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International Journal of Biological... Jun 2024It is well-accepted that the liver plays a vital role in the metabolism of glucose and its homeostasis. Dysregulated hepatic glucose production and utilization, leads to...
It is well-accepted that the liver plays a vital role in the metabolism of glucose and its homeostasis. Dysregulated hepatic glucose production and utilization, leads to type 2 diabetes (T2DM). In the current study, RNA sequencing and qRT-PCR analysis of nanoformulation-treated T2DM mice (TG group) revealed beneficial crosstalk of PCK-1 silencing with other pathways involved in T2DM. The comparison of precise genetic expression profiles of the different experimental groups showed significantly improved hepatic glucose, fatty acid metabolism and several other T2DM-associated crucial markers after the nanoformulation treatment. As a result of these improvements, we observed a significant acceleration in wound healing and improved insulin signaling in vascular endothelial cells in the TG group as compared to the T2DM group. Enhanced phosphorylation of PI3K/Akt pathway proteins in the TG group resulted in increased angiogenesis as observed by the increased expression of endothelial cell markers (CD31, CD34) thereby improving endothelial dysfunctions in the TG group. Additionally, therapeutic nanoformulation has been observed to improve the inflammatory cytokine profile in the TG group. Overall, our results demonstrated that the synthesized therapeutic nanoformulation referred to as GPR8:PCK-1 holds the potential in ameliorating hyperglycemia-associated complications such as delayed wound healing in diabetes.
Topics: Animals; Mice; Diabetes Mellitus, Type 2; Wound Healing; RNA, Small Interfering; Homeostasis; Glucose; Male; Diabetes Mellitus, Experimental; Signal Transduction; Liver; Phosphoenolpyruvate Carboxykinase (GTP)
PubMed: 38772464
DOI: 10.1016/j.ijbiomac.2024.132504 -
Comparative Biochemistry and... Sep 2024Owing to population growth and environmental pollution, freshwater aquaculture has been rapidly shrinking in recent years. Aquaculture in saline-alkaline waters is a...
Owing to population growth and environmental pollution, freshwater aquaculture has been rapidly shrinking in recent years. Aquaculture in saline-alkaline waters is a crucial strategy to meet the increasing demand for aquatic products. The Chinese mitten crab is an important economic food in China, but the molecular mechanism by which it tolerates carbonate alkalinity (CA) in water remains unclear. Here, we found that enzyme activities of the tricarboxylic acid (TCA) cycle in the gills, such as citrate synthase, isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and malate dehydrogenase, were markedly reduced under CA stress induced by 40 mM NaHCO. Secondly, the TCA cycle in the gills is inhibited under acute CA stress, according to proteomic and metabolomic analyses. The expressions of six enzymes, namely aconitate hydratase, isocitrate dehydrogenase, 2-oxoglutarate dehydrogenase, dihydrolipoyl dehydrogenase, succinate-CoA ligase, and malate dehydrogenase, were downregulated, resulting in the accumulation of phosphoenolpyruvic acid, citric acid, cis-aconitate, and α-ketoglutaric acid. Finally, we testified that if the TCA cycle is disturbed by malonate, the survival rate increases in CA water. To our knowledge, this is the first study to show that the TCA cycle in the gills is inhibited under CA stress. Overall, the results provide new insights into the molecular mechanism of tolerance to saline-alkaline water in crabs, which helped us expand the area for freshwater aquaculture and comprehensively understand the physiological characteristics of crab migration.
Topics: Animals; Citric Acid Cycle; Gills; Brachyura; Carbonates; Stress, Physiological
PubMed: 38772315
DOI: 10.1016/j.cbd.2024.101245 -
Diabetes Jun 2024The canonical model of glucose-induced increase in insulin secretion involves the metabolism of glucose via glycolysis and the citrate cycle, resulting in increased ATP... (Review)
Review
The canonical model of glucose-induced increase in insulin secretion involves the metabolism of glucose via glycolysis and the citrate cycle, resulting in increased ATP synthesis by the respiratory chain and the closure of ATP-sensitive K+ (KATP) channels. The resulting plasma membrane depolarization, followed by Ca2+ influx through L-type Ca2+ channels, then induces insulin granule fusion. Merrins and colleagues have recently proposed an alternative model whereby KATP channels are controlled by pyruvate kinase, using glycolytic and mitochondrial phosphoenolpyruvate (PEP) to generate microdomains of high ATP/ADP immediately adjacent to KATP channels. This model presents several challenges. First, how mitochondrially generated PEP, but not ATP produced abundantly by the mitochondrial F1F0-ATP synthase, can gain access to the proposed microdomains is unclear. Second, ATP/ADP fluctuations imaged immediately beneath the plasma membrane closely resemble those in the bulk cytosol. Third, ADP privation of the respiratory chain at high glucose, suggested to drive alternating, phased-locked generation by mitochondria of ATP or PEP, has yet to be directly demonstrated. Finally, the approaches used to explore these questions may be complicated by off-target effects. We suggest instead that Ca2+ changes, well known to affect both ATP generation and consumption, likely drive cytosolic ATP/ADP oscillations that in turn regulate KATP channels and membrane potential. Thus, it remains to be demonstrated that a new model is required to replace the existing, mitochondrial bioenergetics-based model.
Topics: Insulin-Secreting Cells; KATP Channels; Glucose; Humans; Animals; Adenosine Triphosphate; Mitochondria; Insulin; Adenosine Diphosphate; Models, Biological; Insulin Secretion
PubMed: 38768365
DOI: 10.2337/dbi23-0031 -
Plant Molecular Biology May 2024Pyruvate kinase (Pyk, EC 2.7.1.40) is a glycolytic enzyme that generates pyruvate and adenosine triphosphate (ATP) from phosphoenolpyruvate (PEP) and adenosine...
Pyruvate kinase (Pyk, EC 2.7.1.40) is a glycolytic enzyme that generates pyruvate and adenosine triphosphate (ATP) from phosphoenolpyruvate (PEP) and adenosine diphosphate (ADP), respectively. Pyk couples pyruvate and tricarboxylic acid metabolisms. Synechocystis sp. PCC 6803 possesses two pyk genes (encoded pyk1, sll0587 and pyk2, sll1275). A previous study suggested that pyk2 and not pyk1 is essential for cell viability; however, its biochemical analysis is yet to be performed. Herein, we biochemically analyzed Synechocystis Pyk2 (hereafter, SyPyk2). The optimum pH and temperature of SyPyk2 were 7.0 and 55 °C, respectively, and the K values for PEP and ADP under optimal conditions were 1.5 and 0.053 mM, respectively. SyPyk2 is activated in the presence of glucose-6-phosphate (G6P) and ribose-5-phosphate (R5P); however, it remains unaltered in the presence of adenosine monophosphate (AMP) or fructose-1,6-bisphosphate. These results indicate that SyPyk2 is classified as PykA type rather than PykF, stimulated by sugar monophosphates, such as G6P and R5P, but not by AMP. SyPyk2, considering substrate affinity and effectors, can play pivotal roles in sugar catabolism under nonphotosynthetic conditions.
Topics: Synechocystis; Pyruvate Kinase; Phosphoenolpyruvate; Glucose-6-Phosphate; Ribosemonophosphates; Substrate Specificity; Hydrogen-Ion Concentration; Bacterial Proteins; Kinetics; Temperature
PubMed: 38758412
DOI: 10.1007/s11103-023-01401-0 -
The EMBO Journal Jun 2024Phosphoglycerate mutase 1 (PGAM1) is a key node enzyme that diverts the metabolic reactions from glycolysis into its shunts to support macromolecule biosynthesis for...
Phosphoglycerate mutase 1 (PGAM1) is a key node enzyme that diverts the metabolic reactions from glycolysis into its shunts to support macromolecule biosynthesis for rapid and sustainable cell proliferation. It is prevalent that PGAM1 activity is upregulated in various tumors; however, the underlying mechanism remains unclear. Here, we unveil that pyruvate kinase M2 (PKM2) moonlights as a histidine kinase in a phosphoenolpyruvate (PEP)-dependent manner to catalyze PGAM1 H11 phosphorylation, that is essential for PGAM1 activity. Moreover, monomeric and dimeric but not tetrameric PKM2 are efficient to phosphorylate and activate PGAM1. In response to epidermal growth factor signaling, Src-catalyzed PGAM1 Y119 phosphorylation is a prerequisite for PKM2 binding and the subsequent PGAM1 H11 phosphorylation, which constitutes a discrepancy between tumor and normal cells. A PGAM1-derived pY119-containing cell-permeable peptide or Y119 mutation disrupts the interaction of PGAM1 with PKM2 and PGAM1 H11 phosphorylation, dampening the glycolysis shunts and tumor growth. Together, these results identify a function of PKM2 as a histidine kinase, and illustrate the importance of enzyme crosstalk as a regulatory mode during metabolic reprogramming and tumorigenesis.
Topics: Glycolysis; Humans; Phosphoglycerate Mutase; Phosphorylation; Animals; Thyroid Hormones; Mice; Thyroid Hormone-Binding Proteins; Neoplasms; Membrane Proteins; Cell Line, Tumor; Carrier Proteins
PubMed: 38750259
DOI: 10.1038/s44318-024-00110-8 -
Physiology and Molecular Biology of... Apr 2024In our study on the effect of cadmium (Cd) toxicity (200 µM) on the growth of (L.) Moench plants, cultivated with arbuscular mycorrhizal fungi (AMF) () and/or under...
In our study on the effect of cadmium (Cd) toxicity (200 µM) on the growth of (L.) Moench plants, cultivated with arbuscular mycorrhizal fungi (AMF) () and/or under seaweed treatment (3% extract) (), we found that AMF increased the tolerance of sorghum to cadmium stress, either alone or in combination with the seaweed treatment. Morphological parameters were higher in these two culture conditions, with increased chlorophyll content. AMF reduced Cd accumulation in roots and inhibited its translocation to the aerial part, while seaweed treatment alone significantly increased Cd accumulation in leaves and roots without affecting plant growth compared to stressed witnesses. Treatment with AMF and/or attenuated oxidative stress, measured by activation of superoxide dismutase, and resulted in a significant decrease in malondialdehyde and superoxide ions (O) in treated plants. Furthermore, it induced significant alterations in carbon and nitrogen metabolic pathways, with a significant increase in the activity of enzymes such as glutamine synthetase, glutamate synthase (GOGAT), glutamate dehydrogenase, phosphoenolpyruvate carboxylase, aspartate aminotransferase and isocitrate dehydrogenase in the leaves of each treated plant. These results confirm that AMF, algae extract and their combination can improve the biochemical parameters of sorghum under Cd stress, through modification of the antioxidant response on one hand, and improved nitrogen absorption and assimilation efficiency on the other.
PubMed: 38737317
DOI: 10.1007/s12298-024-01446-5 -
International Journal of Molecular... Apr 2024Recently, the increase in marine temperatures has become an important global marine environmental issue. The ability of energy supply in marine animals plays a crucial...
Recently, the increase in marine temperatures has become an important global marine environmental issue. The ability of energy supply in marine animals plays a crucial role in avoiding the stress of elevated temperatures. The investigation into anaerobic metabolism, an essential mechanism for regulating energy provision under heat stress, is limited in mollusks. In this study, key enzymes of four anaerobic metabolic pathways were identified in the genome of scallop , respectively including five opine dehydrogenases (CfOpDHs), two aspartate aminotransferases (CfASTs) divided into cytoplasmic (CfAST1) and mitochondrial subtype (CfAST2), and two phosphoenolpyruvate carboxykinases (CfPEPCKs) divided into a primitive type (CfPEPCK2) and a cytoplasmic subtype (CfPEPCK1). It was surprising that lactate dehydrogenase (LDH), a key enzyme in the anaerobic metabolism of the glucose-lactate pathway in vertebrates, was absent in the genome of scallops. Phylogenetic analysis verified that CfOpDHs clustered according to the phylogenetic relationships of the organisms rather than substrate specificity. Furthermore, , , and displayed distinct expression patterns throughout the developmental process and showed a prominent expression in muscle, foot, kidney, male gonad, and ganglia tissues. Notably, displayed the highest level of expression among these genes during the developmental process and in adult tissues. Under heat stress, the expression of exhibited a general downregulation trend in the six tissues examined. The expression of also displayed a downregulation trend in most tissues, except in striated muscle showing significant up-regulation at some time points. Remarkably, was significantly upregulated in all six tested tissues at almost all time points. Therefore, we speculated that the glucose-succinate pathway, catalyzed by , serves as the primary anaerobic metabolic pathway in mollusks experiencing heat stress, with catalyzing the glucose-opine pathway in striated muscle as supplementary. Additionally, the high and stable expression level of is crucial for the maintenance of the essential functions of aspartate aminotransferase (AST). This study provides a comprehensive and systematic analysis of the key enzymes involved in anaerobic metabolism pathways, which holds significant importance in understanding the mechanism of energy supply in mollusks.
Topics: Animals; Pectinidae; Glucose; Heat-Shock Response; Anaerobiosis; Phylogeny; Succinic Acid; Metabolic Networks and Pathways; Aspartate Aminotransferases
PubMed: 38731961
DOI: 10.3390/ijms25094741 -
Environment International May 2024Heavy metals are commonly released into the environment through industrial processes such as mining and refining. The rapid industrialization that occurred in South...
Heavy metals are commonly released into the environment through industrial processes such as mining and refining. The rapid industrialization that occurred in South Korea during the 1960s and 1970s contributed significantly to the economy of the country; however, the associated mining and refining led to considerable environmental pollution, and although mining is now in decline in South Korea, the detrimental effects on residents inhabiting the surrounding areas remain. The bioaccumulation of toxic heavy metals leads to metabolic alterations in human homeostasis, with disruptions in this balance leading to various health issues. This study used metabolomics to explore metabolomic alterations in the plasma samples of residents living in mining and refining areas. The results showed significant increases in metabolites involved in glycolysis and the surrounding metabolic pathways, such as glucose-6-phosphate, phosphoenolpyruvate, lactate, and inosine monophosphate, in those inhabiting polluted areas. An investigation of the associations between metabolites and blood clinical parameters through meet-in-the-middle analysis indicated that female residents were more affected by heavy metal exposure, resulting in more metabolomic alterations. For women, inhabiting the abandoned mine area, metabolites in the glycolysis and pentose phosphate pathways, such as ribose-5-phosphate and 3-phosphoglycerate, have shown a negative correlation with albumin and calcium. Finally, Mendelian randomization(MR) was used to determine the causal effects of these heavy metal exposure-related metabolites on heavy metal exposure-related clinical parameters. Metabolite biomarkers could provide insights into altered metabolic pathways related to exposure to toxic heavy metals and improve our understanding of the molecular mechanisms underlying the health effects of toxic heavy metal exposure.
Topics: Humans; Metals, Heavy; Female; Environmental Exposure; Republic of Korea; Male; Adult; Metabolomics; Mining; Middle Aged; Environmental Pollution; Environmental Pollutants
PubMed: 38723457
DOI: 10.1016/j.envint.2024.108709 -
Cytokine Jul 2024Sepsis is understood as the result of initiating systemic inflammation derived from an inadequate host response against pathogens. In its acute phase, sepsis is marked...
Sepsis is understood as the result of initiating systemic inflammation derived from an inadequate host response against pathogens. In its acute phase, sepsis is marked by an exacerbated reaction to infection, tissue damage, organ failure, and metabolic dysfunction. Among these, hypoglycemia, characterized by disorders of the gluconeogenesis pathway, is related to one of the leading causes of mortality in septic patients. Recent research has investigated the involvement of sympathetic efferent neuroimmune pathways during systemic inflammation. These pathways can be stimulated by several centrally administered drugs, including Angiotensin-(1-7) (Ang-(1-7)). Therefore, the present study aims to evaluate the effects of central treatment with Ang-(1-7) on hypoglycemia during endotoxemia. For this, male Wistar Hannover rats underwent stereotaxic surgery for intracerebroventricular (i.c.v.) administration of Ang-(1-7) and cannulation of the jugular vein for lipopolysaccharide (LPS) injection. Our results demonstrate that LPS was capable of inducing hypoglycemia and that prior central treatment with Ang-(1-7) attenuated this effect. Our data also show that Ang-(1-7) reduced plasma concentrations of TNF-α, IL-1β, IL-6, and nitric oxide, in addition to the decrease and increase of hepatic IL-6 and IL-10 respectively, in animals subjected to systemic inflammation by LPS, resulting in the reduction of systemic and hepatic inflammation, thus attenuating the deleterious effects of LPS on phosphoenolpyruvate carboxykinase protein content. In summary, the data suggest that central treatment with Ang-(1-7) attenuates hypoglycemia induced by endotoxemia, probably through anti-inflammatory action, leading to reestablishing hepatic gluconeogenesis.
Topics: Animals; Angiotensin I; Male; Sepsis; Peptide Fragments; Rats, Wistar; Hypoglycemia; Rats; Lipopolysaccharides; Inflammation; Liver; Nitric Oxide; Hepatitis; Endotoxemia; Cytokines; Gluconeogenesis; Blood Glucose; Tumor Necrosis Factor-alpha
PubMed: 38723454
DOI: 10.1016/j.cyto.2024.156637 -
Cell Metabolism Jun 2024The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) and its transition to hepatocellular carcinoma (HCC) are unknown....
The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) and its transition to hepatocellular carcinoma (HCC) are unknown. Here, we identified that an IF 5:2 regimen prevents NASH development as well as ameliorates established NASH and fibrosis without affecting total calorie intake. Furthermore, the IF 5:2 regimen blunted NASH-HCC transition when applied therapeutically. The timing, length, and number of fasting cycles as well as the type of NASH diet were critical parameters determining the benefits of fasting. Combined proteome, transcriptome, and metabolome analyses identified that peroxisome-proliferator-activated receptor alpha (PPARα) and glucocorticoid-signaling-induced PCK1 act co-operatively as hepatic executors of the fasting response. In line with this, PPARα targets and PCK1 were reduced in human NASH. Notably, only fasting initiated during the active phase of mice robustly induced glucocorticoid signaling and free-fatty-acid-induced PPARα signaling. However, hepatocyte-specific glucocorticoid receptor deletion only partially abrogated the hepatic fasting response. In contrast, the combined knockdown of Ppara and Pck1 in vivo abolished the beneficial outcomes of fasting against inflammation and fibrosis. Moreover, overexpression of Pck1 alone or together with Ppara in vivo lowered hepatic triglycerides and steatosis. Our data support the notion that the IF 5:2 regimen is a promising intervention against NASH and subsequent liver cancer.
Topics: PPAR alpha; Animals; Fasting; Carcinoma, Hepatocellular; Non-alcoholic Fatty Liver Disease; Humans; Mice; Liver Neoplasms; Mice, Inbred C57BL; Male; Phosphoenolpyruvate Carboxykinase (GTP); Intracellular Signaling Peptides and Proteins; Liver; Liver Cirrhosis; Signal Transduction; Intermittent Fasting
PubMed: 38718791
DOI: 10.1016/j.cmet.2024.04.015