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Journal of Pharmaceutical and... Sep 2023Polygonatum cyrtonema Hua polysaccharide (PCP) is the main bioactive compound derived from the herb Polygonati Rhizoma, known for its anti-fatigue, antioxidant,...
Polygonatum cyrtonema Hua polysaccharide (PCP) is the main bioactive compound derived from the herb Polygonati Rhizoma, known for its anti-fatigue, antioxidant, immunomodulatory, and anti-inflammatory properties. However, its effectiveness on alleviating chemotherapy-induced muscle atrophy has been unclear. In this study, we utilized proteomic analysis to investigate the effects and mechanisms of PCP on gemcitabine plus cisplatin (GC) induced muscle atrophy in mice. Quality control analysis revealed that the functional PCP, rich in glucose, is a heterogeneous polysaccharide comprised of nine monosaccharides. PCP (64 mg/kg) significantly alleviated body muscle, organ weight loss, and muscle fiber atrophy in chemotherapy-induced cachectic mice. Moreover, PCP suppressed the decrease in serum immunoglobulin levels and the increase in pro-inflammatory factor interleukin-6 (IL-6). Proteomic analysis demonstrated that PCP contributed to the homeostasis of protein metabolism in gastrocnemius muscle. Diacylglycerol kinase (DGKζ) and cathepsin L (CTSL) were identified as primary PCP targets. Furthermore, the IL-6/STAT3/CTSL and DGKζ/FoxO/Atrogin1 signaling pathways were validated. Our findings suggest that PCP exerts an anti-atrophy effect on chemotherapy-induced muscle atrophy by regulating the autophagy-lysosome and ubiquitin-proteasome systems.
Topics: Mice; Animals; Cachexia; Polygonatum; Interleukin-6; Proteomics; Muscular Atrophy; Polysaccharides; Cisplatin; Antineoplastic Agents
PubMed: 37336040
DOI: 10.1016/j.jpba.2023.115533 -
Plant Physiology Apr 2024The accumulation of triacylglycerol (TAG) in vegetative tissues is necessary to adapt to changing temperatures. It has been hypothesized that TAG accumulation is...
The accumulation of triacylglycerol (TAG) in vegetative tissues is necessary to adapt to changing temperatures. It has been hypothesized that TAG accumulation is required as a storage location for maladaptive membrane lipids. The TAG acyltransferase family has five members (DIACYLGLYCEROL ACYLTRANSFERSE1/2/3 and PHOSPHOLIPID:DIACYLGLYCEROL ACYLTRANSFERASE1/2), and their individual roles during temperature challenges have either been described conflictingly or not at all. Therefore, we used Arabidopsis (Arabidopsis thaliana) loss of function mutants in each acyltransferase to investigate the effects of temperature challenge on TAG accumulation, plasma membrane integrity, and temperature tolerance. All mutants were tested under one high- and two low-temperature regimens, during which we quantified lipids, assessed temperature sensitivity, and measured plasma membrane electrolyte leakage. Our findings revealed reduced effectiveness in TAG production during at least one temperature regimen for all acyltransferase mutants compared to the wild type, resolved conflicting roles of pdat1 and dgat1 by demonstrating their distinct temperature-specific actions, and uncovered that plasma membrane integrity and TAG accumulation do not always coincide, suggesting a multifaceted role of TAG beyond its conventional lipid reservoir function during temperature stress.
Topics: Arabidopsis; Diacylglycerol O-Acyltransferase; Arabidopsis Proteins; Triglycerides; Acyltransferases; Cold Temperature; Cell Membrane; Hot Temperature; Gene Expression Regulation, Plant; Mutation
PubMed: 38386316
DOI: 10.1093/plphys/kiae074 -
The Journal of Cell Biology Jun 2024Lipid droplets (LDs) are composed of a core of neutral lipids wrapped by a phospholipid (PL) monolayer containing several hundred proteins that vary between different...
Lipid droplets (LDs) are composed of a core of neutral lipids wrapped by a phospholipid (PL) monolayer containing several hundred proteins that vary between different cells or organisms. How LD proteins target to LDs is still largely unknown. Here, we show that RNAi knockdown or gene mutation of let-767, encoding a member of hydroxysteroid dehydrogenase (HSD), displaced the LD localization of three well-known LD proteins: DHS-3 (dehydrogenase/reductase), PLIN-1 (perilipin), and DGAT-2 (diacylglycerol O-acyltransferase 2), and also prevented LD growth in Caenorhabditis elegans. LET-767 interacts with ARF-1 (ADP-ribosylation factor 1) to prevent ARF-1 LD translocation for appropriate LD protein targeting and lipid homeostasis. Deficiency of LET-767 leads to the release of ARF-1, which further recruits and promotes translocation of ATGL-1 (adipose triglyceride lipase) to LDs for lipolysis. The displacement of LD proteins caused by LET-767 deficiency could be reversed by inhibition of either ARF-1 or ATGL-1. Our work uncovers a unique LET-767 for determining LD protein targeting and maintaining lipid homeostasis.
Topics: Homeostasis; Lipase; Lipid Droplet Associated Proteins; Lipid Droplets; Lipid Metabolism; Lipids; Lipolysis; Proteins; Caenorhabditis elegans; Animals; Alcohol Oxidoreductases; Caenorhabditis elegans Proteins
PubMed: 38551495
DOI: 10.1083/jcb.202311024 -
Stress Biology Jul 2023This brief article highlights the key findings of the study conducted by Sha et al. (Nature, doi:10.1038/s41586-023-06205-2, 2023), focusing on the cloning of the RBL1...
This brief article highlights the key findings of the study conducted by Sha et al. (Nature, doi:10.1038/s41586-023-06205-2, 2023), focusing on the cloning of the RBL1 gene from rice, which is associated with lesion mimic mutant (LMM) traits. The RBL1 gene encodes a cytidine diphosphate diacylglycerol (CDP-DAG) synthase and plays a crucial role in regulating cell death and immunity by controlling phosphatidylinositol biosynthesis. The rbl1 mutant shows autoimmunity with multi-pathogen resistance but with severe yield penalty. Using genome editing techniques, the research team successfully generated an elite allele of RBL1 that not only restores rice yield but also provides broad-spectrum resistance against both bacterial and fungal pathogens. These findings demonstrate the potential of utilizing genome editing to enhance crop productivity and pathogen resistance.
PubMed: 37676404
DOI: 10.1007/s44154-023-00102-4 -
Journal of Diabetes and Its... Sep 2023Protein kinase C (PKC) is a family of serine/threonine protein kinases that play an important role in many organs and systems and whose activation contributes... (Review)
Review
Protein kinase C (PKC) is a family of serine/threonine protein kinases that play an important role in many organs and systems and whose activation contributes significantly to endothelial dysfunction in diabetes. The increase in diacylglycerol (DAG) under high glucose conditions mediates PKC activation and synthesis, which stimulates oxidative stress and inflammation, resulting in impaired endothelial cell function. This article reviews the contribution of PKC to the development of diabetes-related endothelial dysfunction and summarizes the drugs that inhibit PKC activation, with the aim of exploring therapeutic modalities that may alleviate endothelial dysfunction in diabetic patients.
Topics: Humans; Protein Kinase C; Diabetes Mellitus; Signal Transduction; Oxidative Stress; Vascular Diseases
PubMed: 37540984
DOI: 10.1016/j.jdiacomp.2023.108565 -
Cancers Nov 2023Reprogramming of fatty acid metabolism promotes cell growth and metastasis through a variety of processes that stimulate signaling molecules, energy storage, and...
Reprogramming of fatty acid metabolism promotes cell growth and metastasis through a variety of processes that stimulate signaling molecules, energy storage, and membrane biosynthesis in endometrial cancer. Oleic acid is one of the most important monounsaturated fatty acids in the human body, which appears to have both pro- and anti-tumorigenic activities in various pre-clinical models. In this study, we evaluated the potential anti-tumor effects of oleic acid in endometrial cancer cells and the mouse model of endometrial cancer. Oleic acid increased lipogenesis, inhibited cell proliferation, caused cell cycle G1 arrest, induced cellular stress and apoptosis, and suppressed invasion in endometrial cancer cells. Targeting of diacylglycerol acyltransferases 1 and 2 effectively increased the cytotoxicity of oleic acid. Moreover, oleic acid significantly increased the expression of wild-type PTEN, and knockdown of PTEN by shRNA partially reversed the anti-proliferative and anti-invasive effects of oleic acid. Inhibition of the AKT/mTOR pathway by ipatasertib effectively increased the anti-tumor activity of oleic acid in endometrial cancer cells. Oleic acid treatment (10 mg/kg, daily, oral) for four weeks significantly inhibited tumor growth by 52.1% in the mice. Our findings demonstrated that oleic acid exhibited anti-tumorigenic activities, dependent on the PTEN/AKT/mTOR signaling pathway, in endometrial cancer.
PubMed: 38001668
DOI: 10.3390/cancers15225407 -
Cell Communication and Signaling : CCS Nov 2023Diabetes mellitus, known for its complications, especially vascular complications, is becoming a globally serious social problem. Atherosclerosis has been recognized as... (Review)
Review
Diabetes mellitus, known for its complications, especially vascular complications, is becoming a globally serious social problem. Atherosclerosis has been recognized as a common vascular complication mechanism in diabetes. The diacylglycerol (DAG)-protein kinase C (PKC) pathway plays an important role in atherosclerosis. PKCs can be divided into three subgroups: conventional PKCs (cPKCs), novel PKCs (nPKCs), and atypical PKCs (aPKCs). The aim of this review is to provide a comprehensive overview of the role of the PKCδ pathway, an isoform of nPKC, in regulating the function of endothelial cells, vascular smooth muscle cells, and macrophages in diabetic atherosclerosis. In addition, potential therapeutic targets regarding the PKCδ pathway are summarized. Video Abstract.
Topics: Humans; Endothelial Cells; Protein Kinase C; Diabetes Mellitus; Protein Isoforms; Biology
PubMed: 37974282
DOI: 10.1186/s12964-023-01361-4 -
Cell Reports May 2024Triacylglyceride (TAG) synthesis in the small intestine determines the absorption of dietary fat, but the underlying mechanisms remain to be further studied. Here, we...
Triacylglyceride (TAG) synthesis in the small intestine determines the absorption of dietary fat, but the underlying mechanisms remain to be further studied. Here, we report that the RNA-binding protein HuR (ELAVL1) promotes TAG synthesis in the small intestine. HuR associates with the 3' UTR of Dgat2 mRNA and intron 1 of Mgat2 pre-mRNA. Association of HuR with Dgat2 3' UTR stabilizes Dgat2 mRNA, while association of HuR with intron 1 of Mgat2 pre-mRNA promotes the processing of Mgat2 pre-mRNA. Intestinal epithelium-specific HuR knockout reduces the expression of DGAT2 and MGAT2, thereby reducing the dietary fat absorption through TAG synthesis and mitigating high-fat-diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) and obesity. Our findings highlight a critical role of HuR in promoting dietary fat absorption.
Topics: Triglycerides; Animals; ELAV-Like Protein 1; Intestinal Absorption; Mice; Diet, High-Fat; Humans; Mice, Inbred C57BL; Male; Diacylglycerol O-Acyltransferase; Non-alcoholic Fatty Liver Disease; Obesity; RNA, Messenger; Dietary Fats; Mice, Knockout; 3' Untranslated Regions; Acyltransferases
PubMed: 38748875
DOI: 10.1016/j.celrep.2024.114238 -
Oncogene Jan 2024Impaired macroautophagy/autophagy flux has been implicated in the treatment of prostate cancer (PCa). However, the mechanism underlying autophagy dysregulation in PCa...
Impaired macroautophagy/autophagy flux has been implicated in the treatment of prostate cancer (PCa). However, the mechanism underlying autophagy dysregulation in PCa remains unknown. In the current study, we investigated the role of diacylglycerol acyltransferases 1 (DGAT1) and its potential effects on cellular energy homeostasis and autophagy flux in PCa. The results of immunohistochemical staining suggested that DGAT1 expression was positively corrected with tumor stage and node metastasis, indicating DGAT1 is an important factor involved in the development and progression of PCa. Furthermore, targeting DGAT1 remarkably inhibited cell proliferation in vitro and suppressed PCa growth in xenograft models by triggering severe oxidative stress and subsequently autophagy flux blockage. Mechanically, DGAT1 promoted PCa progression by maintaining cellular energy homeostasis, preserving mitochondrial function, protecting against reactive oxygen species, and subsequently promoting autophagy flux via regulating lipid droplet formation. Moreover, we found that fenofibrate exhibits as an upstream regulator of DGAT1. Fenofibrate performed its anti-PCa effect involved the aforementioned mechanisms, and partially dependent on the regulation of DGAT1. Collectively. These findings indicate that DGAT1 regulates PCa lipid droplets formation and is essential for PCa progression. Targeting DGAT1 might be a promising method to control the development and progression of PCa. Schematic representation of DGAT1 affects autophagy flux by regulating lipid homeostasis and maintaining mitochondrial function in prostate cancer (PCa). PCa is characterized up-regulation of DGAT1, leading to the translocation of free fatty acids into lipid droplets, thereby preventing PCa cell from lipotoxicity. Inhibition of DGAT1 suppresses growth of PCa by inducing oxidative stress and subsequently autophagy flux blockage. Further, the current results revealed that fenofibrate exhibits as an upstream regulator of DGAT1, and fenofibrate plays an anti-PCa role partially dependent on the regulation of DGAT1, suggesting a potential therapeutic approach to ameliorate this refractory tumor.
Topics: Humans; Male; Autophagy; Diacylglycerol O-Acyltransferase; Fenofibrate; Oxidative Stress; Prostate; Prostatic Neoplasms
PubMed: 37973951
DOI: 10.1038/s41388-023-02878-1 -
American Journal of Physiology. Lung... Jul 2024Signal transduction by G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and immunoreceptors converge at the activation of phospholipase C (PLC) for... (Review)
Review
Signal transduction by G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and immunoreceptors converge at the activation of phospholipase C (PLC) for the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP) into inositol 1,4,5-trisphosphate (IP) and diacylglycerol (DAG). This is a point for second-messenger bifurcation where DAG via protein kinase C (PKC) and IP via calcium activate distinct protein targets and regulate cellular functions. IP signaling is regulated by multiple calcium influx and efflux proteins involved in calcium homeostasis. A family of lipid kinases belonging to DAG kinases (DGKs) converts DAG to phosphatidic acid (PA), negatively regulating DAG signaling and pathophysiological functions. PA, through a series of biochemical reactions, is recycled to produce new molecules of PIP. Therefore, DGKs act as a central switch in terminating DAG signaling and resynthesis of membrane phospholipids precursor. Interestingly, calcium and PKC regulate the activation of α and ζ isoforms of DGK that are predominantly expressed in airway and immune cells. Thus, DGK forms a feedback and feedforward control point and plays a crucial role in fine-tuning phospholipid stoichiometry, signaling, and functions. In this review, we discuss the previously underappreciated complex and intriguing DAG/DGK-driven mechanisms in regulating cellular functions associated with asthma, such as contraction and proliferation of airway smooth muscle (ASM) cells and inflammatory activation of immune cells. We highlight the benefits of manipulating DGK activity in mitigating salient features of asthma pathophysiology and shed light on DGK as a molecule of interest for heterogeneous diseases such as asthma.
Topics: Asthma; Humans; Diacylglycerol Kinase; Animals; Signal Transduction; Diglycerides; Protein Kinase C
PubMed: 38742284
DOI: 10.1152/ajplung.00091.2024