; PPAR alpha; Fatty Acids; Energy Metabolism
PubMed: 37533230
DOI: 10.1002/ptr.7965 -
Open Medicine (Warsaw, Poland) 2023Hyperlipidemia is a metabolic disorder, which is a major risk factor for atherosclerosis, stroke, and coronary heart disease. Although lipid-lowering treatments have... (Review)
Review
Hyperlipidemia is a metabolic disorder, which is a major risk factor for atherosclerosis, stroke, and coronary heart disease. Although lipid-lowering treatments have been extensively studied, safer treatments with fewer adverse effects are needed. Rhubarb is a traditional Chinese medicine that has lipid-lowering, anti-inflammatory, and antioxidant properties. Disturbance in lipid metabolism is the basis of tissue damage caused by hyperlipidemia and plays a key role in the development of hyperlipidemia; however, the molecular mechanisms by which rhubarb regulates lipid metabolism to lower lipid levels are yet to be elucidated. We conducted this study to summarize the phytochemical constituents of and provide a comprehensive review of the molecular mechanisms underlying the regulation of lipid metabolism during hyperlipidemia treatment. It was found that rhubarb extracts, including emodin, rhubarb acid, and rhubarb phenol, regulate total cholesterol, triglyceride, TNF-α, and IL-1β levels through signaling pathways such as C/EBP α, 3T3-L1, PPAR α, and AMPK, thereby improving the hyperlipidemic state. This suggests that rhubarb is a natural drug with lipid-lowering potential, and an in-depth exploration of its lipid-lowering mechanism can provide new ideas for the prevention and treatment of hyperlipidemia.
PubMed: 37808167
DOI: 10.1515/med-2023-0812 -
International Journal of Molecular... Jul 2023Adipose tissue (AT) secretes pro- and anti-inflammatory cytokines involved in AT homeostasis, including tumor necrosis factor-α (TNFα) and irisin. The functionality of...
Adipose tissue (AT) secretes pro- and anti-inflammatory cytokines involved in AT homeostasis, including tumor necrosis factor-α (TNFα) and irisin. The functionality of AT is based on a regulated equilibrium between adipogenesis and extracellular matrix (ECM) remodeling. We investigated the contributions of adipose progenitors (ASCs) and adipocytes (AMCs) to TNFα-induced ECM remodeling and a possible implication of irisin in AT impairment in obesity. ASCs and AMCs were exposed to TNFα treatment and nuclear factor-kappa (NF-kB) pathway was investigated: Tissue Inhibitor of Metalloproteinase (TIMP-1), Twist Family Transcription Factor 1 (TWIST-1), and peroxisome proliferator-activated receptor-γ (PPARγ) expression levels were analyzed. The proteolytic activity of matrix metalloproteinases (MMPs) -2 and -9 was analyzed by zymography, and the irisin protein content was measured by ELISA. In inflamed AMCs, a TIMP-1/TWIST-1 imbalance leads to a drop in PPARγ. Adipogenesis and lipid storage ability impairment come with local tissue remodeling due to MMP-9 overactivation. In vitro and ex vivo measurements confirm positive correlations among inflammation, adipose secreting irisin levels, and circulating irisin levels in patients with visceral obesity. Our findings identify the NF-kB downstream effectors as molecular initiators of AT dysfunction and suggest irisin as a possible AT damage and obesity predictive factor.
Topics: Humans; Adipose Tissue; Fibronectins; NF-kappa B; Obesity; PPAR gamma; Tissue Inhibitor of Metalloproteinase-1; Tumor Necrosis Factor-alpha
PubMed: 37569456
DOI: 10.3390/ijms241512082 -
International Immunopharmacology Oct 2023Astrocytes are crucially involved in neuroinflammation. Activated astrocytes exhibit at least two phenotypes, A1 (neurotoxic) and A2 (neuroprotective). The A1 phenotype...
Astrocytes are crucially involved in neuroinflammation. Activated astrocytes exhibit at least two phenotypes, A1 (neurotoxic) and A2 (neuroprotective). The A1 phenotype is the major reactive astrocyte phenotype involved in aging and neurodegenerative diseases. Telmisartan, which is an antihypertensive agent, is a promising neuroprotective agent. This study aimed to investigate the effects of telmisartan on the phenotype of reactive astrocytes. Astrocytes were activated by culturing with the conditioned medium derived from lipopolysaccharide-stimulated microglia. This conditioned medium induced early, transient A2 astrocyte conversion (within 24 h) and late, sustained A1 conversion (beginning at 24 h and lasting up to 7 days), with a concomitant increase in the production of pro-inflammatory cytokines (interleukin [IL]-1β, tumor necrosis factor [TNF]α, and IL-6) and phosphorylation of nuclear factor-κB (NF-κB)/p65. Telmisartan treatment promoted and inhibited A2 and A1 conversion, respectively. Telmisartan reduced total and phosphorylated p65 protein levels. Losartan, a specific angiotensin II type-1 receptor (AT1R) blocker, did not influence the reactive state of astrocytes. Additionally, AT1R activation by angiotensin II did not induce the expression of pro-inflammatory cytokines and A1/A2 markers, indicating that the AT1R signaling pathway is not involved in the astrocyte-mediated inflammatory response. A peroxisome proliferator-activated receptor γ (PPARγ) antagonist reversed the effects of telmisartan. Moreover, telmisartan-induced p65 downregulation was reversed by the proteasome inhibitor MG132. These results indicate that telmisartan suppresses activated microglia-induced neurotoxic A1 astrocyte conversion through p65 degradation. Our findings contribute towards the elucidation of the anti-inflammatory activity of telmisartan in brain disorders.
Topics: Telmisartan; NF-kappa B; PPAR gamma; Astrocytes; Microglia; Angiotensin II; Culture Media, Conditioned; Angiotensin II Type 1 Receptor Blockers; Cytokines; Tumor Necrosis Factor-alpha
PubMed: 37544025
DOI: 10.1016/j.intimp.2023.110761 -
Journal of Neuroinflammation Nov 2023Cyanidin-3-O-glucoside (C3G) is a natural anthocyanin with antioxidant, anti-inflammatory, and antitumor properties. However, as the effects of C3G on the amyloidogenic...
Cyanidin-3-O-glucoside (C3G) is a natural anthocyanin with antioxidant, anti-inflammatory, and antitumor properties. However, as the effects of C3G on the amyloidogenic pathway, autophagy, tau phosphorylation, neuronal cell death, and synaptic plasticity in Alzheimer's disease models have not been reported, we attempted to investigate the same in the brains of APPswe/PS1ΔE9 mice were analyzed. After oral administration of C3G (30 mg/kg/day) for 16 weeks, the cortical and hippocampal regions in the brains of APPswe/PS1ΔE9 mice were analyzed. C3G treatment reduced the levels of soluble and insoluble Aβ (Aβ40 and Aβ42) peptides and reduced the protein expression of the amyloid precursor protein, presenilin-1, and β-secretase in the cortical and hippocampal regions. And C3G treatment upregulated the expression of autophagy-related markers, LC3B-II, LAMP-1, TFEB, and PPAR-α and downregulated that of SQSTM1/p62, improving the autophagy of Aβ plaques and neurofibrillary tangles. In addition, C3G increased the protein expression of phosphorylated-AMPK/AMPK and Sirtuin 1 and decreased that of mitogen-activated protein kinases, such as phosphorylated-Akt/Akt and phosphorylated-ERK/ERK, thus demonstrating its neuroprotective effects. Furthermore, C3G regulated the PI3K/Akt/GSK3β signaling by upregulating phosphorylated-Akt/Akt and phosphorylated-GSK3β/GSK3β expression. C3G administration mitigated tau phosphorylation and improved synaptic function and plasticity by upregulating the expression of synapse-associated proteins synaptophysin and postsynaptic density protein-95. Although the potential of C3G in the APPswe/PS1ΔE9 mouse models has not yet been reported, oral administration of the C3G is shown to protect the brain and improve cognitive behavior.
Topics: Mice; Animals; Mice, Transgenic; Anthocyanins; Glycogen Synthase Kinase 3 beta; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; AMP-Activated Protein Kinases; Alzheimer Disease; Cognition; Brain; Glucosides; Amyloid beta-Peptides
PubMed: 37978414
DOI: 10.1186/s12974-023-02950-3