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BMC Endocrine Disorders Mar 2024A better understanding of adipose tissue (AT) dysfunction, which includes morphological and functional changes such as adipocyte hypertrophy as well as impaired...
BACKGROUND
A better understanding of adipose tissue (AT) dysfunction, which includes morphological and functional changes such as adipocyte hypertrophy as well as impaired adipogenesis, lipid storage/mobilization, endocrine and inflammatory responses, is needed in the context of obesity. One dimension of AT dysfunction, secretory adiposopathy, often assessed as a low plasma adiponectin (A)/leptin (L) ratio, is commonly observed in obesity. The aim of this study was to examine markers of AT development and metabolism in 67 women of varying age and adiposity (age: 40-62 years; body mass index, BMI: 17-41 kg/m) according to levels of adiponectinemia, leptinemia or the plasma A/L ratio.
METHODS
Body composition, regional AT distribution and circulating adipokines were determined. Lipolysis was measured from glycerol release in subcutaneous abdominal (SCABD) and omental (OME) adipocytes under basal, isoproterenol-, forskolin (FSK)- and dibutyryl-cyclic AMP (DcAMP)-stimulated conditions. Adipogenesis (C/EBP-α/β/δ, PPAR-γ2 and SREBP-1c) and lipid metabolism (β2-ARs, HSL, FABP4, LPL and GLUT4) gene expression (RT-qPCR) was assessed in both fat depots. Participants in the upper versus lower tertile of adiponectin, leptin or the A/L ratio were compared.
RESULTS
Basal lipolysis was similar between groups. Women with a low plasma A/L ratio were characterized by higher adiposity and larger SCABD and OME adipocytes (p<0.01) compared to those with a high ratio. In OME adipocytes, women in the low adiponectinemia tertile showed higher isoproterenol-stimulated lipolysis (0.01
CONCLUSIONS
Secretory adiposopathy assessed as the plasma A/L ratio, more so than adiponectin or leptin levels alone, discriminates low and elevated lipolysis in OME and SCABD adipocytes despite similar AT expression of selected genes involved in lipid metabolism.
Topics: Female; Humans; Adult; Middle Aged; Adiponectin; Leptin; Isoproterenol; Adipose Tissue; Obesity
PubMed: 38481206
DOI: 10.1186/s12902-024-01567-8 -
International Journal of Molecular... Mar 2024-retinylidene--retinylethanolamine (A2E) has been associated with age-related macular degeneration (AMD) physiopathology by inducing cell death, angiogenesis and...
-retinylidene--retinylethanolamine (A2E) has been associated with age-related macular degeneration (AMD) physiopathology by inducing cell death, angiogenesis and inflammation in retinal pigmented epithelial (RPE) cells. It was previously thought that the A2E effects were solely mediated via the retinoic acid receptor (RAR)-α activation. However, this conclusion was based on experiments using the RAR "specific" antagonist RO-41-5253, which was found to also be a ligand and partial agonist of the peroxisome proliferator-activated receptor (PPAR)-γ. Moreover, we previously reported that inhibiting PPAR and retinoid X receptor (RXR) transactivation with norbixin also modulated inflammation and angiogenesis in RPE cells challenged in the presence of A2E. Here, using several RAR inhibitors, we deciphered the respective roles of RAR, PPAR and RXR transactivations in an in vitro model of AMD. We showed that BMS 195614 (a selective RAR-α antagonist) displayed photoprotective properties against toxic blue light exposure in the presence of A2E. BMS 195614 also significantly reduced the AP-1 transactivation and mRNA expression of the inflammatory interleukin (IL)-6 and vascular endothelial growth factor (VEGF) induced by A2E in RPE cells in vitro, suggesting a major role of RAR in these processes. Surprisingly, however, we showed that (1) Norbixin increased the RAR transactivation and (2) AGN 193109 (a high affinity pan-RAR antagonist) and BMS 493 (a pan-RAR inverse agonist), which are photoprotective against toxic blue light exposure in the presence of A2E, also inhibited PPARs transactivation and RXR transactivation, respectively. Therefore, in our in vitro model of AMD, several commercialized RAR inhibitors appear to be non-specific, and we propose that the phototoxicity and expression of IL-6 and VEGF induced by A2E in RPE cells operates through the activation of PPAR or RXR rather than by RAR transactivation.
Topics: Anti-Inflammatory Agents; Carotenoids; Drug Inverse Agonism; Inflammation; Macular Degeneration; para-Aminobenzoates; Peroxisome Proliferator-Activated Receptors; Quinolines; Retinoic Acid Receptor alpha; Retinoid X Receptors; Retinoids; Transcriptional Activation; Vascular Endothelial Growth Factor A
PubMed: 38474284
DOI: 10.3390/ijms25053037 -
Physiological Research Mar 2024Although electrical muscle stimulation (EMS) of skeletal muscle effectively prevents muscle atrophy, its effect on the breakdown of muscle component proteins is unknown....
Skeletal Muscle Electrical Stimulation Prevents Progression of Disuse Muscle Atrophy via Forkhead Box O Dynamics Mediated by Phosphorylated Protein Kinase B and Peroxisome Proliferator-Activated Receptor gamma Coactivator-1alpha.
Although electrical muscle stimulation (EMS) of skeletal muscle effectively prevents muscle atrophy, its effect on the breakdown of muscle component proteins is unknown. In this study, we investigated the biological mechanisms by which EMS-induced muscle contraction inhibits disuse muscle atrophy progression. Experimental animals were divided into a control group and three experimental groups: immobilized (Im; immobilization treatment), low-frequency (LF; immobilization treatment and low-frequency muscle contraction exercise), and high-frequency (HF; immobilization treatment and high-frequency muscle contraction exercise). Following the experimental period, bilateral soleus muscles were collected and analyzed. Atrogin-1 and Muscle RING finger 1 (MuRF-1) mRNA expression levels were significantly higher for the experimental groups than for the control group but were significantly lower for the HF group than for the Im group. Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) mRNA and protein expression levels in the HF group were significantly higher than those in the Im group, with no significant differences compared to the Con group. Both the Forkhead box O (FoxO)/phosphorylated FoxO and protein kinase B (AKT)/phosphorylated AKT ratios were significantly lower for the Im group than for the control group and significantly higher for the HF group than for the Im group. These results, the suppression of atrogin-1 and MuRF-1 expression for the HF group may be due to decreased nuclear expression of FoxO by AKT phosphorylation and suppression of FoxO transcriptional activity by PGC-1alpha. Furthermore, the number of muscle contractions might be important for effective EMS.
Topics: Animals; Proto-Oncogene Proteins c-akt; Transcription Factors; PPAR gamma; Muscle, Skeletal; Muscular Atrophy; Muscle Proteins; RNA, Messenger; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
PubMed: 38466009
DOI: 10.33549/physiolres.935157 -
Cell & Bioscience Mar 2024To understand how liver sinusoidal endothelial cells (LSECs) respond to nonalcoholic steatohepatitis (NASH).
AIM
To understand how liver sinusoidal endothelial cells (LSECs) respond to nonalcoholic steatohepatitis (NASH).
METHODS
We profiled single-LSEC from livers of control and MCD-fed mice. The functions of C-Kit-LSECs were determined using coculture and bone marrow transplantation (BMT) methods.
RESULTS
Three special clusters of single-LSEC were differentiated. C-Kit-LSECs of cluster 0, Msr1-LSECs of cluster 1 and Bmp4Selp-VECs of cluster 2 were revealed, and these cells with diverse ectopic expressions of genes participated in regulation of endothelial, fibrosis and lipid metabolism in NASH. The number of C-Kit-primary LSECs isolated from MCD mice was lower than control mice. Immunofluorescence co-staining of CD31 and C-KIT showed C-Kit-LSECs located in hepatic sinusoid were also reduced in NASH patients and MCD mice, compared to AIH patients and control mice respectively. Interestingly, lipotoxic hepatocytes/HSCs cocultured with C-Kit-LSECs or the livers of MCD mice receipting of C-Kit-BMCs (bone marrow cells) showed less steatosis, inflammation and fibrosis, higher expression of prolipolytic FXR and PPAR-α, lower expression of TNF-α and α-SMA. Furthermore, coculturing or BMT of C-Kit-endothelial derived cells could increase the levels of hepatic mitochondrial LC3B, decrease the degree of mitochondrial damage and ROS production through activating Pink1-mediated mitophagy pathway in NASH.
CONCLUSIONS
Hence, a novel transcriptomic view of LSECs was revealed to have heterogeneity and complexity in NASH. Importantly, a cluster of C-Kit-LSECs was confirmed to recovery Pink1-related mitophagy and NASH progression.
PubMed: 38461242
DOI: 10.1186/s13578-024-01215-7 -
Frontiers in Pharmacology 2024Bleomycin is an effective antibiotic with a significant anticancer properties, but its use is limited due to its potential to induce dose-dependent pulmonary fibrosis....
Bleomycin is an effective antibiotic with a significant anticancer properties, but its use is limited due to its potential to induce dose-dependent pulmonary fibrosis. Therefore, this study aimed to assess the therapeutic potential of Capsaicin as an additional treatment to enhance patient tolerance to Bleomycin compared to the antifibrotic drug Pirfenidone. Pulmonary fibrosis was induced in rats through by a single intratracheal Bleomycin administration in day zero, followed by either Capsaicin or Pirfenidone treatment for 7 days. After the animals were sacrificed, their lungs were dissected and examined using various stains for macroscopic and histopathological evaluation. Additionally, the study assessed various antioxidant, anti-inflammatory, and antifibrotic parameters were assessed. Rats exposed to Bleomycin exhibited visible signs of fibrosis, histopathological alterations, increased collagen deposition, and elevated mucin content. Bleomycin also led to heightened increased inflammatory cells infiltration in the bronchoalveolar lavage, elevated fibrosis biomarkers such as hydroxyproline, alpha-smooth muscle actin (α-SMA) and transforming growth factor-beta (TGF-β1), increased inflammatory markers including tumor necrosis factor-alpha (TNF-α), interlukine-6 (Il-6), interlukine-1β (Il-1β) nuclear factor-kappa B (NF-κB), and Cyclooxygenase-2 (COX-2), and transforming growth factor-beta (TGF-β1),. Furthermore, it reduced the expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ), increased oxidative stress biomarkers like nitric oxide (NO), malondialdehyde (MDA), myeloperoxidase (MPO) and protein carbonyl. Bleomycin also decreased the expression of nuclear factor erythroid 2-related factor 2 (Nrf-2), reduced glutathione (GSH), total antioxidant capacity, and the activities of catalase and superoxide dismutase (SOD). Treating the animals with Capsaicin and Pirfenidone following Bleomycin exposure resulted in improved lung macroscopic and microscopic characteristics, reduced collagen deposition (collagen I and collagen III) and mucin content, decreased inflammatory cell infiltration, lowered levels of hydroxyproline, α-SMA, and TGF-β1, decreased TNF-α, Il-6, Il-1β, NF-κB, and COX-2, increased PPAR-γ and Nrf-2 expression, and improvement improved in all oxidative stress biomarkers. In summary, Capsaicin demonstrates significant antifibrotic activity against Bleomycin-induced lung injury that may be attributed, at least in part, to the antioxidant and anti-inflammatory activities of Capsaicin mediated by upregulation of PPAR-γ and Nrf-2 expression and decreasing. TGF-β1, NF-κB and COX II proteins concentrations.
PubMed: 38449809
DOI: 10.3389/fphar.2024.1333715 -
Neurobiology of Disease May 2024DYT-TOR1A (DYT1) dystonia, characterized by reduced penetrance and suspected environmental triggers, is explored using a "second hit" DYT-TOR1A rat model. We aim to...
DYT-TOR1A (DYT1) dystonia, characterized by reduced penetrance and suspected environmental triggers, is explored using a "second hit" DYT-TOR1A rat model. We aim to investigate the biological mechanisms driving the conversion into a dystonic phenotype, focusing on the striatum's role in dystonia pathophysiology. Sciatic nerve crush injury was induced in ∆ETorA rats, lacking spontaneous motor abnormalities, and wild-type (wt) rats. Twelve weeks post-injury, unbiased RNA-sequencing was performed on the striatum to identify differentially expressed genes (DEGs) and pathways. Fenofibrate, a PPARα agonist, was introduced to assess its effects on gene expression. F-FDG autoradiography explored metabolic alterations in brain networks. Low transcriptomic variability existed between naïve wt and ∆ETorA rats (17 DEGs). Sciatic nerve injury significantly impacted ∆ETorA rats (1009 DEGs) compared to wt rats (216 DEGs). Pathway analyses revealed disruptions in energy metabolism, specifically in fatty acid β-oxidation and glucose metabolism. Fenofibrate induced gene expression changes in wt rats but failed in ∆ETorA rats. Fenofibrate increased dystonia-like movements in wt rats but reduced them in ∆ETorA rats. F-FDG autoradiography indicated modified glucose metabolism in motor and somatosensory cortices and striatum in both ∆ETorA and wt rats post-injury. Our findings highlight perturbed energy metabolism pathways in DYT-TOR1A dystonia, emphasizing compromised PPARα agonist efficacy in the striatum. Furthermore, we identify impaired glucose metabolism in the brain network, suggesting a potential shift in energy substrate utilization in dystonic DYT-TOR1A rats. These results contribute to understanding the pathophysiology and potential therapeutic targets for DYT-TOR1A dystonia.
Topics: Rats; Animals; Dystonia; Rodentia; Fluorodeoxyglucose F18; Fenofibrate; PPAR alpha; Dystonic Disorders; Brain; Energy Metabolism; Glucose
PubMed: 38442845
DOI: 10.1016/j.nbd.2024.106462 -
Journal of Ethnopharmacology May 2024Inflammatory bowel disease (IBD) presents a risk of carcinogenesis, which escalates with the duration of IBD. Persistent histological inflammation is considered to be...
Anchang Yuyang Decoction inhibits experimental colitis-related carcinogenesis by regulating PPAR signaling pathway and affecting metabolic homeostasis of host and microbiota.
ETHNOPHARMACOLOGICAL RELEVANCE
Inflammatory bowel disease (IBD) presents a risk of carcinogenesis, which escalates with the duration of IBD. Persistent histological inflammation is considered to be the driving factor of colitis carcinogenesis. Effective control of inflammation is helpful to prevent and treat colitis-related colorectal cancer (CAC). Anchang Yuyang Decoction (AYD), a traditional Chinese medicine (TCM) formula, is originated from the ancient prescription of TCM for treating colitis and colorectal cancer. AYD has demonstrated efficacy in treating IBD and potential anti-carcinogenic properties.
AIM OF THE STUDY
This research aims to assess the therapeutic efficacy of AYD in ameliorating experimental colitis-related carcinogenesis induced by AOM/DSS. It further seeks to elucidate its potential mechanisms by integrating multiple omics sequencing approaches.
MATERIALS AND METHODS
A rat model for colitis-related carcinogenesis was developed using azoxymethane (AOM)/dextran sulfate sodium (DSS). UPLC-MS identified AYD's chemical constituents. Rats were administered varying doses of AYD (18.37, 9.19 and 4.59 g/kg) orally for 53 days, with mesalazine as a positive control. The study evaluated anti-carcinogenic effects by examining adenoma number, adenoma load, abnormal crypt foci (ACF), histopathological damage, and tumor-related protein expression. Anti-inflammatory and reparative effects were assessed through body weight, disease activity index (DAI), colon length, spleen index, inflammatory cytokine levels, and tight junction protein expression. The effects on intestinal microbiota and host metabolism were explored through 16S rRNA sequencing, targeted short-chain fatty acid (SCFA) metabonomics, and non-targeted colon metabolomics. Potential AYD targets were identified through transcriptomic sequencing and validated by qRT-PCR and western blotting.
RESULTS
AYD significantly reduced adenoma number, adenoma load, neoplasm-associated lesions, ACF, and tumor-related protein expression (e.g., p53, PCNA) in AOM/DSS-induced rats, thus impeding colitis-related carcinogenesis progression. AYD also alleviated histopathological damage and inflammation, promoting intestinal mucosal barrier repair. Furthermore, AYD modulated intestinal flora structure, enhanced SCFA production, and regulated colon metabolites. Transcriptomic sequencing revealed a significant impact on the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Subsequent qRT-PCR and western blotting experiments indicated AYD's influence in up-regulating PPAR-γ and down-regulating PPAR-α, PPAR-β/δ, and related proteins (thrombomodulin [Thbd], fatty acid binding protein 5 [Fabp5], stearoyl-CoA desaturase 2 [Scd2], phospholipid transfer protein [Pltp]).
CONCLUSIONS
This study demonstrates AYD's ability to inhibit experimental colitis-related carcinogenesis induced by AOM/DSS. Its mechanism likely involves modulation of the PPAR signaling pathway, impacting intestinal microbiota and host metabolic equilibrium.
Topics: Rats; Animals; Mice; Peroxisome Proliferator-Activated Receptors; RNA, Ribosomal, 16S; Chromatography, Liquid; Tandem Mass Spectrometry; Colitis; Inflammation; Signal Transduction; Inflammatory Bowel Diseases; Carcinogenesis; Azoxymethane; Gastrointestinal Microbiome; Colorectal Neoplasms; Homeostasis; Adenoma; Dextran Sulfate; Disease Models, Animal; Mice, Inbred C57BL; Colon
PubMed: 38428656
DOI: 10.1016/j.jep.2024.117995 -
Signal Transduction and Targeted Therapy Mar 2024Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family (PGC-1s), consisting of three members encompassing PGC-1α, PGC-1β, and PGC-1-related... (Review)
Review
Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family (PGC-1s), consisting of three members encompassing PGC-1α, PGC-1β, and PGC-1-related coactivator (PRC), was discovered more than a quarter-century ago. PGC-1s are essential coordinators of many vital cellular events, including mitochondrial functions, oxidative stress, endoplasmic reticulum homeostasis, and inflammation. Accumulating evidence has shown that PGC-1s are implicated in many diseases, such as cancers, cardiac diseases and cardiovascular diseases, neurological disorders, kidney diseases, motor system diseases, and metabolic disorders. Examining the upstream modulators and co-activated partners of PGC-1s and identifying critical biological events modulated by downstream effectors of PGC-1s contribute to the presentation of the elaborate network of PGC-1s. Furthermore, discussing the correlation between PGC-1s and diseases as well as summarizing the therapy targeting PGC-1s helps make individualized and precise intervention methods. In this review, we summarize basic knowledge regarding the PGC-1s family as well as the molecular regulatory network, discuss the physio-pathological roles of PGC-1s in human diseases, review the application of PGC-1s, including the diagnostic and prognostic value of PGC-1s and several therapies in pre-clinical studies, and suggest several directions for future investigations. This review presents the immense potential of targeting PGC-1s in the treatment of diseases and hopefully facilitates the promotion of PGC-1s as new therapeutic targets.
Topics: Humans; PPAR gamma; Oxidative Stress; Neoplasms; Inflammation; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
PubMed: 38424050
DOI: 10.1038/s41392-024-01756-w -
Frontiers in Bioscience (Landmark... Feb 2024Chronic obstructive pulmonary disease (COPD) is a complex respiratory disorder influenced by various factors and involving multiple genes. Respiratory dysfunction in... (Review)
Review
Chronic obstructive pulmonary disease (COPD) is a complex respiratory disorder influenced by various factors and involving multiple genes. Respiratory dysfunction in COPD patients leads to hypoxia, resulting in limited oxygen uptake. Peroxisome proliferator-activated receptor alpha () is a plateau-adapted gene that regulates respiratory function in populations adapted to high-altitude areas through multiple pathways. Interestingly, expression is higher in long-term inhabiting Tibetan populations that have adapted to the plateau environment. However, in patients with COPD, the expression of is downregulated, leading to dysregulation of the hypoxia-inducible factor pathway. Moreover, abnormal PPARA expression in lung epithelial cells triggers inflammatory responses, oxidative stress, and disrupted lipid metabolism, thereby exacerbating disease progression. Thus, this paper explored the mechanism underlying the role of plateau-adapted in COPD, providing essential theoretical insights into the treatment and prevention of COPD in high-altitude regions.
Topics: Humans; PPAR alpha; Hypoxia; Pulmonary Disease, Chronic Obstructive; Lung; Oxidative Stress
PubMed: 38420801
DOI: 10.31083/j.fbl2902068 -
Nature Communications Feb 2024Circulating monocytes participate in pain chronification but the molecular events that cause their deployment are unclear. Using a mouse model of hyperalgesic priming...
Circulating monocytes participate in pain chronification but the molecular events that cause their deployment are unclear. Using a mouse model of hyperalgesic priming (HP), we show that monocytes enable progression to pain chronicity through a mechanism that requires transient activation of the hydrolase, N-acylethanolamine acid amidase (NAAA), and the consequent suppression of NAAA-regulated lipid signaling at peroxisome proliferator-activated receptor-α (PPAR-α). Inhibiting NAAA in the 72 hours following administration of a priming stimulus prevented HP. This effect was phenocopied by NAAA deletion and depended on PPAR-α recruitment. Mice lacking NAAA in CD11b cells - monocytes, macrophages, and neutrophils - were resistant to HP induction. Conversely, mice overexpressing NAAA or lacking PPAR-α in the same cells were constitutively primed. Depletion of monocytes, but not resident macrophages, generated mice that were refractory to HP. The results identify NAAA-regulated signaling in monocytes as a control node in the induction of HP and, potentially, the transition to pain chronicity.
Topics: Humans; Amidohydrolases; Enzyme Inhibitors; Hyperalgesia; Lipids; Monocytes; Pain; PPAR alpha; Animals; Mice
PubMed: 38402219
DOI: 10.1038/s41467-024-46139-5