PPARγ Signaling Research Articles

The Loss of PPARγ Expression and Signaling Is a Key Feature of Cutaneous Actinic Disease and Squamous Cell Carcinoma: Association with Tumor Stromal Inflammation.

Given the importance of peroxisome proliferator-activated receptor (PPAR)-gamma in epidermal inflammation and carcinogenesis, we analyzed the transcriptomic changes observed in epidermal PPARγ-deficient mice (Pparg-/-epi). A gene set enrichment analysis revealed a close association with epithelial malignancy, inflammatory cell chemotaxis, and cell survival. Single-cell sequencing of Pparg-/-epi mice verified changes to the stromal compartment, including increased inflammatory cell infiltrates, particularly neutrophils, and an increase in fibroblasts expressing myofibroblast marker genes. A comparison of transcriptomic data from Pparg-/-epi and publicly available human and/or mouse actinic keratoses (AKs) and cutaneous squamous cell carcinomas (SCCs) revealed a strong correlation between the datasets. Importantly, PPAR signaling was the top common inhibited canonical pathway in AKs and SCCs. Both AKs and SCCs also had significantly reduced PPARG expression and PPARγ activity z-scores. Smaller reductions in PPARA expression and PPARα activity and increased PPARD expression but reduced PPARδ activation were also observed. Reduced PPAR activity was also associated with reduced PPARα/RXRα activity, while LPS/IL1-mediated inhibition of RXR activity was significantly activated in the tumor datasets. Notably, these changes were not observed in normal sun-exposed skin relative to non-exposed skin. Finally, Ppara and Pparg were heavily expressed in sebocytes, while Ppard was highly expressed in myofibroblasts, suggesting that PPARδ has a role in myofibroblast differentiation. In conclusion, these data provide strong evidence that PPARγ and possibly PPARα represent key tumor suppressors by acting as master inhibitors of the inflammatory changes found in AKs and SCCs.

Progress on the Anti-Inflammatory Activity and Structure-Efficacy Relationship of Polysaccharides from Medical and Edible Homologous Traditional Chinese Medicines.

Medicinal food varieties developed according to the theory of medical and edible homologues are effective at preventing and treating chronic diseases and in health care. As of 2022, 110 types of traditional Chinese medicines from the same source of medicine and food have been published by the National Health Commission. Inflammation is the immune system's first response to injury, infection, and stress. Chronic inflammation is closely related to many diseases such as atherosclerosis and cancer. Therefore, timely intervention for inflammation is the mainstay treatment for other complex diseases. However, some traditional anti-inflammatory drugs on the market are commonly associated with a number of adverse effects, which seriously affect the health and safety of patients. Therefore, the in-depth development of new safe, harmless, and effective anti-inflammatory drugs has become a hot topic of research and an urgent clinical need. Polysaccharides, one of the main active ingredients of medical and edible homologous traditional Chinese medicines (MEHTCMs), have been confirmed by a large number of studies to exert anti-inflammatory effects through multiple targets and are considered potential natural anti-inflammatory drugs. In addition, the structure of medical and edible homologous traditional Chinese medicines' polysaccharides (MEHTCMPs) may be the key factor determining their anti-inflammatory activity, which makes the underlying the anti-inflammatory effects of polysaccharides and their structure-efficacy relationship hot topics of domestic and international research. However, due to the limitations of the current analytical techniques and tools, the structures have not been fully elucidated and the structure-efficacy relationship is relatively ambiguous, which are some of the difficulties in the process of developing and utilizing MEHTCMPs as novel anti-inflammatory drugs in the future. For this reason, this paper summarizes the potential anti-inflammatory mechanisms of MEHTCMPs, such as the regulation of the Toll-like receptor-related signaling pathway, MAPK signaling pathway, JAK-STAT signaling pathway, NLRP3 signaling pathway, PI3K-AKT signaling pathway, PPAR-γ signaling pathway, Nrf2-HO-1 signaling pathway, and the regulation of intestinal flora, and it systematically analyzes and evaluates the relationships between the anti-inflammatory activity of MEHTCMPs and their structures.

Fatty acid metabolism affects hepatocellular carcinoma progression via the PPAR-γ signaling pathway and fatty acid β-oxidation

PurposeThis study aimed to explore novel targets for hepatocellular carcinoma (HCC) treatment by investigating the role of fatty acid metabolism. MethodsRNA-seq and clinical data of HCC were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Bioinformatic analyses were employed to identify differentially expressed genes (DEGs) related to prognosis. A signature was then constructed using the Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression to classify HCC patients from the TCGA database into low-risk and high-risk groups. The predictive performance of the signature was evaluated through principal components analysis (PCA), Kaplan Meier (KM) survival analysis, receiver operating characteristics (ROC) curves, nomogram, genetic mutations, drug sensitivity analysis, immunological correlation analysis, and enrichment analysis. Single-cell maps were constructed to illustrate the distribution of core genes. Immunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR), and western blot were employed to verify the expression of core genes. The function of one core gene was validated through a series of in vitro assays, including cell viability, colony formation, wound healing, trans-well migration, and invasion assays. The results were analyzed in the context of relevant signaling pathways. ResultsBioinformatic analyses identified 15 FAMGs that were related to prognosis. A 4-gene signature was constructed, and patients were divided into high- and low-risk groups according to the signature. The high-risk group exhibited a poorer prognosis compared to the low-risk group in both the training (P < 0.001) and validation (P = 0.020) sets. Furthermore, the risk score was identified as an independent predictor of OS (P < 0.001, HR = 8.005). The incorporation of the risk score and clinicopathologic features into a nomogram enabled the effective prediction of patient prognosis. The model was able to effectively predict the immune microenvironment, drug sensitivity to chemotherapy, and gene mutation for each group. Single-cell maps demonstrated that FAMGs in the model were distributed in tumor cells. Enrichment analyses revealed that the cell cycle, fatty acid β oxidation and PPAR signaling pathways were the most significant pathways. Among the four key prognostically related FAMGs, Spermine Synthase (SMS) was selected and validated as a potential oncogene affecting cell cycle, PPAR-γ signaling pathway and fatty acid β oxidation in HCC. ConclusionsThe risk characteristics based on FAMGs could serve as independent prognostic indicators for predicting HCC prognosis and could also serve as evaluation criteria for gene mutations, immunity, and chemotherapy drug therapy in HCC patients. Meanwhile, targeted fatty acid metabolism could be used to treat HCC through related signaling pathways.

Nobiletin Regulates Polyinosinic-polycytidylic Acid-induced Inflammation in Macrophages Partially via the PPAR-γ Signaling Pathway.

Macrophage dysregulation is a common pathogenic feature of viruses that provides extensive targets for antiviral therapy. Nobiletin, a polymethoxylated flavonoid found in citrus fruits, has a multitude of effects. We investigated the effect of nobiletin on polyinosinic-polycytidylic acid (poly(I:C))-induced inflammation in RAW264.7 cells. Nobiletin inhibited the production of poly(I:C)-induced inflammatory factors, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and CXCL10. High-throughput sequencing revealed that nobiletin inhibited the expression of TNF-α, IL-6, and CXCL10 and promoted the expression of CD206, Chil3, and Vcam1. In the Kyoto Encyclopedia of Genes and Genomes enrichment analyses, the upregulated differential genes were significantly enriched in the peroxisome proliferator-activated receptor (PPAR) signaling pathway. The PPAR-γ inhibitor T0070907 significantly reversed the inhibitory effects of nobiletin on IL-6 and CXCL10 but had no significant effect on TNF-α secretion. Thus, nobiletin regulated poly(I:C)-induced inflammatory responses in RAW264.7 cells partially via the PPAR-γ signaling pathway.

Rosiglitazone Promotes Oligodendrocyte Development and Myelin Formation of Repeated Neonatal Sevoflurane Exposure via PPARγ Signaling.

Sevoflurane is one of the most commonly used general anesthetics for children and infants. Recent research indicates that repeated exposure to sevoflurane in neonates induces cognitive and fine motor deficits. Peroxisome proliferator-activated receptor-γ (PPARγ) agonists have garnered significant attention as potential therapies for a variety of neurological conditions. In this research, we evaluated whether pretreatment with rosiglitazone in neonatal mice could address myelination defects, cognitive impairment, and fine motor dysfunction via PPARγ. The mice were exposed to 3% sevoflurane for 2h on postnatal days 6-8 (P6-P8). Behavioral tests were conducted from P29 to P34. Additionally, we evaluated morphological and functional changes related to myelin. Our results showed that rosiglitazone pretreatment significantly ameliorated the cognitive and fine motor impairments of repeated neonatal sevoflurane exposure. In addition, rosiglitazone pretreatment promoted oligodendrocyte precursor cells (OPCs) differentiation and myelination. This suggests that rosiglitazone may be used in clinical settings to enhance the security of neonatal sevoflurane exposure. Furthermore, PPARγ and fatty acid synthase (FASN) may be mediators for rosiglitazone, which alleviates myelination defects, cognitive impairment, and fine motor dysfunction.

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.

Perinatal nicotine vaping exposure induces pro-myofibroblastic phenotype in rat bone marrow-derived mesenchymal stem cells

Perinatal nicotine exposure via tobacco smoking results in increased proclivity to chronic lung disease (CLD); however, the underlying molecular mechanisms remain incompletely understood. We previously demonstrated that in addition to nicotine’s direct effects on the developing lung, there are also adverse molecular alterations in bone marrow-derived mesenchymal stem cells (BMSCs), which are vital to lung injury repair. Whether perinatal nicotine exposure via electronic-cigarette (e-cig) vaping also adversely affects BMSCs is unknown. This is highly relevant due to marked increase in e-cig vaping including by pregnant women. Hypothesizing that perinatal nicotine exposure via e-cig vaping predisposes BMSCs to a pro-myofibroblastic phenotype, pregnant rat dams were exposed to fresh air (control), vehicle (e-cig without nicotine), or e-cig (e-cig with nicotine) daily during pregnancy and lactation. At postnatal day 21, offspring BMSCs were isolated and studied for cell proliferation, migration, wound healing response, and expression of key Wnt and PPARγ signaling intermediates (β-catenin, LEF-1, PPARγ, ADRP and C/EBPα) and myogenic markers (fibronectin, αSMA, calponin) proteins using immunoblotting. Compared to controls, perinatal e-cig exposure resulted in significant decrease in BMSC proliferation, migration, and wound healing response. The expression of key Wnt signaling intermediates (β-catenin, LEF-1) and myogenic markers (fibronectin, αSMA, calponin) increased significantly, while PPARγ signaling intermediates (PPARγ, ADRP, and C/EBPα) decreased significantly. Based on these data, we conclude that perinatally e-cig exposed BMSCs demonstrate pro-myofibroblastic phenotype and impaired injury-repair potential, indicating a potentially similar susceptibility to CLD following perinatal nicotine exposure via vaping as seen following parenteral perinatal nicotine exposure.

Knockdown of AMIGO2 suppresses proliferation and migration through regulating PPAR-γ in bladder cancer

PurposeThis study aims to reveal the relationship between AMIGO2 and proliferation, migration and tumorigenicity of bladder cancer, and explore the potential molecular mechanisms.MethodsThe expression level of AMIGO2 is measured by qRT-PCR and immunohistochemistry (IHC). Stable AMIGO2 knockdown cell lines T24 and 5637 were established by lentivirus transfection. Cell Counting Kit (CCK-8 assay) was produced to determine cell proliferation, flow cytometry analysis was utilized to detect cell cycle, and wound healing assay was proceeded to test migration ability of bladder cancer cells. Xenograft mouse model was established for investigating the effect of AMIGO2 on tumor formation in vivo. The RNA Sequencing technology was applied to explore the underlying mechanisms. The expression level of PPAR-γ was measured by Western Blot.ResultsAMIGO2 was upregulated in bladder cancer cells and tissues. Inhibited expression of AMIGO2 suppresses cell proliferation and migration. Low AMIGO2 expression inhibited tumorigenicity of 5637 in nude mice. According to RNA-Seq and bioinformatics analysis, 917 DEGs were identified. The DEGs were mainly enriched in cell–cell adhesion, peroxisome proliferators-activated receptors (PPARs) signaling pathway and some other pathways. PPAR-γ is highly expressed in bladder cancer cell lines T24 and 5637, but when AMIGO2 is knocked down in T24 and 5637, the expression level of PPAR-γ is also decreased, and overexpression of PPAR-γ could reverse the suppression effect of cell proliferation and migration caused by the inhibition of AMIGO2.ConclusionAMIGO2 is overexpressed in bladder cancer cells and tissues. Knockdown of AMIGO2 suppresses bladder cancer cell proliferation and migration. These processes might be regulated by PPAR-γ signaling pathway.

FoxO1-modulated macrophage polarization regulates osteogenesis via PPAR-γ signaling

Periodontitis, a common chronic inflammatory disease, epitomizes a significant impairment in the host immune system and an imbalance of bone metabolism. Macrophage polarization, a dynamic process dictated by the microenvironment, intricately contributes to the interplay between the immune system and bone remodeling, namely the osteoimmune system. Forkhead box protein O1 (FoxO1) has been shown to play a dramatic role in mediating oxidative stress, bone mass, as well as cellular metabolism. Nevertheless, the function and underlying mechanisms of FoxO1 in regulating macrophage polarization-mediated osteogenesis in periodontitis remain to be further elucidated. Here, we found that FoxO1 expression was closely linked to periodontitis, accompanied by aggravated inflammation. Notably, FoxO1 knockdown skewed macrophage polarization from M1 to the antiinflammatory M2 phenotype under inflammatory conditions, which rescued the impaired osteogenic potential. Mechanistically, we revealed that the enhancement of the transcription of peroxisome proliferator-activated receptor (PPAR) signaling in FoxO1-knockdown macrophages. In agreement with this contention, GW9662, a specific inhibitor of PPAR-γ signaling, greatly aggravated macrophage polarization from M2 to the M1 phenotype and attenuated osteogenic potential under inflammatory conditions. Additionally, PPAR-γ signaling agonist rosiglitazone (RSG) was applied to address ligature-induced periodontitis with attenuated inflammation. Our data lend conceptual credence to the function of FoxO1 in mediating macrophage polarization-regulated osteogenesis which serves as a novel therapeutic target for periodontitis.

Amorfrutin B Compromises Hypoxia/Ischemia-induced Activation of Human Microglia in a PPARγ-dependent Manner: Effects on Inflammation, Proliferation Potential, and Mitochondrial Status

Amorfrutin B is a selective PPARγ modulator that we demonstrated to be a promising neuroprotective compound in cellular models of stroke and perinatal asphyxia. Although neuronal mechanisms of amorfrutin B-evoked neuroprotection have been identified, none of them reflects the actions of the compound on microglia, which play a pivotal role in brain response to hypoxia/ischemia. Here, we provide evidence for amorfrutin B-induced effects on human microglia subjected to hypoxia/ischemia; the compound counteracts inflammation, and influences mitochondrial status and proliferation potential in a PPARγ-dependent manner. Post-treatment with amorfrutin B decreased the IBA1 fluorescence intensity, reduced caspase-1 activity, and downregulated IL1B/IL-1β and TNFA but not IL10/IL-10 expression, which was upregulated. Amorfrutin B also stimulated PPARγ signaling, as evidenced by increased mRNA and/or protein levels of PPARγ and PGC1α. In addition, amorfrutin B reversed the hypoxia/ischemia-evoked effects on mitochondria-related parameters, such as mitochondrial membrane potential, BCL2/BCL2 expression and metabolic activity, which were correlated with diminished proliferation potential of microglia. Interestingly, the inhibitory effect of amorfrutin B on the proliferation potential and mitochondrial function of microglia is opposite to the stimulatory effect of amorfrutin B on mouse neuronal survival, as evidenced by increased neuronal viability and reduced neurodegeneration. In summary, this study showed for the first time that amorfrutin B compromises hypoxia/ischemia-induced activation of human microglia in a PPARγ-dependent manner, which involves inhibiting inflammation, normalizing mitochondrial status, and controlling proliferation potential. These data extend the protective potential of amorfrutin B in the pharmacotherapy of hypoxic/ischemic brain injury, targeting not only neurons but also activated microglia.Graphical

Pirfenidone Reverts Global DNA Hypomethylation, Promoting DNMT1/UHRF/PCNA Coupling Complex in Experimental Hepatocarcinoma.

Hepatocellular carcinoma (HCC) development is associated with altered modifications in DNA methylation, changing transcriptional regulation. Emerging evidence indicates that DNA methyltransferase 1 (DNMT1) plays a key role in the carcinogenesis process. This study aimed to investigate how pirfenidone (PFD) modifies this pathway and the effect generated by the association between c-Myc expression and DNMT1 activation. Rats F344 were used for HCC development using 50 mg/kg of diethylnitrosamine (DEN) and 25 mg/kg of 2-Acetylaminofluorene (2-AAF). The HCC/PFD group received simultaneous doses of 300 mg/kg of PFD. All treatments lasted 12 weeks. On the other hand, HepG2 cells were used to evaluate the effects of PFD in restoring DNA methylation in the presence of the inhibitor 5-Aza. Histopathological, biochemical, immunohistochemical, and western blot analysis were carried out and our findings showed that PFD treatment reduced the amount and size of tumors along with decreased Glipican-3, β-catenin, and c-Myc expression in nuclear fractions. Also, this treatment improved lipid metabolism by modulating PPARγ and SREBP1 signaling. Interestingly, PFD augmented DNMT1 and DNMT3a protein expression, which restores global methylation, both in our in vivo and in vitro models. In conclusion, our results suggest that PFD could slow down HCC development by controlling DNA methylation.

APOA5 alleviates reactive oxygen species to promote oxaliplatin resistance in PIK3CA-mutated colorectal cancer.

Although platinum-based chemotherapy is the frontline regimen for colorectal cancer (CRC), drug resistance remains a major challenge affecting its therapeutic efficiency. However, there is limited research on the correlation between chemotherapy resistance and lipid metabolism, including PIK3CA mutant tumors. In this present study, we found that PIK3CA-E545K mutation attenuated cell apoptosis and increased the cell viability of CRC with L-OHP treatment in vitro and in vivo. Mechanistically, PIK3CA-E545K mutation promoted the nuclear accumulation of SREBP1, which promoted the transcription of Apolipoprotein A5 (APOA5). APOA5 activated the PPARγ signaling pathway to alleviate reactive oxygen species (ROS) production following L-OHP treatment, which contributed to cell survival of CRC cells. Moreover, APOA5 overexpression enhanced the stemness-related traits of CRC cells. Increased APOA5 expression was associated with PIK3CA mutation in tumor specimens and poor response to first-line chemotherapy, which was an independent detrimental factor for chemotherapy sensitivity in CRC patients. Taken together, this study indicated that PIK3CA-E545K mutation promoted L-OHP resistance by upregulating APOA5 transcription in CRC, which could be a potent target for improving L-OHP chemotherapeutic efficiency. Our study shed light to improve chemotherapy sensitivity through nutrient management in CRC.

HPGD: An Intermediate Player in Microglial Polarization and Multiple Sclerosis Regulated by Nr4a1.

HPGD encodes 15-Hydroxyprostaglandin dehydrogenase catalyzing the decomposition of prostaglandin E2 and has not been reported in multiple sclerosis (MS). We previously found that Nr4a1 regulated microglia polarization and inhibited the progression of experimental autoimmune encephalomyelitis (EAE). Bioinformatics analysis suggested that HPGD might be regulated by Nr4a1. Therefore, this study aimed to explore the role of HPGD in microglia polarization and determine whether HPGD mediates the inhibition of EAE by Nr4a1. C57BL/6 mice were treated with MOG35-55 peptide to induce EAE. BV-2 cells were treated with LPS/IL-4 to induce M1/M2 polarization. We then analyzed the pathological changes of spinal cord tissue, detected the expression levels of M1/M2 genes in tissues and cells, and explored the effect of HPGD on PPARγ activation to clarify the role of HPGD in EAE. The interaction between HPGD and Nr4a1 was verified by ChIP and pull-down assay. HPGD was downregulated in the spinal cord of EAE mice and HPGD overexpression alleviated the progression of EAE. Experiments in vitro and in vivo revealed that HPGD inhibited M1 polarization, promoted M2 polarization and increased PPARγ-DNA complex level. Nr4a1 could bind to the promoter of HPGD and its overexpression increased HPGD level. HPGD overexpression (or knockdown) reversed the effect of Nr4a1 knockdown (or overexpression) on M1/2 polarization. HPGD is regulated by Nr4a1 and inhibits the progression of EAE through shifting the M1/M2 polarization and promoting the activation of PPARγ signaling pathway. This study provides potential targets and basis for the development of MS therapeutic drugs.

Epithelial hypoxia maintains colonization resistance against Candida albicans

Antibiotic treatment promotes the outgrowth of intestinal Candida albicans, but the mechanisms driving this fungal bloom remain incompletely understood. We identify oxygen as a resource required for post-antibiotic C.albicans expansion. C.albicans depleted simple sugars in the ceca of gnotobiotic mice but required oxygen to grow on these resources invitro, pointing to anaerobiosis as a potential factor limiting growth in the gut. Clostridia species limit oxygen availability in the large intestine by producing butyrate, which activates peroxisome proliferator-activated receptor gamma (PPAR-γ) signaling to maintain epithelial hypoxia. Streptomycin treatment depleted Clostridia-derived butyrate to increase epithelial oxygenation, but the PPAR-γ agonist 5-aminosalicylic acid (5-ASA) functionally replaced Clostridia species to restore epithelial hypoxia and colonization resistance against C.albicans. Additionally, probiotic Escherichia coli required oxygen respiration to prevent a post-antibiotic bloom of C.albicans, further supporting the role of oxygen in colonization resistance. We conclude that limited access to oxygen maintains colonization resistance against C.albicans.

Anti-adipogenesis and anti-obesity potential of alliin mediated by modulating glycolipid metabolism via activating PPARγ signaling.

Garlic exhibits hypolipidemic, hypoglycemic, and cardiovascular benefits. The inconsistent results of garlic preparations on adipogenesis have caused more confusion in the public and academia. The compounds responsible for the anti-adipogenesis effect of garlic remain unknown. The present study aimed to verify the real anti-adipogenesis and anti-obesity component in garlic and explored its possible effects in metabolic syndrome. We verified the real anti-adipogenesis and anti-obesity components of garlic in 3T3-L1 preadipocytes and a 10-week-high fat diet (HFD)-induced obese mice. In vitro, two water-soluble and four typical lipid-soluble compounds of garlic were tested for their anti-adipogenesis. Then, the water-soluble compound, alliin, and two processing methods produced garlic oils, were evaluated in vivo study. Mice received oral administration of alliin (25mg/kg) and garlic oils (15mg/kg) daily for 8weeks. Serum lipids, parameters of obesity, and indicators involved in regulating glycolipid metabolism were examined. Our findings confirmed that both water-soluble and lipid-soluble organosulfur compounds of garlic contributed to garlic's anti-adipogenesis effect, in which water-soluble sulfides, especially alliin, exhibited greater potency. Alliin possessed potent effects of anti-obesity and improvement in glucose and lipid metabolism in HFD-induced obese mice. Alliin mediated these effects partly attributed to its modulation of enzymatic activities within glycolipid metabolism and activating PPARγ signaling pathway. In contrast to odorous lipid-soluble sulfides, alliin is odorless, stable, and safe, and is an ideal nutraceutical or even medicinal candidates for the treatment of metabolic diseases. Alliin could be used to standardize the quality of garlic products.

Structural Studies on the Binding Mode of Bisphenols to PPARγ.

Bisphenol A (BPA) and bisphenol B (BPB) are widely used in the production of plastics, and their potential adverse health effects, particularly on endocrine disruption and metabolic health, have raised concern. Peroxisome proliferator-activated receptor gamma (PPARγ) plays a pivotal role in metabolic regulation and adipogenesis, making it a target of interest in understanding the development of obesity and associated health impacts. In this study, we employ X-ray crystallography and molecular dynamics (MD) simulations to study the interaction of PPARγ with BPA and BPB. Crystallographic structures reveal the binding of BPA and BPB to the ligand binding domain of PPARγ, next to C285, where binding of partial agonists as well as antagonists and inverse agonists of PPARγ signaling has been previously observed. However, no interaction of BPA and BPB with Y437 in the activation function 2 site is observed, showing that these ligands cannot stabilize the active conformation of helix 12 directly. Furthermore, free energy analyses of the MD simulations revealed that I341 has a large energetic contribution to the BPA and BPB binding modes characterized in this study.

SLC7A5 correlated with malignancies and immunotherapy response in bladder cancer

BackgroundMetabolic reprogramming contributes to bladder cancer development. This study aimed to understand the role of SLC7A5 in bladder cancer.MethodsWe systematically analyzed the correlation between SLC7A5 and bladder cancer through various approaches, including bioinformatics, western blotting, cell cycle analysis, cell proliferation assays, and invasion experiments. We also investigated the immunological features within the tumor microenvironment (TME), encompassing cancer immune cycles, immune modulators, immune checkpoints, tumor-infiltrating immune cells (TIIC), T cell inflammation scores, and treatment responses. Additionally, for a comprehensive assessment of the expression patterns and immunological roles of SLC7A5, pan-cancer analysis was performed using cancer genomics datasets.ResultsSLC7A5 was associated with adverse prognosis in bladder cancer patients, activating the Wnt pathway and promoting bladder cancer cell cycle progression, proliferation, migration, and invasion. Based on the evidence that SLC7A5 positively correlated with immunomodulators, TIIC, the cancer immune cycle, immune checkpoint and T cell inflammation scores, we also found that SLC7A5 was associated with the inflammatory tumor immune microenvironment. EGFR-targeted therapy, cancer immunotherapy, and radiation therapy were effective for patients with high SLC7A5 expression in bladder cancer. Low SLC7A5 patients were, however, sensitive to targeted therapies and anti-angiogenic therapy, such as blocking β-catenin network, PPAR-γ and FGFR3 signaling. Anti-SLC7A5 combined with cancer immunotherapy may have greater effectiveness than either therapy alone. Furthermore, we observed specific overexpression of SLC7A5 in TME of various cancers.ConclusionSLC7A5 can predict therapeutic response to immunotherapy, radiotherapy and chemotherapy in bladder cancer patients. Targeting SLC7A5 in combination with immunotherapy may be a potentially appropriate treatment option.

Molecular regulation of PPARγ/RXRα signaling by the novel cofactor ZFP407.

Cofactors interacting with PPARγ can regulate adipogenesis and adipocyte metabolism by modulating the transcriptional activity and selectivity of PPARγ signaling. ZFP407 was previously demonstrated to regulate PPARγ target genes such as GLUT4, and its overexpression improved glucose homeostasis in mice. Here, using a series of molecular assays, including protein-interaction studies, mutagenesis, and ChIP-seq, ZFP407 was found to interact with the PPARγ/RXRα protein complex in the nucleus of adipocytes. Consistent with this observation, ZFP407 ChIP-seq peaks significantly overlapped with PPARγ ChIP-seq peaks, with more than half of ZFP407 peaks overlapping with PPARγ peaks. Transcription factor binding motifs enriched in these overlapping sites included CTCF, RARα/RXRγ, TP73, and ELK1, which regulate cellular development and function within adipocytes. Site-directed mutagenesis of frequent PPARγ phosphorylation or SUMOylation sites did not prevent its regulation by ZFP407, while mutagenesis of ZFP407 domains potentially necessary for RXR and PPARγ binding abrogated any impact of ZFP407 on PPARγ activity. These data suggest that ZFP407 controls the activity of PPARγ, but does so independently of post-translational modifications, likely by direct binding, establishing ZFP407 as a newly identified PPARγ cofactor. In addition, ZFP407 ChIP-seq analyses identified regions that did not overlap with PPARγ peaks. These non-overlapping peaks were significantly enriched for the transcription factor binding motifs of TBX19, PAX8, HSF4, and ZKSCAN3, which may contribute to the PPARγ-independent functions of ZFP407 in adipocytes and other cell types.

Two peptides LLRLTDL and GYALPCDCL inhibit foam cell formation through activating PPAR-γ/LXR-α signaling pathway in oxLDL-treated RAW264.7 macrophages.

Foam cell formation plays a pivotal role in atherosclerosis-associated cardiovascular diseases. Bioactive peptides generated from marine sources have been found to provide multifunctional health advantages. In the present study, we investigated the anti-atherosclerotic effects of LLRLTDL (Bu1) and GYALPCDCL (Bu2) peptides, isolated from ark shell protein hydrolysates by assessing their inhibitory effect on oxidized LDL (oxLDL)-induced foam cell formation. The two peptides showed a promising anti-atherosclerotic effect by inhibiting foam cell formation, which was evidenced by inhibiting lipid accumulation in oxLDL-treated RAW264.7 macrophages and oxLDL-treated primary human aortic smooth muscle cells (HASMC). Two peptides effectively reduced total cholesterol, free cholesterol, cholesterol ester, and triglyceride levels by upregulating cholesterol efflux and downregulating cholesterol influx. Expression of cholesterol influx-related proteins such as SR-A1 and CD36 were reduced, whereas cholesterol efflux-related proteins such as ATP-binding cassette transporter ABCA-1 and ABCG-1 were highly expressed. In addition, Bu1 and Bu2 peptides increased PPAR-γ and LXR-α expression. However, PPAR-γ siRNA transfection reversed the foam cell formation inhibitory activity of Bu1 and Bu2 peptides. Furthermore, the synergistic effect of Bu1 and Bu2 peptides on foam cell formation inhibition was observed with PPAR-γ agonist thiazolidinediones, indicating that PPAR-γ signaling pathway plays a key role in foam cell formation of macrophages. Beyond their impact on foam cell formation, Bu1 and Bu2 peptides demonstrated anti-inflammatory potential by inhibiting the generation of pro-inflammatory cytokines and nitric oxide and NF-κB nuclear activation. Taken together, these results suggest that Bu1 and Bu2 peptides may be useful for atherosclerosis and associated anti-inflammatory therapies.

Cannabidiol prevents LPS-induced inflammation by inhibiting the NLRP3 inflammasome and iNOS activity in BV2 microglia cells via CB2 receptors and PPARγ

Neuroinflammation stands as a critical player in the pathogenesis of diverse neurological disorders, with microglial cells playing a central role in orchestrating the inflammatory landscape within the central nervous system. Cannabidiol (CBD) has gained attention for its potential to elicit anti-inflammatory responses in microglia, offering promising perspectives for conditions associated with neuroinflammation. Here we investigated whether the NLRP3 inflammasome and inducible nitric oxide synthase (iNOS) are involved in the protective effects of CBD, and if their modulation is dependent on cannabinoid receptor 2 (CB2) and PPARγ signalling pathways. We found that treatment with CBD attenuated pro-inflammatory markers in lipopolysaccharide (LPS)-challenged BV2 microglia in a CB2- and PPARγ-dependent manner. At a molecular level, CBD inhibited the LPS-induced pro-inflammatory responses by suppressing iNOS and NLRP3/Caspase-1-dependent signalling cascades, resulting in reduced nitric oxide (NO), interleukin-1β (IL-1β), and tumour necrosis factor-alpha (TNF-α) concentrations. Notably, the protective effects of CBD on NLRP3 expression, Caspase-1 activity, and IL-1β concentration were partially hindered by the antagonism of both CB2 receptors and PPARγ, while iNOS expression and NO secretion were dependent exclusively on PPARγ activation, with no CB2 involvement. Interestingly, CBD exhibited a protective effect against TNF-α increase, regardless of CB2 or PPARγ activation. Altogether, these findings indicate that CB2 receptors and PPARγ mediate the anti-inflammatory effects of CBD on the NLRP3 inflammasome complex, iNOS activity and, ultimately, on microglial phenotype. Our results highlight the specific components responsible for the potential therapeutic applications of CBD on neuroinflammatory conditions.