PPARγ Activation Research Articles

Decoration of GW9662 scaffold with a fragment-like hit via copper-catalyzed azide-alkyne cycloaddition reaction into peroxisome proliferator-activated receptor γ agonists

PPARγ is a member of nuclear receptor superfamily, which possesses a large Y-shaped cavity in the ligand-binding pocket. GW9662 is a well-known PPARγ antagonist which covalently reacts with the Cys285 residue via nucleophilic substitution. In contrast to its irreversibility, the ability of GW9662 to prevent other ligands from accessing the ligand-binding pocket is partly defective. By focusing on this incompleteness, we develop an integrated approach to create a new PPARγ agonist by using a structure of GW9662 as a scaffold for linking with a fragment compound. A screening of 1,040 compounds identified a partner ligand which synergistically activates PPARγ transcription in combination with GW9662. We introduced an azido or alkyne group to GW9662 or the identified fragment hit, respectively, and then connected the two structures via copper-catalyzed azide-alkyne cycloaddition. A coupling reaction provided a series of hybrid structure with triazole linker, among which the compounds with a bent configuration function as a partial PPARγ agonist. These results highlight a potential utility of GW9662 for the decoration with a fragment compound to develop a covalent agonist for PPARγ activation.

Molecular docking of sterol derivatives in Tagetes erecta Linn. as an antiatherosclerotic agents through activation of PPARγ and LXRα receptors

Atherosclerosis is a condition characterized by inflammation in the arteries, which is linked with the accumulation of lipids and alterations in metabolism. Considering that atherosclerosis is the main factor causing death in the world, it is necessary to carry out immediate prevention and treatment to reduce the risk of developing clinical severity. The creation of foam cells, which originate from macrophages, is considered a key element in cardiovascular ailments, particularly in the advancement of atherosclerosis. Two types of the nuclear receptors known as Peroxisome proliferator-activated receptor γ (PPARγ) and liver X receptor α (LXRα), which serve as a primary regulator of cholesterol, intracellular lipid homeostasis and they are instrumental in the process of reverse cholesterol transport (RCT). Activation of these receptors could potentially decrease foam cell formation, consequently lowering the risk of atherogenesis and reducing cardiovascular disease risk. This research aims to determine sterol derivative compounds in Tagetes erecta Linn. which have the best interaction and potential as anti-atherosclerosis through peroxisome proliferator-activated receptor γ (PPARγ) and liver X receptor α (LXRα) activation. The analysis of this study is using docking molecular analysis. The parameters observed in this study were docking score, visualization results, absorption, distribution, metabolism, excretion profile, and toxicity value. The molecular docking outcomes indicate that β-sitosterol and 7β-hydroxysitosterol possess the most favorable binding energy values. They exhibit a positive pharmacokinetic profile, with the exception of gastrointestinal absorption and respiratory toxicity.

PPARγ activation ameliorates cognitive impairment and chronic microglial activation in the aftermath of r-mTBI

Chronic neuroinflammation and microglial activation are key mediators of the secondary injury cascades and cognitive impairment that follow exposure to repetitive mild traumatic brain injury (r-mTBI). Peroxisome proliferator-activated receptor-γ (PPARγ) is expressed on microglia and brain resident myeloid cell types and their signaling plays a major anti-inflammatory role in modulating microglial responses. At chronic timepoints following injury, constitutive PPARγ signaling is thought to be dysregulated, thus releasing the inhibitory brakes on chronically activated microglia. Increasing evidence suggests that thiazolidinediones (TZDs), a class of compounds approved from the treatment of diabetes mellitus, effectively reduce neuroinflammation and chronic microglial activation by activating the peroxisome proliferator-activated receptor-γ (PPARγ). The present study used a closed-head r-mTBI model to investigate the influence of the TZD Pioglitazone on cognitive function and neuroinflammation in the aftermath of r-mTBI exposure. We revealed that Pioglitazone treatment attenuated spatial learning and memory impairments at 6 months post-injury and reduced the expression of reactive microglia and astrocyte markers in the cortex, hippocampus, and corpus callosum. We then examined whether Pioglitazone treatment altered inflammatory signaling mechanisms in isolated microglia and confirmed downregulation of proinflammatory transcription factors and cytokine levels. To further investigate microglial-specific mechanisms underlying PPARγ-mediated neuroprotection, we generated a novel tamoxifen-inducible microglial-specific PPARγ overexpression mouse line and examined its influence on microglial phenotype following injury. Using RNA sequencing, we revealed that PPARγ overexpression ameliorates microglial activation, promotes the activation of pathways associated with wound healing and tissue repair (such as: IL10, IL4 and NGF pathways), and inhibits the adoption of a disease-associated microglia-like (DAM-like) phenotype. This study provides insight into the role of PPARγ as a critical regulator of the neuroinflammatory cascade that follows r-mTBI in mice and demonstrates that the use of PPARγ agonists such as Pioglitazone and newer generation TZDs hold strong therapeutic potential to prevent the chronic neurodegenerative sequelae of r-mTBI.

Unveiling the Unexplored Multifactorial Potential of 5-Aminosalicylic Acid in Diabetic Wound Therapy.

Diabetic wounds (DWs) are considered chronic complications observed in patients suffering from type 2 diabetes mellitus (DM). Usually, DWs originate from the interplay of inflammation, oxidation, impaired tissue re-epithelialization, vasculopathy, nephropathy, and neuropathy, all of which are related to insulin resistance and sensitivity. The conventional approaches available for the treatment of DWs are mainly confined to the relief of wound pressure, debridement of the wound, and management of infection. In this paper, we speculate that treatment of DWs with 5-aminosalicylic acid (5-ASA) and subsequent activation of peroxisome proliferator-activated receptor gamma (PPAR-γ) and transforming growth factor beta (TGF-β) via the AhR pathway might be highly beneficial for DW patients. This estimation is based on several lines of evidence showing that 5-ASA and PPAR-γ activation are involved in the restoration of insulin sensitivity, re-epithelialization, and microcirculation. Additionally, 5-ASA and TGF-β activate inflammation and the production of pro-inflammatory mediators. Suitable stabilized formulations of 5-ASA with high absorption rates are indispensable for scrutinizing its probable pharmacological benefits since 5-ASA is known to possess lower solubility profiles because of its reduced permeability through skin tissue. In vitro and in vivo studies with stabilized formulations and a control (placebo) are mandatory to determine whether 5-ASA indeed holds promise for the curative treatment of DWs.

Cynara cardunculus L. inhibits adipogenic differentiation of 3T3-L1 cells via activation of AMPK signaling pathway

Promotion of brown adipose tissue phenotype, able to transform energy into heat, is a promising target against obesity development. We investigated the effects of a standardized extract from Cynara cardunculus L. (CCLE) leaves, considered a waste food resource, on adipogenesis inhibition in 3T3-L1 cells, through the thermogenic process involvement. CCLE inhibited adipogenesis (C/EBPβ, PPAR-γ, FABP4, SREBP-1, and FASN) and increased thermogenesis via upregulation of AMPK phosphorylation. Furthermore, CCLE induced FOXO1 pathway as adipogenesis repressive mechanism affecting PPAR-γ activity and induced the expression of cell cycle inhibitor p21. However, pretreatment with the AMPK inhibitor compound C abolished CCLE effects on FOXO1, p21, C/EBPβ, and PPAR-γ. These data confirmed that the antiadipogenic effect of the extract is related to AMPK activation. Therefore, this work provides new perspectives for the use of this extract in obesity prevention and management. Additionally, reuse/recycling of waste food resources provides added value from a circular economy perspective.

Association between genetically proxied PPARG activation and psoriasis vulgaris: a Mendelian randomization study

Background Psoriasis is a common autoimmune disease in clinical practice, and previous observational studies have suggested that PPARG agonists such as Pioglitazone may be potential therapeutic agents. However, due to interference from various confounding factors, different observational studies have not reached a unified conclusion. We aim to evaluate the potential use of PPARG agonists for treating psoriasis from a new perspective through drug-targeted Mendelian randomization (MR) analysis. Materials and methods This study includes data on 8,876 individuals for acute myocardial infarction from GWAS, and LDL cholesterol data from 343,621 Europeans. FinnGen contributed psoriasis vulgaris data for 403,972 individuals. The DrugBank10 databases function to identify genes encoding protein products targeted by active constituents of lipid-modifying targets. A two-sample MR analysis and summary-data-based MR (SMR) analysis estimated the associations between expressions of drug target genes and symptoms of psoriasis vulgaris. A multivariable MR study was further conducted to examine if the observed association was direct association. Results SMR analysis revealed that enhanced PPARG gene expression in the blood (equivalent to a one standard deviation increase) was a protective factor for psoriasis vulgaris (beta = −0.2017, se = 0.0723, p = 0.0053). Besides, there exists an MR association between LDL mediated by PPARG and psoriasis vulgaris outcomes (beta = −3.9169, se = 0.5676, p = 5.17E-12). These results indicate that PPARG is a therapeutic target for psoriasis, suggesting that psoriasis may be a potential indication for PPARG agonists. Conclusion This study confirms that therapeutic activation of PPARG helps suppress the development of psoriasis. Psoriasis may be a new indication for PPARG agonists, such as Pioglitazone. In the future, new anti-psoriatic drugs could be developed targeting PPARG.

Upregulation of peroxisome proliferator-activated receptor γ with resorcinol alleviates reactive oxygen species generation and lipid accumulation in neuropathic lysosomal storage diseases

Neuropathic lysosomal storage diseases (NLSDs), including ceroid lipofuscinosis neuronal 3 (CLN3) disease and Gaucher disease type 2 (GD2), are typically present in adolescents; however, there are no approved therapies. CLN3 disease is the most common of the 13 types of neuronal ceroid lipofuscinosis, and Gaucher disease is the most common type of lysosomal storage disease. These NLSDs share oxidative stress and lysosomal dysfunction with Parkinson’s disease. In this study, we used patient-derived cells (PDCs) and resorcinol to develop a therapeutic agent based on peroxisome proliferator-activated receptor γ (PPARγ) activation. PPARγ is a major regulator of autophagy and reactive oxygen species (ROS). Resorcinol, a polyphenolic compound, has been reported to exhibit PPARγ agonistic potential. Protein levels were analyzed by immunoblotting and immunofluorescence microscopy. Changes in cellular metabolism, including ROS levels, lipid droplet content, and lysosomal activity, were measured by flow cytometry. Resorcinol reduced ROS levels by suppressing hypoxia-inducible factor 1α levels in CLN3-PDCs. Resorcinol upregulated autophagy and reduced lipid accumulation in CLN3-PDCs; however, these effects were abolished by autophagy inhibitors. Resorcinol increased nuclear PPARγ levels in CLN3-PDCs, and PPARγ antagonists abolished the therapeutic effects of resorcinol. Moreover, Resorcinol upregulated nuclear PPARγ levels and lysosomal activity in GD2-PDCs, and reduced lipid accumulation and ROS levels. In summary, resorcinol alleviated the shared pathogenesis of CLN3 disease and GD2 through PPARγ upregulation. These findings suggest that resorcinol is a potential therapeutic candidate for alleviating NLSD progression.

Cardioprotective effects of nanoparticles green formulated by Spinacia oleracea extract on isoproterenol-induced myocardial infarction in mice by the determination of PPAR-γ/NF-κB pathway

Abstract We developed a contemporary cardioprotective medication using silver nanoparticles (AgNPs) loaded with Spinacia oleracea to treat isoproterenol (ISO)-induced myocardial infarction in mice, focusing on the PPAR-γ/NF-κB pathway. The physicochemical techniques, such as Fourier-transform infrared spectroscopy, field emission scanning electron microscopy, ultraviolet–visible spectroscopy, and energy dispersive X-ray analysis, were employed to characterize the AgNPs. In the in vivo experiment, myocardial infarction was induced in mice by administering ISO subcutaneously at a dose of 40 mg/kg every 12 h for a total of three times. The mice were divided into five groups in a random manner: (1 and 2) ISO + AgNPs at varying doses (10 and 20 μg/mL) and time points; (3) ISO; and (4) control. Following the treatment, cardiac function was assessed through electrocardiogram, as well as biochemical and histochemical analyses. In the study, we examined the inflammatory reactions and cell death in human coronary artery endothelial cells exposed to lipopolysaccharide (LPS). The PPAR-γ/NF-κB activation by LPS and the resulting cytokine production were checked using real-time PCR and western blot techniques. The typical ST segment depression in myocardial infarction mice is significantly inhibited by the administration of AgNPs. Additionally, the treatment with AgNPs leads to a significant improvement in ventricular wall infarction, a decrease in mortality rate, and inhibition of myocardial injury marker levels. Furthermore, the application of AgNPs resulted in a decrease in the inflammatory environment within the hearts of mice with myocardial infarction. This effectively prevented the increase in TNF-α, IL-1β, and IL-6. The gene expression normalization of PPAR-γ/NF-κB/IκB-α/IKKα/β and PPAR-γ phosphorylation could potentially be linked to the advantageous impacts of AgNPs. In the context of an in vitro experiment, the administration of AgNPs demonstrated a notable decrease in cell death and inflammation cytokines expression inhibition. The myocardial infarction mice in the pre + post-ISO group appear to experience more noticeable cardioprotective effects from the treatment with AgNPs than those in the post-ISO group. Our research findings demonstrate that AgNPs possess cardioprotective efficacies in ISO-induced myocardial infarction. This beneficial effect may be attributed to the PPAR-γ activation and the NF-κB signaling inhibition. Consequently, our study presents a novel remedial approach for myocardial infarction treatment in clinical settings.

Cyanidin-3-O-glucoside attenuates LPS-induced endometritis in mice via regulating PPARγ activation

Endometritis is a common disease that endangers human and animal health. Cyanidin-3-O-glucoside (C3G), a kind of anthocyanin, exists in a variety of plants and shows many biological activities. Here, we investigated the effect and mechanism of C3G on LPS-induced endometritis in mice. The results showed that C3G significantly decreased wet to dry weight (W/D) ratio of uterine, improved uterine pathological injury, and inhibited MPO activity. Further mechanism investigation showed that the activation of NFκB pathway and the levels of TNF-a, IL-1β, and IL-6 were significantly suppressed after C3G treatment. Conversely, C3G promoted LPS-induced the activation of the PPARγ/ABCA1 pathway. Interestingly, the anti-inflammatory effect of C3G was significantly weakened by GW9662, a PPARγ inhibitor. In addition, the anti-oxidative stress effect of C3G was also found. For the first time, our results showed that treatment with C3G might be a new strategy for treating endometritis.

Exploring fingerprints for antidiabetic therapeutics related to peroxisome proliferator-activated receptor gamma (PPARγ) modulators: A chemometric modeling approach

This study demonstrated the correlation of molecular structures of Peroxisome proliferator-activated receptor gamma (PPARγ) modulators and their biological activities. Bayesian classification, and recursive partitioning (RP) studies have been applied to a dataset of 323 PPARγ modulators with diverse scaffolds. The results provide a deep insight into the important sub-structural features modulating PPARγ. The molecular docking analysis again confirmed the significance of the identified sub-structural features in the modulation of PPARγ activity. Molecular dynamics simulations further underscored the stability of the complexes formed by investigated modulators with PPARγ. Overall, the integration of many computational approaches unveiled key structural motifs essential for PPARγ modulatory activity that will shed light on the development of effective modulators in the future.

PPARγ activation ameliorates PM2.5-induced renal tubular injury by inhibiting ferroptosis and epithelial–mesenchymal transition

Exposure to fine particulate matter (PM2.5) has been associated with the development and progression of renal disease. Peroxisome proliferator-activated receptor gamma (PPARγ), a key transcription factor involved in inflammation as well as lipid and glucose metabolism, helps maintain the integrity of tubular epithelial cells. However, the precise role of PPARγ in PM2.5-induced tubular injury remains unclear. In this study, we investigated the regulatory effects of PPARγ on PM2.5-induced ferroptotic stress and epithelial–mesenchymal transition (EMT) in tubular (HK-2) cells. We found that downregulation of PPARγ expression was correlated with EMT in PM2.5-exposed cells. Pretreatment with the PPARγ agonist 15d-PGJ2 protected the cells from EMT by reducing ferroptotic stress, whereas that with the PPARγ antagonist GW9662 promoted EMT. Furthermore, pretreatment with ferrostatin-1 (Fer-1) significantly prevented PM2.5-induced EMT and downregulation of PPARγ expression. Notably, overexpression of PPARγ blocked PM2.5-induced downregulation of E-cadherin and GPX4 expression and upregulation of α-SMA expression. This study highlights the complex associations of PPARγ with ferroptosis and EMT in PM2.5-exposed tubular cells. Our findings suggest that PPARγ activation confers protection against PM2.5-induced renal injury.

Interrogating the estrogen-mediated regulation of adrenocortical Klotho expression using ovariectomized albino rat model exposed to repeated restraint stress.

Reproductive aging is associated with altered stress response and many other menopausal symptoms. Little is known about the adrenal expression of the anti-aging protein Klotho or how it is modulated by estrogen in ovariectomized stressed rats. Fifty-six Wistar female rats were assigned into seven equal groups. Sham-operated (Sham), sham stressed (Sham/STS), ovariectomized (OVR), ovariectomized stressed (OVR/STS), ovariectomized stressed rosiglitazone-treated (OVR/STS/R), ovariectomized stressed estrogen-treated (OVR/STS/E), and ovariectomized stressed estrogen/GW9662 co-treated (OVR/STS/E/GW) groups. All stressed rats were subjected daily to a one-hour restraint stress test for 19days.At the end of the experiment, blood was collected for serum corticosterone (CORT) analysis. Adrenal tissues were obtainedand prepared for polymerase chain reaction (PCR) assay, hematoxylin and eosin (H&E), immunohistochemistry-based identification of Klotho and PPAR-γ, and Oil Red O (ORO) staining. The rise in serum CORT was negligible in the OVR/STS group, in contrast to the Sham/STS group. The limited CORT response in the former group was restored by estrogen and rosiglitazone and blocked by estrogen/GW9226 co-administration. ORO-staining revealed a more evident reduction in the adrenal fat in the OVR/STS group, which was reversed by estrogen and counteracted by GW. Also, there was a comparable expression pattern of Klotho and PPAR-γ in the adrenals. The adrenal Klotho decreased in the OVR/STS group, but was reversed by estrogen treatment. GW9226/estrogen co-treatment interfered with the regulatory effect of estrogen on Klotho. The study suggested modulation of the adrenal Kotho expression by estrogen, in the ovariectomized rats subjected to a restraint stress test. This estrogen-provided adrenal protection might be mediated by PPAR-γ activation.

Potential Antidiabetic Activity of β-sitosterol from Zingiber roseum Rosc. via Modulation of Peroxisome Proliferator-activated Receptor Gamma (PPARγ).

To evaluate the antidiabetic potential of β-sitosterol from Zingiber roseum. Diabetes mellitus is a cluster of metabolic disorders, and 90% of diabetic patients are affected with Type II diabetes (DM2). For the treatment of DM2, thiazolidinedione drugs (TZDs) were proposed, but recent studies have shown that TZDs have several detrimental effects, such as weight gain, kidney enlargement (hypertrophy), fluid retention, increased risk of bone fractures, and potential harm to the liver (hepatotoxicity). That is why a new molecule is needed to treat DM2. The current research aimed to assess the efficacy of β-Sitosterol from methanolic extract of Zingiber roseum in managing diabetes via PPARγ modulation. Zingiber roseum was extracted using methanol, and GC-MS was employed to analyze the extract. Through homology modeling, PPARγ structure was predicted. Molecular docking, MD simulation, free binding energies, QSAR, ADMET, and bioactivity and toxicity scores were all used during the in-depth computer-based research. Clinically, agonists of synthetic thiazolidinedione (TZDs) have been used therapeutically to treat DM2, but these TZDs are associated with significant risks. Hence, GC-MS identified phytochemicals to search for a new PPAR-γ agonist. Based on the in-silico investigation, β-sitosterol was found to have a higher binding affinity (-8.9 kcal/mol) than standard drugs. MD simulations and MMGBSA analysis also demonstrated that β-sitosterol bound to the PPAR-γ active site stably. It can be concluded that β-sitosterol from Z. roseum attenuates Type-II diabetes by modulating PPARγ activity.

Glucose transporter 1 is essential for the resolution of methicillin-resistant S. aureus skin and soft tissue infections

Skin/soft tissue infections (SSTIs) caused by methicillin-resistant Staphylococcus aureus (MRSA) pose a major healthcare burden. Distinct inflammatory and resolution phases comprise the host immune response to SSTIs. Resolution is a myeloid PPARγ-dependent anti-inflammatory phase that is essential for the clearance of MRSA. However, the signals activating PPARγ to induce resolution remain unknown. Here, we demonstrate that myeloid glucose transporter 1 (GLUT-1) is essential for the onset of resolution. MRSA-challenged macrophages are unsuccessful in generating an oxidative burst or immune radicals in the absence of GLUT-1 due to a reduction in the cellular NADPH pool. This translates invivo as a significant reduction in lipid peroxidation products required for the activation of PPARγ in MRSA-infected mice lacking myeloid GLUT-1. Chemical induction of PPARγ during infection circumvents this GLUT-1 requirement and improves resolution. Thus, GLUT-1-dependent oxidative burst is essential for the activation of PPARγ and subsequent resolution of SSTIs.

Protective effects of pioglitazone in renal ischemia-reperfusion injury (RIRI): focus on oxidative stress and inflammation.

Renal ischemia-reperfusion injury (RIRI) is a critical phenomenon that compromises renal function and is the most serious health concern related to acute kidney injury (AKI). Pioglitazone (Pio) is a known agonist of peroxisome proliferator-activated receptor-gamma (PPAR-γ). PPAR-γ is a nuclear receptor that regulates genes involved in inflammation, metabolism, and cellular differentiation. Activation of PPAR-γ is associated with antiinflammatory and antioxidant effects, which are relevant to the pathophysiology of RIRI. This study aimed to investigate the protective effects of Pio in RIRI, focusing on oxidative stress and inflammation. We conducted a comprehensive literature search using electronic databases, including PubMed, ScienceDirect, Web of Science, Scopus, and Google Scholar. The results of this study demonstrated that Pio has antioxidant, anti-inflammatory, and anti-apoptotic activities that counteract the consequences of RIRI. The study also discussed the underlying mechanisms, including the modulation of various pathways such as TNF-α, NF-κB signaling systems, STAT3 pathway, KIM-1 and NGAL pathways, AMPK phosphorylation, and autophagy flux. Additionally, the study presented a summary of various animal studies that support the potential protective effects of Pio in RIRI. Our findings suggest that Pio could protect the kidneys from RIRI by improving antioxidant capacity and decreasing inflammation. Therefore, these findings support the potential of Pio as a therapeutic strategy for preventing RIRI in different clinical conditions.

Oxidative Stress and the Nrf2/PPARγ Axis in the Endometrium: Insights into Female Fertility.

Successful pregnancy depends on precise molecular regulation of uterine physiology, especially during the menstrual cycle. Deregulated oxidative stress (OS), often influenced by inflammatory changes but also by environmental factors, represents a constant threat to this delicate balance. Oxidative stress induces a reciprocally regulated nuclear factor erythroid 2-related factor 2/peroxisome proliferator-activated receptor-gamma (Nrf2/PPARγ) pathway. However, increased PPARγ activity appears to be a double-edged sword in endometrial physiology. Activated PPARγ attenuates inflammation and attenuates OS to restore redox homeostasis. However, it also interferes with physiological processes during the menstrual cycle, such as hormonal signaling and angiogenesis. This review provides an elucidation of the molecular mechanisms that support the interplay between PPARγ and OS. Additionally, it offers fresh perspectives on the Nrf2/PPARγ pathway concerning endometrial receptivity and its potential implications for infertility.

Cellular Effects of Cationic Copper(II) Schiff Base Complexes: Anti-Inflammatory and Antiproliferative Properties.

A series of potassium isothiocyanato-(N-salicylidene-aminoacidato) cuprates (1-5) with the general formula of the monomeric unit K[Cu(sal-aa)(NCS)] ⋅ xH2O (x=0 or 2), containing a Schiff-base ligand (H2sal-aa) derived from natural amino acids such as glycine, DL-α-alanine, DL-valine, DL-phenylalanine and β-alanine, and salicylaldehyde, was screened for in vitro antiradical and major cellular effects against selected cancerous and normal cells. The complexes exhibited strong antioxidant properties against superoxide in vitro and a protective effect on DNA under Fenton-like reaction conditions. Screening of their cellular effects revealed moderate in vitro cytotoxicity against human cancer cell lines (A2780, A2780R and MCF-7), with IC50 values of 25-35 μM, and relatively low toxicity to normal fibroblast MRC-5 cells (with IC50 values>50 μM). Additional experiments performed on A2780 cells revealed that the most potent complex 5 significantly increased the number of A2780 cells arrested in the G2/M phase of the cell cycle and triggered intracellular oxidative stress. The selected flow cytometry experiments (detection of apoptosis/autophagy and activation of caspases 3/7 and depletion of mitochondrial membrane potential) did not reveal the dominant mechanism underlying the cytotoxicity of the complexes but clearly differentiated their molecular effects from those of the reference drug cisplatin. All the complexes exerted anti-inflammatory effects by modulating the levels of the proinflammatory cytokines TNF-α and IL-1β in LPS-activated THP-1 macrophage-like cells. Complex 5 also slightly influenced the activity of the upstream NF-κB transcription factor, while no effect on PPARγ activation was detected.

New Insights into the Role of PPARγ in Skin Physiopathology.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor expressed in many tissues, including skin, where it is essential for maintaining skin barrier permeability, regulating cell proliferation/differentiation, and modulating antioxidant and inflammatory responses upon ligand binding. Therefore, PPARγ activation has important implications for skin homeostasis. Over the past 20 years, with increasing interest in the role of PPARs in skin physiopathology, considerable effort has been devoted to the development of PPARγ ligands as a therapeutic option for skin inflammatory disorders. In addition, PPARγ also regulates sebocyte differentiation and lipid production, making it a potential target for inflammatory sebaceous disorders such as acne. A large number of studies suggest that PPARγ also acts as a skin tumor suppressor in both melanoma and non-melanoma skin cancers, but its role in tumorigenesis remains controversial. In this review, we have summarized the current state of research into the role of PPARγ in skin health and disease and how this may provide a starting point for the development of more potent and selective PPARγ ligands with a low toxicity profile, thereby reducing unwanted side effects.

Macrophage polarization as a novel endpoint for assessing combined risk of phthalate esters

Combined exposure to phthalate esters (PAEs) has garnered increasing attention due to potential synergistic effects on human health. This study aimed to develop an in vitro model using human macrophages to evaluate the combined toxicity of PAEs and explore the underlying mechanisms. A high-throughput screening system was engineered by expressing a PPRE-eGFP reporter in THP-1 monocytes to monitor macrophage polarization upon PAEs exposure. Individual PAEs exhibited varied inhibitory effects on M2 macrophage polarization, with mono(2-ethylhexyl) phthalate (MEHP) being the most potent. Isobologram analysis revealed additive interactions when MEHP was combined with other PAEs, resulting in more pronounced suppression of M2 markers compared to individual compounds. Mechanistic studies suggested PAEs may exert effects by modulating PPARγ activity to inhibit M2 polarization. Notably, an equimolar mixture of six PAEs showed additive inhibition of M2 markers. In vivo experiments corroborated the combined hepatotoxic effects, with mice exposed to a PAEs mixture exhibiting reduced liver weight, dyslipidemia, and decreased hepatic M2 macrophages compared to DEHP alone. Transcriptome analysis highlighted disruptions in PPAR signaling, and distinct pathway alterations on cholesterol metabolism in the mixture group. Collectively, these findings underscore the importance of evaluating mixture effects and provide a novel approach for hazard assessment of combined PAEs exposure with implications for environmental health risk assessment.

Cilostazol protects against gastric ulcers by regulating PPAR-γ, HO-1, PECAM-1, pErk-1, NF-κB, Bcl-2, and cleaved caspase-3 protein expression

Millions of individuals worldwide, across all age groups, suffer from the widespread health issue of gastric ulcers. In many experiments, cilostazol (Cls), a phosphodiesterase-3 inhibitor, was recently shown to have anti-ulcer activity. Notably, Cls increases the expression and transcriptional activity of PPAR-γ in vitro and in vivo. This study aimed to evaluate the protective effect of Cls against ethanol-induced gastric ulcers and clarify the possible underlying mechanisms with an emphasis on the role of PPAR-γ. Male albino rats were treated with ethanol to induce gastric ulcers, or they were pretreated with Cls, omeprazole (Omp), GW9662, or Cls + GW9662 for 14 consecutive days before receiving ethanol. Cls protects against ethanol-induced gastric ulcers. Cls treatment significantly reduced ethanol-induced upregulation of the pro-inflammatory markers (IL-1β, IL-6, TNF-α, and NF-κB), MDA (a marker of lipid peroxidation), and caspase-3 and cleaved caspase-3 (apoptotic markers). On the other hand, Cls treatment counteracted ethanol-induced downregulation of PPAR-γ, pErk-1, HO-1 and GSH (antioxidant markers), PECAM-1 and NO (healing markers), and Bcl-2 (antiapoptotic marker). However, when combined with GW9662, a potent antagonist of PPAR-γ, Cls loses its effects. In conclusion, these results suggest that PPAR-γ and pErk-1 are essential for Cls’s protective effects against ethanol-induced gastric ulcers.Graphical abstract