Search Results (244)

Background: High Mobility Group Box 1 is a mediator in inflammation, acting as a damage-associated molecular pattern molecule in various diseases. This review examines its role in nasal inflammatory disorders, such as chronic rhinosinusitis and allergic rhinitis. Methods: A comprehensive review of recent literature was conducted using a refined PubMed search strategy, focusing on studies published from 2015 onward and targeting HMGB1’s role in nasal inflammatory diseases. Results: HMGB1 emerges as a central factor in amplifying and modulating inflammatory responses through interactions with multiple receptors. It regulates cytokine production, epithelial–mesenchymal transition, and tissue remodeling, particularly in eosinophilic CRS. While discrepancies in the literature highlight its context-dependent activity, therapeutic strategies like glycyrrhetinic acid and PPAR-γ agonists demonstrate potential in modulating its effects. Conclusions: HMGB1 represents a promising diagnostic biomarker and therapeutic target in nasal inflammatory diseases. However, due to its intrinsic nature and multiple localizations, much remains to be understood. It is precisely by reflecting on its role as an “inflammatory crossroads” that we aim to underscore the need for targeted translational research to elucidate the molecular mechanisms and therapeutic applications of HMGB1. Full article

Hyperuricemia (HUA) is a metabolic disorder characterized by abnormal purine metabolism and/or reduced uric acid (UA) excretion. Chicory (Cichorium intybus L.), recognized in Traditional Chinese Medicine, is noted for its anti-HUA effects, particularly in enhancing intestinal UA excretion, though the underlying mechanisms remain unclear. Studies indicate that disruptions in gut microbiota and its metabolites are associated with HUA, and chicory has been demonstrated to ameliorate gut microbiota dysbiosis. Among gut microbiota-derived metabolites, butyrate, a short-chain fatty acid, plays a crucial role in gut functions and is linked to HUA. Therefore, butyrate may be pivotal in elucidating the mechanism by which chicory promotes intestinal UA excretion. This study aims to investigate whether chicory facilitates intestinal UA excretion through gut microbiota-derived butyrate and to elucidate the underlying mechanism. We employed an integrated methodology combining network biology with the NHANES database analysis to explore the pathological relationship between butyrate and HUA. Our findings were subsequently validated through animal experiments. We administered chicory to rats with HUA to ascertain whether butyrate serves as the key gut microbiota metabolite through which chicory promotes intestinal UA excretion. Furthermore, we utilized western blotting to assess the expression of core targets within the PPARγ-ABCG2 pathway associated with butyrate under conditions where animals received butyrate supplements and PPARγ agonists separately. The network biology indicates that butyrate is a crucial short-chain fatty acid influencing HUA. Analyses of NHANES data and animal experiments further confirm a significant negative correlation between butyrate and serum uric acid (SUA) levels. HUA rats exhibited intestinal barrier damage, impaired intestinal UA excretion, reduced butyrate levels, and decreased expression of PPARγ and ABCG2 proteins. Intervention with chicory in HUA rats repaired intestinal barrier damage, enhanced intestinal UA excretion, and increased both butyrate levels and the expression of PPARγ and ABCG2 proteins. Similarly, interventions with butyrate supplements or PPARγ agonists in HUA rats effectively promoted intestinal UA excretion and increased the expression of PPARγ and ABCG2 proteins. This study demonstrates that butyrate is a key metabolite produced by gut microbiota, through which chicory regulates gut microbiota to enhance intestinal UA excretion. The underlying mechanism involves the activation of the PPARγ-ABCG2 pathway, which is facilitated by elevated butyrate levels in the intestine. Full article

Recent advances in cannabinoid-based therapies identified the natural CB2 receptor agonist β-caryophyllene (BCP) as a promising anti-inflammatory and neuroprotective agent. To further explore its therapeutic potential on the management of neurodegenerative disorders, in the present study we investigated the ability of BCP to prevent neuroinflammation and promote neuroprotection by using both in vitro and ex vivo models of β-amyloid induced neurotoxicity. Our data showed that BCP significantly protected human microglial HMC3 cells from Aβ_25-35-induced cytotoxicity, reducing the release of pro-inflammatory cytokines (TNF-α, IL-6) while enhancing IL-10 secretion. These effects were associated with a reduced activation of the NF-κB pathway, which emerged as a central mediator of BCP action. Notably, the use of CB2R- or PPARγ-selective antagonists revealed that the observed NF-κB inhibition by BCP may involve the coordinated activation of both canonical (e.g., CB2R) and non-canonical (e.g., PPARγ) receptors. Moreover, BCP restored the expression of SIRT1, PGC-1α, and BDNF, indicating the involvement of neurotrophic pathways. Clear neuroprotective properties for BCP have been highlighted in Aβ_1-42-treated brain slice preparations, where BCP demonstrated the rescue of both the amyloid-dependent depression of BDNF expression and long-term synaptic potentiation (LTP) impairment. Overall, our results suggest that BCP constitutes an attractive natural molecule for the treatment of Aβ-induced neuroinflammation and synaptic dysfunction, warranting further exploration for its clinical application. Full article

The oil extract derived from black soldier fly (Hermetia illucens) larvae (BSFL) is characterized by a distinctive fatty acid composition and bioactive compounds with demonstrated anti-inflammatory properties, as shown in our previous work. The present study aims to mechanistically explore the immunomodulatory effects of a saponified form of BSFL oil (MBSFL) and its potential interaction with metabolic signaling pathways. Using Pam3CSK4-polarized M1 primary human peripheral blood mononuclear cells (PBMCs), we demonstrate that MBSFL phenotypically suppressed the secretion of pro-inflammatory cytokines TNFα, IL-6, IL-17, and GM-CSF (p < 0.01) without altering anti-inflammatory cytokine levels (TGFβ1, IL-13, and IL-4). A phosphoproteomic analysis of Pam3CSK4-stimulated THP-1 macrophages revealed MBSFL-mediated downregulation of CK2 and ERK kinases (p < 0.05), key regulators of NF-κB signaling activation. We confirmed that MBSFL directly inhibits NF-κB p65 nuclear translocation (p < 0.05), using both immunofluorescence staining and a western blot analysis of nuclear and cytoplasmic fractions. In the context of metabolism, using a luciferase reporter assay, we demonstrate that MBSFL functions as a weak agonist of PPARγ and PPARδ (p < 0.05), which are nuclear receptors involved in lipid metabolism and immune regulation. However, subsequent immunoblotting revealed a macrophage polarization-dependent regulation: MBSFL upregulated PPARγ in M0 macrophages but did not prevent its suppression upon Pam3CSK4 stimulation, whereas it specifically enhanced PPARδ expression during M1 polarization (p < 0.05). This study provides novel experimental evidence supporting our hypothesis of MBSFL’s role in immunometabolism. We demonstrate for the first time that MBSFL acts as a dual regulator by suppressing NF-κB-mediated inflammation while promoting PPARδ activity—an inverse relationship with potential relevance to immunometabolic disorders. Full article

Background: This study investigates the effects of cadmium chloride (CdCl₂) on hippocampal peroxisome proliferator-activated receptor gamma (PPARγ) expression and examines whether PPARγ activation mediates the neuroprotective effects of quercetin (QUR). Methods: Sixty adult male rats were included in this study, separated into 12 rats per group as follows: control, CdCl₂ (0.5 mg/kg), CdCl₂ + PPARγ agonist (Pioglitazone, 10 mg/kg), CdCl₂ + QUR (25 mg/kg), and CdCl₂ + QUR + PPARγ antagonist (GW9662, 1 mg/kg). Treatments were administered orally for 30 days. At the end of the experiment, behavioral memory tests, hippocampal histology, markers of cholinergic function, neuroplasticity, oxidative stress, inflammation, and apoptosis, as well as transcription levels of some genes were carried out. Results: CdCl₂ exposure significantly reduced hippocampal PPARγ mRNA and DNA binding potential and nuclear levels. Additionally, CdCl₂ impaired spatial, short-term, and recognition memory, decreased granular cell density in the dentate gyrus (DG), and reduced levels of neuroprotective factors, including Nrf2, brain-derived neurotrophic factor (BDNF), acetylcholine (ACh), and several antioxidant enzymes including heme-oxygenase-1 (HO-1) and superoxide dismutase (SOD), as well as reduced glutathione (GSH). Conversely, CdCl₂ elevated levels of oxidative stress, inflammation, and apoptosis markers such as interleukin-6 (IL-6), malondialdehyde (MDA), Bax, tumor necrosis factor-α (TNF-α), and cleaved caspase-3. QUR and Pioglitazone reversed these effects, restoring expression and PPARγ activation, improving memory, and modulating antioxidant and anti-inflammatory pathways. In contrast, blocking PPARγ with GW9662 negated the neuroprotective effects of QUR, exacerbating oxidative stress and inflammation by reversing all their beneficial effects. Conclusions: Activation of PPARγ by QUR or Pioglitazone offers a promising therapeutic strategy for mitigating CdCl₂-induced neurotoxicity. Full article

Peroxisome proliferator-activated receptors (PPARs), composed of the α/δ/γ subtypes, are ligand-activated nuclear receptors/transcription factors that sense endogenous fatty acids or therapeutic drugs to regulate lipid/glucose metabolism and oxidative stress. PPAR forms a multiprotein complex with a retinoid X receptor and corepressor complex in an unliganded/inactive state, and ligand binding induces the replacement of the corepressor complex with the coactivator complex to initiate the transcription of various genes, including the metabolic and antioxidant ones. We investigated the processes by which the corepressor is replaced with the coactivator or in which two coactivators compete for the PPARα/δ/γ-ligand-binding domains (LBDs) using single- and dual-emission fluorescence resonance energy transfer (FRET) assays. Single-FRET revealed that the respective PPARα/δ/γ-selective agonists (pemafibrate, seladelpar, and pioglitazone) induced the dissociation of the two corepressor peptides, NCoR1 and NCoR2, from the PPARα/δ/γ-LBDs and the recruitment of the two coactivator peptides, CBP and TRAP220. Meanwhile, dual-FRET demonstrated that these processes are simultaneous and that the four coactivator peptides, CBP, TRAP220, PGC1α, and SRC1, were competitively recruited to the PPARα/δ/γ-LBDs with different preferences upon ligand activation. Furthermore, the five newly obtained cocrystal structures using X-ray diffraction, PPARα-LBDs–NCoR2/CBP/TRAP220/PGC1α and PPARγ-LBD–NCoR2, were co-analyzed with those from our previous studies. This illustrates that these coactivators bound to the same PPARα-LBD loci via their consensus LXXLL motifs in the liganded state; that NCoR1/NCoR2 corepressors bound to the same loci via the IXXXL sequences within their consensus LXXXIXXXL motifs in the unliganded state; and that ligand activation induced AF-2 helix 12 formation that interfered with corepressor binding and created a binding space for the coactivator. These PPARα/γ-related biochemical and physicochemical findings highlight the coregulator dynamics on limited PPARα/δ/γ-LBDs loci. Full article

Caigua (Cyclanthera pedata (L.) Schrad.) is a traditional herbal remedy traditionally used in Latin America for its health benefits and to treat metabolic disorders, including diabetes. Despite interest in its herbal use, the phytochemical properties of caigua’s secondary metabolites are poorly known. This study aimed to isolate the main flavone glycosides from the leaves of caigua landrace cultivated in the Camonica Valley (Italy) using flash chromatography and evaluate their potential activity toward peroxisome proliferator-activated receptors (PPARs) and transient receptor potential (TRP) ion channels through luciferase and intracellular calcium assays. We found that the caigua species-specific flavone glycoside, chrysin-6-C-fucopyranoside, showed potent and selective activity toward PPARγ, with no effects on other PPAR subtypes or TRP channels. These findings indicate that the caigua plant could offer a safer alternative to conventional PPARγ agonists, whose use as antidiabetic drugs is limited by severe side effects that currently restrict the clinical use of conventional PPAR agonists. Full article

Changes in skin pigmentation, like hyperpigmentation or moles, can affect appearance and social life. Unlike locally containable moles, malignant melanomas are aggressive and can spread rapidly, disproportionately affecting younger individuals with a high potential for metastasis. Research has shown that the peroxisome proliferator-activated receptor gamma (PPAR-γ) and its ligands exhibit protective effects against melanoma. As a transcription factor, PPAR-γ is crucial in functions like fatty acid storage and glucose metabolism. Activation of PPAR-γ promotes lipid uptake and enhances sensitivity to insulin. In many cases, it also inhibits the growth of cancer cell lines, like breast, gastric, lung, and prostate cancer. In melanoma, PPAR-γ regulates cell proliferation, differentiation, apoptosis, and survival. During tumorigenesis, it controls metabolic changes and the immunogenicity of stromal cells. PPAR-γ agonists can target hypoxia-induced angiogenesis in tumor therapy, but their effects on tumors can be suppressive or promotional, depending on the tumor environment. Published data show that PPAR-γ-targeting agents can be effective in specific groups of patients, but further studies are needed to understand lesser-known biological effects of PPAR-γ and address the existing safety concerns. This review provides a summary of the current understanding of PPAR-γ and its involvement in melanoma. Full article

Endocrine-disrupting chemicals (EDCs) are notable for their persistence, bioaccumulation, and associations with cancer. Human nuclear receptors (hNRs) are primary targets disrupted by these persistent EDCs, resulting in alterations to xenobiotic metabolism, lipid homeostasis, and endocrine function, which can lead to carcinogenic effects. Despite their hazardous effects, comprehensive studies on EDC interactions and their impacts on hNRs remain limited. Here, we profiled the interactions of persistent EDCs, including PFAS, plastic additives, bisphenols, polybrominated diphenyl ethers, and phthalates, with key hNRs such as PXR, CAR, PPARα, PPARγ, PPARδ, AR, and RORγt. Through controlled molecular docking simulations, we observed strong binding of the EDCs to these receptors. Further analysis showed that EDCs exhibit strong binding activity towards hNRs by preferentially interacting with hydrophobic amino acids, namely leucine, isoleucine, methionine, and phenylalanine. PFAS demonstrated the highest binding affinity, characterized by a combination of complementary hydrophobic interactions from their fluorinated carbon chains and polar interactions from their functional groups (e.g., carboxylate, sulfonate) across all receptors. Distinct polycyclic and hydrophobic trends, contributing to strong NR binding, were evident in non-PFAS and nonplastic EDCs. The hNR activity assay in HepG2 cells revealed agonistic effects of dicyclohexyl phthalate (DCHP) and di-2-ethylhexyl phthalate (DEHP) on most receptors, except for PPARα. The hNR transcription factor pathway assay in HepG2 cells demonstrated increased gene expression of VDRE and PXR, suggesting potential chronic effects on xenobiotic metabolism and calcium homeostasis. Overall, our findings demonstrate the need for further research into the endocrine disruption and carcinogenic effects of these persistent EDCs. Full article

This review explores the promising potential of repurposing type 2 diabetes (T2D) medications for the treatment of Parkinson’s disease (PD), highlighting the shared pathophysiological mechanisms between these two age-related conditions, such as oxidative stress, mitochondrial dysfunction, and ferroptosis. The overlap suggests that existing diabetes drugs could target the common pathways involved in both conditions. Specifically, the review discusses how T2D medications, including metformin (Met), peroxisome-proliferator-activated receptor gamma (PPAR-γ) agonists, sodium-glucose cotransporter-2 (SGLT2) inhibitors, incretins, and dipeptidyl-peptidase 4 (DPP-4) inhibitors, can improve mitochondrial function, reduce neuroinflammation and oxidative stress, and potentially inhibit ferroptosis. The connection between ferroptosis and existing treatments, including diabetes medication, are only beginning to be explored. The limited data can be attributed also to the complexity of mechanisms involved in ferroptosis and Parkinson’s disease and to the fact that the specific role of ferroptosis in Parkinson’s disease pathogenesis has not been a primary focus until recent. Despite the promising preclinical evidence, clinical findings are mixed, underscoring the need for further research to elucidate these drugs’ roles in neurodegeneration. Repurposing existing diabetes medications that have well-established safety profiles for Parkinson’s disease treatment could significantly reduce the time and cost associated with drug development and could offer a more comprehensive approach to managing Parkinson’s disease compared to treatments targeting a single mechanism. Full article

Background/Objectives: The reduction of oleic acid (OA)-induced steatosis in HepG2 cells observed upon treatment with the glucagon-like peptide-1 receptor agonist (GLP-1RA) Exendin-4 (Ex-4) is associated with the modulation of the expression of several microRNAs, long non-coding RNAs (lncRNAs), and mRNAs. Notably, MALAT1, an lncRNA, shows significant downregulation in the presence of Ex-4 as compared to OA alone. In this study, we aimed to explore the role of MALAT1 in the positive impact of Ex-4 on OA-induced lipid accumulation in HepG2 cells. Methods: Steatosis in HepG2 cells was induced by treating them with 400 µM OA. The effect of Ex-4 on steatosis was examined by treating the steatotic cells with 200 nM of EX-4 for 3 h. MALAT1 was silenced with siRNA, while gene expression was quantified using qRT-PCR. Results: In the presence of Ex-4, the silencing of MALAT1 did not exert any discernible influence on de novo lipogenesis genes such as PPARγ and SREBP1. However, MALAT1 silencing significantly affected, to varying degrees, the expression levels of several lipid metabolism genes such as FAS, ACADL, CPT1A, and MTTP. Conclusions: Further investigations are warranted to fully decipher the role of the Ex-4-MALAT1 in the positive impact of GLP-1RAs on steatosis. Full article

Leonurus cardiaca L. is known in Europe for its cardioactivity—also in interrelation with known risk factors of the metabolic syndrome—just as L. japonicus Houtt. in East Asia; however, up to now, no active constituents could be identified. The three sub-types of PPARs (α, δ, and γ), are involved in controlling the lipid metabolism in the liver and skeletal muscles. Although PPARδ especially is a potential therapeutic target for the metabolic syndrome, insulin resistance, and obesity, no PPARδ agonists with clinical potential have presently been developed. Therefore, nineteen dominant isolated constituents of both species were screened for activity on the metabolic syndrome related PPAR α, δ, and γ in a newly developed luciferase reporter gene assay. Eight phenylethanoid glycosides not previously detected in L. cardiaca, including the novel cardiaphenyloside A, as well as the iridoids ajugol and harpagide were found via bioassay-guided isolation and structural elucidation of spectroscopic and chemical evidence. For the PPARδ experiment, all nineteen isolated constituents and GW0742 (positive control) were added to the medium of transfected COS-1 cells and further processed according to a standardized luciferase assay protocol. Only the major iridoid 7-chloro-6-desoxy-harpagide displayed significant activity in the PPARδ assay at 50 μg/mL, while the result for 100 μg/mL was higher than for the GW0742 positive control. Rutin, chicoric acid, and cardiaphenyloside A at 100 μg/mL showed PPARα agonistic activity. For PPARγ, no significant effects were observed. This activity of Leonurus extracts and especially of their active constituent 7-chloro-6-desoxy-harpagide on the δ subtype of the PPAR system strongly indicates their potential for anti-obesity therapy. Full article

Garlic (Allium sativum L.) is one of the oldest known useful plants, valued for thousands of years. This plant contains many biologically active compounds, including polyphenols, sterols, cysteine-sulfoxides, carbohydrates, proteins, and amino acids. The aim of our study was to compare the antioxidant potential, cytotoxicity, and apoptosis induction properties of four garlic cultivars—Harnaś, Ornak, Violeta, and Morado—in human squamous carcinoma (SCC-15) cells, colon adenocarcinoma (CACO-2) cells, and normal fibroblasts (BJ). Additionally, we investigated the mRNA and protein expression of peroxisome proliferator-activated receptor gamma (PPARγ), microtubule-associated protein 1 light chain 3 (LC3A), superoxide dismutase 1 (SOD1), and catalase (CAT) after treatment with the studied garlic extracts. Our study demonstrated that high ROS production was correlated with the strong toxicity of the garlic extracts. All studied extracts produced a lesser increase in ROS in normal BJ fibroblasts and were less toxic to these cells. The expression patterns of PPARγ, LC3A, SOD1, and CAT, along with chromatographic analysis, suggest differing mechanisms among the garlic cultivars. The highest levels of catechin, a known PPARγ agonist, were detected in the Harnaś (3.892 µg/mL) and Ornak (3.189 µg/mL) cultivars. A high catechin content was correlated with similar changes in PPARγ and related SOD1 and LC3A. Our findings showed the health-promoting and anticancer properties of garlic. However, we could not definitively identify which polyphenol or how it is involved in PPARγ activation. Further studies are required to elucidate the role of PPARγ in the mechanism of action of garlic extracts. Full article

Dual PPARα/γ agonists can normalize both glucose and lipid metabolism in patients with type 2 diabetes mellitus. The development of such drugs faced the detection of various toxic effects in phase III clinical trials. However, two drugs of this class managed to pass all stages of clinical trials, which makes the search for new dual PPARα/γ agonists promising. In the present study, a series of dihydrobetulonic acid amides differing in the length of the amino-alcohol linker and incorporating a pharmacophore fragment of (S)-2-ethoxy-3-phenylpropanoic acid were synthesized. The in vitro study showed that the length of the aminoalcohol linker dramatically affects the level of activation of PPAR-α and γ receptors. The synthesized compounds were tested for their ability to improve glycemic control and to counter lipid abnormalities in C57Bl/6 Ay/a mice at a dose of 30 mg/kg. Of all the compounds tested, the dihydrobetulonic acid derivative with an aminoethanol linker (15a) had the most pronounced effect in improving insulin sensitivity and glucose tolerance, and in reducing blood triglyceride levels. In addition, 15a dramatically counteracted the pathological changes in the liver, pancreas, kidney, and brown fat tissue that are characteristic of type 2 diabetes. Full article

Familial partial lipodystrophies (FPLDs) are very rare inherited disorders characterized by partial loss of adipose tissue from the upper and lower extremities. At least seven subtypes of FPLD have been identified and are mostly dominantly inherited. FPLD type 3 is caused by mutations in the PPARγ gene, which encodes for the protein peroxisome proliferator-activated receptor gamma (PPARγ). We identified a Saudi female with PFLD3 presented with partial lipoatrophy, uncontrolled diabetes, severe hypertriglyceridemia, and recurrent pancreatitis. The clinical and biochemical findings in this proband were described before and after treatment with Pioglitazone in addition to the conventional treatment. DNA extraction and whole exome sequencing (WES) were performed to detect the variant. The mutant gene was subjected to Sanger analysis to confirm the results. We applied five specific computational prediction tools to assess the pathogenicity of variation, namely the MT, DANN, CADD, BayesDel, and fitCons tools. We assessed protein modeling and stability with the AlphaFold-generated structures for both wild-type and mutant proteins. Finally, we conducted molecular docking using the AutoDock Vina virtual docking. Upon whole exome sequencing, a c.1024C>T p.(Gln342Ter) missense mutation was detected in the PPARγ gene associated with FPLD3. This variant is a novel mutation that has not been described in all genome databases. Sanger analysis confirmed the heterogenicity and pathogenicity of this variant. All five computational prediction tools indicate that this variant is considered highly pathogenic. Our patient showed a dramatic response to Pioglitazone, a synthetic PPARγ agonist. From structural modeling, we found that the enhanced binding affinity of the mutant PPARγ protein to Pioglitazone likely improves the activation of PPARγ, enhancing its transcriptional activity and resulting in better clinical outcomes. These findings extend the spectrum of PPARγ mutations responsible for FPLD3 and highlight the potential for personalized treatment strategies based on genetic mutations. Full article