scholarly journals Lactate promotes macrophage HMGB1 lactylation, acetylation, and exosomal release in polymicrobial sepsis

2021 ◽  
Author(s):  
Kun Yang ◽  
Min Fan ◽  
Xiaohui Wang ◽  
Jingjing Xu ◽  
Yana Wang ◽  
...  
Keyword(s):  
Lactate Production ◽  
High Mobility ◽  
Polymicrobial Sepsis ◽  
Extracellular Lactate ◽  
G Protein Coupled ◽  
Circulating Levels ◽  
Endothelium Permeability ◽  
Dependent Mechanism

AbstractHigh circulating levels of lactate and high mobility group box-1 (HMGB1) are associated with the severity and mortality of sepsis. However, it is unclear whether lactate could promote HMGB1 release during sepsis. The present study demonstrated a novel role of lactate in HMGB1 lactylation and acetylation in macrophages during polymicrobial sepsis. We found that macrophages can uptake extracellular lactate via monocarboxylate transporters (MCTs) to promote HMGB1 lactylation via a p300/CBP-dependent mechanism. We also observed that lactate stimulates HMGB1 acetylation by Hippo/YAP-mediated suppression of deacetylase SIRT1 and β-arrestin2-mediated recruitment of acetylases p300/CBP to the nucleus via G protein-coupled receptor 81 (GPR81). The lactylated/acetylated HMGB1 is released from macrophages via exosome secretion which increases endothelium permeability. In vivo reduction of lactate production and/or inhibition of GPR81-mediated signaling decreases circulating exosomal HMGB1 levels and improves survival outcome in polymicrobial sepsis. Our results provide the basis for targeting lactate/lactate-associated signaling to combat sepsis.

A Review on Melatonin’s Effects in Cancer: Potential Mechanisms

2018 ◽  
Vol 18 (7) ◽  
pp. 985-992 ◽  
Author(s):  
Aysegul Hanikoglu ◽  
Ertan Kucuksayan ◽  
Rana Cagla Akduman ◽  
Tomris Ozben
Keyword(s):  
Systematic Review ◽  
Antioxidant Activity ◽  
Membrane Receptors ◽  
Cancer Development ◽  
Secretory Product ◽  
Prevention And Treatment ◽  
G Protein Coupled

This systematic review aims to elucidate the role of melatonin (N-acetyl-5-metoxy-tryptamine) (MLT) in the prevention and treatment of cancer. MLT is a pineal gland secretory product, an evolutionarily highly conserved molecule; it is also an antioxidant and an impressive protector of mitochondrial bioenergetic activity. MLT is characterized by an ample range of activities, modulating the physiology and molecular biology of the cell. Its physiological functions relate principally to the interaction of G Protein-Coupled MT1 and MT2 trans-membrane receptors (GPCRs), a family of guanidine triphosphate binding proteins. MLT has been demonstrated to suppress the growth of various tumours both, in vivo and in vitro. In this review, we analyze in depth, the antioxidant activity of melatonin, aiming to illustrate the cancer treatment potential of the molecule, by limiting or reversing the changes occurring during cancer development and growth.

scholarly journals PAR-4/Ca2+-calpain pathway activation stimulates platelet-derived microparticles in hyperglycemic type 2 diabetes

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Alessandra Giannella ◽  
Giulio Ceolotto ◽  
Claudia Maria Radu ◽  
Arianna Cattelan ◽  
Elisabetta Iori ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Normal Glucose Tolerance ◽  
Calpain Inhibitor ◽  
Pathway Activation ◽  
Normal Glucose ◽  
Circulating Levels ◽  
Dependent Mechanism

Abstract Background Patients with type 2 diabetes (T2DM) have a prothrombotic state that needs to be fully clarified; microparticles (MPs) have emerged as mediators and markers of this condition. Thus, we investigate, in vivo, in T2DM either with good (HbA1c ≤ 7.0%; GGC) or poor (HbA1c > 7.0%; PGC) glycemic control, the circulating levels of MPs, and in vitro, the molecular pathways involved in the release of MPs from platelets (PMP) and tested their pro-inflammatory effects on THP-1 transformed macrophages. Methods In 59 T2DM, and 23 control subjects with normal glucose tolerance (NGT), circulating levels of CD62E+, CD62P+, CD142+, CD45+ MPs were determined by flow cytometry, while plasma levels of ICAM-1, VCAM-1, IL-6 by ELISA. In vitro, PMP release and activation of isolated platelets from GGC and PGC were investigated, along with their effect on IL-6 secretion in THP-1 transformed macrophages. Results We found that MPs CD62P+ (PMP) and CD142+ (tissue factor-bearing MP) were significantly higher in PGC T2DM than GGC T2DM and NGT. Among MPs, PMP were also correlated with HbA1c and IL-6. In vitro, we showed that acute thrombin exposure stimulated a significantly higher PMP release in PGC T2DM than GGC T2DM through a more robust activation of PAR-4 receptor than PAR-1 receptor. Treatment with PAR-4 agonist induced an increased release of PMP in PGC with a Ca2+-calpain dependent mechanism since this effect was blunted by calpain inhibitor. Finally, the uptake of PMP derived from PAR-4 treated PGC platelets into THP-1 transformed macrophages promoted a marked increase of IL-6 release compared to PMP derived from GGC through the activation of the NF-kB pathway. Conclusions These results identify PAR-4 as a mediator of platelet activation, microparticle release, and inflammation, in poorly controlled T2DM.

scholarly journals Blocking circ-CNST suppresses malignant behaviors of osteosarcoma cells and inhibits glycolysis through circ-CNST-miR-578-LDHA/PDK1 ceRNA networks

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Rui Hu ◽  
Shan Chen ◽  
Jianxin Yan
Keyword(s):  
Colony Formation ◽  
Lactate Production ◽  
Glucose Consumption ◽  
Pyruvate Dehydrogenase Kinase ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Physical Interaction ◽  
U2os Cells

Abstract Background CircRNA CNST (circ-CNST) is a newly identified biomarker for prognosis of osteosarcoma (OS). However, its role in OS progression remains to be well documented. Methods Expression of circ-CNST, microRNA (miR)-578, lactate dehydrogenase A (LDHA), and pyruvate dehydrogenase kinase 1 (PDK1) was detected by quantitative real-time polymerase chain reaction and Western blotting. The physical interaction was confirmed by dual-luciferase reporter assay. Cell behaviors and glycolysis were measured by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay, colony formation assay, flow cytometry, transwell assays, xenograft experiment, and commercial kits. Results Circ-CNST was upregulated in human OS tissues and cells, accompanied with downregulation of miR-578 and upregulation of LDHA and PDK1. There were negative correlations between miR-578 expression and circ-CNST or LDHA/PDK1 in OS tissues. Moreover, high circ-CNST/LDHA/PDK1 or low miR-578 might predict shorter overall survival, advanced TNM stages, and lymph node metastasis. Physically, miR-578 was targeted by circ-CNST, and miR-578 could target LDHA/PDK1. Functionally, blocking circ-CNST and restoring miR-578 enhanced apoptosis rate and suppressed cell proliferation, colony formation, migration, and invasion in 143B and U2OS cells, accompanied with decreased glucose consumption, lactate production, and adenosine triphosphate (ATP)/adenosine diphosphate (ADP) ratio. Furthermore, in vivo growth of U2OS cells was retarded by silencing circ-CNST. Depletion of miR-578 could counteract the suppressive role of circ-CNST deficiency in 143B and U2OS cells, and restoring LDHA or PDK1 partially reversed the role of miR-578 inhibition as well. Conclusion Circ-CNST knockdown could antagonize malignant behaviors and glycolysis of OS cells by regulating miR-578-LDHA/PDK1 axes.

scholarly journals Hyperinsulinemia, But Not Other Factors Associated with Insulin Resistance, Acutely Enhances Colorectal Epithelial Proliferation in Vivo

Endocrinology ◽  
2006 ◽  
Vol 147 (4) ◽  
pp. 1830-1837 ◽  
Author(s):  
Thien T. Tran ◽  
Dinaz Naigamwalla ◽  
Andrei I. Oprescu ◽  
Loretta Lam ◽  
Gail McKeown-Eyssen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Epithelial Cells ◽  
Dependent Manner ◽  
Epithelial Proliferation ◽  
Euglycemic Clamp ◽  
The Individual ◽  
Dose Dependent ◽  
Circulating Levels

The similarity in risk factors for insulin resistance and colorectal cancer (CRC) led to the hypothesis that markers of insulin resistance, such as elevated circulating levels of insulin, glucose, fatty acids, and triglycerides, are energy sources and growth factors in the development of CRC. The objective was thus to examine the individual and combined effects of these circulating factors on colorectal epithelial proliferation in vivo. Rats were fasted overnight, randomized to six groups, infused iv with insulin, glucose, and/or Intralipid for 10 h, and assessed for 5-bromo-2-deoxyuridine labeling of replicating DNA in colorectal epithelial cells. Intravenous infusion of insulin, during a 10-h euglycemic clamp, increased colorectal epithelial proliferation in a dose-dependent manner. The addition of hyperglycemia to hyperinsulinemia did not further increase proliferation. Intralipid infusion alone did not affect proliferation; however, the combination of insulin, glucose, and Intralipid infusion resulted in greater hyperinsulinemia than the infusion of insulin alone and further increased proliferation. Insulin infusion during a 10-h euglycemic clamp decreased total IGF-I levels and did not affect insulin sensitivity. These results provide evidence for an acute role of insulin, at levels observed in insulin resistance, in the proliferation of colorectal epithelial cells in vivo.

scholarly journals The P2Y6 Receptor Stimulates Bone Resorption by Osteoclasts

Endocrinology ◽  
2011 ◽  
Vol 152 (10) ◽  
pp. 3706-3716 ◽  
Author(s):  
Isabel R. Orriss ◽  
Ning Wang ◽  
Geoffrey Burnstock ◽  
Timothy R. Arnett ◽  
Alison Gartland ◽  
...  
Keyword(s):  
Cell Function ◽  
Bone Cell ◽  
Extracellular Nucleotides ◽  
P2y6 Receptor ◽  
Tomographic Analysis ◽  
G Protein Coupled ◽  
Resorptive Activity

Accumulating evidence indicates that extracellular nucleotides, signaling through P2 receptors, play a significant role in bone remodeling. Osteoclasts (the bone-resorbing cell) and osteoblasts (the bone-forming cell) display expression of the G protein-coupled P2Y6 receptor, but the role of this receptor in modulating cell function is unclear. Here, we demonstrate that extracellular UDP, acting via P2Y6 receptors, stimulates the formation of osteoclasts from precursor cells, while also enhancing the resorptive activity of mature osteoclasts. Furthermore, osteoclasts derived from P2Y6 receptor-deficient (P2Y6R−/−) animals displayed defective function in vitro. Using dual energy x-ray absorptiometry scanning and microcomputed tomographic analysis we showed that P2Y6R−/− mice have increased bone mineral content, cortical bone volume, and cortical thickness in the long bones and spine, whereas trabecular bone parameters were unaffected. Histomorphometric analysis showed the perimeter of the bone occupied by osteoclasts on the endocortical and trabecular surfaces was decreased in P2Y6R−/− mice. Taken together these results show the P2Y6 receptor may play an important role in the regulation of bone cell function in vivo.

scholarly journals Lactate Dehydrogenase Is the Key Enzyme for Pneumococcal Pyruvate Metabolism and Pneumococcal Survival in Blood

2014 ◽  
Vol 82 (12) ◽  
pp. 5099-5109 ◽  
Author(s):  
Paula Gaspar ◽  
Firas A. Y. Al-Bayati ◽  
Peter W. Andrew ◽  
Ana Rute Neves ◽  
Hasan Yesilkaya
Keyword(s):  
Lactate Dehydrogenase ◽  
Lactate Production ◽  
Virulence Gene ◽  
Redox Balance ◽  
Central Metabolism ◽  
Content Type ◽  
Virulence Gene Expression ◽  
Key Enzyme

ABSTRACTStreptococcus pneumoniaeis a fermentative microorganism and causes serious diseases in humans, including otitis media, bacteremia, meningitis, and pneumonia. However, the mechanisms enabling pneumococcal survival in the host and causing disease in different tissues are incompletely understood. The available evidence indicates a strong link between the central metabolism and pneumococcal virulence. To further our knowledge on pneumococcal virulence, we investigated the role of lactate dehydrogenase (LDH), which converts pyruvate to lactate and is an essential enzyme for redox balance, in the pneumococcal central metabolism and virulence using an isogenicldhmutant. Loss of LDH led to a dramatic reduction of the growth rate, pinpointing the key role of this enzyme in fermentative metabolism. The pattern of end products was altered, and lactate production was totally blocked. The fermentation profile was confirmed byin vivonuclear magnetic resonance (NMR) measurements of glucose metabolism in nongrowing cell suspensions of theldhmutant. In this strain, a bottleneck in the fermentative steps is evident from the accumulation of pyruvate, revealing LDH as the most efficient enzyme in pyruvate conversion. An increase in ethanol production was also observed, indicating that in the absence of LDH the redox balance is maintained through alcohol dehydrogenase activity. We also found that the absence of LDH renders the pneumococci avirulent after intravenous infection and leads to a significant reduction in virulence in a model of pneumonia that develops after intranasal infection, likely due to a decrease in energy generation and virulence gene expression.

scholarly journals Long noncoding RNA XIST suppresses tumorigenesis and enhances radiosensitivity in neuroblastoma cells through regulating miR-653-5p/HK2 axis

2020 ◽  
Author(s):  
Liping Mu ◽  
Lili Wang ◽  
Shaoming Zhang ◽  
Qinghua Wang
Keyword(s):  
Colony Formation ◽  
Noncoding Rna ◽  
Neuroblastoma Cells ◽  
Lactate Production ◽  
Xenograft Model ◽  
Glucose Consumption ◽  
Luciferase Reporter ◽  
Glucose Assay

Abstract Background: Abnormal expression of long noncoding RNAs (lncRNAs) was usually involved in tumorigenesis and radiosensitivity of various cancers. The aim of this study was to explore the biological function and regulatory mechanism of lncRNA X-inactive specific transcript (XIST) in tumorigenesis and radiosensitivity of neuroblastoma (NB).Methods: The expression levels of XIST, microRNA-653-5p (miR-653-5p) and hexokinase 2 (HK2) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Methylthiazolyldiphenyl tetrazolium bromide (MTT) assay, colony formation assay and transwell assay were utilized to detect cell viability, colony formation and cell invasion abilities. Glucose consumption or lactate production was measured by glucose assay kit or lactate assay kit, respectively. The mice xenograft model was established to investigate the role of XIST in vivo. The interaction between miR-653-5p and XIST or HK2 was predicted by starBase v2.0 and verified by dual-luciferase reporter assay. Western blot was used to measure the protein expression of HK2.Results: XIST and HK2 were highly expressed whilst miR-653-5p was lowly expressed in NB tissues and cells. XIST knockdown inhibited tumorigenesis by repressing NB cell proliferation and invasion. Meanwhile, XIST downregulation increased the radiosensitivity via inhibiting colony formation rates and glycolysis. Moreover, miR-653-5p could bind to XIST and its downregulation reversed the effects of XIST knockdown on tumorigenesis and radiosensitivity. Additionally, HK2 was a direct target of miR-653-5p and its overexpression attenuated the effects of miR-653-5p restoration on suppression of tumorigenesis and promotion of radiosensitivity. Besides, XIST functioned as a molecular sponge of miR-653-5p to regulate HK2 expression. Furthermore, XIST knockdown also suppressed tumor growth by upregulating miR-653-5p and downregulating HK2 in vivo.Conclusion: XIST interference inhibited tumorigenesis and increased radiosensitivity in NB by regulating miR-653-5p/HK2 axis, providing a novel therapeutic strategy for NB.

C5a-induced myocardial ischemia: role for CD18-dependent PMN localization and PMN-platelet interactions

1993 ◽  
Vol 265 (5) ◽  
pp. H1750-H1761 ◽  
Author(s):  
M. P. Fletcher ◽  
G. L. Stahl ◽  
J. C. Longhurst
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Myocardial Ischemia ◽  
Myocardial Segment ◽  
Artery Blood Flow ◽  
Arterial Blood ◽  
Pmn Functions ◽  
Dependent Mechanism

Intracoronary C5a in swine decreases coronary blood flow and regional myocardial segment shortening, responses mediated by thromboxane (Tx) A2-induced coronary vasoconstriction and intramyocardial trapping of granulocytes (PMNs). We sought to determine the origin of TxA2 and to investigate the role of CD18-dependent PMN function by utilizing an anti-CD18 monoclonal antibody, IB4. Isolated C5a-stimulated PMNs or platelets did not produce TxB2. However, together, C5a-stimulated PMNs and platelets produced TxB2. IB4 bound porcine PMN surface CD18 and blocked C5a-induced PMN functions. In vivo, IB4 loading (2 mg/kg) transiently decreased arterial blood pressure and circulating platelet counts in six of nine animals (390 +/- 31 vs. 176 +/- 41 X 10(6)/ml, control vs. IB4; P < 0.002) and significantly ameliorated C5a-induced decreases in coronary venous PMN count (-4.1 +/- 0.6 vs. -1.4 +/- 0.8 X 10(6) cells/ml), coronary artery blood flow (-10 +/- 1 vs. -4 +/- 1 ml/min), and segment shortening (-15 +/- 2 vs. -8 +/- 2%, C5a vs. C5a + IB4). We conclude that 1) production of TxB2 in response to C5a is mediated by a PMN-platelet interaction, 2) IB4 functionally blocks CD18 on porcine PMNs, and 3) C5a-induced myocardial PMN extraction is mediated, in part, by a CD18-dependent mechanism. These results suggest that PMN-platelet interactions and CD18-dependent PMN extraction are important in C5a-induced myocardial ischemia.

scholarly journals Knockdown of LINC01694 inhibits growth of gallbladder cancer cells via miR-340-5p/Sox4

2020 ◽  
Vol 40 (4) ◽  
Author(s):  
Lei Liu ◽  
Yuexiang Yan ◽  
Guanyu Zhang ◽  
Chengxue Chen ◽  
Weihong Shen ◽  
...  
Keyword(s):  
Gallbladder Cancer ◽  
High Mobility ◽  
Tumor Formation ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Normal Tissues ◽  
Qrt Pcr ◽  
Rna Immunoprecipitation

Abstract Purpose: The indispensable role of long non-coding RNAs (lncRNAs) in tumorigenesis has been increasingly reported. In the present study, LINC01694 was found to regulate the proliferation, invasion, as well as apoptosis in gallbladder cancer (GBC) cells through sponging miR-340-5p. Methods: LINC01694 level in GBC cells was quantified by quantitative real-time polymerase chain reaction (qRT-PCR). The proliferation, invasion, and apoptosis were determined by Cell Counting Kit-8 (CCK-8), Transwell, and flow cytometry, respectively. The expression of Sry-related high-mobility group box 4 (Sox4) was detected by Western blot (WB). The interaction between LINC01694 and miR-340-5p was measured by dual-luciferase reporter (DLR) assay, RNA immunoprecipitation (RIP) test, and RNA pull-down. Tumor formation was examined by in vivo experiment. Results: qRT-PCR illustrated that cancerous tissues had higher LINC01694 than normal tissues. Survival analysis demonstrated that the prognosis of patients with high LINC01694 was significantly poorer than those with low LINC01694. Down-regulation of LINC01694 slowed down the proliferation and invasion in GBC cells and accelerated the apoptosis. DLR assay indicated that LINC01694 elevated Sox4 expression by regulating miR-340-5p. LINC01694 functioned as miR-340-5p sponge to inhibit Sox4 expression. Conclusion: LINC01694 level is elevated in GBC by regulating miR-340-5p/Sox4 axis, which indicates the poor prognosis of the patients.

Role of LPXRFamide peptide in the neuroendocrine regulation of reproduction in fish

2011 ◽  
Vol 6 (5) ◽  
pp. 853-860 ◽  
Author(s):  
Md. Shahjahan ◽  
Hironori Ando
Keyword(s):  
Gonadal Development ◽  
Gonadotropin Releasing Hormone ◽  
Fish Reproduction ◽  
Lower Vertebrates ◽  
Hypothalamic Control ◽  
G Protein Coupled ◽  
Made In

AbstractThe decapeptide gonadotropin-releasing hormone (GnRH) is the primary factor responsible for the hypothalamic control of gonadotropin (GTH) secretion. This review focuses on a family of neuropeptides, LPXRFamide (LPXRFa) peptides, which have been implicated in the regulation of GTH secretion. LPXRFa acts on the pituitary via a G protein-coupled receptor, LPXRFa-R, to enhance gonadal development and maintenance by increasing gonadotropin release and synthesis. Because LPXRFa exists and functions in several fish species, LPXRFa is considered to be a key neurohormone in fish reproduction control. The precursors to LPXRFamide peptides encoded plural LPXRFamide peptides and were highly divergent in vertebrates, particularly in lower vertebrates. Tissue distribution analyses indicated that LPXRFamide peptides were highly concentrated in the hypothalamus and other brainstem regions. In view of the localization and expression of LPXRFamide peptides in the hypothalamo-hypophysial system, LPXRFamide peptide in fish increase GTH release in vitro and in vivo. This review summarizes the advances made in our understanding of the biosynthesis, mode of action and functional significance of LPXRFa, a newly discovered key neurohormone.

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