Peroxisome Proliferator-activated Receptor Signaling Research Articles

Eucommia ulmoides Oliv. leaf extract: Effects on growth, antioxidant capacity, and lipid metabolism in Red swamp crayfish (Procambarus clarkii)

The addition of Eucommia ulmoides Oliv. leaf extract (ELE) enhances growth, immunity and antioxidant capacity in crustaceans, which has not been studied on the red swamp crayfish (Procambarus clarkii). Hence, this study aimed to investigate the effect of ELE on the growth, antioxidant capacity, digestive enzymes activities, and lipid metabolism of red swamp crayfish. A total of 240 individuals of red swamp crayfish were randomly assigned to four groups. Each group was fed with feed a diet supplemented with varying doses of ELE: 0 g/kg (CK), 0.5 g/kg (T2), 1.0 g/kg (T3), and 1.5 g/kg (T4). After 30 days, the results indicated that T2 group exhibited a significantly higher final average weight, weight gain rate, and specific growth rate compared to the CK (P<0.05). Significantly lower feed conversion ratios than the CK (P<0.05) were observed in the T2 and T3 groups. For antioxidant indicators, hepatopancreas superoxide dismutase (SOD) activity was observed to significantly increased in the T3 and T4 groups, while levels of malondialdehyde (MDA) in which were significantly reduced in hepatopancreas and hemolymph (P<0.05). Regarding biochemical indicators and intestinal function, significant enhancement of lipase (LPS) activity was observed in the T2 group, which decreased in the T4, compared to the CK (P<0.05). Moreover, significant decrease of the glucose (GLU), total triglyceride (TG), and total cholesterol (TC) content of the hemolymph (P<0.05) were observed in the T4 group. Transcriptome analysis revealed that differentially expressed genes in the T4 group were primarily enriched in peroxisome proliferator-activated receptor (PPAR), and lipid metabolism pathways. Furthermore, it seems that ELE supplements significantly upregulated the expression of apoa-II, acaox1, acox3, me1, and plin1 in the PPAR signaling pathway to regulate lipid metabolism. In conclusion, 0.5 g/kg and 1.5 g/kg ELL addition amount can enhance growth performance, antioxidant capacity, and lipid metabolism of red swamp crayfish.

Berberine Ameliorates High-fat-induced Insulin Resistance in HepG2 Cells by Modulating PPARs Signaling Pathway.

Berberine (BBR), also known as berberine hydrochloride, was isolated from the rhizomes of the Coptis chinensis. Studies have reported that BBR plays an important role in glycolipid metabolism, including insulin (IR). The targets, and molecular mechanisms of BBR against hyperlipid-induced IR is worthy to be further studied. The related targets of BBR were identified via Pharmmapper database and relevant targets of diabetes were obtained through GeneCards and Online Mendelian Inheritance in Man (OMIM) database. The common targets were employed with the STRING database and visualized with the protein-protein interactions (PPI) network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed to explore the biological progress and pathways. In vitro, human hepatocellular carcinomas (HepG2) cell was used as experimental cell line, and an insulin resistant HepG2 cell model (IR-HepG2) was constructed using free fatty acid induction. After intervention with BBR, glucose consumption and uptake in HepG2 cells were observed. Molecular docking was used to test the interaction between BBR and key targets, and real-time fluorescence quantitative PCR was used to detect the regulatory effect of BBR on related targets. 262 overlapped targets were extracted from BBR and diabetes. In the KEGG enrichment analysis, the peroxisome proliferator activated receptor (PPAR) signaling pathway was included. In vitro experiments, BBR can significantly increase sugar consumption and uptake in IR HepG2 cells, while PPAR inhibitors can weaken the effect of BBR on IR-HepG2. The PPAR signaling pathway is one of the important pathways for BBR to improve high-fat-induced insulin resistance in HepG2 cells.

Exercise and tumor proteome: Insights from a neuroblastoma model

Background/Aim: The impact of exercise on pediatric tumor biology is essentially unknown. We investigated the effects of regular exercise on tumor proteome profile (as assessed with liquid chromatography with tandem mass spectrometry) in a mouse model of one of the most aggressive childhood malignancies, high-risk neuroblastoma (HR-NB). Methods: Tumor samples of 14 male mice (aged 6-8 weeks) that were randomly allocated into an exercise (5-week combined aerobic and resistance training) or nonexercise control group (6 and 8 mice per group, respectively) were analyzed. The Search Tool for the Retrieval of Interacting Genes/Proteins database was used to generate a protein-protein interaction (PPI) network and enrichment analyses. The Systems Biology Triangle (SBT) algorithm was applied for analyses at the functional category level. Results: Tumors of exercised mice showed a higher and lower abundance of 101 and 150 proteins, respectively, compared to controls [false discovery rate (FDR)&lt;0.05], which were enriched in metabolic pathways, aminoacid metabolism, regulation of hormone levels, and peroxisome proliferator-activated receptor signaling pathway (FDR&lt;0.05). The SBT algorithm indicated that 184 and 126 categories showed a lower and higher abundance, respectively, in the tumors of exercised mice (FDR&lt;0.01). Categories with lower abundance were involved in energy production while those with higher abundance were related to transcription/translation, apoptosis, and tumor suppression. Conclusion: Regular exercise altered the abundance of hundreds of intratumoral proteins and molecular pathways, particularly those involved in energy metabolism, apoptosis, and tumor suppression. These findings provide preliminary evidence of the molecular mechanisms underlying potential effects of exercise in HR-NB.

Integrated transcriptomics and proteomics analyses reveal the ameliorative effect of hepatic damage in tilapia caused by polystyrene microplastics with chlorella addition

Fish exhibit varying responses to polystyrene microplastics (MPs) depending on particle size. Previous studies suggested that microorganisms adhering to the surface of MPs can induce toxic effects. In this study, Tilapia were exposed to MPs of control (group A), 75 nm (B), 7.5 μm (C), 750 μm (D), as well as combinations of all sizes (E) and 75 nm MPs with Chlorella vulgaris addition (F) for 7, 10 and 14 days. Histopathological changes in liver of tilapia were assessed using enzyme activities, transcriptomics and proteomics. The results showed that in groups combined MPs of different particle sizes and those supplemented with chlorella, MPs were localized on the surface of goblet cells, leading to vacuoles, constricted hepatic sinuses and nuclei displacement. Exposure to 7.5 and 750 μm MPs significantly increased the contents of fatty acid synthase (FAS), adenosine triphosphate (ATP), acetyl-CoA carboxylase (ACC), lipoprotein lipase (LPL), total cholesterol (TC), total triglyceride (TG) contents at 7 and 10 days. In particular, cytochrome p450 1a1 (EROD), reactive oxygen species (ROS) and superoxide dismutase (SOD) were markedly elevated following exposure to MPs. Apoptotic markers caspase-3, and inflammatory markers, including tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β), had a similar upward trend in comparisons of group C vs A at 7 d, group D vs A at 14 d. The peroxisome proliferator activated receptor (PPAR) signaling pathway, spliceosome, was highly enriched during the 7-day exposure of medium sized MPs, while largest MPs in the comparison of group D vs A at 14 d activated pathways such as phagosome, apoptosis, salmonella infection. Transcriptomic analysis revealed that after 14 days, the kyoto encyclopedia of genes and genomes (KEGG) pathways associated with protein processing in endoplasmic reticulum and the PPAR signaling has been significantly enriched in the Chlorella-supplemented group, which was further confirmed via the proteomic analysis. Overall, the findings highlight the size-dependent effects of MPs on histopathological changes, gene and protein expression in the liver of tilapia, and C. vulgaris effectively attenuated liver damages, likely through modulation of endoplasmic reticulum protein processing and PPAR signaling pathways.

Elucidation of the molecular mechanism of type 2 diabetes mellitus affecting the progression of nonalcoholic steatohepatitis using bioinformatics and network pharmacology: A review.

Increasing evidence suggests that patients with diabetes are at increased risk of developing nonalcoholic steatohepatitis (NASH), but the underlying mechanisms that affect the progression of NASH remain unclear. In this study, we used bioinformatics and network pharmacology methods to explore the differentially expressed genes of NASH and the related genes of type 2 diabetes mellitus, and a total of 46 common targets were obtained. Gene ontology showed that the common targets were mainly involved in biological processes such as glucocorticoid, hormone, and bacterium responses. The Kyoto Encyclopedia of Genes and Genomes enrichment analysis signal pathways were mainly in colorectal cancer, amphetamine addition, the peroxisome proliferator-activated receptor signaling pathway, and the toll-like receptor signaling pathway. The protein-protein interaction network identified 8 hub genes, and the co-expression network was analyzed to obtain 7 related functions and mutual proportions of hub genes. A total of 120 transcription factors were predicted for hub genes. Hub genes were closely related to immune cells, including neutropils and eosinophils. In addition, we identified 15 potential candidate drugs based on hub genes that are promising for the treatment of NASH. Type 2 diabetes mellitus can affect the progression of NASH by changing hormone levels and inflammatory responses through multiple targets and signaling pathways. Eight hub genes are expected to be potential targets for subsequent treatment.

Causal relationship between varicose veins and mean corpuscular hemoglobin concentration based on Mendelian randomization study

BackgroundIncreased hemoglobin concentrations may increase the risk of varicose veins. However, the underlying relationship between them was not yet understood.MethodsMendelian randomization (MR) analysis was performed to investigate causal effect between mean corpuscular hemoglobin concentration (MCHC, exposure factor) and varicose veins (outcome). Afterward, sensitivity analysis was used to ensure the reliability of MR analysis results. Then Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of SNPs were performed. A search tool for recurring instances of neighbouring genes (STRING) database was used to construct a protein-protein interaction (PPI) network.ResultsTherefore, the inverse-variance weighted (IVW) results showed there existed a causal relationship between MCHC and varicose veins (p = 0.0026), with MCHC serving as a significant risk factor. (odd ratio [OR] = 1.2321). In addition, the validity of the results of the forward MR analysis was verified by sensitivity analysis. Further, a PPI network of 92 single-nucleotide polymorphisms (SNPs) which used for forward MR analysis related genes was constructed. And they were found to be closely associated with the peroxisome proliferator-activated receptor (PPAR) signalling pathway and cellular response to external stimulus by enrichment analysis. In addition, we clarified that the effect of varicose veins on MCHC was minimal by reverse MR analysis, suggesting that the results of forward MR analysis were not disturbed by reverse results.ConclusionThis study found a causal relationship between varicose veins and MCHC, which provided strong evidence for the effect of hemoglobin on varicose veins, and a new thought for the diagnosis and prevention of varicose veins in the future.

Apoptosis and Oxidative Stress in Human Intestinal Epithelial Caco-2 Cells Caused by Marine Phycotoxin Azaspiracid-2.

When humans consume seafood contaminated by lipophilic polyether phycotoxins, such as azaspiracids (AZAs), the toxins are mainly leached and absorbed in the small intestine, potentially causing intestinal damage. In this study, human intestinal epithelial Caco-2 cells were used to investigate the adverse effects of azaspiracid-2 (AZA-2) on human intestinal epithelial cells. Cell viability, apoptosis, oxidative damage and mitochondrial ultrastructure were investigated, and ribonucleic acid sequence (RNA-seq) analysis was applied to explore the potential mechanisms of AZA-2 toxicity to Caco-2 cells. Results showed that AZA-2 significantly reduced the proliferation of Caco-2 cells in a concentration-dependent response, and the 48 h EC50 of AZA-2 was 12.65 nmol L-1. AZA-2 can induce apoptosis in Caco-2 cells in a dose-dependent manner. Visible mitochondrial swelling, cristae disintegration, membrane rupture and autophagy were observed in Caco-2 cells exposed to AZA-2. Reactive oxygen species (ROS) and malondialdehyde (MDA) content were significantly increased in Caco-2 cells after 48 h of exposure to 1 and 10 nmol L-1 of AZA-2. Transcriptome analysis showed that KEGG pathways related to cellular oxidative damage and lipid metabolism were affected, mainly including mitophagy, oxidative phosphorylation, cholesterol metabolism, vitamin digestion and absorption, bile secretion and the peroxisome proliferator-activated receptor signaling pathway. The cytotoxic effects of AZA-2 on Caco-2 cells may be associated with ROS-mediated autophagy and apoptosis in mitochondrial cells. Results of this study improve understanding of the cytotoxicity and molecular mechanisms of AZA-2 on Caco-2 cells, which is significant for protecting human health.

A proteomics-based study of the mechanism of oxymatrine to ameliorate hepatic fibrosis in mice

ObjectiveThis study investigated the protective effect of oxymatrine (OMT) on carbon tetrachloride (CCl4)-induced hepatic fibrosis in mice and explored its possible targets and signaling pathways. MethodsMale BALB/c mice were randomly divided into blank control, model, positive drug (silymarin), and OMT administration groups, respectively, with 10 mice in each group. Hepatic fibrosis was induced in mice using CCl4 and the corresponding drug intervention was given. After the final administration, ultrasonography tests, blood tests, and analysis of liver differential proteins using tandem mass tag labeling and liquid chromatography-mass spectrometry were performed. ResultsOMT intervention ameliorated CCl4-induced hepatic fibrosis in mice, significantly reduced serum alanine aminotransferase and aspartate aminotransferase levels, down-regulated the expression of fibrosis factors, such as type IV collagen IV, laminin, type III procollagen III, and alpha-smooth muscle actin, and improved liver function. The results of the proteomic analysis showed that the intervention of OMT significantly down-regulated 130 out of 440 up-regulated proteins and up-regulated 70 out of 294 down-regulated proteins, primarily involving the transient receptor potential (TRP) signaling pathway, the peroxisome proliferator-activated receptors (PPAR) signaling pathway, and the metabolic pathway of arachidonic acid. The main differential proteins involved were Cyp2c37, SCP-2, and Tbxas1. In addition, OMT intervention significantly reversed the expression of sterol carrier protein-2 (SCP2) and upregulated the expression of peroxisome proliferator-activated receptor gamma, Cyp2c37, and transient receptor potential cation channel subfamily V member 1 proteins. ConclusionOMT inhibited the proliferative capacity of hepatic stellate cells, induced apoptotic properties, and suppressed the development of fibrosis by elevating Cyp2c37/TRP signaling axis activity and upregulating PPAR pathway activity by inhibiting SCP2.

Transcriptomics-based analysis reveals hexafluoropropylene oxide trimer acid (HFPO-TA) induced kidney damage and lipid metabolism disorders in SD rats

Hexafluoropropylene oxide trimer acid (HFPO-TA) is an emerging environmental pollutant that can accumulate in air and surface water. Currently, it has been widely used in fluoropolymer industry, which could cause serious environmental pollution. Due to the high bioaccumulation, the accumulation of pollutants may have an adverse effect on the normal physiological function of the kidneys. However, the toxic effects of HFPO-TA on the kidney are unknown. In this study, we investigated the toxic effects of HFPO-TA exposure on the rat kidney and its mechanism of action. Male SD rats were divided into 4 groups: control group (Ctrl group), L group (0.125 mg/kg/d), M group (0.5 mg/kg/d) and H group (2 mg/kg/d). After 14 consecutive days of gavage, periodic acid‑silver methenamine (PASM) and hematoxylin-eosin (HE) staining were used to examine the structure of the kidneys. We also used transcriptome sequencing (RNA-seq) to identify differentially expressed genes (DEGs) in the testes of rats in both the control and high dose groups. Besides, expression of key proteins was analyzed by immunohistochemistry. The results indicated that HFPO-TA can lead to injured renal capsule, change glomerular shape and have a significant impact on the protein expression levels of AQP2, p-AQP2 and PPARα. Additionally, the level of total cholesterol (TC) was obviously decreased after HFPO-TA exposure. RNA-seq analysis showed that HFPO-TA primarily affected peroxisome proliferator-activated receptor (PPAR) signaling pathway that is associated with lipid metabolism and cyclic adenosine monophosphate (cAMP) signaling pathway. In summary, exposure to HFPO-TA can lead to kidney damage and lipid metabolism disorders.

Exploration of Genes Related to Intramuscular Fat Deposition in Xinjiang Brown Cattle.

The aim of this study was to investigate the differentially expressed genes associated with intramuscular fat deposition in the longissimus dorsi muscle of Xinjiang Brown Bulls. The longissimus dorsi muscles of 10 Xinjiang Brown Bulls were selected under the same feeding conditions. The intramuscular fat content of muscle samples was determined by the Soxhlet extraction method, for which 5 samples with high intramuscular fat content (HIMF group) and 5 samples with low intramuscular fat content (LIMF group) were selected. It was found that the intramuscular fat content of the HIMF group was 46.054% higher than that of the LIMF group. Muscle samples produced by paraffin sectioning were selected for morphological observation. It was found that the fat richness of the HIMF group was better than that of the LIMF group. Transcriptome sequencing technology was used to analyze the gene expression differences of longissimus dorsi muscle. Through in-depth analysis of the longissimus dorsi muscle by transcriptome sequencing technology, we screened a total of 165 differentially expressed genes. The results of Gene Ontology (GO) enrichment analysis showed that the differentially expressed genes in the two groups were mainly clustered in biological pathways related to carbohydrate metabolic processes, redox processes and oxidoreductase activities. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the differentially expressed genes were significantly clustered in 15 metabolic pathways, which mainly covered fatty acid metabolism (related to lipid metabolism and glucose metabolism), the pentose phosphate pathway, the Peroxisome Proliferator-Activated Receptor (PPAR) signaling pathway and other important metabolic processes. The three genes that were predominantly enriched in the glycolipid metabolic pathway by analysis were SCD5, CPT1C and FBP2, all of which directly or indirectly affect intramuscular fat deposition. In summary, the present study investigated the differences in gene expression between high and low intramuscular fat content in the longissimus dorsi muscle of Xinjiang Brown Bulls by transcriptome sequencing technology and revealed the related signaling pathways. Therefore, we hypothesized that SCD5, CPT1C and FBP2 were the key genes responsible for the significant differences in intramuscular fat content of the longissimus dorsi muscles in a population of Xinjiang Brown Bulls. We expect that these findings will provide fundamental support for subsequent studies exploring key genes affecting fat deposition characteristics in Xinjiang Brown Bulls.

Mixtures of phthalates disrupt expression of genes related to lipid metabolism and peroxisome proliferator-activated receptor signaling in mouse granulosa cells.

Phthalates are a class of known endocrine disrupting chemicals that are found in common everyday products. Several studies associate phthalate exposure with detrimental effects on ovarian function, including growth and development of the follicle and production of steroid hormones. We hypothesized that dysregulation of the ovary by phthalates may be mediated by phthalate toxicity towards granulosa cells, a major cell type in ovarian follicles responsible for key steps of hormone production and nourishing the developing oocyte. To test the hypothesis that phthalates target granulosa cells, we harvested granulosa cells from adult CD-1 mouse ovaries and cultured them for 96 hours in vehicle control, a phthalate mixture, or a phthalate metabolite mixture (0.1-100 μg/mL). After culture, we measured metabolism of the phthalate mixture into monoester metabolites by the granulosa cells, finding that granulosa cells do not significantly contribute to ovarian metabolism of phthalates. Immunohistochemistry of phthalate metabolizing enzymes in whole ovaries confirmed that these enzymes are not strongly expressed in granulosa cells of antral follicles and that ovarian metabolism of phthalates likely occurs primarily in the stroma. RNA sequencing of treated granulosa cells identified 407 differentially expressed genes, with overrepresentation of genes from lipid metabolic processes, cholesterol metabolism, and peroxisome proliferator-activated receptor (PPAR) signaling pathways. Expression of significantly differentially expressed genes related to these pathways was confirmed using qPCR. Our results agree with previous findings that phthalates and phthalate metabolites have different effects on the ovary, but both interfere with PPAR signaling in granulosa cells.

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.

Perfluorohexanesulfonic Acid (PFHxS) Impairs Lipid Homeostasis in Zebrafish Larvae through Activation of PPARα.

Perfluorohexanesulfonic acid (PFHxS), an emerging short-chain per- and polyfluoroalkyl substance, has been frequently detected in aquatic environments. Adverse outcome pathway studies have shown that perfluorinated compounds impair lipid homeostasis through peroxisome proliferator activated receptors (PPARs). However, many of these studies were performed at high concentrations and may thus be a result of overt toxicity. To better characterize the molecular and key events of PFHxS to biota, early life-stage zebrafish (Danio rerio) were exposed to concentrations detected in the environment (0.01, 0.1, 1, and 10 μg/L). Lipidomic and transcriptomic evaluations were integrated to predict potential molecular targets. PFHxS significantly impaired lipid homeostasis by the dysregulation of glycerophospholipids, fatty acyls, glycerolipids, sphingolipids, prenol lipids, and sterol lipids. Informatic analyses of the lipidome and transcriptome indicated alterations of the PPAR signaling pathway, with downstream changes to retinol, linoleic acid, and glycerophospholipid metabolism. To assess the role of PPARs, potential binding of PFHxS to PPARs was predicted and animals were coexposed to a PPAR antagonist (GW6471). Molecular simulation indicated PFHxS had a 27.1% better binding affinity than oleic acid, an endogenous agonist of PPARα. Antagonist coexposures rescued impaired glycerophosphocholine concentrations altered by PFHxS. These data indicate PPARα activation may be an important molecular initiating event for PFHxS.

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.

The long-chain polyfluorinated alkyl substance perfluorohexane sulfonate (PFHxS) promotes bone marrow adipogenesis

Per- and polyfluoroalkyl substances (PFAS) bioaccumulate in different organ systems, including bone. While existing research highlights the adverse impact of PFAS on bone density, a critical gap remains in understanding the specific effects on the bone marrow microenvironment, especially the bone marrow adipose tissue (BMAT). Changes in BMAT have been linked to various health consequences, such as the development of osteoporosis and the progression of metastatic tumors in bone. Studies presented herein demonstrate that exposure to a mixture of five environmentally relevant PFAS compounds promotes marrow adipogenesis in vitro and in vivo. We show that among the components of the mixture, PFHxS, an alternative to PFOS, has the highest propensity to accumulate in bone and effectively promote marrow adipogenesis. Utilizing RNAseq approaches, we identified the peroxisome proliferator-activated receptor (PPAR) signaling as a top pathway modulated by PFHxS exposure. Furthermore, we provide results suggesting the activation and involvement of PPAR-gamma (PPARγ) in PFHxS-mediated bone marrow adipogenesis, especially in combination with high-fat diet. In conclusion, our findings demonstrate the potential impact of elevated PFHxS levels, particularly in occupational settings, on bone health, and specifically bone marrow adiposity. This study contributes new insights into the health risks of PFHxS exposure, urging further research on the relationship between environmental factors, diet, and adipose tissue dynamics.

Identification of potential key lipid metabolism-related genes involved in tubular injury in diabetic kidney disease by bioinformatics analysis.

Accumulating evidences indicate that abnormalities in tubular lipid metabolism play a crucial role in the development of diabetic kidney disease (DKD). We aim to identify novel lipid metabolism-related genes associated with tubular injury in DKD by utilizing bioinformatics approaches. Differentially expressed genes (DEGs) between control and DKD tubular tissue samples were screened from the Gene Expression Omnibus (GEO) database, and then were intersected with lipid metabolism-related genes. Hub genes were further determined by combined weighted gene correlation network analysis (WGCNA) and protein-protein interaction (PPI) network. We performed enrichment analysis, immune analysis, clustering analysis, and constructed networks between hub genes and miRNAs, transcription factors and small molecule drugs. Receiver operating characteristic (ROC) curves were employed to evaluate the diagnostic efficacy of hub genes. We validated the relationships between hub genes and DKD with external datasets and our own clinical samples. There were 5 of 37 lipid metabolism-related DEGs identified as hub genes. Enrichment analysis demonstrated that lipid metabolism-related DEGs were enriched in pathways such as peroxisome proliferator-activated receptors (PPAR) signaling and pyruvate metabolism. Hub genes had potential regulatory relationships with a variety of miRNAs, transcription factors and small molecule drugs, and had high diagnostic efficacy. Immune infiltration analysis revealed that 13 immune cells were altered in DKD, and hub genes exhibited significant correlations with a variety of immune cells. Through clustering analysis, DKD patients could be classified into 3 immune subtypes and 2 lipid metabolism subtypes, respectively. The tubular expression of hub genes in DKD was further verified by other external datasets, and immunohistochemistry (IHC) staining showed that except ACACB, the other 4 hub genes (LPL, AHR, ME1 and ALOX5) exhibited the same results as the bioinformatics analysis. Our study identified several key lipid metabolism-related genes (LPL, AHR, ME1 and ALOX5) that might be involved in tubular injury in DKD, which provide new insights and perspectives for exploring the pathogenesis and potential therapeutic targets of DKD.

PPAR beta/gamma mediates the antihypertensive activity of a synbiotic preparation of Bifidobacterium lactis and Lactobacillus acidophilus in spontaneous hypertensive rats

BackgroundHypertension is a global public health concern. A synbiotic preparation containing Bifidobacterium lactis and Lactobacillus acidophilus has been used as adjunct therapy for hypertension. We sought to elucidate the antihypertensive activity of this preparation and explore the underlying mechanisms. Methods and resultsBlood pressure in rats was measured using the tail-cuff method. Colonization of the gastrointestinal tract by the two probiotics was determined by real-time quantitative polymerase chain reaction (qPCR). Mechanistic studies were performed by proteomic analyses based on liquid chromatography-mass spectrometry and STRING database and metabolomic analyses using the UHPLC-Q-TOF/MS platform and peroxisome proliferator-activated receptor (PPAR)β/γ antagonists. Although biochemical analysis of blood samples showed that the synbiotic preparation did not alter the levels of angiotensin II, aldosterone, or cortisol, it significantly lowered the systolic blood pressure in the treatment group. Moreover, the synbiotic preparation contributed to the localization of the two probiotics in the ileum and colon of the treatment group. Proteomics, immunochemistry, and real-time qPCR analyses showed that administration of the synbiotic preparation activated the PPAR signaling pathway in the ileum and significantly upregulated PPARβ and PPARγ. The antagonist studies further confirmed this finding. In addition, metabolomic analyses demonstrated that among the 27 metabolites that showed significant differences between the control and model groups, administration of the synbiotic preparation significantly upregulated lysophosphatidylethanolamine and phosphatidylcholine in the ileum of the treatment group. ConclusionThe results of the study suggest that the novel synbiotic preparation reduces blood pressure by altering the composition of the intestinal microbiota, regulating PPAR signaling pathway, and activating the PPARβ and PPARγ cascade reactions in the ileum.

Gestational organophosphate esters (OPEs) exposure in association with placental DNA methylation levels of peroxisome proliferator-activated receptors (PPARs) signaling pathway-related genes

BackgroundOrganophosphate esters (OPEs) exposure could affect offspring health. However, the underlying mechanisms are not well documented. ObjectivesBased on a birth cohort study, we aimed to investigate the associations among gestational OPEs exposure, placental DNA methylation levels of peroxisome proliferator-activated receptor (PPAR) signaling pathway-related genes, and fetal growth. MethodsWe measured the concentrations of eight OPE metabolites in maternal urine samples and neonatal anthropometric measurements in 733 mother-child pairs. In 327 placental samples, we assessed the DNA methylation levels of 14 genes which were involved in the PPARs signaling pathway and expressed in placenta. Multiple linear regression models were used to examine the associations of OPEs exposure with placental DNA methylation, and of OPEs and placental DNA methylation with neonatal anthropometric measurements. Causal mediation analyses were conducted to examine the potential mediating role of placental DNA methylation in the pathway between OPEs exposure and fetal growth. ResultsWe observed a general pattern of OPEs exposure being associated with hypermethylation of candidate genes, with statistically significant associations identified for several OPEs with RXRA, ACAA1, ACADL, ACADM, PLTP, and NR1H3 methylation. Further, gestational exposure to BCIPP, DPP, BBOEP, ∑NCl-OPEs, and ∑OPEs tended to be associated with lower anthropometric measurements, with more significant associations observed on arm circumference, and abdominal and back skinfold thickness. Notably, RXRA, ACAA1, ACOX1, CPT2, ACADM, and NR1H3 methylation tended to be associated with lower neonatal anthropometric measurements, especially for abdominal and back skinfold thickness. Moreover, mediation analyses showed that 19.42 % of the total effect of DPP on the back skinfold thickness was mediated by changes in RXRA methylation, and there was a significant indirect effect of RXRA methylation. ConclusionsGestational OPEs exposure could disrupt the placental DNA methylation levels of PPAR signaling pathway-related genes, which might contribute to the effect of OPEs on fetal growth.

Reveal the mechanism of hepatic oxidative stress in mice induced by photo-oxidation milk using multi-omics analysis techniques

IntroductionPhoto-oxidation is recognized as a contributor to the deterioration of milk quality, posing potential safety hazards to human health. However, there has been limited investigation into the impact of consuming photo-oxidized milk on health. ObjectivesThis study employs multi-omics analysis techniques to elucidate the mechanisms by which photo-oxidized milk induces oxidative stress in the liver. MethodsMouse model was used to determine the effect of the gavage administration of milk with varying degrees of photo-oxidation on the mouse liver. The damage degree was established by measuring serum markers indicative of oxidative stress, and with a subsequent histopathological examination of liver tissues. In addition, comprehensive metabolome, lipidome, and transcriptome analyses were conducted to elucidate the underlying molecular mechanisms of hepatic damage caused by photo-oxidized milk. ResultsA significant elevation in the oxidative stress levels and the presence of hepatocellular swelling and inflammation subsequent to the gavage administration of photo-oxidized milk to mice. Significant alterations in the levels of metabolites such as lumichrome, all-trans-retinal, L-valine, phosphatidylglycerol, and phosphatidylcholine within the hepatic tissue of mice. Moreover, photo-oxidized milk exerted a pronounced detrimental impact on the glycerophospholipid metabolism of mice liver. The peroxisome proliferator-activated receptors (PPAR) signaling pathway enrichment appreciated in the animals that consumed photo-oxidized milk further supports the substantial negative influence of photo-oxidized milk on hepatic lipid metabolism. Gene set enrichment and interaction analyses revealed that photo-oxidized milk inhibited the cytochrome P450 pathway in mice, while also affecting other pathways associated with cellular stress response and lipid biosynthesis. ConclusionThis comprehensive study provides significant evidence regarding the potential health risks associated with photo-oxidized milk, particularly in terms of hepatic oxidative damage. It establishes a scientific foundation for assessing the safety of such milk and ensuring the quality of dairy products.

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.