-
Biomedicines Dec 2023Type 2 diabetes mellitus (T2DM) is a chronic progressive disease due to insulin resistance. Oxidative stress complicates the etiology of T2DM. Saxagliptin is a selective...
BACKGROUND
Type 2 diabetes mellitus (T2DM) is a chronic progressive disease due to insulin resistance. Oxidative stress complicates the etiology of T2DM. Saxagliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor, while Pioglitazone is a thiazolidinedione insulin sensitizer. This study aimed to assess the effect of Saxagliptin and Pioglitazone monotherapy and combination therapy on the biochemical and biological parameters in streptozotocin (STZ)-induced diabetic rats.
METHODS
The study included thirty-five male albino rats. Diabetes mellitus was induced by intraperitoneal STZ injection (35 mg/kg). For a 1-month duration, rats were divided into five groups. Glucose homeostasis traits, lipid profiles, kidney functions, liver enzymes, and oxidative stress markers were measured. Gene expression of miRNA-29a, phosphoenolpyruvate carboxykinase (PEPCK), phosphoinositide-3-kinase (PI3K), and interleukin 1 beta (IL-1β) was assessed using qRT-PCR.
RESULTS
At a 1-month treatment duration, combination therapy improves oxidative stress markers more than either drug alone. The combination therapy had significantly higher levels of SOD, catalase, and GSH and lower levels of MDA compared to the monotherapy. Additionally, the diabetic group showed a significant increase in the expression levels of miRNA-29a, PEPCK, and IL-1β and a significant decrease in PI3K compared to the normal control group. However, combination therapy of Saxagliptin and Pioglitazone was more effective than either Saxagliptin or Pioglitazone alone in reversing these results, especially for PEPCK and IL-1β.
CONCLUSIONS
Our findings revealed that combining Saxagliptin and Pioglitazone improves glycemic control and genetic and epigenetic expression profiles, which play an essential regulatory role in normal metabolism.
PubMed: 38137521
DOI: 10.3390/biomedicines11123300 -
Foods (Basel, Switzerland) Dec 2023The aim of this study was to investigate the antidiabetic effect of the extract from (SPPE) on type 2 diabetes mellitus (T2DM) mice. SPPE treatment alleviated...
The aim of this study was to investigate the antidiabetic effect of the extract from (SPPE) on type 2 diabetes mellitus (T2DM) mice. SPPE treatment alleviated hyperglycemia, insulin resistance (IR), liver and pancreatic tissue damage, hyperlipidemia and hepatic oxidative stress resulting from T2DM. SPPE reversed phosphoenolpyruvate carboxylase (PEPCK) and hexokinase (HK) activities to improve gluconeogenesis and glycogen storage in the liver. Furthermore, SPPE modulated glucose metabolism by regulating the levels of mRNA expression involving the PI3K/Akt/FOXO1/G6pase/GLUT2 pathway and could inhibit fatty acid synthesis by reducing the gene expression levels of fatty acid synthase (FAS) and acetyl-CoA carboxylase-1 (ACC-1). A 16 sRNA analysis indicated that SPPE treatment also reversed gut dysbiosis by increasing the abundance of beneficial bacteria ( and ) and suppressing the proliferation of harmful bacteria ( and ). Untargeted metabolomics results indicated that histidine metabolism, nicotinate and nicotinamide metabolism and fatty acid biosynthesis were significantly influenced by SPPE. Thus, SPPE may be applied as an effective dietary supplement or drug in the management of T2DM.
PubMed: 38137213
DOI: 10.3390/foods12244409 -
BMC Complementary Medicine and Therapies Dec 2023Artichoke (Cynara scolymus L.) is a typical element of a traditional Mediterranean diet and has potential health advantages for insulin resistance (IR) and type 2...
Artichoke (Cynara scolymus L.) water extract alleviates palmitate-induced insulin resistance in HepG2 hepatocytes via the activation of IRS1/PI3K/AKT/FoxO1 and GSK-3β signaling pathway.
BACKGROUND
Artichoke (Cynara scolymus L.) is a typical element of a traditional Mediterranean diet and has potential health advantages for insulin resistance (IR) and type 2 diabetes mellitus (T2DM). This study aims to evaluate the effect and underlying mechanism of artichoke water extract (AWE) on palmitate (PA)-induced IR in human hepatocellular carcinoma (HepG2) cells.
METHODS
The effect of AWE on cell viability was determined using CCK8 assay. Cellular glucose uptake, glucose consumption, glucose production, and glycogen content were assessed after AWE treatment. The gene expression and protein levels were examined by real-time polymerase chain reaction (qRT-PCR) and western blotting.
RESULTS
The results showed that AWE dose-dependently increased cell viability in IR HepG2 cells (P < 0.01). AWE treatment significantly promoted glucose uptake and consumption, decreased glucose production, and increased the cellular glycogen content in IR HepG2 cells (P < 0.01). Mechanistically, AWE elevated the phosphorylation and total protein levels of major insulin signaling molecules in IR HepG2 cells, which resulted in a decrease in the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) and the inhibition of glycogen synthase (GS) phosphorylation in IR HepG2 cells. Furthermore, the protective effect of AWE on IR HepG2 cells might be ascribed to the inhibition of the endoplasmic reticulum (ER) stress.
CONCLUSION
We conclude that AWE may improve glucose metabolism by regulating IRS1/PI3K/AKT/FoxO1 and GSK-3β signaling associated with the inhibition of ER stress in IR HepG2 cells induced by PA.
Topics: Humans; Insulin Resistance; Cynara scolymus; Glycogen Synthase Kinase 3 beta; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Diabetes Mellitus, Type 2; Palmitates; Signal Transduction; Hepatocytes; Glucose; Glycogen; Insulin Receptor Substrate Proteins
PubMed: 38102588
DOI: 10.1186/s12906-023-04275-3 -
Molecular Medicine Reports Feb 2024Tea () seed cake is a potential resource that contains a wealth of bioactive compounds. However, the high toxicity of tea saponins in tea seed cake restricts its...
Tea () seed cake is a potential resource that contains a wealth of bioactive compounds. However, the high toxicity of tea saponins in tea seed cake restricts its applications. The present study aimed to i) develop a method of extracting bioactive compounds and reducing tea saponins during the process of tea seed cake extraction and ii) investigate the anti‑insulin resistance effect of tea seed saponin‑reduced extract (TSSRE) in a palmitic acid (PA)‑induced insulin resistance HepG2‑cell model. The concentration of tea saponins in TSSRE was ~10‑fold lower than that in tea seed crude extract (TSCE) after the saponin‑reduction process. In addition, TSSRE cytotoxicity was significantly lower than that of TSCE in HepG2 cells. TSSRE treatment improved glucose consumption as well as glucose transporter (GLUT) 2 and GLUT4 expression levels in PA‑stimulated HepG2 cells. Moreover, TSSRE enhanced the phosphorylation of the insulin receptor substrate 1/protein kinase B/forkhead box protein O1/glycogen synthase kinase 3β and inhibited the elevated expression of phosphoenolpyruvate carboxykinase in PA‑exposed HepG2 cells. The effect of TSSRE on the mediation of the insulin signaling pathway was attributed to the inhibition of PA‑induced mitogen‑activated protein kinase activation. The findings of the present study indicated that TSSRE ameliorates hepatic insulin resistance by ameliorating insulin signaling and inhibiting inflammation-related pathways.
Topics: Humans; Insulin Resistance; Hep G2 Cells; Palmitic Acid; Saponins; Proto-Oncogene Proteins c-akt; Insulin; Glucose; Seeds; Tea
PubMed: 38099345
DOI: 10.3892/mmr.2023.13149 -
Chemical Science Dec 2023Phosphorylation is thought to be one of the fundamental reactions for the emergence of metabolism. Nearly all enzymatic phosphorylation reactions in the anabolic core of...
Phosphorylation is thought to be one of the fundamental reactions for the emergence of metabolism. Nearly all enzymatic phosphorylation reactions in the anabolic core of microbial metabolism act on carboxylates to give acyl phosphates, with a notable exception - the phosphorylation of pyruvate to phosphoenolpyruvate (PEP), which involves an enolate. We wondered whether an ancestral mechanism for the phosphorylation of pyruvate to PEP could also have involved carboxylate phosphorylation rather than the modern enzymatic form. The phosphorylation of pyruvate with PO as a model phosphorylating agent was found to indeed occur carboxylate phosphorylation, as verified by mechanistic studies using model substrates, time course experiments, liquid and solid-state NMR spectroscopy, and DFT calculations. The generated acyl phosphate subsequently undergoes an intramolecular phosphoryl transfer to yield PEP. A single phosphorylation mechanism acting on carboxylates appears sufficient to initiate metabolic networks that include PEP, strengthening the case that metabolism emerged from self-organized chemistry.
PubMed: 38098731
DOI: 10.1039/d3sc04116f -
Scientific Reports Dec 2023Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease characterized by complex lung pathogenesis affecting approximately three million people...
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease characterized by complex lung pathogenesis affecting approximately three million people worldwide. While the molecular and cellular details of the IPF mechanism is emerging, our current understanding is centered around the lung itself. On the other hand, many human diseases are the products of complex multi-organ interactions. Hence, we postulate that a dysfunctional crosstalk of the lung with other organs plays a causative role in the onset, progression and/or complications of IPF. In this study, we employed a generative computational approach to identify such inter-organ mechanism of IPF. This approach found unexpected molecular relatedness of IPF to neoplasm, diabetes, Alzheimer's disease, obesity, atherosclerosis, and arteriosclerosis. Furthermore, as a potential mechanism underlying this relatedness, we uncovered a putative molecular crosstalk system across the lung and the liver. In this inter-organ system, a secreted protein, kininogen 1, from hepatocytes in the liver interacts with its receptor, bradykinin receptor B1 in the lung. This ligand-receptor interaction across the liver and the lung leads to the activation of calmodulin pathways in the lung, leading to the activation of interleukin 6 and phosphoenolpyruvate carboxykinase 1 pathway across these organs. Importantly, we retrospectively identified several pre-clinical and clinical evidence supporting this inter-organ mechanism of IPF. In conclusion, such feedforward and feedback loop system across the lung and the liver provides a unique opportunity for the development of the treatment and/or diagnosis of IPF. Furthermore, the result illustrates a generative computational framework for machine-mediated synthesis of mechanisms that facilitates and complements the traditional experimental approaches in biomedical sciences.
Topics: Humans; Retrospective Studies; Idiopathic Pulmonary Fibrosis; Lung
PubMed: 38081956
DOI: 10.1038/s41598-023-49281-0 -
World Journal of Diabetes Nov 2023Impaired glucose tolerance (IGT) is a homeostatic state between euglycemia and hyperglycemia and is considered an early high-risk state of diabetes. When IGT occurs,...
BACKGROUND
Impaired glucose tolerance (IGT) is a homeostatic state between euglycemia and hyperglycemia and is considered an early high-risk state of diabetes. When IGT occurs, insulin sensitivity decreases, causing a reduction in insulin secretion and an increase in glucagon secretion. Recently, vascular endothelial growth factor B (VEGFB) has been demonstrated to play a positive role in improving glucose metabolism and insulin sensitivity. Therefore, we constructed a mouse model of IGT through high-fat diet feeding and speculated that VEGFB can regulate hyperglycemia in IGT by influencing insulin-mediated glucagon secretion, thus contributing to the prevention and cure of prediabetes.
AIM
To explore the potential molecular mechanism and regulatory effects of VEGFB on insulin-mediated glucagon in mice with IGT.
METHODS
We conducted experiments through systematic VEGFB knockout and pancreatic-specific VEGFB overexpression. Insulin and glucagon secretions were detected enzyme-linked immunosorbent assay, and the protein expression of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) was determined using western blot. Further, mRNA expression of forkhead box protein O1, phosphoenolpyruvate carboxykinase, and glucose-6 phosphatase was detected quantitative polymerase chain reaction, and the correlation between the expression of proteins was analyzed bioinformatics.
RESULTS
In mice with IGT and VEGFB knockout, glucagon secretion increased, and the protein expression of PI3K/AKT decreased dramatically. Further, in mice with VEGFB overexpression, glucagon levels declined, with the activation of the PI3K/AKT signaling pathway.
CONCLUSION
VEGFB/vascular endothelial growth factor receptor 1 can promote insulin-mediated glucagon secretion by activating the PI3K/AKT signaling pathway to regulate glucose metabolism disorders in mice with IGT.
PubMed: 38077805
DOI: 10.4239/wjd.v14.i11.1643 -
Molecular Therapy Oncolytics Dec 2023Aerobic glycolysis is a hallmark property of cancer metabolism. Enolase is a glycolytic enzyme that catalyzes the conversion of 2-phosphoglycerate into... (Review)
Review
Aerobic glycolysis is a hallmark property of cancer metabolism. Enolase is a glycolytic enzyme that catalyzes the conversion of 2-phosphoglycerate into phosphoenolpyruvate. In mammals, enolases exist in three isoforms, encoded by the genes , , and . The altered expression of enolases is a common occurrence in various types of cancer. Although most published studies on enolases have predominantly focused on the role of ENO1 in cancer, ENO2 and ENO3 have recently emerged as crucial regulatory molecules in cancer development. Significant progress has been made in understanding their multifaceted roles in oncogenesis. In this comprehensive review, we provide an overview of the structure, subcellular localization, diagnostic and prognostic significance, biological functions, and molecular mechanisms of ENO2 and ENO3 in cancer progression. The importance of enolase in cancer development makes it a novel therapeutic target for clinical applications. Furthermore, we discuss anticancer agents designed to target enolases and summarize their anticancer efficacy in both and studies.
PubMed: 38075246
DOI: 10.1016/j.omto.2023.100750 -
International Journal of Molecular... Nov 2023The pressure to reduce mineral fertilization and the amount of pesticides used has become a factor limiting production growth, as has the elimination of many crop...
The pressure to reduce mineral fertilization and the amount of pesticides used has become a factor limiting production growth, as has the elimination of many crop protection chemicals from the market. A key condition for this to be an effective form of protection is the use of varieties with higher levels of resistance. The most effective and fastest way to assist in the selection and control of pathogens is the conducting of genome-wide association studies. These are useful tools for identifying candidate genes, especially when combined with QTL mapping to map and validate loci for quantitative traits. The aim of this study was to identify new markers coupled to genes that determine maize plant resistance to fusarium head blight through the use of next-generation sequencing, association and physical mapping, and to optimize diagnostic procedures to identify selected molecular markers coupled to plant resistance to this fungal disease. As a result of field experiments and molecular analyses, molecular markers coupled to potential genes for resistance to maize ear fusariosis were selected. The newly selected markers were tested against reference genotypes. As a result of the analyses, it was found that two markers (11801 and 20607) out of the ten that were tested differentiated between susceptible and resistant genotypes. Marker number 11801 proved to be the most effective, with a specious product of 237 bp appearing for genotypes 1, 3, 5, 9 and 10. These genotypes were characterized by a field resistance of 4-6 on the 9° scale (1 being susceptible, 9 being resistant) and for all genotypes except 16 and 20, which were characterized by a field resistance of 9. In the next step, this marker will be tested on a wider population of extreme genotypes in order to use it for the preliminary selection of fusarium-resistant genotypes, and the phosphoenolpyruvate carboxylase kinase 1 gene coupled to it will be subjected to expression analysis.
Topics: Fusarium; Zea mays; Quantitative Trait Loci; Disease Resistance; Genome-Wide Association Study; High-Throughput Nucleotide Sequencing; Technology; Plant Diseases
PubMed: 38069033
DOI: 10.3390/ijms242316712 -
International Journal of Molecular... Nov 2023During glycolysis, the muscle isoform of pyruvate kinase PKM2 produces ATP in exchange for dephosphorylation of phosphoenolpyruvate (PEP) into pyruvate. PKM2 has been...
During glycolysis, the muscle isoform of pyruvate kinase PKM2 produces ATP in exchange for dephosphorylation of phosphoenolpyruvate (PEP) into pyruvate. PKM2 has been considered as a tumor-promoting factor in most cancers, whereas the regulatory role of PKM2 during head and neck carcinogenesis remained to be delineated. PKM2 mRNA and protein expression was examined in head and neck tumorous specimens. The role of PKM2 in controlling cellular malignancy was determined in shRNA-mediated PKM2-deficient head and neck squamous cell carcinoma (HNSC) cells. In agreement with the results in other cancers, PKM2 expression is enriched in both mouse and human HNSC tissues. Nevertheless, PKM2 mRNA expression reversely correlated with tumor stage, and greater recurrence-free survival rates are evident in the PKM2 HNSC population, arguing that PKM2 may be tumor-suppressive. Multifaceted analyses showed a greater in vivo xenografic tumor growth and an enhanced cisplatin resistance in response to PKM2 loss, whereas PKM2 silencing led to reduced cell motility. At the molecular level, metabolic shifts towards mitochondrial metabolism and activation of oncogenic Protein kinase B (PKB/Akt) and extracellular signal-regulated kinase (ERK) signals were detected in PKM2-silencing HNSC cells. In sum, our findings demonstrated that PKM2 differentially modulated head and neck tumorigenicity via metabolic reprogramming.
Topics: Animals; Humans; Mice; Carcinogenesis; Cell Line, Tumor; Cisplatin; Glycolysis; Head and Neck Neoplasms; Pyruvate Kinase; RNA, Messenger; Squamous Cell Carcinoma of Head and Neck
PubMed: 38068962
DOI: 10.3390/ijms242316639