Targeting Peroxisome Proliferator-activated Receptor Research Articles

Feasibility and Advantages of Designing Proteolysis Targeting Chimeras Targeting Peroxisome Proliferator-activated Receptors for Cancer Treatment

Feasibility and Advantages of Designing Proteolysis Targeting Chimeras Targeting Peroxisome Proliferator-activated Receptors for Cancer Treatment

Unlocking new avenues for neuropsychiatric disease therapy: the emerging potential of Peroxisome proliferator-activated receptors as promising therapeutic targets.

Peroxisome proliferator-activated receptors (PPARs) are transcription factors that regulate variousphysiological processes such as inflammation, lipid metabolism, and glucose homeostasis. Recent studies suggestthat targeting PPARs could be beneficial in treating neuropsychiatric disorders by modulating neuronal function andsignaling pathways in the brain. PPAR-α, PPAR-δ, and PPAR-γ have been found to play important roles incognitive function, neuroinflammation, and neuroprotection. Dysregulation of PPARs has been associated withneuropsychiatric disorders like bipolar disorder, schizophrenia, major depression disorder, and autism spectrumdisorder. The limitations and side effects of current treatments have prompted research to target PPARs as apromising novel therapeutic strategy. Preclinical and clinical studies have shown the potential of PPAR agonistsand antagonists to improve symptoms associated with these disorders. This review aims to provide an overview of the current understanding of PPARs in neuropsychiatricdisorders, their potential as therapeutic targets, and the challenges and future directions for developingPPAR-basedtherapies. An extensive literature review of various search engines like PubMed, Medline, Bentham, Scopus, andEMBASE (Elsevier) databases was carried out with the keywords "PPAR, Neuropsychiatric disorders, Oxidativestress, Inflammation, Bipolar Disorder, Schizophrenia, Major depression disorder, Autism spectrum disorder,molecular pathway". Although PPARs present a hopeful direction for innovative therapeutic approaches inneuropsychiatric conditions, additional research is required to address obstacles and convert this potential intoclinically viable and individualized treatments.

MicroRNA-144-3p Inhibits Host Lipid Catabolism and Autophagy by Targeting PPARα and ABCA1 During Mycobacterium Tuberculosis Infection.

MicroRNA-mediated metabolic reprogramming recently has been identified as an important strategy for Mycobacterium tuberculosis (Mtb) to evade host immune responses. However, it is unknown what role microRNA-144-3p (miR-144-3p) plays in cellular metabolism during Mtb infection. Here, we report the meaning of miR-144-3p-mediated lipid accumulation for Mtb-macrophage interplay. Mtb infection was shown to upregulate the expression of miR-144-3p in macrophages. By targeting peroxisome proliferator-activated receptor α (PPARα) and ATP-binding cassette transporter A1 (ABCA1), miR-144-3p overexpression promoted lipid accumulation and bacterial survival in Mtb-infected macrophages, while miR-144-3p inhibition had the opposite effect. Furthermore, reprogramming of host lipid metabolism by miR-144-3p suppressed autophagy in response to Mtb infection. Our findings uncover that miR-144-3p regulates host metabolism and immune responses to Mtb by targeting PPARα and ABCA1, suggesting a potential host-directed tuberculosis therapy by targeting the interface of miRNA and lipid metabolism.

Associations between synthetic phenols, phthalates, and placental growth/function: a longitudinal cohort with exposure assessment in early pregnancy.

Is exposure to environmental chemicals associated with modifications of placental morphology and function? Phthalates, a class of ubiquitous chemicals, showed an association with altered placental weight, placental vascular resistance (PVR), and placental efficiency. Only a few epidemiological studies have assessed the effects of phenols and phthalates on placental health. Their results were affected by exposure measurement errors linked to the rapid excretion of these compounds and the reliance on a limited number of spot urine samples to assess exposure. A prospective mother-child cohort, with improved exposure assessment for non-persistent chemicals, recruited participants between 2014 and 2017. Sample size ranged between 355 (placental parameters measured at birth: placental weight and placental-to-fetal weight ratio (PFR): a proxy for placental efficiency) and 426 (placental parameters measured during pregnancy: placental thickness and vascular resistance). Phenols (four parabens, two bisphenols, triclosan, and benzophenone-3), 13 phthalate metabolites, and two non-phthalate plasticizer metabolites were measured in within-subject pools of repeated urine samples collected during the second and third trimesters of pregnancy (median = 21 samples/trimester/woman). Placental thickness and PVR were measured during pregnancy. The placenta was weighed at birth and the PFR was computed. Both adjusted linear regression and Bayesian Kernel Machine Regression were used to evaluate associations between phenols and phthalates (alone or as a mixture) and placental parameters. Effect modification by child sex was also investigated. Several phthalate metabolites were negatively associated with placental outcomes. Monobenzyl phthalate (MBzP) concentrations, during the second and third trimesters of pregnancy, were associated with a decrease in both placental weight at birth (β = -20.1 g [95% CI: -37.8; -2.5] and β = -17.4 g [95% CI: -33.2; -1.6], for second and third trimester, respectively) and PFR (β = -0.5 [95% CI: -1, -0.1] and β = -0.5 [95% CI: -0.9, -0.1], for the second and third trimester, respectively). Additionally, MBzP was negatively associated with PVR during the third trimester (β= -0.9 [95% CI: -1.8; 0.1]). Mono-n-butyl phthalate (MnBP), was negatively associated with PVR in both trimesters (β = -1.3, 95% CI: [-2.3, -0.2], and β = -1.2, 95% CI: [-2.4, -0.03], for the second and third trimester, respectively). After stratification for child sex, Σ diisononyl phthalate (DiNP) (either second or third-trimester exposures, depending on the outcomes considered) was associated with decreased PVR in the third trimester, as well as decreased placental weight and PFR in males. No associations were observed for phenol biomarkers. False positives cannot be ruled out. Therefore, chemicals that were associated with multiple outcomes (MnBP and DiNP) or reported in existing literature as associated with placental outcomes (MBzP) should be considered as the main results. Our results are consistent with in vitro studies showing that phthalates target peroxisome proliferator-activated receptor γ, in the family of nuclear receptors involved in key placental development processes such as trophoblast proliferation, migration, and invasion. In addition to placental weight at birth, we studied placental parameters during pregnancy, which could provide a broader view of how environmental chemicals affect maternal-fetal exchanges over the course of pregnancy. Our findings contribute to the increasing evidence indicating adverse impacts of phthalate exposure on placental health. This work was supported by the French Research Agency-ANR (MEMORI project ANR-21-CE34-0022). The SEPAGES cohort was supported by the European Research Council (N°311765-E-DOHaD), the European Community's Seventh Framework Programme (FP7/2007-206-N°308333-892 HELIX), the European Union's Horizon 2020 research and innovation programme (N° 874583 ATHLETE Project, N°825712 OBERON Project), the French Research Agency-ANR (PAPER project ANR-12-PDOC-0029-01, SHALCOH project ANR-14-CE21-0007, ANR-15-IDEX-02 and ANR-15-IDEX5, GUMME project ANR-18-CE36-005, ETAPE project ANR-18-CE36-0005-EDeN project ANR-19-CE36-0003-01), the French Agency for Food, Environmental and Occupational Health & Safety-ANSES (CNAP project EST-2016-121, PENDORE project EST-2016-121, HyPAxE project EST-2019/1/039, PENDALIRE project EST-2022-169), the Plan Cancer (Canc'Air project), the French Cancer Research Foundation Association de Recherche sur le Cancer-ARC, the French Endowment Fund AGIR for chronic diseases-APMC (projects PRENAPAR, LCI-FOT, DysCard), the French Endowment Fund for Respiratory Health, the French Fund-Fondation de France (CLIMATHES-00081169, SEPAGES 5-00099903, ELEMENTUM-00124527). N.J. was supported by a doctoral fellowship from the University Grenoble Alpes. V.M. was supported by a Sara Borrell postdoctoral research contract (CD22/00176), granted by Instituto de Salud Carlos III (Spain) and NextGenerationEU funds. The authors declare no conflict of interest. ClinicalTrials.gov NCT02852499.

The Role of Nuclear Receptors in the Pathogenesis and Treatment of Non-alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is a global health burden closely linked to insulin resistance, obesity, and type 2 diabetes. The complex pathophysiology of NAFLD involves multiple cellular pathways and molecular factors. Nuclear receptors (NRs) have emerged as crucial regulators of lipid metabolism and inflammation in NAFLD, offering potential therapeutic targets for NAFLD. Targeting PPARs and FXRs has shown promise in ameliorating NAFLD symptoms and halting disease progression. However, further investigation is needed to address side effects and personalize therapy approaches. This review summarizes the current understanding of the involvement of NRs in the pathogenesis of NAFLD and explores their therapeutic potential. We discuss the role of several NRs in modulating lipid homeostasis in the liver, including peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs), farnesoid X receptors (FXRs), REV-ERB, hepatocyte nuclear factor 4α (HNF4α), constitutive androstane receptor (CAR) and pregnane X receptor (PXR).The expanding knowledge of NRs in NAFLD offers new avenues for targeted therapies, necessitating exploration of novel treatment strategies and optimization of existing approaches to combat this increasingly prevalent disease.

Identification of antidiabetic inhibitors from Allophylus villosus and Mycetia sinensis by targeting α-glucosidase and PPAR-γ: In-vitro, in-vivo, and computational evidence

Diabetes mellitus (DM) is a metabolic disorder arising from insulin deficiency and defectiveness of the insulin receptor functioning on transcription factor where the body loses control to regulate glucose metabolism in β-cells, pancreatic and liver tissues to homeostat glucose level. Mainstream medicines used for DM are incapable of restoring normal glucose homeostasis and have side effects where medicinal plant-derived medicine administrations have been claimed to cure diabetes or at least alleviate the significant symptoms and progression of the disease by the traditional practitioners. This study focused on screening phytocompounds and their pharmacological effects on anti-hyperglycemia on Swiss Albino mice of n-hexane, ethyl acetate, and ethanol extract of both plants Mycetia sinensis and Allophylus villosus as well as the in-silico investigations. Qualitative screening of phytochemicals and total phenolic and flavonoid content estimation were performed significantly in vitro analysis. FTIR and GC–MS analysis précised the functional groups and phytochemical investigations where FTIR scanned 14, 23 & 17 peaks in n-hexane, ethyl acetate, and ethanol extracts of Mycetia sinensis whereas the n-hexane, ethyl acetate, and ethanol extracts of Allophylus villosus scanned 11 peaks, 18 peaks, and 29 peaks, respectively. In GC–MS, 24 chemicals were identified in Mycetia sinensis extracts, whereas 19 were identified in Allophylus villosus extracts. Moreover, both plants' ethyl acetate and ethanol fractioned extracts were reported significantly (p < 0.05) with concentrations of 250 mg and 500 mg on mice for oral glucose tolerance test, serum creatinine test and serum alkaline phosphatase test. In In silico study, a molecular docking study was done on these 43 phytocompounds identified from Mycetia sinensis and Allophylus villosus to identify their binding affinity to the target Alpha Glucosidase (AG) and Peroxisome proliferator-activated receptor gamma protein (PPARG). Therefore, ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis, quantum mechanics-based DFT (density-functional theory), and molecular dynamics simulation were done to assess the effectiveness of the selected phytocompounds. According to the results, phytocompounds such as 2,4-Dit-butyl phenyl 5-hydroxypentanoate and Diazo acetic acid (1S,2S,5R)-2-isopropyl-5-methylcyclohexyl obtained from Mycetia sinensis and Allophylus villosus extract possess excellent antidiabetic activities.

Syringaresinol alleviates IgG immune complex induced acute lung injury via activating PPARγ and suppressing pyroptosis

Acute lung injury (ALI) is a life-threatening condition characterized by severe lung inflammation and tissue damage. In this study, we investigate the potential therapeutic efficacy of (+)-Syringaresinol (SYG), a natural compound known for its antioxidant and anti-inflammatory properties, in alleviating ALI induced by IgG immune complexes (IgG-IC). Using MH-S cells as a model, we explore SYG's ability to target peroxisome proliferator-activated receptor gamma (PPARγ) and its anti-inflammatory properties. Our comprehensive investigation aims to elucidate the specific molecular mechanisms underlying SYG's effects against pyroptosis, as revealed through transcriptomic analysis. Validation in C57BL/6 mice provides in vivo support. Our findings indicate that SYG effectively mitigates IgG-IC-induced lung damage, as evidenced by a significant reduction in lung inflammation and tissue injury. SYG treatment notably decreases pro-inflammatory cytokine levels (TNF-α, IL-6, IL-1β) in both lung tissue and cells. Molecular docking analysis reveals SYG's robust binding to PPARγ, leading to the inhibition of IgG-IC-induced inflammatory signaling pathways. Additionally, transcriptomic analysis unveils SYG's potential in suppressing macrophage pyroptosis, potentially through the downregulation of key inflammatory mediators (NLRP3, GSDMD, Caspase-1). In summary, our study presents compelling evidence supporting SYG as an effective therapeutic agent for ALI. SYG's activation of PPARγ contributes to the suppression of NF-κB and C/EBPs expression, thereby mitigating inflammation. Moreover, SYG demonstrates the ability to inhibit macrophage pyroptosis by targeting the NLRP3/GSDMD/caspase-1 axis.

Current Clinical Trial Status and Future Prospects of PPAR-Targeted Drugs for Treating Nonalcoholic Fatty Liver Disease.

The number of patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is increasing globally and is raising serious concerns regarding the increasing medical and economic burden incurred for their treatment. The progression of NASH to more severe conditions such as cirrhosis and hepatocellular carcinoma requires liver transplantation to avoid death. Therefore, therapeutic intervention is required in the NASH stage, although no therapeutic drugs are currently available for this. Several anti-NASH candidate drugs have been developed that enable treatment via the modulation of distinct signaling cascades and include a series of drugs targeting peroxisome proliferator-activated receptor (PPAR) subtypes (PPARα/δ/γ) that are considered to be attractive because they can regulate both systemic lipid metabolism and inflammation. Multiple PPAR dual/pan agonists have been developed but only a few of them have been evaluated in clinical trials for NAFLD/NASH. Herein, we review the current clinical trial status and future prospects of PPAR-targeted drugs for treating NAFLD/NASH. In addition, we summarize our recent findings on the binding modes and the potencies/efficacies of several candidate PPAR dual/pan agonists to estimate their therapeutic potentials against NASH. Considering that the development of numerous PPAR dual/pan agonists has been abandoned because of their serious side effects, we also propose a repositioning of the already approved, safety-proven PPAR-targeted drugs against NAFLD/NASH.

MicroRNAs targeting peroxisome proliferator-activated receptor (PPAR) gene are differentially expressed in low birth weight placentae

IntroductionPeroxisome proliferator-activated receptors (PPARs) are activated by natural ligands like fatty acids and influence placental angiogenesis and pregnancy outcome. However, the underlying molecular mechanisms are not clear. This study aims to investigate the association of maternal and placental fatty acid levels with DNA methylation and microRNA regulation of PPARs in the placentae of women delivering low birth weight (LBW) babies. MethodsThis study includes 100 women delivering normal birth weight (NBW) baby and 70 women delivering LBW baby. Maternal and placental fatty acids levels were estimated by gas chromatograph. Gene promoter methylation and mRNA expression of PPARs was analyzed using Epitect Methyl-II PCR assay kit and RT-PCR respectively. Expression of miRNAs targeting PPAR mRNA were analyzed using a Qiagen miRCURY LNA PCR Array on RT-PCR. ResultsPlacental docosahexaenoic acid (DHA) levels and placental mRNA expression of PPARα and PPARγ were lower (p < 0.05 for all) in the LBW group. Differential expression of miRNAs (upregulated miR-33a-5p and miR-22-5p; downregulated miR-301a-5p, miR-518d-5p, miR-27b-5p, miR-106a-5p, miR-21-5p, miR-548d-5p, miR-17-5p and miR-20a-5p) (p < 0.05 for all) was observed in the LBW group. Maternal and placental polyunsaturated fatty acids and total omega-3 fatty acids were positively associated while saturated fatty acids were negatively associated with expression of miRNAs (p < 0.05 for all). Placental expression of miRNAs were positively associated with birth weight (p < 0.05 for all). DiscussionOur data suggests that maternal fatty acid status is associated with changes in the placental expression of miRNAs targeting PPAR gene in women delivering LBW babies.

MiR-4433a-3p promotes granulosa cell apoptosis by targeting peroxisome proliferator-activated receptor alpha and inducing immune cell infiltration in polycystic ovarian syndrome.

Granulosa cell (GC) proliferation and apoptosis are critical events of the ovum energy supply, which lead to follicular growth retardation or atresia, and various ovulatory obstacles, eventually resulting in the development of ovarian disorders such as polycystic ovarian syndrome (PCOS). Apoptosis and dysregulated miRNA expression in GCs are manifestations of PCOS. miR-4433a-3p has been reported to be involved in apoptosis. However, there is no study reporting the roles of miR-4433a-3p in GC apoptosis and PCOS progression. miR-4433a-3p and peroxisome proliferator-activated receptor alpha (PPAR-α) levels in GCs of PCOS patients or in tissues of a PCOS rat model were examined by quantitative polymerase chain reaction and immunohistochemistry. Bioinformatics analyses and luciferase assays were used to examine the association between miR-4433a-3p and PPAR-α, as well as PPAR-α and immune cell infiltration, in PCOS patients. miR-4433a-3p expression in GCs of PCOS patients was increased. miR-4433a-3p overexpression inhibited the growth of the human granulosa-like tumor cell line (KGN) and promoted apoptosis, while co-treatment with PPAR-α and miR-4433a-3p mimic rescued miR-4433a-3p-induced apoptosis. PPAR-α was a direct target of miR-4433a-3p and its expression was decreased in PCOS patients. PPAR-α expression was also positively correlated with the infiltration of activated CD4+ T cells, eosinophils, B cells, gamma delta T cells, macrophages, and mast cells, but negatively correlated with the infiltration of activated CD8+ T cells, CD56+ bright natural killer cells, immature dendritic cells, monocytes, plasmacytoid dendritic cells, neutrophils, and type 1T helper cells in PCOS patients. The miR-4433a-3p/PPAR-α/immune cell infiltration axis may function as a novel cascade to alter GC apoptosis in PCOS.

Hepatic fibrosis: Targeting peroxisome proliferator-activated receptor alpha from mechanism to medicines.

Liver fibrosis is the result of sustained chronic liver injury and inflammation leading to hepatocyte cell death followed by the formation of fibrous scars, which is the hallmark of NASH and alcoholic steatohepatitis and can lead to cirrhosis, HCC, and liver failure. Although progress has been made in understanding the pathogenesis and clinical consequences of hepatic fibrosis, therapeutic strategies for this disease are limited. Preclinical studies suggest that peroxisome proliferator-activated receptor alpha plays an important role in preventing the development of liver fibrosis by activating genes involved in detoxifying lipotoxicity and toxins, transrepressing genes involved in inflammation, and inhibiting activation of hepatic stellate cells. Given the robust preclinical data, several peroxisome proliferator-activated receptor alpha agonists have been tested in clinical trials for liver fibrosis. Here, we provide an update on recent progress in understanding the mechanisms by which peroxisome proliferator-activated receptor alpha prevents fibrosis and discuss the potential of targeting PPARα for the development of antifibrotic treatments.

The Strategy of Targeting Peroxisome Proliferator-Activated Receptor (PPAR) in the Treatment of Neuropsychiatric Disorders.

Peroxisome proliferator-activated receptors (PPARs) are nonsteroid nuclear receptors and transcription factorsthat regulate several neuroinflammatory and metabolic processes, recently involved in several neuropsychiatric conditions, including Alzheimer's disease, Parkinson's disease, major depressive disorder, post-traumatic stress disorder (PTSD), schizophrenia spectrum disorders, and autism spectrum disorders. PPARs are ligand-activated receptors that, following stimulation, induce neuroprotective effects by decreasing neuroinflammatory processes through inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) expression and consequent suppression of pro-inflammatory cytokine production. PPARs heterodimerize with the retinoid X-receptor (RXR) and bind to PPAR-responsive regulatory elements (PPRE) in the promoter region of target genes involved in lipid metabolism, synthesis of cholesterol, catabolism of amino acids, and inflammation. Interestingly, PPARs are considered functionally part of the extended endocannabinoid (eCB) system that includes the classic eCB, anandamide, which act at cannabinoid receptor types 1 (CB1) and 2 (CB2) and are implicated in the pathophysiology of stress-related neuropsychiatric disorders. In preclinical studies, PPAR stimulation improves anxiety and depression-like behaviors by enhancing neurosteroid biosynthesis. The peculiar functional role of PPARs by exerting anti-inflammatory and neuroprotective effects and their expression localization in neurons and glial cells of corticolimbic circuits make them particularly interesting as novel therapeutic targets for several neuropsychiatric disorders characterized by underlying neuroinflammatory/neurodegenerative mechanisms. Herein, we discuss the pathological hallmarks of neuropsychiatric conditions associated with neuroinflammation, as well as the pivotal role of PPARs with a special emphasis on the subtype alpha (PPAR-α) as a suitable molecular target for therapeutic interventions.

Effect of Insulin and Pioglitazone on Protein Phosphatase 2A Interaction Partners in Primary Human Skeletal Muscle Cells Derived from Obese Insulin-Resistant Participants.

Skeletal muscle insulin resistance is a major contributor to type-2 diabetes (T2D). Pioglitazone is a potent insulin sensitizer of peripheral tissues by targeting peroxisome proliferator-activated receptor gamma. Pioglitazone has been reported to protect skeletal muscle cells from lipotoxicity by promoting fatty acid mobilization and insulin signaling. However, it is unclear whether pioglitazone increases insulin sensitivity through changes in protein-protein interactions involving protein phosphatase 2A (PP2A). PP2A regulates various cell signaling pathways such as insulin signaling. Interaction of the catalytic subunit of PP2A (PP2Ac) with protein partners is required for PP2A specificity and activity. Little is known about PP2Ac partners in primary human skeletal muscle cells derived from lean insulin-sensitive (Lean) and obese insulin-resistant (OIR) participants. We utilized a proteomics method to identify PP2Ac interaction partners in skeletal muscle cells derived from Lean and OIR participants, with or without insulin and pioglitazone treatments. In this study, 216 PP2Ac interaction partners were identified. Furthermore, 26 PP2Ac partners exhibited significant differences in their interaction with PP2Ac upon insulin treatments between the two groups. Multiple pathways and molecular functions are significantly enriched for these 26 interaction partners, such as nonsense-mediated decay, metabolism of RNA, RNA binding, and protein binding. Interestingly, pioglitazone restored some of these abnormalities. These results provide differential PP2Ac complexes in Lean and OIR in response to insulin/pioglitazone, which may help understand molecular mechanisms underpinning insulin resistance and the insulin-sensitizing effects of pioglitazone treatments, providing multiple targets in various pathways to reverse insulin resistance and prevent and/or manage T2D with less drug side effects.

Potential of Therapeutic Small Molecules in Apoptosis Regulation in the Treatment of Neurodegenerative Diseases: An Updated Review.

Neurodegenerative disorders (NDs) include Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) and the common feature of NDs is the progressive death of specific neurons in the brain. Apoptosis is very important in developing the nervous system, nonetheless an elevated level of cell death has been observed in the case of NDs. NDs are different in terms of their neuronal vulnerability and clinical manifestations, however they have some overlapping neurodegenerative pathways. It has been demonstrated by several studies with cell lines and animal models that apoptosis has a significant contribution to make in advancing AD, ALS, HD, and PD. Numerous dying neurons were also identified in the brains of individuals with NDs and these conditions were found to be linked with substantial cell loss along with common characteristics of apoptosis including activation of caspases and cysteine-proteases, DNA fragmentation, and chromatin condensation. It has been demonstrated that several therapeutic agents including antioxidants, minocycline, GAPDH ligands, p53 inhibitors, JNK (c-Jun N-Terminal Kinase) inhibitors, glycogen synthase kinase-3 inhibitor, non-steroidal anti-inflammatory drugs, D2 dopamine receptor agonists, FK506, cell cycle inhibitors, statins, drugs targeting peroxisome proliferator-activated receptors, and gene therapy have the potential to provide protection to neurons against apoptosis. Therefore, the use of these potential therapeutic agents might be beneficial in the treatment of NDs. In this review, we have summarized the pathways that are linked with apoptotic neuronal death in the case of various NDs. We have particularly focused on the therapeutic agents that have neuroprotective properties and the potential to regulate apoptosis in NDs.

Peroxisome Proliferator-Activated Receptors Regulate Hepatic Immunity and Assist in the Treatment of Primary Biliary Cholangitis.

Fibrates, which are agonists of peroxisome proliferator-activated receptor alpha, have received increasing attention in the treatment of primary biliary cholangitis. Reduced alkaline phosphatase levels and improved clinical outcomes were observed in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid (UDCA) monotherapy4 when treated with bezafibrate or fenofibrate combined with UDCA. In contrast to obeticholic acid, which exacerbates pruritus in patients, fibrates have been shown to relieve pruritus. Clinical trial outcomes show potential for the treatment of primary biliary cholangitis by targeting peroxisome proliferator-activated receptors. It is currently agreed that primary biliary cholangitis is an autoimmune-mediated cholestatic liver disease, and peroxisome proliferator-activated receptor is a nuclear receptor that regulates the functions of multiple immune cells, thus playing an important role in regulating innate and adaptive immunity. Therefore, this review focuses on the immune disorder of primary biliary cholangitis and summarizes the regulation of hepatic immunity when peroxisome proliferator-activated receptors are targeted for treating primary biliary cholangitis.

An integrated study of Shenling Baizhu San against hyperuricemia: Efficacy evaluation, core target identification and active component discovery

Ethnopharmacological relevanceShenling Baizhu San (SLBZ) is a famous Traditional Chinese Medicine (TCM) formula that strengthens the spleen for replenishing qi, removing dampness, and inducing diuresis to relieve diarrhea. Combining the TCM interpretation that dampness is a vital pathogenesis factor in hyperuricemia occurrence and development, SLBZ has excellent potential against hyperuricemia from the perspective of TCM theories. Aim of the studyThis study aimed to investigate the efficacy of SLBZ against hyperuricemia and its possible mechanism with emphasis on the active components and the core targets. Materials and methodsIn the present study, we employed meta-analysis and a hyperuricemia quail model to evaluate the uric acid-lowering effect of SLBZ. Bodyweight, serum uric acid, and excreta uric acid levels in quails were assessed. Subsequently, we analyzed the potential active components and core targets of SLBZ against hyperuricemia by network pharmacology and calculated their interaction using molecular docking. Furthermore, the hyperuricemia rats treated with interfering agents of core targets were established to determine the central role of selected targets in hyperuricemia progression. Besides, we isolated and characterized the primary renal tubular epithelial cells of quails to verify the active components and core targets of SLBZ against hyperuricemia. Western blotting was used to observe the expression of core targets treated with active components under the stimulation of interfering agents. ResultsData from meta-analysis and animal experiments showed that SLBZ could work effectively against hyperuricemia. Hyperuricemia quails treated with SLBZ displayed significantly reduced serum uric acid levels accompanied by increased excretion of uric acid. According to network pharmacology and molecular docking results, 34 potential active components and the core target peroxisome proliferator-activated receptor gamma (PPARγ) for SLBZ against hyperuricemia were identified. The decreased serum uric acid levels in hyperuricemia rats treated with rosiglitazone, an agonist of PPARγ, confirms the essential role of PPARγ in the pathological process of hyperuricemia. Moreover, we first successfully isolated and characterized the primary renal tubular epithelial cells of quails and observed enhanced phosphorylation of PPARγ at Ser273 in cells handled with high-level uric acid. Whereas, the enhanced expression of p-PPARγ Ser273 could be down-regulated by luteolin and naringenin, two active components of SLBZ against hyperuricemia. ConclusionIn summary, SLBZ is a promising anti-hyperuricemia agent, and luteolin and naringenin are the active components for SLBZ against hyperuricemia by down-regulating phosphorylation of PPARγ at Ser273.

Advanced Glycation End Products Induced Mitochondrial Dysfunction of Chondrocytes through Repression of AMPKα-SIRT1-PGC-1α Pathway

Introduction: Our previous studies have demonstrated advanced glycation end products (AGEs) was an important mediator in osteoarthritis (OA) which may induce mitochondrial dysfunction. AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and its downstream target peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) are the critical sensors that regulate mitochondrial biogenesis and have been recognized as therapeutic targets in OA. This study was designed to test whether AGEs caused mitochondrial dysfunction through modulation of AMPKα/SIRT1/PGC-1α. Methods: We knocked down or overexpressed AMPKα, SIRT1, and PGC-1α by small interfering RNA or plasmid DNA transfection, respectively. Mitochondrial membrane potential (△Ψ) was detected by tetraethylbenzimidazolyl carbocyanine iodide (JC-1) fluorescence probe. Results: The results showed that AGEs impaired △Ψ, intracellular ATP level, and mitochondrial DNA content, linked to decreased AMPKα, SIRT1, and PGC-1α expression in chondrocyte. AMPKα pharmacologic activation or overexpression of AMPKα, SIRT1, and PGC-1α reversed impairments of mitochondrial biogenesis, oxidative stress, and inflammation in AGEs-induced chondrocytes. However, AMPKα activation using AICAR had decreased capacity to increase each of those same effect readouts in AGEs-treated SIRT1-siRNA or PGC-1α-siRNA chondrocyte. Conclusion: Taken together, AGEs reduced the AMPKα/SIRT1/PGC-1α signaling in chondrocytes, leading to mitochondrial dysfunction as a result of increased oxidative stress, inflammation, and apoptosis. These results indicated that target AMPK may be as a novel therapeutic strategy for AGEs-related OA prevention.

Targeting PPARs Signaling Pathways in Cardiotoxicity by Natural Compounds.

Cardiotoxicity can be a complication of both drugs and a variety of other chemicals that affects morbidity, quality of life, and even mortality. The accumulation of lipids and inflammation have been implicated in the development of cardiotoxicity. The peroxisome proliferator-activated receptors (PPARs), a family of transcription factors, have a role in controlling the cardiac expression of genes involved in lipid and glucose metabolism and the inflammatory response. The different PPAR isoforms, PPARα, PPARγ, and PPARβ/δ, have a role in multiple functions in cardiac tissue. The protective nature of several naturally occurring chemicals (NCs) against cardiotoxicity by targeting PPARα and PPARγ has been reported. The literature related to the ability of several NCs to modulate cardiotoxicity through targeting the AMP-activated protein kinase (AMPK)/the PPARγ coactivator-1 alpha (PGC-1α)/PPARα, the PPARα/the nuclear factor-kappa B (NF-κB), and the PPARγ/the nuclear factor-erythroid 2 related factors 2 (Nrf2)/the heme oxygenase-1 (HO-1)/NF-κB signaling pathways are reviewed.

Fenofibrate-Nicotinamide Cocrystals: Molecular Docking Studies and Evaluation in Tablet Dosage Form

The objectives of present investigation were to evaluate prepared cocrystals of fenofibrate and nicotinamide for pre-compression characteristics, docking studies for target peroxisome proliferator-activated receptor alpha, evaluate performance of cocrystals in tablet dosage form and to carry out in vivo antihyperlipidemic activity. The cocrystals were prepared by antisolvent addition method. Docking studies of cocrystals and pure fenofibrate against of target peroxisome proliferator-activated receptor alpha were carried out by using PyRx (version 0.8) docking tool, AutoDock Vina as docking program. The prepared cocrystals were evaluated for pre-compression properties like angle of repose, bulk density and Carr’s index. Cocrystals were formulated in tablet dosage form and evaluated for official and unofficial quality control tests. The antihyperlipidemic activity carried out in rats by using Triton X-100 induced hyperlipidemia model. Cocrystals binds with peroxisome proliferator-activated receptor alpha with more binding affinity as compared with fenofibrate. Cocrystal shows binding energy of -9.3 kcal/mol while fenofibrate shows -8.5 kcal/mol. The pre-compression properties were within the limits of United States Pharmacopeia guidelines. The pure fenofibrate tablet showed 24.7 % drug release at the end of 90 min and cocrystal based tablet showed 100 % at 45 min. There was no statistically significant difference in values for all biochemical parameters in case of in vivo activity for cocrystals in comparison with pure fenofibrate. From the docking studies we can conclude that cocrystals showed stronger more substantial formed stable complexes with target peroxisome proliferator-activated receptor alpha, but no statistically significant difference in pharmacodynamic studies.

Metabolomic Analysis Reveals the Therapeutic Effects of MBT1805, a Novel Pan-Peroxisome Proliferator-Activated Receptor Agonist, on α-Naphthylisothiocyanate-Induced Cholestasis in Mice.

Background and Aims: Therapeutic drugs that are used to treat cholestatic liver disease are limited; however, the results of clinical trials on primary biliary cholangitis treatment targeting peroxisome proliferator-activated receptors (PPARs) are encouraging. In this study, we aimed to identify the effects of MBT1805, a novel balanced PPARα/γ/δ agonist, on cholestasis induced by α-naphthylisothiocyanate (ANIT) and elucidate the underlying mechanisms through untargeted and bile acid-targeted metabolomic analysis. Methods: Levels of serum biochemical indicators (transaminase, aspartate transaminase, alkaline phosphatase, and total bilirubin) and liver histopathology were analyzed to evaluate the therapeutic effects of MBT1805 on ANIT-induced cholestasis in C57BL/6 mice. Untargeted and bile acid-targeted metabolomic analysis of liver tissues was performed using ultrahigh-performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-MC/MC). qRT-PCR and Western blot analysis were carried out to measure the expression of key enzymes and transporters regulating bile acid synthesis, biotransformation, and transport. Results: MBT1805 significantly improved abnormal levels of liver biochemical indicators and gallbladder enlargement induced by ANIT. Histopathological analysis showed that MBT1805 effectively relieved ANIT-induced necrosis, vacuolation, and inflammatory infiltration. Untargeted metabolomic analysis identified 27 metabolites that were involved in the primary biliary acid biosynthesis pathway. In addition, bile acid-targeted metabolomics showed that MBT1805 could alleviate the abnormal bile acid content and composition induced by ANIT. Furthermore, qRT-PCR and Western blot results confirmed that MBT1805 could effectively regulate bile acid synthesis, biotransformation, and transport which helps relieve cholestasis. Conclusions: MBT1805 is a potential candidate drug for cholestasis, with a balanced PPARα/γ/δ activation effect.