-
International Journal of Molecular... May 2024Thaumatin-like proteins (TLPs) in plants are involved in diverse biotic and abiotic stresses, including antifungal activity, low temperature, drought, and high salinity....
Thaumatin-like proteins (TLPs) in plants are involved in diverse biotic and abiotic stresses, including antifungal activity, low temperature, drought, and high salinity. However, the roles of the genes are rarely reported in early flowering. Here, the gene family was identified in . The 49 genes were classified into 10 clusters, and gene structures, conserved motifs, and expression patterns were analyzed in these genes. Among 49 genes, the transcription level is preferentially high in stems, and GUS staining signals were mainly detected in the phloem tissues of the pro::GUS transgenic poplars. We generated transgenic plants overexpressing the gene, and its overexpression lines showed early flowering phenotypes. However, the expression levels of main flowering regulating genes were not significantly altered in these -overexpressing plants. Our data further showed that overexpression of the gene led to a reactive oxygen species (ROS) burst in , which might advance the development process of transgenic plants. In addition, subcellular localization of -fused green fluorescent protein (GFP) was in peroxisome, as suggested by tobacco leaf transient transformation. Overall, this work provides a comprehensive analysis of the gene family in and an insight into the role of TLPs in woody plants.
Topics: Populus; Plant Proteins; Phloem; Gene Expression Regulation, Plant; Arabidopsis; Plants, Genetically Modified; Multigene Family; Phylogeny; Reactive Oxygen Species; Flowers; Genome, Plant
PubMed: 38892187
DOI: 10.3390/ijms25115990 -
Cells Jun 2024Precise control of neuronal activity is crucial for the proper functioning of neurons. How lipid homeostasis contributes to neuronal activity and how much of it is...
Precise control of neuronal activity is crucial for the proper functioning of neurons. How lipid homeostasis contributes to neuronal activity and how much of it is regulated by cells autonomously is unclear. In this study, we discovered that absence of the lipid regulator , a functional ortholog of the peroxisome proliferator-activated receptor (PPAR) in , resulted in defective pathogen avoidance behavior against (PA14). Functional NHR-49 was required in the neurons, and more specifically, in a set of oxygen-sensing body cavity neurons, URX, AQR, and PQR. We found that lowering the neuronal activity of the body cavity neurons improved avoidance in mutants. Calcium imaging in URX neurons showed that mutants displayed longer-lasting calcium transients in response to an O upshift, suggesting that excess neuronal activity leads to avoidance defects. Cell-specific rescue of NHR-49 in the body cavity neurons was sufficient to improve pathogen avoidance, as well as URX neuron calcium kinetics. Supplementation with oleic acid also improved avoidance behavior and URX calcium kinetics, suggesting that the defective calcium response in the neuron is due to lipid dysfunction. These findings highlight the role of cell-autonomous lipid regulation in neuronal physiology and immune behavior.
Topics: Animals; Caenorhabditis elegans; Lipid Metabolism; Caenorhabditis elegans Proteins; Neurons; Pseudomonas aeruginosa; Calcium; Mutation; Avoidance Learning; Receptors, Cytoplasmic and Nuclear
PubMed: 38891110
DOI: 10.3390/cells13110978 -
Cells May 2024This study explores the impact of environmental pollutants on nuclear receptors (CAR, PXR, PPARα, PPARγ, FXR, and LXR) and their heterodimerization partner, the...
This study explores the impact of environmental pollutants on nuclear receptors (CAR, PXR, PPARα, PPARγ, FXR, and LXR) and their heterodimerization partner, the Retinoid X Receptor (RXR). Such interaction may contribute to the onset of non-alcoholic fatty liver disease (NAFLD), which is initially characterized by steatosis and potentially progresses to steatohepatitis and fibrosis. Epidemiological studies have linked NAFLD occurrence to the exposure to environmental contaminants like PFAS. This study aims to assess the simultaneous activation of nuclear receptors via perfluorooctanoic acid (PFOA) and RXR coactivation via Tributyltin (TBT), examining their combined effects on steatogenic mechanisms. Mice were exposed to PFOA (10 mg/kg/day), TBT (5 mg/kg/day) or a combination of them for three days. Mechanisms underlying hepatic steatosis were explored by measuring nuclear receptor target gene and lipid metabolism key gene expressions, by quantifying plasma lipids and hepatic damage markers. This study elucidated the involvement of the Liver X Receptor (LXR) in the combined effect on steatosis and highlighted the permissive nature of the LXR/RXR heterodimer. Antagonistic effects of TBT on the PFOA-induced activation of the Pregnane X Receptor (PXR) and Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) were also observed. Overall, this study revealed complex interactions between PFOA and TBT, shedding light on their combined impact on liver health.
Topics: Animals; Trialkyltin Compounds; Caprylates; Mice; Fluorocarbons; Male; Mice, Inbred C57BL; Liver X Receptors; Liver; Retinoid X Receptors; Fatty Liver; Receptors, Cytoplasmic and Nuclear; Lipid Metabolism; Non-alcoholic Fatty Liver Disease
PubMed: 38891072
DOI: 10.3390/cells13110940 -
Journal of Thoracic Disease May 2024Chronic obstructive pulmonary disease (COPD) is significantly influenced by oxidative stress. Recent studies have elucidated the anti-oxidative stress properties of...
BACKGROUND
Chronic obstructive pulmonary disease (COPD) is significantly influenced by oxidative stress. Recent studies have elucidated the anti-oxidative stress properties of peroxisome proliferator-activated receptors γ (PPARγ), augmenting its known anti-inflammatory effects. The exact influence of PPARγ on oxidative stress in COPD remains elusive. This study aimed to investigate the potential mechanism by which PPARγ counteracts the oxidative stress instigated by cigarette smoke in macrophages.
METHODS
Macrophages were cultured and exposed to 1% cigarette smoke extract (CSE), 1 µg/mL erythromycin (EM), and 10 µmol/mL GW9662 (a PPARγ antagonist). Reactive oxygen species (ROS) in macrophages was identified using fluorescent microscopy. PPARγ expression was ascertained through reverse transcription-polymerase chain reaction (RT-PCR) and Western blot techniques. The superoxide dismutase (SOD) in macrophage supernatant was measured by enzyme linked immunosorbent assay (ELISA), as was malondialdehyde (MDA).
RESULTS
Our results shown that cigarette smoke stimulated macrophages to increase ROS release, decrease the expression of PPARγ, increase the expression of MDA and decrease the expression of SOD. After PPARγ inhibitor acted on macrophages stimulated by cigarette smoke, the expression of MDA was inhibited and the content of SOD increased. When EM was used to treat macrophages stimulated by cigarette smoke, the expression of ROS decreased, the expression of PPARγ increased, the expression of MDA decreased and the expression of SOD increased.
CONCLUSIONS
This study suggests that PPARγ plays an anti-oxidative role by inhibiting the expression of MDA and promoting the expression of SOD. Cigarette smoke induces oxidative stress by inhibiting PPARγ pathway. EM inhibits oxidative stress by activating PPARγ pathway.
PubMed: 38883674
DOI: 10.21037/jtd-23-1647 -
Frontiers in Endocrinology 2024Diabetes mellitus is an independent risk factor for heart failure, and diabetes-induced heart failure severely affects patients' health and quality of life. Cuproptosis...
Potential molecular and cellular mechanisms of the effects of cuproptosis-related genes in the cardiomyocytes of patients with diabetic heart failure: a bioinformatics analysis.
BACKGROUND
Diabetes mellitus is an independent risk factor for heart failure, and diabetes-induced heart failure severely affects patients' health and quality of life. Cuproptosis is a newly defined type of programmed cell death that is thought to be involved in the pathogenesis and progression of cardiovascular disease, but the molecular mechanisms involved are not well understood. Therefore, we aimed to identify biomarkers associated with cuproptosis in diabetes mellitus-associated heart failure and the potential pathological mechanisms in cardiomyocytes.
MATERIALS
Cuproptosis-associated genes were identified from the previous publication. The GSE26887 dataset was downloaded from the GEO database.
METHODS
The consistency clustering was performed according to the cuproptosis gene expression. Differentially expressed genes were identified using the limma package, key genes were identified using the weighted gene co-expression network analysis(WGCNA) method, and these were subjected to immune infiltration analysis, enrichment analysis, and prediction of the key associated transcription factors. Consistency clustering identified three cuproptosis clusters. The differentially expressed genes for each were identified using limma and the most critical MEantiquewhite4 module was obtained using WGCNA. We then evaluated the intersection of the MEantiquewhite4 output with the three clusters, and obtained the key genes.
RESULTS
There were four key genes: , , , and . , , and were negatively associated with multiple immune factors, while was positively associated, and T-cells accounted for a major proportion of this relationship with the immune system. Four enriched pathways were found to be associated: arachidonic acid metabolism, peroxisomes, fatty acid metabolism, and dorsoventral axis formation, which may be regulated by the transcription factor MECOM, through a change in protein structure.
CONCLUSION
HSDL2, BCO2, CORIN, and SNORA80E may regulate cardiomyocyte cuproptosis in patients with diabetes mellitus-associated heart failure through effects on the immune system. The product of the cuproptosis-associated gene is probably involved in myocardial fibrosis in patients with diabetes, which leads to the development of cardiac insufficiency.
Topics: Myocytes, Cardiac; Humans; Heart Failure; Computational Biology; Gene Expression Profiling; Gene Regulatory Networks; Ferroptosis; Diabetic Cardiomyopathies
PubMed: 38883603
DOI: 10.3389/fendo.2024.1370387 -
Cureus May 2024Tenosynovial giant cell tumor (TGCT) is a monoarticular fibrohistiocytic benign or locally aggressive soft tissue tumor that originates from the synovium of joints,...
BACKGROUND
Tenosynovial giant cell tumor (TGCT) is a monoarticular fibrohistiocytic benign or locally aggressive soft tissue tumor that originates from the synovium of joints, bursae, and tendon sheaths. It has an inflammatory neoplastic nature, with a clinical presentation ranging from pain, swelling, stiffness, and limited range of movement to joint instability and blockage. Its uncommon incidence leads to a poorly understood pathogenesis. Localized forms of TGCT (LTGCT) can cause significant morbidity, interfere with daily patient activities, and decrease the patient's quality of life in challenging cases. This study aimed to investigate the immunohistochemical expression of PPARγ (peroxisome proliferator-activated receptor gamma) and P53 in LTGCT to understand the disease better and offer potential therapeutic targets.
METHODS
The study is cross-sectional, in which 27 LTGCT cases were collected from the Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt. Solitary and multiple LTGCT cases retrieved between January 2018 and December 2022 were included, and immunohistochemically stained with anti-PPARγ and P53 antibodies. The TGCT samples were excluded if they were insufficient for sectioning, processing, and interpretation, over-fixed, had process artifacts, or were of the diffuse TGCT type. Scoring of stain expression was performed by ImageJ (National Institutes of Health, Bethesda, MD) analysis using the threshold method and was expressed in percent area/high power field. Clinicopathological correlations were analyzed.
RESULTS
All the 27 collected LTGCT cases were located in the small joints of patients' hands. Cases with solitary LGTCTs constituted 55.6% (n = 15), while 44.4% (n = 12) had multiple LTGCTs related to one affected site/case (e.g., multiple tumors in one finger). PPARγ was expressed in the cytoplasm of mononuclear and multinucleated tumor cells and foamy histiocytes, while P53 expression was mainly in mononuclear cells' nuclei. PPARγ significantly correlated with P53 expression (r = 0.9 and P = 0.000). PPARγ (r = 0.4 and P = 0.02) and P53 (r = 0.5 and P = 0.01) were positively correlated with tumor size. Only P53 expression was positively correlated with tumor multiplicity (r = 0.4 and P = 0.03). Using the receiver operating characteristic curve test, the P53 cutoff score detecting the multiplicity of TGCTs was ≥20.5%, with a 75% sensitivity and 80% specificity.
CONCLUSION
PPARγ and P53 have a significant role in LTGCT growth, while P53 plays a role in tumor multiplicity. They can be possible targets in LTGCTs unfit for excision.
PubMed: 38882990
DOI: 10.7759/cureus.60377 -
Circulation Jun 2024HIF (hypoxia inducible factor) regulates many aspects of cardiac function. We and others previously showed that chronic HIF activation in the heart in mouse models...
BACKGROUND
HIF (hypoxia inducible factor) regulates many aspects of cardiac function. We and others previously showed that chronic HIF activation in the heart in mouse models phenocopies multiple features of ischemic cardiomyopathy in humans, including mitochondrial loss, lipid accumulation, and systolic cardiac dysfunction. In some settings, HIF also causes the loss of peroxisomes. How, mechanistically, HIF promotes cardiac dysfunction is an open question.
METHODS
We used mice lacking cardiac pVHL (von Hippel-Lindau protein) to investigate how chronic HIF activation causes multiple features of ischemic cardiomyopathy, such as autophagy induction and lipid accumulation. We performed immunoblot assays, RNA sequencing, mitochondrial and peroxisomal autophagy flux measurements, and live cell imaging on hearts and isolated cardiomyocytes. We used CRISPR-Cas9 gene editing in mice to validate a novel mediator of cardiac dysfunction in the setting of chronic HIF activation.
RESULTS
We identify a previously unknown pathway by which cardiac HIF activation promotes the loss of mitochondria and peroxisomes. We found that DEPP1 (decidual protein induced by progesterone 1) is induced under hypoxia in a HIF-dependent manner and localizes inside mitochondria. DEPP1 is both necessary and sufficient for hypoxia-induced autophagy and triglyceride accumulation in cardiomyocytes ex vivo. DEPP1 loss increases cardiomyocyte survival in the setting of chronic HIF activation ex vivo, and whole-body Depp1 loss decreases cardiac dysfunction in hearts with chronic HIF activation caused by loss in vivo.
CONCLUSIONS
Our findings identify DEPP1 as a key component in the cardiac remodeling that occurs with chronic ischemia.
PubMed: 38881449
DOI: 10.1161/CIRCULATIONAHA.123.066628 -
Cell Death Discovery Jun 2024Peroxisomal L-bifunctional enzyme (EHHADH) plays a role in the classic peroxisomal fatty acid β-oxidation pathway; however, the relationship between EHHADH expression...
Peroxisomal L-bifunctional enzyme (EHHADH) plays a role in the classic peroxisomal fatty acid β-oxidation pathway; however, the relationship between EHHADH expression and diabetic kidney disease has not been well understood. Here, we found that endogenous EHHADH levels were strongly correlated with the progression and severity of diabetic nephropathy in T2D patients. EHHADH knockout mice exhibited worsened renal tubular injury in diabetic mice. Furthermore, EHHADH is a modulator of pexophagy. In renal tubular epithelial cells (RTECs) in vitro, the knockdown of EHHADH induced a dramatic loss of peroxisomes. The loss of peroxisomes in EHHADH-deficient RTECs was restored by either an autophagic inhibitor 3-methyladenine or bafilomycin A1 both in vitro and in vivo. NBR1 was required for pexophagy in EHHADH-knockdown cells, where the level of reactive oxygen species (ROS) was increased, while inhibition of ROS blocked pexophagy. In summary, our findings revealed EHHADH deficiency accelerated renal injury in DKD as a modulator of pexophagy.
PubMed: 38879653
DOI: 10.1038/s41420-024-02066-4 -
Journal of Dairy Science Jun 2024Mitochondrial dysfunction has been reported to occur in the mammary gland of dairy cows suffering from ketosis. Prohibitin 2 (PHB2) plays a crucial role in regulating...
Mitochondrial dysfunction has been reported to occur in the mammary gland of dairy cows suffering from ketosis. Prohibitin 2 (PHB2) plays a crucial role in regulating mitophagy, which clears impaired mitochondria to maintain normal mitochondrial function. Therefore, the current study aimed to investigate how PHB2 mediates mitophagy, thereby influencing mitochondrial function in the bovine mammary epithelial cell MAC-T. First, mammary gland tissue and blood samples were collected from healthy cows (control; n = 15, BHB <0.6 mM) and cows with clinical ketosis (CK; n = 15, BHB >3.0 mM). Compared with the control group, the CK group exhibited lower dry matter intake (DMI), milk production, milk protein, milk lactose, and serum glucose. In contrast, milk fat, serum nonesterified fatty acids (NEFA) and BHB were greater in CK group. The protein abundance of PHB2, peroxisome proliferator activated receptor-γ coactivator-1α (PGC-1α), mitofusin 2 (MFN2) in whole cell lysates (WCL), as well as PHB2, sequestosome-1 (SQSTM1, also called p62), microtubule-associated protein 1 light chain 3-II (LC3-II), and ubiquitinated proteins in mitochondrial fraction were significantly lower in the CK group. ATP content of mammary gland tissue in CK group was lower than that of healthy cows. Second, MAC-T were cultured and treated with NEFA (0, 0.3, 0.6, 1.2 mM). MAC-T treated with 1.2 mM NEFA displayed decreased protein abundance of PHB2, PGC-1α, MFN2 in WCL, as well as protein abundance of PHB2, p62, LC3-II, and ubiquitinated proteins in mitochondrial fraction. The content of ATP and JC-1 aggregates in 1.2 mM NEFA group were lower than in the 0 mM NEFA group. Additionally, 1.2 mM NEFA disrupted the fusion between mitochondria and lysosomes. MAC-T were then pretreated with 100 nM rapamycin, followed by treatment with or without NEFA. Rapamycin alleviated impaired mitophagy and mitochondria dysfunction induced by 1.2 mM NEFA. Third, MAC-T were transfected with small interfering RNA to silence PHB2 or a plasmid for overexpression of PHB2, followed by treatment with or without NEFA. The silencing of PHB2 aggravated 1.2 mM NEFA induced impaired mitophagy and mitochondrial dysfunction, whereas the overexpression of PHB2 alleviated these effects. Overall, this study provides evidence that PHB2, in regulation of mitophagy, is a mechanism for bovine mammary epithelial cells to counteract NEFA-induced mitochondrial dysfunction.
PubMed: 38876225
DOI: 10.3168/jds.2024-24800 -
Redox Biology Aug 2024α-Ketoglutarate (AKG), a crucial intermediate in the tricarboxylic acid cycle, has been demonstrated to mitigate hyperlipidemia-induced dyslipidemia and endothelial...
α-Ketoglutarate (AKG), a crucial intermediate in the tricarboxylic acid cycle, has been demonstrated to mitigate hyperlipidemia-induced dyslipidemia and endothelial damage. While hyperlipidemia stands as a major trigger for non-alcoholic fatty liver disease, the protection of AKG on hyperlipidemia-induced hepatic metabolic disorders remains underexplored. This study aims to investigate the potential protective effects and mechanisms of AKG against hepatic lipid metabolic disorders caused by acute hyperlipidemia. Our observations indicate that AKG effectively alleviates hepatic lipid accumulation, mitochondrial dysfunction, and loss of redox homeostasis in P407-induced hyperlipidemia mice, as well as in palmitate-injured HepG2 cells and primary hepatocytes. Mechanistic insights reveal that the preventive effects are mediated by activating the AMPK-PGC-1α/Nrf2 pathway. In conclusion, our findings shed light on the role and mechanism of AKG in ameliorating abnormal lipid metabolic disorders in hyperlipidemia-induced fatty liver, suggesting that AKG, an endogenous mitochondrial nutrient, holds promising potential for addressing hyperlipidemia-induced fatty liver conditions.
Topics: Animals; Hyperlipidemias; Mice; Oxidative Stress; Humans; NF-E2-Related Factor 2; AMP-Activated Protein Kinases; Ketoglutaric Acids; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Signal Transduction; Hep G2 Cells; Mitochondria; Male; Lipid Metabolism; Hepatocytes; Fatty Liver; Disease Models, Animal; Liver
PubMed: 38875959
DOI: 10.1016/j.redox.2024.103230