-
Scientific Reports Jan 2024Premature ovarian failure (POF) caused by chemotherapy is a growing concern for female reproductive health. The use of metformin (MET), which has anti-oxidative and...
Premature ovarian failure (POF) caused by chemotherapy is a growing concern for female reproductive health. The use of metformin (MET), which has anti-oxidative and anti-inflammatory effects, in the treatment of POF damaged by chemotherapy drugs remains unclear. In this study, we investigated the impact of MET on POF caused by cyclophosphamide (CTX) combined with busulfan (BUS) and M1 macrophages using POF model mice and primary granule cells (GCs). Our findings demonstrate that intragastric administration of MET ameliorates ovarian damage and alleviates hormonal disruption in chemotherapy-induced POF mice. This effect is achieved through the reduction of inflammatory and oxidative stress-related harm. Additionally, MET significantly relieves abnormal inflammatory response, ROS accumulation, and senescence in primary GCs co-cultured with M1 macrophages. We also observed that this protective role of MET is closely associated with the AMPK/PPAR-γ/SIRT1 pathway in cell models. In conclusion, our results suggest that MET can protect against chemotherapy-induced ovarian injury by inducing the expression of the AMPK pathway while reducing oxidative damage and inflammation.
Topics: Humans; Mice; Female; Animals; Primary Ovarian Insufficiency; AMP-Activated Protein Kinases; Peroxisome Proliferator-Activated Receptors; Sirtuin 1; Metformin; Granulosa Cells; Antineoplastic Agents
PubMed: 38228655
DOI: 10.1038/s41598-024-51990-z -
Cells Feb 2024proliferates by budding, which includes the formation of a cytoplasmic protrusion called the 'bud', into which DNA, RNA, proteins, organelles, and other materials are... (Review)
Review
proliferates by budding, which includes the formation of a cytoplasmic protrusion called the 'bud', into which DNA, RNA, proteins, organelles, and other materials are transported. The transport of organelles into the growing bud must be strictly regulated for the proper inheritance of organelles by daughter cells. In yeast, the RING-type E3 ubiquitin ligases, Dma1 and Dma2, are involved in the proper inheritance of mitochondria, vacuoles, and presumably peroxisomes. These organelles are transported along actin filaments toward the tip of the growing bud by the myosin motor protein, Myo2. During organelle transport, organelle-specific adaptor proteins, namely Mmr1, Vac17, and Inp2 for mitochondria, vacuoles, and peroxisomes, respectively, bridge the organelles and myosin. After reaching the bud, the adaptor proteins are ubiquitinated by the E3 ubiquitin ligases and degraded by the proteasome. Targeted degradation of the adaptor proteins is necessary to unload vacuoles, mitochondria, and peroxisomes from the actin-myosin machinery. Impairment of the ubiquitination of adaptor proteins results in the failure of organelle release from myosin, which, in turn, leads to abnormal dynamics, morphology, and function of the inherited organelles, indicating the significance of proper organelle unloading from myosin. Herein, we summarize the role and regulation of E3 ubiquitin ligases during organelle inheritance in yeast.
Topics: Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Ubiquitin-Protein Ligases; Peroxisomes; Myosins; Ubiquitins; Cell Cycle Proteins; Mitochondrial Proteins
PubMed: 38391905
DOI: 10.3390/cells13040292 -
Diabetologia Apr 2024The peroxisome proliferator-activated receptor-γ coactivator α (PGC-1α) plays a critical role in the maintenance of glucose, lipid and energy homeostasis by...
AIM/HYPOTHESIS
The peroxisome proliferator-activated receptor-γ coactivator α (PGC-1α) plays a critical role in the maintenance of glucose, lipid and energy homeostasis by orchestrating metabolic programs in multiple tissues in response to environmental cues. In skeletal muscles, PGC-1α dysregulation has been associated with insulin resistance and type 2 diabetes but the underlying mechanisms have remained elusive. This research aims to understand the role of TET3, a member of the ten-eleven translocation (TET) family dioxygenases, in PGC-1α dysregulation in skeletal muscles in obesity and diabetes.
METHODS
TET expression levels in skeletal muscles were analysed in humans with or without type 2 diabetes, as well as in mouse models of high-fat diet (HFD)-induced or genetically induced (ob/ob) obesity/diabetes. Muscle-specific Tet3 knockout (mKD) mice were generated to study TET3's role in muscle insulin sensitivity. Genome-wide expression profiling (RNA-seq) of muscle tissues from wild-type (WT) and mKD mice was performed to mine deeper insights into TET3-mediated regulation of muscle insulin sensitivity. The correlation between PGC-1α and TET3 expression levels was investigated using muscle tissues and in vitro-derived myotubes. PGC-1α phosphorylation and degradation were analysed using in vitro assays.
RESULTS
TET3 expression was elevated in skeletal muscles of humans with type 2 diabetes and in HFD-fed and ob/ob mice compared with healthy controls. mKD mice exhibited enhanced glucose tolerance, insulin sensitivity and resilience to HFD-induced insulin resistance. Pathway analysis of RNA-seq identified 'Mitochondrial Function' and 'PPARα Pathway' to be among the top biological processes regulated by TET3. We observed higher PGC-1α levels (~25%) in muscles of mKD mice vs WT mice, and lower PGC-1α protein levels (~25-60%) in HFD-fed or ob/ob mice compared with their control counterparts. In human and murine myotubes, increased PGC-1α levels following TET3 knockdown contributed to improved mitochondrial respiration and insulin sensitivity. TET3 formed a complex with PGC-1α and interfered with its phosphorylation, leading to its destabilisation.
CONCLUSIONS/INTERPRETATION
Our results demonstrate an essential role for TET3 in the regulation of skeletal muscle insulin sensitivity and suggest that TET3 may be used as a potential therapeutic target for the metabolic syndrome.
DATA AVAILABILITY
Sequences are available from the Gene Expression Omnibus ( https://www.ncbi.nlm.nih.gov/geo/ ) with accession number of GSE224042.
Topics: Animals; Humans; Mice; Diabetes Mellitus, Type 2; Dioxygenases; Glucose; Insulin Resistance; Muscle, Skeletal; Obesity; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Transcription Factors
PubMed: 38216792
DOI: 10.1007/s00125-023-06073-5 -
Oncology Letters Dec 2023The peroxisome serves a significant role in the occurrence and development of cancers. Specifically, the peroxisomal biogenesis factor 13 (PEX13) is crucial to the...
The peroxisome serves a significant role in the occurrence and development of cancers. Specifically, the peroxisomal biogenesis factor 13 (PEX13) is crucial to the occurrence of peroxisomes. However, the biological function of PEX13 in cancers remains unclear. To address this, various portals and databases such as The Cancer Genome Atlas Program, The Genotype-Tissue Expression project, the Gene Expression Profiling Interactive Analysis 2, cBioPortal, the Genomic Identification of Significant Targets In Cancer 2.0, Tumor Immune Estimation Resource 2, SangerBox, LinkedOmics, DAVID and STRING were applied to extract and analyze PEX13 data in tumors. The correlations between PEX13 and prognosis, genetic alterations, PEX13-related gene enrichment analysis, weighted gene co-expression network analysis (WGCNA), protein interaction, long non-coding (lnc)RNA/circular (circ)RNA-micro (mi)RNA network and tumor immunity were explored in various tumors. The lncRNA-miRNA-PEX13 and circRNA-miRNA-PEX13 regulatory networks were identified via miRabel, miRDB, TargetScan and ENCORI portals and Cytoscape tool. assays were applied to verify the biological functions of PEX13 in pancreatic adenocarcinoma (PAAD) cells. The findings revealed that PEX13 is upregulated in various tumors and high PEX13 mRNA expression is associated with poor prognosis in patients with multiple cancers. Genetic alterations in PEX13 such as amplification, mutation and deep deletion have been found in multiple cancers. PEX13-related genes were associated with T cell receptor, signaling pathway and hippo signaling pathway through 'biological process' subontology of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Through WGCNA analysis, it was discovered that PEX13 hub genes were mainly enriched in the Rap1, ErbB and AMPK signaling pathways in PAAD. Immune analysis showed that PEX13 was significantly related to tumor infiltration immune cells, immune checkpoint genes, microsatellite instability, TMB and tumor purity in a variety of tumors. Cell Counting Kit-8, wound healing, Transwell and colony formation assays displayed that PEX13 knockdown could suppress PAAD cell proliferation, migration, invasion, and colony formation , respectively. Overall, PEX13 is a potential predictor of immunotherapeutic and prognostic biomarkers in various malignant tumors, including ACC, KICH, LGG, LIHC and PAAD.
PubMed: 37920431
DOI: 10.3892/ol.2023.14099 -
Frontiers in Plant Science 2023
PubMed: 37920721
DOI: 10.3389/fpls.2023.1293246 -
Protein Science : a Publication of the... Nov 2023The human flavoenzyme D-aspartate oxidase (hDASPO) controls the level of D-aspartate in the brain, a molecule acting as an agonist of NMDA receptors and modulator of...
The human flavoenzyme D-aspartate oxidase (hDASPO) controls the level of D-aspartate in the brain, a molecule acting as an agonist of NMDA receptors and modulator of AMPA and mGlu5 receptors. hDASPO-induced D-aspartate degradation prevents age-dependent deterioration of brain functions and is related to psychiatric disorders such as schizophrenia and autism. Notwithstanding this crucial role, less is known about hDASPO regulation. Here, we report that hDASPO is nitrosylated in vitro, while no evidence of sulfhydration and phosphorylation is apparent: nitrosylation affects the activity of the human flavoenzyme to a limited extent. Furthermore, hDASPO interacts with the primate-specific protein pLG72 (a well-known negative chaperone of D-amino acid oxidase, the enzyme deputed to D-serine degradation in the human brain), yielding a ~114 kDa complex, with a micromolar dissociation constant, promoting the flavoenzyme inactivation. At the cellular level, pLG72 and hDASPO generate a cytosolic complex: the expression of pLG72 negatively affects the hDASPO level by reducing its half-life. We propose that pLG72 binding may represent a protective mechanism aimed at avoiding cytotoxicity due to H O produced by the hDASPO enzymatic degradation of D-aspartate, especially before the final targeting to peroxisomes.
Topics: Animals; Humans; Oxidoreductases; D-Aspartate Oxidase; D-Aspartic Acid; Schizophrenia; Carrier Proteins
PubMed: 37805834
DOI: 10.1002/pro.4802 -
Journal of Nanobiotechnology May 2024With the increasing trend of global aging, sarcopenia has become a significant public health issue. Goji berry, also known as "Gou qi zi" in China, is a traditional...
With the increasing trend of global aging, sarcopenia has become a significant public health issue. Goji berry, also known as "Gou qi zi" in China, is a traditional Chinese herb that can enhance the structure and function of muscles and bones. Otherwise, previous excellent publications illustrated that plant-derived exosome-like nanoparticles can exert good bioactive functions in different aging or disease models. Thus, we issued the hypothesis that Gouqi-derived nanovesicles (GqDNVs) may also have the ability to improve skeletal muscle health, though the effect and its mechanism need to be explored. Hence, we have extracted GqDNVs from fresh berries of Lycium barbarum L. (goji) and found that the contents of GqDNVs are rich in saccharides and lipids. Based on the pathway annotations and predictions in non-targeted metabolome analysis, GqDNVs are tightly associated with the pathways in metabolism. In muscle atrophy model mice, intramuscular injection of GqDNVs improves the cross-sectional area of the quadriceps muscle, grip strength and the AMPK/SIRT1/PGC1α pathway expression. After separately inhibiting AMPK or PGC1α in C2C12 cells with dexamethasone administration, we have found that the activated AMPK plays the chief role in improving cell proliferation induced by GqDNVs. Furthermore, the energy-targeted metabolome analysis in the quadriceps muscle demonstrates that the GqDNVs up-regulate the metabolism of amino sugar and nucleotide sugar, autophagy and oxidative phosphorylation process, which indicates the activation of muscle regeneration. Besides, the Spearman rank analysis shows close associations between the quality and function of skeletal muscle, metabolites and expression levels of AMPK and SIRT1. In this study, we provide a new founding that GqDNVs can improve the quality and function of skeletal muscle accompanying the activated AMPK/SIRT1/PGC1α signaling pathway. Therefore, GqDNVs have the effect of anti-aging skeletal muscle as a potential adjuvant or complementary method or idea in future therapy and research.
Topics: Animals; Sirtuin 1; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Mice; Signal Transduction; Dexamethasone; AMP-Activated Protein Kinases; Muscular Atrophy; Cell Line; Drugs, Chinese Herbal; Male; Muscle, Skeletal; Mice, Inbred C57BL; Nanoparticles; Exosomes
PubMed: 38778385
DOI: 10.1186/s12951-024-02563-9 -
Frontiers in Immunology 2023We have previously demonstrated that a pathologic downregulation of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1α) within the intestinal...
INTRODUCTION
We have previously demonstrated that a pathologic downregulation of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1α) within the intestinal epithelium contributes to the pathogenesis of inflammatory bowel disease (IBD). However, the mechanism underlying downregulation of PGC1α expression and activity during IBD is not yet clear.
METHODS
Mice (male; C57Bl/6, /+; mice, and ) were subjected to experimental colitis and treated with nicotinamide riboside. Western blot, high-resolution respirometry, nicotinamide adenine dinucleotide (NAD+) quantification, and immunoprecipitation were used to in this study.
RESULTS
We demonstrate a significant depletion in the NAD+ levels within the intestinal epithelium of mice undergoing experimental colitis, as well as humans with ulcerative colitis. While we found no decrease in the levels of NAD+-synthesizing enzymes within the intestinal epithelium of mice undergoing experimental colitis, we did find an increase in the mRNA level, as well as the enzymatic activity, of the NAD+-consuming enzyme poly(ADP-ribose) polymerase-1 (PARP1). Treatment of mice undergoing experimental colitis with an NAD+ precursor reduced the severity of colitis, restored mitochondrial function, and increased active PGC1α levels; however, NAD+ repletion did not benefit transgenic mice that lack PGC1α within the intestinal epithelium, suggesting that the therapeutic effects require an intact PGC1α axis.
DISCUSSION
Our results emphasize the importance of PGC1α expression to both mitochondrial health and homeostasis within the intestinal epithelium and suggest a novel therapeutic approach for disease management. These findings also provide a mechanistic basis for clinical trials of nicotinamide riboside in IBD patients.
Topics: Humans; Male; Animals; Mice; NAD; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Colitis; Inflammatory Bowel Diseases; Mice, Transgenic; Mitochondria; Inflammation
PubMed: 37744380
DOI: 10.3389/fimmu.2023.1231700 -
Journal of Clinical and Translational... Dec 2023Peroxisome proliferator-activated receptors (PPARs) are a superfamily of nuclear transcription receptors, consisting of PPARα, PPARγ, and PPARβ/δ, which are highly... (Review)
Review
Peroxisome proliferator-activated receptors (PPARs) are a superfamily of nuclear transcription receptors, consisting of PPARα, PPARγ, and PPARβ/δ, which are highly expressed in the liver. They control and modulate the expression of a large number of genes involved in metabolism and energy homeostasis, oxidative stress, inflammation, and even apoptosis in the liver. Therefore, they have critical roles in the pathophysiology of hepatic diseases. This review provides a general insight into the role of PPARs in liver diseases and some of their agonists in the clinic.
PubMed: 38161499
DOI: 10.14218/JCTH.2023.00334 -
Pharmaceuticals (Basel, Switzerland) Dec 2023Berberine (BBR) is an isoquinoline alkaloid that can be extracted from herbs such as Coptis, Phellodendron, and Berberis. BBR has been widely used as a folk medicine to... (Review)
Review
Berberine (BBR) is an isoquinoline alkaloid that can be extracted from herbs such as Coptis, Phellodendron, and Berberis. BBR has been widely used as a folk medicine to treat various disorders. It is a multi-target drug with multiple mechanisms. Studies have shown that it has antioxidant and anti-inflammatory properties and can also adjust intestinal microbial flora. This review focused on the promising antidiabetic effects of BBR in several cellular, animal, and clinical studies. Based on previous research, BBR significantly reduced levels of fasting blood glucose, hemoglobin A1C, inflammatory cytokines, and oxidative stress markers. Furthermore, BBR stimulated insulin secretion and improved insulin resistance through different pathways, including up-regulation of protein expression of proliferator-activated receptor (PPAR)-γ, glucose transporter (GLUT) 4, PI3K/AKT, and AMP-activated protein kinase (AMPK) activation. Interestingly, it was demonstrated that BBR has protective effects against diabetes complications, such as diabetic-induced hepatic damage, cardiovascular disorders, nephropathy, and neuropathy. Furthermore, multiple clinical trial studies have emphasized the ameliorative effects of BBR in type 2 diabetic patients.
PubMed: 38275993
DOI: 10.3390/ph17010007