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Frontiers in Nutrition 2024Previous animal experiments have demonstrated the potential of spermidine to mitigate glucose intolerance, insulin resistance, and hyperinsulinemia. However, there...
BACKGROUND
Previous animal experiments have demonstrated the potential of spermidine to mitigate glucose intolerance, insulin resistance, and hyperinsulinemia. However, there remains a scarcity of epidemiological evidence supporting these findings. Therefore, we aimed to elucidate the associations of serum spermidine with T2DM and FPG.
MATERIALS AND METHODS
The cross-sectional study was conducted from June to August 2019 in the rural areas of Fuxin County, Liaoning Province, China. A total of 4,437 participants were included in the study. The serum spermidine was detected using high-performance liquid chromatography with a fluorescence detector. FPG was measured using the hexokinase method. T2DM was defined as participants with a FPG level of 7.0 mmol/L or greater, or self-reported diagnosis of diabetes by a doctor. Restricted cubic spline model and piecewise linear regression model were used to explore the associations of serum spermidine with T2DM and FPG, respectively.
RESULTS
The mean (SD) age of the participants was 59.3 (10.0) years, with 622 out of 4,437 participants being defined as T2DM. The serum spermidine in participants stratified by age and BMI categories was significantly different, with values of 0.006 and 0.001, respectively. Among all the participants, the association of serum spermidine with T2DM was J-shaped. The log (spermidine) was negatively associated with T2DM (OR = 0.68, 95% CI: 0.52 to 0.92, = 0.01) below the inflection point, while log (spermidine) was not significantly associated with T2DM (OR = 1.97, 95% CI: 0.93 to 4.15, = 0.07) above the inflection point. Among the participants without T2DM, the association of serum spermidine with FPG was inverted J-shaped. The log (spermidine) was positively associated with FPG ( = 0.13, 95% CI: 0.05 to 0.21, = 0.001) below the inflection point, while log (spermidine) was negatively associated with FPG ( = -0.29, 95% CI: -0.42 to -0.16, < 0.001) above the inflection point.
CONCLUSION
In conclusion, non-linear associations of serum spermidine with T2DM and FPG were found in the cross-sectional study in Chinese rural adults. This provided insights into the use of spermidine for the prevention of T2DM, highlighting the potential role in public health prevention strategies of spermidine.
PubMed: 38812932
DOI: 10.3389/fnut.2024.1393552 -
Thoracic Cancer May 2024Non-small-cell lung cancer (NSCLC) is a common malignancy with high morbidity and mortality. Circular RNAs are widely involved in NSCLC progression. However, the...
BACKGROUND
Non-small-cell lung cancer (NSCLC) is a common malignancy with high morbidity and mortality. Circular RNAs are widely involved in NSCLC progression. However, the mechanism of circSLC25A16 in NSCLC has not been reported.
METHODS
The expressions of circSLC25A16, microRNA-335-5p (miR-335-5p), and CDGSH iron-sulfur domain-containing protein 2 (CISD2) were monitored by quantitative real-time fluorescence polymerase chain reaction. Western blot was also carried out to measure the protein levels of CISD2, hexokinase 2 (HK2), and lactate dehydrogenase A (LDHA). For functional analysis, cell counting kit-8 assay, 5-ethynyl-2'-deoxyuridine, flow cytometry, transwell, and wound healing assays were utilized to examine cell proliferation, apoptosis, and migration. Glucose uptake and lactate production were detected using commercial kits. The relationship between miR-335-5p and circSLC25A16 or CISD2 was verified by dual-luciferase reporter and RNA immunoprecipitation assays. Furthermore, tumor xenograft was established to explore the function of circSLC25A16 in vivo.
RESULTS
CircSLC25A16 and CISD2 were overexpressed in NSCLC, but miR-335-5p was downregulated. CircSLC25A16 acted as a miR-335-5p sponge, and silencing of circSLC25A16 arrested cell proliferation, migration, and glycolysis, and promoted apoptosis, but these impacts were resumed by miR-335-5p inhibition. CISD2 was a miR-335-5p target, and overexpression of CISD2 abolished the suppressive function of miR-335-5p mimic on the malignant behavior of NSCLC cells. CircSLC25A16 could adsorb miR-335-5p to mediate CISD2 expression. Additionally, silencing circSLC25A16 restrained the growth of NSCLC tumor xenograft in vivo.
CONCLUSION
CircSLC25A16 facilitated NSCLC progression via the miR-335-5p/CISD2 axis, implying that circSLC25A16 may serve as a novel biomarker for NSCLC treatment.
PubMed: 38803052
DOI: 10.1111/1759-7714.15163 -
Scientific Reports May 2024Microglia are natural immune cells in the central nervous system, and the activation of microglia is accompanied by a reprogramming of glucose metabolism. In our study,...
Microglia are natural immune cells in the central nervous system, and the activation of microglia is accompanied by a reprogramming of glucose metabolism. In our study, we investigated the role of long non-coding RNA taurine-upregulated gene 1 (TUG1) in regulating microglial glucose metabolism reprogramming and activation. BV2 cells were treated with Lipopolysaccharides (LPS)/Interferon-γ (IFN-γ) to establish a microglial activation model. The glycolysis inhibitor 2-Deoxy-D-glucose (2-DG) was used as a control. The expression levels of TUG1 mRNA and proinflammatory cytokines such as Interleukin-1β (IL-1β), Interleukin -6, and Tumor Necrosis Factor-α mRNA and anti-inflammatory cytokines such as IL-4, Arginase 1(Arg1), CD206, and Ym1 were detected by RT-qPCR. TUG1 was silenced using TUG1 siRNA and knocked out using CRISPR/Cas9. The mRNA and protein expression levels of key enzymes involved in glucose metabolism, such as Hexokinase2, Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), Lactate dehydrogenase, Glucose 6 phosphate dehydrogenase, and Pyruvate dehydrogenase (PDH), were determined by RT-qPCR and Western blotting. The glycolytic rate of microglial cells was measured using Seahorse. Differential metabolites were determined by metabolomics, and pathway enrichment was performed using these differential metabolites. Our findings revealed that the expression of TUG1 was elevated in proinflammatory-activated microglia and positively correlated with the levels of inflammatory factors. The expression of anti-inflammatory cytokines such as IL-4, Arg1, CD206, and Ym1 were decreased when induced with LPS/IFN-γ. However, this decrease was reversed by the treatment with 2-DG. Silencing of GAPDH led to an increase in the expression of TUG1 and inflammatory factors. TUG1 knockout (TUG1KO) inhibited the expression of glycolytic key enzymes and promoted the expression of oxidative phosphorylation key enzymes, shifting the metabolic profile of activated microglia from glycolysis to oxidative phosphorylation. Additionally, TUG1KO reduced the accumulation of metabolites, facilitating the restoration of the tricarboxylic acid cycle and enhancing oxidative phosphorylation in microglia. Furthermore, the downregulation of TUG1 was found to reduce the expression of both proinflammatory and anti-inflammatory cytokines under normal conditions. Interestingly, when induced with LPS/IFN-γ, TUG1 downregulation showed a potentially beneficial effect on microglia in terms of inflammation. Downregulation of TUG1 expression inhibits glycolysis and facilitates the shift of microglial glucose metabolism from glycolysis to oxidative phosphorylation, promoting their transformation towards an anti-inflammatory phenotype and exerting anti-inflammatory effects in BV2.
Topics: Microglia; Animals; RNA, Long Noncoding; Glucose; Mice; Lipopolysaccharides; Glycolysis; Cytokines; Inflammation; Interferon-gamma; beta-N-Acetylhexosaminidases; Cell Line; Mannose Receptor; Mannose-Binding Lectins; Deoxyglucose; Interleukin-4; Interleukin-1beta; Metabolic Reprogramming; Arginase; Hexokinase; Lectins
PubMed: 38802677
DOI: 10.1038/s41598-024-62966-4 -
Cancer Science May 2024Aberrant signaling in tumor cells induces nonmetabolic functions of some metabolic enzymes in many cellular activities. As a key glycolytic enzyme, the nonmetabolic...
Aberrant signaling in tumor cells induces nonmetabolic functions of some metabolic enzymes in many cellular activities. As a key glycolytic enzyme, the nonmetabolic function of hexokinase 2 (HK2) plays a role in tumor immune evasion. However, whether HK2, dependent of its nonmetabolic activity, plays a role in human pancreatic ductal adenocarcinoma (PDAC) tumorigenesis remains unclear. Here, we demonstrated that HK2 acts as a protein kinase and phosphorylates IκBα at T291 in PDAC cells, activating NF-κB, which enters the nucleus and promotes the expression of downstream targets under hypoxia. HK2 nonmetabolic activity-promoted activation of NF-κB promotes the proliferation, migration, and invasion of PDAC cells. These findings provide new insights into the multifaceted roles of HK2 in tumor development and underscore the potential of targeting HK2 protein kinase activity for PDAC treatment.
PubMed: 38801832
DOI: 10.1111/cas.16204 -
Regenerative Therapy Jun 2024We aimed to examine whether heparin-binding epidermal growth factor-like growth factor (HB-EGF) affects the lung fibrosis process through the activation of p38 protein...
OBJECTIVE
We aimed to examine whether heparin-binding epidermal growth factor-like growth factor (HB-EGF) affects the lung fibrosis process through the activation of p38 protein in mitogen-activated protein kinases (MAPK) signaling pathway, as well as the expression of downstream inflammatory factors.
METHODS
The expression levels of HB-EGF, collagen type I (COL-I), and hexokinase 2 (HK2) in peripheral blood mononuclear cells (PBMCs) of patients with connective tissue disease-related interstitial lung disease (CTD-ILD) were examined by qPCR, Western blotting and ELISA.
RESULTS
In vitro experiments showed that HB-EGF was increased in almost all subtypes [rheumatoid arthritis (RA), systemic sclerosis (SSc) and idiopathic inflammatory myopathies (IIMs)] as well as in all groups (P < 0.05). For embryonic lung fibroblast (A549) cells, the expression levels of HK2 and α-smooth muscle actin (α-SMA) genes were elevated during 0-4 h and then plateaued. Transforming growth factor-β1 (TGF-β1) induced fibrosis in human embryonic lung fibroblasts (MRC-5) cells and A549 for a certain period of time, but the degree of induction varied, which may be related to the redifferentiability of cells at different spatial locations. Moreover, HB-EGF at concentrations above 1 ng/ml stimulation increased COL-I expression (P < 0.05), and for α-SMA gene, even 1 ng/ml concentration of HB-EGF had a stimulatory effect, and different concentrations of HB-EGF did activate the expression of p38 in a concentration-dependent manner within a certain concentration range, and by The qPCR results showed that for interleukin 6 (IL-6), an inflammatory factor regulated downstream of p38, the expression was significantly increased in A549 cells compared to control (P < 0.05), but tumor necrosis factor-α (TNF-α) expression was downregulated (P < 0.05), but for interleukin-1β (IL-1β) gene, there was no significant difference in A549 cells, and expression was downregulated in MRC-5 cells. Therefore, it is suggested that HB-EGF regulates the expression of inflammatory factors through p38 will be differential across cells.
CONCLUSION
Our study shows that HB-EGF can suppress pulmonary fibrosis through downstream activation of p38/MAPK pathway activity, as well as the expression of various inflammatory factors downstream of it.
PubMed: 38798743
DOI: 10.1016/j.reth.2024.05.002 -
Insects May 2024Parasitoids commonly manipulate their host's metabolism and immunity to facilitate their offspring survival, but the mechanisms remain poorly understood. Here, we...
Parasitoids commonly manipulate their host's metabolism and immunity to facilitate their offspring survival, but the mechanisms remain poorly understood. Here, we deconstructed the manipulation strategy of a newly discovered parasitoid wasp, , which parasitizes . Using RNA-seq, we analyzed transcriptomes of -parasitized and non-parasitized host larvae. A total of 22.29 Gb and 23.85 Gb of clean reads were obtained from the two samples, respectively, and differential expression analysis identified 445 DEGs. Of them, 304 genes were upregulated and 141 genes were downregulated in parasitized hosts compared with non-parasitized larvae. Based on the functional annotations in the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, we found that the genes involved in host nutrition metabolism were significantly upregulated, particularly in carbohydrate, amino acid, and lipid metabolism. We also identified 30 other metabolism-related DEGs, including hexokinase, fatty acid synthase, and UDP-glycosyltransferase (Ugt) genes. We observed that five Bomanin genes (Boms) and six antimicrobial peptides (AMPs) were upregulated. Moreover, a qRT-PCR analysis of 12 randomly selected DEGs confirmed the reproducibility and accuracy of the RNA-seq data. Our results provide a comprehensive transcriptomic analysis of how manipulates its host, laying a solid foundation for studies on the regulatory mechanisms employed by parasitoid wasps in their hosts.
PubMed: 38786908
DOI: 10.3390/insects15050352 -
Cureus Apr 2024Introduction Diabetes and cancer are commonly linked together. The possible links include insulin resistance, hyperinsulinemia, hyperglycemia, oxidative stress, and...
Introduction Diabetes and cancer are commonly linked together. The possible links include insulin resistance, hyperinsulinemia, hyperglycemia, oxidative stress, and chronic inflammation. These are factors that have potential promoting effects on the progression of cancer in many ways. Measurement of prostate-specific antigen (PSA) is widely applied for early detection of prostate cancer. However, several factors influence serum PSA levels in men including age, benign prostatic hyperplasia, prostatitis, and body mass index (BMI). The risk of several malignancies is increased in diabetes but the risk of prostate carcinoma in diabetic patients is reduced secondary to lowering of testosterone levels during the state of hyperinsulinemia. A negative association between serum PSA levels and metformin use is also an explanation of low cancer prostate incidence with diabetes. Objective The study aims to evaluate the PSA levels in diabetic patients with poor glycemic control i.e., glycated hemoglobin (HbA1c) ≥ 7%) vs good glycemic control (HbA1c < 7%). Materials and methods Samples of PSA in diabetic patients collected in the Department of Biochemistry at Indira Gandhi Institute of Medical Sciences (IGIMS), Patna, were included. The observational study was carried out on clinically diagnosed 318 cases of diabetes attending both the outpatient and inpatient Department, IGIMS, Patna. Six ml venous blood samples were collected from patients after obtaining informed consent and ethical clearance. Patient details regarding age, complete clinical details, and general physical examinations were recorded. Serum levels of PSA, fasting plasma glucose (FPG) and HbA1c were analyzed and values were compared. The serum level of PSA was estimated by the chemiluminescent immunoassay (CLIA) method on an automated immunoassay analyzer in the Department of Biochemistry, maintaining all the quality control precautions using a control, calibrator, and reagent kit. HbA1c estimation was by chromatography technique. Fasting plasma glucose was estimated using the hexokinase method on an automated chemistry analyzer. Statistical analyses were performed using SPSS software, version 16.0 (SPSS Inc., Chicago). The median and interquartile range were calculated for numerical variables. Covariance analysis was used in the comparisons among groups. The Mann-Whitney U test was applied to detect the comparison between the two groups. Significance was determined by the P value. P value<0.05 was considered significant. Result Serum PSA value was found to be higher in (the good glycemic control group) with a median of 0.99 with an interquartile range of 3.14, than in (the bad glycemic control group) with a median of 0.49 with an interquartile range of 3.9, and the difference is statistically significant. The difference is also statistically significant in the subgroup (i) with PSA value <4 ng/ml. In subgroups (ii) and (iii), PSA values 4 ng/ml-8 ng/ml and PSA values >8 ng/ml respectively, no significant differences were found. Conclusion It was found that serum prostate-specific antigen levels have been lower in diabetic patients with poor glycemic control than in good glycemic control. Future studies with a larger sample size and detailed information on diabetes duration and management are recommended.
PubMed: 38774165
DOI: 10.7759/cureus.58680 -
Journal of Translational Medicine May 2024Chaperonin Containing TCP1 Subunit 6 A (CCT6A) is a prominent protein involved in the folding and stabilization of newly synthesized proteins. However, its roles and...
BACKGROUND
Chaperonin Containing TCP1 Subunit 6 A (CCT6A) is a prominent protein involved in the folding and stabilization of newly synthesized proteins. However, its roles and underlying mechanisms in lung adenocarcinoma (LUAD), one of the most aggressive cancers, remain elusive.
METHODS
Our study utilized in vitro cell phenotype experiments to assess CCT6A's impact on the proliferation and invasion capabilities of LUAD cell lines. To delve into CCT6A's intrinsic mechanisms affecting glycolysis and proliferation in lung adenocarcinoma, we employed transcriptomic sequencing and liquid chromatography-mass spectrometry analysis. Co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation (CHIP) assays were also conducted to substantiate the mechanism.
RESULTS
CCT6A was found to be significantly overexpressed in LUAD and associated with a poorer prognosis. The silencing of CCT6A inhibited the proliferation and migration of LUAD cells and elevated apoptosis rates. Mechanistically, CCT6A interacted with STAT1 protein, forming a complex that enhances the stability of STAT1 by protecting it from ubiquitin-mediated degradation. This, in turn, facilitated the transcription of hexokinase 2 (HK2), a critical enzyme in aerobic glycolysis, thereby stimulating LUAD's aerobic glycolysis and progression.
CONCLUSION
Our findings reveal that the CCT6A/STAT1/HK2 axis orchestrated a reprogramming of glucose metabolism and thus promoted LUAD progression. These insights position CCT6A as a promising candidate for therapeutic intervention in LUAD treatment.
Topics: Humans; Glycolysis; Adenocarcinoma of Lung; Hexokinase; STAT1 Transcription Factor; Cell Proliferation; Lung Neoplasms; Chaperonin Containing TCP-1; Cell Line, Tumor; Disease Progression; Cell Movement; Gene Expression Regulation, Neoplastic; Apoptosis; Signal Transduction; Neoplasm Invasiveness
PubMed: 38750462
DOI: 10.1186/s12967-024-05284-7 -
Biomolecules & Biomedicine May 2024Dysregulation of glycolysis is frequently linked to aggressive tumor activity in colorectal cancer (CRC). Although serine peptidase inhibitor, Kazal type 4 (SPINK4) has...
Dysregulation of glycolysis is frequently linked to aggressive tumor activity in colorectal cancer (CRC). Although serine peptidase inhibitor, Kazal type 4 (SPINK4) has been linked to CRC, its exact linkage to glycolytic processes and gene expression remains unclear. Differentially expressed genes (DEGs) were screened from two CRC-related datasets (GSE32323 and GSE141174), followed by expression and prognostic analysis of SPINK4. In vitro techniques such as flow cytometry, western blotting, transwell assay, and quantitative real-time polymerase chain reaction (qRT-PCR) were used to assess SPINK4 expression in CRC cells. Its effects on apoptosis, glycolysis, and the cell cycle were also investigated. Finally, the impact of SPINK4 overexpression on tumor development was assessed using a xenograft model, while histological and immunohistochemical analyses characterized SPINK4 expression patterns in CRC tissues. SPINK4 expression was downregulated in CRC, correlating with poor patient prognosis. In vitro assays confirmed that overexpression of SPINK4 reduced CRC cell proliferation, invasion, and migration, while its knockdown promoted these processes and caused G1 arrest. SPINK4 also regulated apoptosis by altering caspase activation and Bcl-2 expression. Besides, SPINK4 overexpression altered glycolytic activity, reduced 2-Deoxy-D-glucose (2-DG) absorption, and controlled critical glycolytic enzymes, resulting in alterations in metabolic pathways, whereas SPINK4 knockdown reversed this effect. SPINK4 overexpression significantly reduced tumor volume in vivo, indicating its inhibitory role in carcinogenesis. Moreover, high expression of SPINK4, hexokinase 2 (HK2), glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and pyruvate kinase M2 (PKM2) was observed in CRC tissues. As a key inhibitor of glycolytic metabolism in CRC, SPINK4 promises metabolic intervention in CRC therapy due to its impact on tumor growth and cell proliferation.
PubMed: 38747892
DOI: 10.17305/bb.2024.10338 -
PloS One 2024In the current study we investigated the impact of combination of rutin and vitamin A on glycated products, the glyoxalase system, oxidative markers, and inflammation in...
In the current study we investigated the impact of combination of rutin and vitamin A on glycated products, the glyoxalase system, oxidative markers, and inflammation in animals fed a high-fat high-fructose (HFFD) diet. Thirty rats were randomly divided into six groups (n = 5). The treatments, metformin (120 mg/kg), rutin (100 mg/kg), vitamin A (43 IU/kg), and a combination of rutin (100 mg/kg) and vitamin A (43 IU/kg) were given to relevant groups of rats along with high-fructose high-fat diet for 42 days. HbA1c, D-lactate, Glyoxylase-1, Hexokinase 2, malondialdehyde (MDA), glutathione peroxidase (GPx), catalase (CAT), nuclear transcription factor-B (NF-κB), interleukin-6 (IL-6), interleukin-8 (IL-8) and histological examinations were performed after 42 days. The docking simulations were conducted using Auto Dock package. The combined effects of rutin and vitamin A in treated rats significantly (p < 0.001) reduced HbA1c, hexokinase 2, and D-lactate levels while preventing cellular damage. The combination dramatically (p < 0.001) decreased MDA, CAT, and GPx in treated rats and decreased the expression of inflammatory cytokines such as IL-6 andIL-8, as well as the transcription factor NF-κB. The molecular docking investigations revealed that rutin had a strong affinity for several important biomolecules, including as NF-κB, Catalase, MDA, IL-6, hexokinase 2, and GPx. The results propose beneficial impact of rutin and vitamin A as a convincing treatment strategy to treat AGE-related disorders, such as diabetes, autism, alzheimer's, atherosclerosis.
Topics: Animals; Rutin; Oxidative Stress; Fructose; Rats; Diet, High-Fat; Vitamin A; Inflammation; Male; Hyperglycemia; Molecular Docking Simulation; Rats, Wistar; Disease Models, Animal; Glycosylation; Metformin; Glycated Hemoglobin; NF-kappa B; Hexokinase; Catalase
PubMed: 38723008
DOI: 10.1371/journal.pone.0303060