Deoxyribenucleoside triphosphate (dNTP) pools were measured in normal BALB/c3T3 cells, transformation-treated cells and transformed cells with reverse-phase HPLC. The fluctuation of dNTP pools was similar after transf...Deoxyribenucleoside triphosphate (dNTP) pools were measured in normal BALB/c3T3 cells, transformation-treated cells and transformed cells with reverse-phase HPLC. The fluctuation of dNTP pools was similar after transformation treatment with alkylating mutagen glycidyl methacrylate(GMA) or Nmethyl- N'- nitro N- nitrosoguanidine (MNNG ). However,the gap between deoxyguanosine triphosphate + deoxyadenosine triphosphate (dGTP + dATP) pools and deoxythymidine triphosphate + deoxycytidine triphosphate (dTTP + dCTP) pools was greatly intensified. The measurements also indicated that the dNTP pools in transformed cells were quite different from those in normal cells. The results suggested that dNTP pools may play an important role in cell transformation展开更多
The design and development of selective recognition and sensing systems for biologically important nucleoside triphosphates(NTPs)have attracted significant attention in recent years,owing to their critical roles in ce...The design and development of selective recognition and sensing systems for biologically important nucleoside triphosphates(NTPs)have attracted significant attention in recent years,owing to their critical roles in cellular processes.In this study,we report the synthesis of two tetraphenylethene-based tetraimidazolium cyclophanes(1 and 2)through a one-step S_(N)2 reaction.These cyclophanes are capable of recognizing NTPs by forming stable 1:1 host-vip complexes in aqueous solution.Of particular interest,cyclophane 1 demonstrates exceptional selectivity for guanosine triphosphate(GTP),distinguishing it from other nucleoside triphosphates such as ATP,CTP,and UTP.This selective recognition is accompanied by distinct and measurable fluorescence responses,which are significantly enhanced upon binding to GTp,enabling the potential for sensitive detection.This study highlights the potential of tetraphenylethene-based tetraimidazolium cyclophanes as a highly selective and sensitive sensor for GTP,offering new insights into the design of molecular systems for the recognition of biologically relevant nucleotides.展开更多
Modified deoxy-and ribo-nucleoside triphosphates are chemically synthesized in multiple steps due to the protection and deprotection of the nucleoside functionalities.To conveniently synthesize the S-modified triphosp...Modified deoxy-and ribo-nucleoside triphosphates are chemically synthesized in multiple steps due to the protection and deprotection of the nucleoside functionalities.To conveniently synthesize the S-modified triphosphates for enzymatically preparing phosphorothioate DNAs and RNAs(PS-DNA and PS-RNA) as potential therapeutics,herein we report a one-pot strategy to synthesize the deoxy-and ribo-nucleoside 5'-(α-P-thio)triphosphates(dNTPαS and NTPαS) without protecting any nucleoside functionalities.This facile synthesis is achieved by treating the nucleosides with a mild phosphitylating reagent,reacting selectively with the 5'-hydroxyl group of each unprotected nucleoside,followed by sulfurization and hydrolysis to afford the crude dNTPαS and NTPαS analogs(mixtures of Sp and Rp diastereomers).We also demonstrated that after just simple precipitation(without HPLC and ion-exchange purification),the quality of the synthesized dNTPαS and NTPαS analogs is excellent for direct DNA polymerization and RNA transcription,respectively.Since Klenow DNA polymerase and T7 RNA polymerase accept the Sp diastereomers of dNTPαS and NTPαS analogs,respectively,while the Rp diastereomers are neither substrates nor inhibitors,the diastereomerically-pure PS-DNAs and PS-RNAs can be conveniently synthesized enzymatically.展开更多
Background Intestinal inflammation is an energy-consuming process that may alter energy supply and demand in poultry.During inflammation,the intestinal energy metabolic profile and the patterns of energy partitioning ...Background Intestinal inflammation is an energy-consuming process that may alter energy supply and demand in poultry.During inflammation,the intestinal energy metabolic profile and the patterns of energy partitioning remain unclear.This study investigated the effects of intestinal inflammation on energy intake,heat production(HP),retained energy(RE)and intestinal energy metabolites in layer pullets.Methods After 7 d dietary adaption,32“Jing Tint 6”layer pullets with average body weight(1,123.50±8.55 g)were selected from 96 birds,and randomly assigned to two groups(CON:Control group,INFL:Inflammation group)with 8 replicates per group.Indirect calorimetry analysis was conducted over 7 d to determine HP and fasting HP(FHP).During this period,pullets in INFL group received 4 mL/d of 0.6 g/mL dextran sulfate sodium(DSS)via oral gavage to induce intestinal inflammation.After the calorimetry,intestinal tissues were collected post-euthanasia from one bird per replicate for morphological and mucosal metabolomic analysis.Results Birds exhibited significantly lower apparent metabolizable energy(AME)intake(P<0.001)during intestinal inflammation,accompanied by compromised RE and RE as fat(P<0.001),suggesting that birds consumed body energy to sustain energy demands.Targeted metabolomic studies identified 11 energy metabolites differentially expressed in ileal mucosa between CON and INFL groups.Specifically,DSS induction significantly increased(P<0.05)adenosine triphosphate(ATP)level and reduced(P<0.001)nicotinamide adenine dinucleotide(NAD^(+))level in ileal mucosa of pullets.In parallel,metabolic adaptations such as enhanced glycolytic intermediates,reduced amino acids,α-ketoglutarate(α-KG)accumulation and suppressed expression of genes encoding enzymes involved in tricarboxylic acid(TCA)cycle were observed in the inflamed ileum of pullets.Conclusion Immune stimulation by DSS induced a negative energy balance in layer pullets,characterized by reduced AME intake(-190.47 kJ/kg BW^(0.75))and compromised RE(-18.81%of AME intake).Disruption of intestinal energy profiling was observed in inflammation-challenged pullets,such as accumulation ofα-KG and ATP,reduced NAD^(+)and amino acids,which could provide valuable insights for developing effective intervention strategies.展开更多
AIM:To investigate the effects of adenosine triphosphate(ATP)and melatonin,which have antioxidant and antiinflammatory activities,on potential 5-fluorouracil(5-FU)-induced optic nerve damage in rats.METHODS:Twenty-fou...AIM:To investigate the effects of adenosine triphosphate(ATP)and melatonin,which have antioxidant and antiinflammatory activities,on potential 5-fluorouracil(5-FU)-induced optic nerve damage in rats.METHODS:Twenty-four rats were categorized into four groups of six rats:healthy(HG),5-FU(FUG),ATP+5-FU(AFU),and melatonin+5-FU(MFU).ATP(4 mg/kg)and melatonin(10 mg/kg)were administered intraperitoneally and orally,respectively.One hour after ATP and melatonin administration,rats in the AFU,MFU,and FUG were intraperitoneally injected with 5-FU(100 mg/kg).ATP and melatonin were administered once daily for 10d.5-FU was administered at a single dose on days 1,3,and 5 of the experiment.After 10d,the rats were euthanized and optic nerve tissues were extracted.Optic nerve tissues were biochemically and histopathologically examined.RESULTS:ATP and melatonin treatments inhibited the increase in malondialdehyde(MDA)and interleukin-6(IL-6)levels,which were elevated in the FUG.The treatments also prevented the decrease in total glutathione(tGSH)levels and the superoxide dismutase(SOD)and catalase(CAT)activities(P<0.001).This inhibition was higher in the ATP group than in the melatonin group(P<0.001).ATP prevented histopathological damage better than melatonin(P<0.05).CONCLUSION:ATP and melatonin have the potential to be used in alleviating 5-FU-induced optic nerve damage.In addition,ATP treatment shows better protective effects than melatonin.展开更多
BACKGROUND Ectonucleoside triphosphate diphosphohydrolase 6(ENTPD6),a member of the ENTPD family,has been implicated in certain cancers,yet a comprehensive analysis across multiple cancer types remains lacking.AIM To ...BACKGROUND Ectonucleoside triphosphate diphosphohydrolase 6(ENTPD6),a member of the ENTPD family,has been implicated in certain cancers,yet a comprehensive analysis across multiple cancer types remains lacking.AIM To systematically evaluate ENTPD6’s expression,prognostic significance,and functions across multiple cancer types.METHODS In this study,we performed a pan-cancer analysis to investigate the correlation between ENTPD6 expression and various factors,including prognosis,genetic alterations,epigenetic modification,immune infiltration,immunotherapy responses,functional enrichment,and drug sensitivity.A tissue microarray of gastrointestinal tumors was used to validate differential ENTPD6 protein expression.RESULTS Pan-cancer analysis revealed that ENTPD6 expression was significantly elevated in many cancers.Immunohistochemistry staining analysis revealed that ENTPD6 expression was significantly higher in esophageal carcinoma,stomach adenocarcinoma,colon adenocarcinoma,rectal adenocarcinoma,and pancreatic adenocarcinoma compared to normal tissues.Furthermore,ENTPD6 expression was strongly associated with immune-infiltrating cells,particularly clusters of differentiation 8+T cells and natural killer cells,and correlated with immune-related genomic features including tumor mutational burden and microsatellite instability.Pathway analysis indicated that ENTPD6 expression was primarily linked to purine and pyrimidine metabolism pathways.Drug sensitivity analysis revealed that high ENTPD6 expression was sensitive to RDEA119,selumetinib,and PD-0325901.CONCLUSION This pan-cancer study elucidates the pivotal role of ENTPD6 in tumor progression and establishes its potential as a therapeutic target for immunotherapeutic approaches in specific malignancies.展开更多
Pamiparib is a potent and selective oral poly(adenosine diphosphate(ADP)-ribose)-polymerase(PARP)1/2inhibitor(PARPi).Pamiparib has good bioavailability and shows greater cytotoxic potency and similar DNA-trapping capa...Pamiparib is a potent and selective oral poly(adenosine diphosphate(ADP)-ribose)-polymerase(PARP)1/2inhibitor(PARPi).Pamiparib has good bioavailability and shows greater cytotoxic potency and similar DNA-trapping capacity compared to olaparib.It is not affected by adenosine triphosphate(ATP)-binding cassette transporters.展开更多
BACKGROUND Metabolic dysregulation is considered a significant hallmark of hepatocellular carcinoma(HCC).SAC3 domain containing 1(SAC3D1)functions in the cell cycle,and its expression is upregulated in various cancers...BACKGROUND Metabolic dysregulation is considered a significant hallmark of hepatocellular carcinoma(HCC).SAC3 domain containing 1(SAC3D1)functions in the cell cycle,and its expression is upregulated in various cancers.It is known that metabolic changes occur at different stages of the cell cycle to maintain the biosynthesis and replication of both normal and cancer cells.Based on the role of SAC3D1 in mitosis,we hypothesize that abnormal expression of SAC3D1 may affect cellular metabolism.However,it remains unclear whether SAC3D1 mediates the progression of HCC by regulating metabolic reprogramming.AIM To comprehensively elucidate the impact and molecular mechanism of SAC3D1 on the progression of HCC by regulating the metabolic reprogramming.METHODS The constructed SAC3D1 overexpression and knockdown HCC cell lines were used for detecting cell proliferation,migration capabilities,as well as glycolysis and adenosine triphosphate(ATP)production rate assays.They were also employed for examining molecular markers associated with cell migration and glycolysis.The transcriptome sequencing data of cells have revealed the pathways potentially influenced by SAC3D1.The tail vein metastasis model and xenograft tumor experiments were utilized to demonstrate SAC3D1’s tumor-promoting effects in vivo.RESULTS SAC3D1 expression was upregulated and associated with poor prognosis in HCC patients.SAC3D1 enhanced the proliferation and migration abilities and reduced the population dependence of HCC cells in vitro and in vivo.The upregulation of SAC3D1 enhanced cellular glycolysis and ATP production.The cell transcriptome sequencing data revealed that SAC3D1 activated Wnt signaling pathway.SAC3D1 did not modulate the transcription ofβ-Catenin,while might inhibit its degradation.Further investigations indicated that the increase of SAC3D1 leads to moreβ-Catenin accumulating in the nucleus,facilitating the expression of c-Myc,one of the upstream regulatory factors of glycolysis.The iCRT3,an antagonist ofβ-Catenin,could counteract the increase of c-Myc induced by SAC3D1,while also downregulating the expression of glycolysis-related proteins.CONCLUSION This study found that SAC3D1 enhances HCC cell glycolysis and ATP production via theβ-Catenin/c-Myc signaling axis,thereby promoting the progression of HCC.展开更多
Recent increases in infectious diseases affecting the central nervous system have raised concerns about their role in neuroinflammation and neurodegeneration.Viral pathogens or their products can invade the central ne...Recent increases in infectious diseases affecting the central nervous system have raised concerns about their role in neuroinflammation and neurodegeneration.Viral pathogens or their products can invade the central nervous system and cause damage,leading to meningitis,encephalitis,meningoencephalitis,myelitis,or post-infectious demyelinating diseases.Although neuroinflammation initially has a protective function,chronic inflammation can contribute to the development of neurodegenerative diseases.Mechanisms such as protein aggregation and cellular disturbances are implicated with specific viruses such as herpes simplex virus type 1 and Epstein-Barr virus being associated with Alzheimer's disease and multiple sclerosis,respectively.Extracellular nucleotides,particularly adenosine triphosphate and its metabolites are released from activated,infected,and dying cells,acting as alarmins mediating neuroinflammation and neurodegeneration.When viruses infect central nervous system cells,adenosine triphosphate is released as an alarmin,triggering inflammatory responses.This process is mediated by purinergic receptors,divided into two families:P1,which responds to adenosine,and P2,activated by adenosine triphosphate and other nucleotides.This review highlights how specific viruses,such as human immunodeficiency virus type 1,Theiler's murine encephalomyelitis virus,herpes simplex virus type 1,Epstein-Barr virus,dengue virus,Zika virus,and severe acute respiratory syndrome coronavirus 2,can initiate inflammatory responses through the release of extracellular nucleotides,particularly adenosine triphosphate,which act as critical mediators in the progression of neuroinflammation and neurodegenerative disorders.A better understanding of purinergic signaling pathways in these diseases may suggest new potential therapeutic strategies for targeting neuroinflammation to mitigate the long-term consequences of viral infections in the central nervous system.展开更多
BACKGROUND Mixed lineage kinase domain-like protein(MLKL)serves as a critical mediator in necroptosis,a form of regulated cell death linked to various liver diseases.This study aims to specifically investigate the rol...BACKGROUND Mixed lineage kinase domain-like protein(MLKL)serves as a critical mediator in necroptosis,a form of regulated cell death linked to various liver diseases.This study aims to specifically investigate the role of MLKL’s adenosine triphosphate(ATP)-binding pocket in facilitating necroptosis-independent pathways that may contribute to liver disease progression.By focusing on this mechanism,we seek to identify potential therapeutic targets that can modulate MLKL activity,offering new strategies for the prevention and treatment of liver-related pathologies.AIM To investigate the possibility of using the ATP-binding pocket-associated,necro-ptosis-independent MLKL pathway as a target for liver diseases.METHODS Cell death following necroptosis stimuli was evaluated using cell proliferation assays,flow cytometry,and electron microscopy in various cells.The human liver organoid system was used to evaluate whether the MLKL ATP pocket-binding inhibitor could attenuate inflammation.Additionally,alcoholic and non-alcoholic fatty liver diseases animal models were used to determine whether MLKL ATP pocket inhibitors could attenuate liver injury.RESULTS While an MLKL ATP pocket-binding inhibitor did not prevent necroptosis-induced cell death in RAW 264.7 cells,it did reduce the necroptosis-led expression of CXCL2,ICAM,and VCAM.Notably,MLKL ATP pocket inhibitor diminishes the expression of CXCL2,ICAM,and VCAM by inhibiting the IκB kinase and nuclear factor kappa-B pathways without inducing necroptosis-induced cell death in two-dimensional cell culture as well as the human-derived liver organoid system.Although MLKL ATP-binding inhibitor was ineffective in non-alcoholic fatty liver disease animal models,MLKL ATP-binding inhibitor attenuated hepatic inflammation in the alcoholic liver disease model.CONCLUSION MLKL ATP pocket-binding inhibitor exerted anti-inflammatory effects through the necroptosis-independent MLKL pathway in an animal model of alcoholic liver disease.展开更多
Background:Extracellular adenosine triphosphate(ATP)is an important signal molecule.In previous studies,intensive research had revealed the crucial roles of family with sequence similarity 3 member A(FAM3A)in controll...Background:Extracellular adenosine triphosphate(ATP)is an important signal molecule.In previous studies,intensive research had revealed the crucial roles of family with sequence similarity 3 member A(FAM3A)in controlling hepatic glucolipid metabolism,isletβcell function,adipocyte differentiation,blood pressure,and other biological and pathophysiological processes.Although mitochondrial protein FAM3A plays crucial roles in the regulation of glucolipid metabolism via stimulating ATP release to activate P2 receptor pathways,its mechanism in promoting ATP release in hepatocytes remains unrevealed.Methods:db/db,high-fat diet(HFD)-fed,and global pannexin 1(PANX1)knockout mice,as well as liver sections of individuals,were used in this study.Adenoviruses and adeno-associated viruses were utilized for in vivo gene overexpression or inhibition.To evaluate the metabolic status in mice,oral glucose tolerance test(OGTT),pyruvate tolerance test(PTT),insulin tolerance test(ITT),and magnetic resonance imaging(MRI)were conducted.Protein-protein interactions were determined by coimmunoprecipitation with mass spectrometry(MS)assays.Results:In livers of individuals and mice with steatosis,the expression of ATP-permeable channel PANX1 was increased(P<0.01).Hepatic PANX1 overexpression ameliorated the dysregulated glucolipid metabolism in obese mice.Mice with hepatic PANX1 knockdown or global PANX1 knockout exhibited disturbed glucolipid metabolism.Restoration of hepatic PANX1 rescued the metabolic disorders of PANX1-deficient mice(P<0.05).Mechanistically,ATP release is mediated by the PANX1-activated protein kinase B-forkhead box protein O1(Akt-FOXO1)pathway to inhibit gluconeogenesis via P2Y receptors in hepatocytes.PANX1-mediated ATP release also activated calmodulin(CaM)(P<0.01),which interacted with c-Jun N-terminal kinase(JNK)to inhibit its activity,thereby deactivating the transcription factor activator protein-1(AP1)and repressing fatty acid synthase(FAS)expression and lipid synthesis(P<0.05).FAM3A stimulated the expression of PANX1 via heat shock factor 1(HSF1)in hepatocytes(P<0.05).Notably,FAM3A overexpression failed to promote ATP release,inhibit the expression of gluconeogenic and lipogenic genes,and suppress gluconeogenesis and lipid deposition in PANX1-deficient hepatocytes and livers.Conclusions:PANX1-mediated release of ATP plays a crucial role in maintaining hepatic glucolipid homeostasis,and it confers FAM3A’s suppressive effects on hepatic gluconeogenesis and lipogenesis.展开更多
OBJECTIVE:To investigate the mechanisms behind the effects of acupuncture in Traditional Chinese Medicine,we delved into the adenosine triphosphate/peripheral purinergic P2X receptor 3(ATP/P2X3)receptor signaling syst...OBJECTIVE:To investigate the mechanisms behind the effects of acupuncture in Traditional Chinese Medicine,we delved into the adenosine triphosphate/peripheral purinergic P2X receptor 3(ATP/P2X3)receptor signaling system as an indicator of the body's energy state,commonly referred to as"Qi".METHODS:The tail-flick test was utilized to explore the impact of acupuncture on pain tolerance threshold(PTT)in mice,while also assessing adenosine(ADO)levels and adenylate energy charge(EC)at Zusanli(ST36).The study further investigated the dose-dependent effects of acupuncture on PTT and ADO levels at Zusanli(ST36).To shed light on the underlying mechanisms of acupuncture's effects,the study examined the impact of ATP,a P2X3 receptor antagonist,and adenosine disodium on PTT following acupuncture administration.RESULTS:Acupuncture at Zusanli(ST36)led to significant improvements in PTT in mice,with the most effective interventions being twirling for 2 min and needle retention for 28 min.These interventions also resulted in significant increases in ATP levels.The effects of acupuncture were further augmented by administration of different doses of ATP at Zusanli(ST36),and pretreatment with a P2X3 receptor antagonist decreased PTT.Adenylate EC peaked at 30 min after intraperitoneal injection of ATP,and pretreatment with various doses of i.p.ATP 30 min prior to acupuncture increased PTT in a dose-dependent manner.Additionally,pretreatment with an i.p.or intramuscular injection of adenosine disodium enhanced the effects of acupuncture.CONCLUSION:This research provides compelling evidence that ATP is involved in the regulation of PTT through acupuncture,revealing new avenues for achieving enhanced clinical outcomes.展开更多
The maintenance of intracellular and extracellular adenosine triphosphate(ATP)levels plays a pivotal role in cardiac function.In recent years,burgeoning at-tention has been directed towards ATP-induced cell death(AICD...The maintenance of intracellular and extracellular adenosine triphosphate(ATP)levels plays a pivotal role in cardiac function.In recent years,burgeoning at-tention has been directed towards ATP-induced cell death(AICD),revealing it as a distinct cellular demise pathway triggered by heightened extracellular ATP concentrations,distinguishing it from other forms of cell death such as apoptosis and necrosis.AICD is increasingly acknowledged as a critical mechanism me-diating the pathogenesis and progression of various cardiovascular maladies,encompassing myocardial ischemia-reperfusion injury,sepsis-induced cardiomy-opathy,hypertrophic cardiomyopathy,arrhythmia,and diabetic cardiomyopathy.Consequently,a comprehensive understanding of the molecular and metabolic underpinnings of AICD in cardiac tissue holds promise for the prevention and amelioration of cardiovascular diseases.This review first elucidates the vital physiological roles of ATP in the cardiovascular system,subsequently delving into the intricate molecular mechanisms and metabolic signatures governing AICD.Furthermore,it addresses the potential therapeutic targets implicated in mitigating AICD for treating cardiovascular diseases,while also delineating the current constraints and future avenues for these innovative therapeutic targets,thereby furnishing novel insights and strategies for the prevention and management of cardiovascular disorders.展开更多
Adenosine triphosphate(ATP),known as a common metabolic product in organism,is not only importance to provide energy in various cellular activities but also is widely explored in the bio-inspired synthetic supramolecu...Adenosine triphosphate(ATP),known as a common metabolic product in organism,is not only importance to provide energy in various cellular activities but also is widely explored in the bio-inspired synthetic supramolecular area which becomes a fascinating topic with the rapid development of biology,chemistry and materials science.In this review,the recent advances about ATP interacted with functional small organic compounds and metal coordinated complexes are summarized.The design principles,its function as an active supramolecular matrix,the associated non-covalent binding modes and assembly induced properties including the optical properties,morphologies are presented in details.Besides,their applications for metal ion detecting,enzyme activity monitoring and drug delivery are described due to their excellently dynamic assembly properties,adjustability,and response to stimuli.Finally,an overview of the existing challenges and future prospects of ATP-induced supramolecular systems are also discussed.展开更多
A distinctive feature of phosphates is their special and significant ability to form inorganic polymeric compounds---condensed phosphates, which are destined to play a considerable role in our ＂high-tech＂ society in...A distinctive feature of phosphates is their special and significant ability to form inorganic polymeric compounds---condensed phosphates, which are destined to play a considerable role in our ＂high-tech＂ society in the future. Numerous olygophosphates, polyphosphates, double condensed phosphates and cyclophosphates with diverse formula, such as double tetra-, octa- and dodecaphosphates were obtained and described by us last years. The offered data are the outcomes of our scientific researches： of synthesis, analysis, and estimation of results in correlation with new achievements in inorganic polymer＇s chemistry. Many double condensed compounds, containing monovalent metals are obtained by us during systematic investigation of polycomponent systems, containing mono- and trivalent metals at temperature range 100-600 ~C. Synthesised condensed phosphates, in fact--inorganic polymers were examined in detail by chemical and thermogravimetric analysis, most compounds were examined by paper chromatography and the structures are determined by X-ray structural techniques/diffraction analysis. During our fundamental researches numerous new （about 70） unknown until now condensed phosphates have been obtained. Dependency of composition VS temperature and molar ratio, reliance of structure from duration of synthesis and radius of the ions are revealed.展开更多
Spermatozoa are highly specialized cells. Adenosine triphosphate （ATP）, which provides the energy for supporting the key functions of the spermatozoa, is formed by 2 metabolic pathways, namely glycolysis and oxidati...Spermatozoa are highly specialized cells. Adenosine triphosphate （ATP）, which provides the energy for supporting the key functions of the spermatozoa, is formed by 2 metabolic pathways, namely glycolysis and oxidative phosphorylation （OXPHOS）. It is produced in the mitochondria through OXPHOS as well as in the head and principal piece of the flagellum through glycolysis. However, there is a great discrepancy as to which method of ATP production is primarily utilized by the spermatozoa for successful fertilization. Mitochondrial respiration is considered to be a more efficient metabolic process for ATP synthesis in comparison to glycolysis. However, studies have shown that the diffusion potential of ATP from the mitochondria to the distal end of the flagellum is not sufficient to support sperm motility, suggesting that glycolysis in the tail region is the preferred pathway for energy production. It is suggested by many investigators that although glycolysis forms the major source of ATP along the flagellum, energy required for sperm motility is mainly produced during mitochondrial respiration. Nevertheless, some studies have shown that when glycolysis is inhibited, proper functioning and motility of spermatozoa remains intact although it is unclear whether such motility can be sustained for prolonged periods of time, or is sufficiently vigorous to achieve optimal fertilization. The purpose of this article is to provide an overview of mammalian sperm energy metabolism and identify the preferred metabolic pathway for ATP generation which forms the basis of energy Droduction in human spermatozoa during fertilization.展开更多
Vitamin D deficiency is a common health issue around the world. We therefore evaluated the associations of semen quality with both serum and seminal plasma vitamin D levels and studied the mechanisms underlying these ...Vitamin D deficiency is a common health issue around the world. We therefore evaluated the associations of semen quality with both serum and seminal plasma vitamin D levels and studied the mechanisms underlying these by incubating spermatozoa with 1,25(OH)2D in vitro. Two hun dred and twenty-two men were in eluded in our study. Vitamin D was detected using an electrochemilumi nesce nee method. Spermatozoa used for in vitro experiments were isolated by density gradient centrifugation. Positive relationships of serum 25(OH)D with semen volume and seminal plasma fructose were identified. Seminal plasma 25(OH)D level showed no relationship with serum 25(OH)D level, while it was inversely associated with sperm concentration and positively correlated with semen volume and sperm kinetic values. In vitro, sperm kinetic parameters in creased after in cubation with 1,25(OH)2D, especially upon in cubation for 30 min with it at a concen tration of 0.1 nmol l-1. Under these in cubation conditions, the upward migratio n of spermatozoa in creased remarkably with increasing ade nosine triphosphate (ATP) con centratio n. The concentrati on of cyclic ade nosine mono phosphate (cAMP) and the activity of protei n kinase A (PKA) were both elevated, and the PKA inhibitor, N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H89) reversed the in crease of ATP producti on. The conce ntrations of cytoplasmic calcium ions and n icotinamide adenine dinucleotide (NADH) were both enhanced, while mitochondrial calcium uniporter (MCU) inhibitor, Ruthenium 360 (Ru360) did not reverse the increase of ATP production. Therefore, seminal plasma vitamin D may be invoIved in regulating sperm motility, and 1,25(OH)2D may enhance sperm motility by promoting the synthesis of ATP both through the cAMP/PKA pathway and the in crease in in tracellular calcium ions.展开更多
文摘Deoxyribenucleoside triphosphate (dNTP) pools were measured in normal BALB/c3T3 cells, transformation-treated cells and transformed cells with reverse-phase HPLC. The fluctuation of dNTP pools was similar after transformation treatment with alkylating mutagen glycidyl methacrylate(GMA) or Nmethyl- N'- nitro N- nitrosoguanidine (MNNG ). However,the gap between deoxyguanosine triphosphate + deoxyadenosine triphosphate (dGTP + dATP) pools and deoxythymidine triphosphate + deoxycytidine triphosphate (dTTP + dCTP) pools was greatly intensified. The measurements also indicated that the dNTP pools in transformed cells were quite different from those in normal cells. The results suggested that dNTP pools may play an important role in cell transformation
基金supported by the National Natural Science Foundation of China(Nos.22301241 and 22371229)the Shaanxi Fundamental Science Research Project for Chemistry and Biology(22JHQ073).
文摘The design and development of selective recognition and sensing systems for biologically important nucleoside triphosphates(NTPs)have attracted significant attention in recent years,owing to their critical roles in cellular processes.In this study,we report the synthesis of two tetraphenylethene-based tetraimidazolium cyclophanes(1 and 2)through a one-step S_(N)2 reaction.These cyclophanes are capable of recognizing NTPs by forming stable 1:1 host-vip complexes in aqueous solution.Of particular interest,cyclophane 1 demonstrates exceptional selectivity for guanosine triphosphate(GTP),distinguishing it from other nucleoside triphosphates such as ATP,CTP,and UTP.This selective recognition is accompanied by distinct and measurable fluorescence responses,which are significantly enhanced upon binding to GTp,enabling the potential for sensitive detection.This study highlights the potential of tetraphenylethene-based tetraimidazolium cyclophanes as a highly selective and sensitive sensor for GTP,offering new insights into the design of molecular systems for the recognition of biologically relevant nucleotides.
基金supported by USA NIH(GM095086)the Georgia Cancer Coalition(GCC) Distinguished Cancer Clinicians and ScientistsUSA National Science Foundation(MCB-0824837)
文摘Modified deoxy-and ribo-nucleoside triphosphates are chemically synthesized in multiple steps due to the protection and deprotection of the nucleoside functionalities.To conveniently synthesize the S-modified triphosphates for enzymatically preparing phosphorothioate DNAs and RNAs(PS-DNA and PS-RNA) as potential therapeutics,herein we report a one-pot strategy to synthesize the deoxy-and ribo-nucleoside 5'-(α-P-thio)triphosphates(dNTPαS and NTPαS) without protecting any nucleoside functionalities.This facile synthesis is achieved by treating the nucleosides with a mild phosphitylating reagent,reacting selectively with the 5'-hydroxyl group of each unprotected nucleoside,followed by sulfurization and hydrolysis to afford the crude dNTPαS and NTPαS analogs(mixtures of Sp and Rp diastereomers).We also demonstrated that after just simple precipitation(without HPLC and ion-exchange purification),the quality of the synthesized dNTPαS and NTPαS analogs is excellent for direct DNA polymerization and RNA transcription,respectively.Since Klenow DNA polymerase and T7 RNA polymerase accept the Sp diastereomers of dNTPαS and NTPαS analogs,respectively,while the Rp diastereomers are neither substrates nor inhibitors,the diastereomerically-pure PS-DNAs and PS-RNAs can be conveniently synthesized enzymatically.
基金supported by the National Key R&D Program of China(2024YFE0111600)the 2115 Talent Development Program of China Agricultural University。
文摘Background Intestinal inflammation is an energy-consuming process that may alter energy supply and demand in poultry.During inflammation,the intestinal energy metabolic profile and the patterns of energy partitioning remain unclear.This study investigated the effects of intestinal inflammation on energy intake,heat production(HP),retained energy(RE)and intestinal energy metabolites in layer pullets.Methods After 7 d dietary adaption,32“Jing Tint 6”layer pullets with average body weight(1,123.50±8.55 g)were selected from 96 birds,and randomly assigned to two groups(CON:Control group,INFL:Inflammation group)with 8 replicates per group.Indirect calorimetry analysis was conducted over 7 d to determine HP and fasting HP(FHP).During this period,pullets in INFL group received 4 mL/d of 0.6 g/mL dextran sulfate sodium(DSS)via oral gavage to induce intestinal inflammation.After the calorimetry,intestinal tissues were collected post-euthanasia from one bird per replicate for morphological and mucosal metabolomic analysis.Results Birds exhibited significantly lower apparent metabolizable energy(AME)intake(P<0.001)during intestinal inflammation,accompanied by compromised RE and RE as fat(P<0.001),suggesting that birds consumed body energy to sustain energy demands.Targeted metabolomic studies identified 11 energy metabolites differentially expressed in ileal mucosa between CON and INFL groups.Specifically,DSS induction significantly increased(P<0.05)adenosine triphosphate(ATP)level and reduced(P<0.001)nicotinamide adenine dinucleotide(NAD^(+))level in ileal mucosa of pullets.In parallel,metabolic adaptations such as enhanced glycolytic intermediates,reduced amino acids,α-ketoglutarate(α-KG)accumulation and suppressed expression of genes encoding enzymes involved in tricarboxylic acid(TCA)cycle were observed in the inflamed ileum of pullets.Conclusion Immune stimulation by DSS induced a negative energy balance in layer pullets,characterized by reduced AME intake(-190.47 kJ/kg BW^(0.75))and compromised RE(-18.81%of AME intake).Disruption of intestinal energy profiling was observed in inflammation-challenged pullets,such as accumulation ofα-KG and ATP,reduced NAD^(+)and amino acids,which could provide valuable insights for developing effective intervention strategies.
文摘AIM:To investigate the effects of adenosine triphosphate(ATP)and melatonin,which have antioxidant and antiinflammatory activities,on potential 5-fluorouracil(5-FU)-induced optic nerve damage in rats.METHODS:Twenty-four rats were categorized into four groups of six rats:healthy(HG),5-FU(FUG),ATP+5-FU(AFU),and melatonin+5-FU(MFU).ATP(4 mg/kg)and melatonin(10 mg/kg)were administered intraperitoneally and orally,respectively.One hour after ATP and melatonin administration,rats in the AFU,MFU,and FUG were intraperitoneally injected with 5-FU(100 mg/kg).ATP and melatonin were administered once daily for 10d.5-FU was administered at a single dose on days 1,3,and 5 of the experiment.After 10d,the rats were euthanized and optic nerve tissues were extracted.Optic nerve tissues were biochemically and histopathologically examined.RESULTS:ATP and melatonin treatments inhibited the increase in malondialdehyde(MDA)and interleukin-6(IL-6)levels,which were elevated in the FUG.The treatments also prevented the decrease in total glutathione(tGSH)levels and the superoxide dismutase(SOD)and catalase(CAT)activities(P<0.001).This inhibition was higher in the ATP group than in the melatonin group(P<0.001).ATP prevented histopathological damage better than melatonin(P<0.05).CONCLUSION:ATP and melatonin have the potential to be used in alleviating 5-FU-induced optic nerve damage.In addition,ATP treatment shows better protective effects than melatonin.
基金Supported by the Science and Technology Program of Gansu Province,No.23JRRA1015the International Science and Technology Cooperation Project of Gansu Provincial Science and Technology Department,No.2023YFWA0009the Innovation and Entrepreneurship Project for Young Talents of Lanzhou Science and Technology Bureau,No.2023-4-18.
文摘BACKGROUND Ectonucleoside triphosphate diphosphohydrolase 6(ENTPD6),a member of the ENTPD family,has been implicated in certain cancers,yet a comprehensive analysis across multiple cancer types remains lacking.AIM To systematically evaluate ENTPD6’s expression,prognostic significance,and functions across multiple cancer types.METHODS In this study,we performed a pan-cancer analysis to investigate the correlation between ENTPD6 expression and various factors,including prognosis,genetic alterations,epigenetic modification,immune infiltration,immunotherapy responses,functional enrichment,and drug sensitivity.A tissue microarray of gastrointestinal tumors was used to validate differential ENTPD6 protein expression.RESULTS Pan-cancer analysis revealed that ENTPD6 expression was significantly elevated in many cancers.Immunohistochemistry staining analysis revealed that ENTPD6 expression was significantly higher in esophageal carcinoma,stomach adenocarcinoma,colon adenocarcinoma,rectal adenocarcinoma,and pancreatic adenocarcinoma compared to normal tissues.Furthermore,ENTPD6 expression was strongly associated with immune-infiltrating cells,particularly clusters of differentiation 8+T cells and natural killer cells,and correlated with immune-related genomic features including tumor mutational burden and microsatellite instability.Pathway analysis indicated that ENTPD6 expression was primarily linked to purine and pyrimidine metabolism pathways.Drug sensitivity analysis revealed that high ENTPD6 expression was sensitive to RDEA119,selumetinib,and PD-0325901.CONCLUSION This pan-cancer study elucidates the pivotal role of ENTPD6 in tumor progression and establishes its potential as a therapeutic target for immunotherapeutic approaches in specific malignancies.
基金supported in part by funding from BeiGene,Ltd.,USA(Grant No.:KPR081)with additional support from the Alessandra Bono Foundation,Italy.
文摘Pamiparib is a potent and selective oral poly(adenosine diphosphate(ADP)-ribose)-polymerase(PARP)1/2inhibitor(PARPi).Pamiparib has good bioavailability and shows greater cytotoxic potency and similar DNA-trapping capacity compared to olaparib.It is not affected by adenosine triphosphate(ATP)-binding cassette transporters.
基金Supported by the Shanghai Yangpu District Science and Technology Commission,No.YPQ202303Shanghai Municipal Health Commission Clinical Research Special Project,No.202240122Shanghai Medical Innovation Research Special Project,No.22Y11908600.
文摘BACKGROUND Metabolic dysregulation is considered a significant hallmark of hepatocellular carcinoma(HCC).SAC3 domain containing 1(SAC3D1)functions in the cell cycle,and its expression is upregulated in various cancers.It is known that metabolic changes occur at different stages of the cell cycle to maintain the biosynthesis and replication of both normal and cancer cells.Based on the role of SAC3D1 in mitosis,we hypothesize that abnormal expression of SAC3D1 may affect cellular metabolism.However,it remains unclear whether SAC3D1 mediates the progression of HCC by regulating metabolic reprogramming.AIM To comprehensively elucidate the impact and molecular mechanism of SAC3D1 on the progression of HCC by regulating the metabolic reprogramming.METHODS The constructed SAC3D1 overexpression and knockdown HCC cell lines were used for detecting cell proliferation,migration capabilities,as well as glycolysis and adenosine triphosphate(ATP)production rate assays.They were also employed for examining molecular markers associated with cell migration and glycolysis.The transcriptome sequencing data of cells have revealed the pathways potentially influenced by SAC3D1.The tail vein metastasis model and xenograft tumor experiments were utilized to demonstrate SAC3D1’s tumor-promoting effects in vivo.RESULTS SAC3D1 expression was upregulated and associated with poor prognosis in HCC patients.SAC3D1 enhanced the proliferation and migration abilities and reduced the population dependence of HCC cells in vitro and in vivo.The upregulation of SAC3D1 enhanced cellular glycolysis and ATP production.The cell transcriptome sequencing data revealed that SAC3D1 activated Wnt signaling pathway.SAC3D1 did not modulate the transcription ofβ-Catenin,while might inhibit its degradation.Further investigations indicated that the increase of SAC3D1 leads to moreβ-Catenin accumulating in the nucleus,facilitating the expression of c-Myc,one of the upstream regulatory factors of glycolysis.The iCRT3,an antagonist ofβ-Catenin,could counteract the increase of c-Myc induced by SAC3D1,while also downregulating the expression of glycolysis-related proteins.CONCLUSION This study found that SAC3D1 enhances HCC cell glycolysis and ATP production via theβ-Catenin/c-Myc signaling axis,thereby promoting the progression of HCC.
基金supported by funds from the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico do Brasil(CNPq)(312286/2023-6,307201/2023-6,and Instituto Nacional Saude Cerebral INSC,No.406020/2022-1)Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior(CAPES)Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro-FAPERJ(E-26/010.002260/2019,E-26/010.001652/2019,E-26/010.101036/2018,E-26/202.774/2018,E-26/210.240/2020,E-26/211.138/2021,26/210.823/2021,E-26/211.325/2021,E-26/210.779/2021,E-26/201.086/2022,E-26/210.312/2022,E-26/203.262/2023,E-26/200.195/2023)(to LEBS)。
文摘Recent increases in infectious diseases affecting the central nervous system have raised concerns about their role in neuroinflammation and neurodegeneration.Viral pathogens or their products can invade the central nervous system and cause damage,leading to meningitis,encephalitis,meningoencephalitis,myelitis,or post-infectious demyelinating diseases.Although neuroinflammation initially has a protective function,chronic inflammation can contribute to the development of neurodegenerative diseases.Mechanisms such as protein aggregation and cellular disturbances are implicated with specific viruses such as herpes simplex virus type 1 and Epstein-Barr virus being associated with Alzheimer's disease and multiple sclerosis,respectively.Extracellular nucleotides,particularly adenosine triphosphate and its metabolites are released from activated,infected,and dying cells,acting as alarmins mediating neuroinflammation and neurodegeneration.When viruses infect central nervous system cells,adenosine triphosphate is released as an alarmin,triggering inflammatory responses.This process is mediated by purinergic receptors,divided into two families:P1,which responds to adenosine,and P2,activated by adenosine triphosphate and other nucleotides.This review highlights how specific viruses,such as human immunodeficiency virus type 1,Theiler's murine encephalomyelitis virus,herpes simplex virus type 1,Epstein-Barr virus,dengue virus,Zika virus,and severe acute respiratory syndrome coronavirus 2,can initiate inflammatory responses through the release of extracellular nucleotides,particularly adenosine triphosphate,which act as critical mediators in the progression of neuroinflammation and neurodegenerative disorders.A better understanding of purinergic signaling pathways in these diseases may suggest new potential therapeutic strategies for targeting neuroinflammation to mitigate the long-term consequences of viral infections in the central nervous system.
基金Supported by the National Research Foundation of Korea Grant Funded by the Korea Government,No.RS-2024-00440477the Korea Institute of Science and Technology Institutional Program,No.2E33111-24-042.
文摘BACKGROUND Mixed lineage kinase domain-like protein(MLKL)serves as a critical mediator in necroptosis,a form of regulated cell death linked to various liver diseases.This study aims to specifically investigate the role of MLKL’s adenosine triphosphate(ATP)-binding pocket in facilitating necroptosis-independent pathways that may contribute to liver disease progression.By focusing on this mechanism,we seek to identify potential therapeutic targets that can modulate MLKL activity,offering new strategies for the prevention and treatment of liver-related pathologies.AIM To investigate the possibility of using the ATP-binding pocket-associated,necro-ptosis-independent MLKL pathway as a target for liver diseases.METHODS Cell death following necroptosis stimuli was evaluated using cell proliferation assays,flow cytometry,and electron microscopy in various cells.The human liver organoid system was used to evaluate whether the MLKL ATP pocket-binding inhibitor could attenuate inflammation.Additionally,alcoholic and non-alcoholic fatty liver diseases animal models were used to determine whether MLKL ATP pocket inhibitors could attenuate liver injury.RESULTS While an MLKL ATP pocket-binding inhibitor did not prevent necroptosis-induced cell death in RAW 264.7 cells,it did reduce the necroptosis-led expression of CXCL2,ICAM,and VCAM.Notably,MLKL ATP pocket inhibitor diminishes the expression of CXCL2,ICAM,and VCAM by inhibiting the IκB kinase and nuclear factor kappa-B pathways without inducing necroptosis-induced cell death in two-dimensional cell culture as well as the human-derived liver organoid system.Although MLKL ATP-binding inhibitor was ineffective in non-alcoholic fatty liver disease animal models,MLKL ATP-binding inhibitor attenuated hepatic inflammation in the alcoholic liver disease model.CONCLUSION MLKL ATP pocket-binding inhibitor exerted anti-inflammatory effects through the necroptosis-independent MLKL pathway in an animal model of alcoholic liver disease.
基金supported by the National Natural Science Foundation of China(82070844,82230024,82025008)the Natural Science Foundation of Beijing(7212123)+1 种基金the Peking University People’s Hospital Research and Development Funds(RZ2023-01)the Peking University Medicine Seed Fund for Interdisciplinary Research(BMU2023YFJHMX002,supported by the Fundamental Research Funds for the Central Universities).
文摘Background:Extracellular adenosine triphosphate(ATP)is an important signal molecule.In previous studies,intensive research had revealed the crucial roles of family with sequence similarity 3 member A(FAM3A)in controlling hepatic glucolipid metabolism,isletβcell function,adipocyte differentiation,blood pressure,and other biological and pathophysiological processes.Although mitochondrial protein FAM3A plays crucial roles in the regulation of glucolipid metabolism via stimulating ATP release to activate P2 receptor pathways,its mechanism in promoting ATP release in hepatocytes remains unrevealed.Methods:db/db,high-fat diet(HFD)-fed,and global pannexin 1(PANX1)knockout mice,as well as liver sections of individuals,were used in this study.Adenoviruses and adeno-associated viruses were utilized for in vivo gene overexpression or inhibition.To evaluate the metabolic status in mice,oral glucose tolerance test(OGTT),pyruvate tolerance test(PTT),insulin tolerance test(ITT),and magnetic resonance imaging(MRI)were conducted.Protein-protein interactions were determined by coimmunoprecipitation with mass spectrometry(MS)assays.Results:In livers of individuals and mice with steatosis,the expression of ATP-permeable channel PANX1 was increased(P<0.01).Hepatic PANX1 overexpression ameliorated the dysregulated glucolipid metabolism in obese mice.Mice with hepatic PANX1 knockdown or global PANX1 knockout exhibited disturbed glucolipid metabolism.Restoration of hepatic PANX1 rescued the metabolic disorders of PANX1-deficient mice(P<0.05).Mechanistically,ATP release is mediated by the PANX1-activated protein kinase B-forkhead box protein O1(Akt-FOXO1)pathway to inhibit gluconeogenesis via P2Y receptors in hepatocytes.PANX1-mediated ATP release also activated calmodulin(CaM)(P<0.01),which interacted with c-Jun N-terminal kinase(JNK)to inhibit its activity,thereby deactivating the transcription factor activator protein-1(AP1)and repressing fatty acid synthase(FAS)expression and lipid synthesis(P<0.05).FAM3A stimulated the expression of PANX1 via heat shock factor 1(HSF1)in hepatocytes(P<0.05).Notably,FAM3A overexpression failed to promote ATP release,inhibit the expression of gluconeogenic and lipogenic genes,and suppress gluconeogenesis and lipid deposition in PANX1-deficient hepatocytes and livers.Conclusions:PANX1-mediated release of ATP plays a crucial role in maintaining hepatic glucolipid homeostasis,and it confers FAM3A’s suppressive effects on hepatic gluconeogenesis and lipogenesis.
基金The National Key R&D Program of China:Biological Mechanisms of Acupoint Function-Effect Associations(No.2019YFC1709003)National Natural Science Foundation of China(NSFC)Top-level Project:Study on the Neuroimmunological Mechanism of Macrophage Phenotypic Polarisation for Antiinflammation Regulated by Acupuncture(No.81873369)+1 种基金National Natural Science Foundation of China Young Science Fund Project:Study on the Neuromodulation Mechanism of Electroacupuncture to Improve Neutropenia after Chemotherapy for Lung Cancer(No.81704146)National Natural Science Foundation of China Key Project:Research on the Initial Kinetic Regulation Mechanism of Acupuncture Effect Based on the Physicochemical Coupling Network of Acupuncture Point Microenvironment(No.82030125)。
文摘OBJECTIVE:To investigate the mechanisms behind the effects of acupuncture in Traditional Chinese Medicine,we delved into the adenosine triphosphate/peripheral purinergic P2X receptor 3(ATP/P2X3)receptor signaling system as an indicator of the body's energy state,commonly referred to as"Qi".METHODS:The tail-flick test was utilized to explore the impact of acupuncture on pain tolerance threshold(PTT)in mice,while also assessing adenosine(ADO)levels and adenylate energy charge(EC)at Zusanli(ST36).The study further investigated the dose-dependent effects of acupuncture on PTT and ADO levels at Zusanli(ST36).To shed light on the underlying mechanisms of acupuncture's effects,the study examined the impact of ATP,a P2X3 receptor antagonist,and adenosine disodium on PTT following acupuncture administration.RESULTS:Acupuncture at Zusanli(ST36)led to significant improvements in PTT in mice,with the most effective interventions being twirling for 2 min and needle retention for 28 min.These interventions also resulted in significant increases in ATP levels.The effects of acupuncture were further augmented by administration of different doses of ATP at Zusanli(ST36),and pretreatment with a P2X3 receptor antagonist decreased PTT.Adenylate EC peaked at 30 min after intraperitoneal injection of ATP,and pretreatment with various doses of i.p.ATP 30 min prior to acupuncture increased PTT in a dose-dependent manner.Additionally,pretreatment with an i.p.or intramuscular injection of adenosine disodium enhanced the effects of acupuncture.CONCLUSION:This research provides compelling evidence that ATP is involved in the regulation of PTT through acupuncture,revealing new avenues for achieving enhanced clinical outcomes.
基金Supported by National Natural Science Foundation of China,No.81960877University Innovation Fund of Gansu Province,No.2021A-076+4 种基金Gansu Province Science and Technology Plan,No.21JR7RA561Natural Science Foundation of Gansu Province,No.21JR1RA267 and No.24JRRA1020Education Technology Innovation Project of Gansu Province,No.2022A-067Open Project of Key Laboratory of Dunhuang Medicine and Transformation of Ministry of Education,No.DHYX21-07,No.DHYX22-05,and No.DHYX21-01and Gansu Province Joint Research Fund Project,No.24JRRA878.
文摘The maintenance of intracellular and extracellular adenosine triphosphate(ATP)levels plays a pivotal role in cardiac function.In recent years,burgeoning at-tention has been directed towards ATP-induced cell death(AICD),revealing it as a distinct cellular demise pathway triggered by heightened extracellular ATP concentrations,distinguishing it from other forms of cell death such as apoptosis and necrosis.AICD is increasingly acknowledged as a critical mechanism me-diating the pathogenesis and progression of various cardiovascular maladies,encompassing myocardial ischemia-reperfusion injury,sepsis-induced cardiomy-opathy,hypertrophic cardiomyopathy,arrhythmia,and diabetic cardiomyopathy.Consequently,a comprehensive understanding of the molecular and metabolic underpinnings of AICD in cardiac tissue holds promise for the prevention and amelioration of cardiovascular diseases.This review first elucidates the vital physiological roles of ATP in the cardiovascular system,subsequently delving into the intricate molecular mechanisms and metabolic signatures governing AICD.Furthermore,it addresses the potential therapeutic targets implicated in mitigating AICD for treating cardiovascular diseases,while also delineating the current constraints and future avenues for these innovative therapeutic targets,thereby furnishing novel insights and strategies for the prevention and management of cardiovascular disorders.
基金the Zhejiang Provincial Natural Science Foundation of China(Nos.LR22B010001,LQ23B010001)the National Natural Science Foundation of China(Nos.22201057,21871297)+1 种基金the Natural Science Foundation of Guangdong Province for Distinguished Young Scholars(No.2019B151502051)the Hangzhou Normal University(Nos.2021QDL001,2021QDL065)。
文摘Adenosine triphosphate(ATP),known as a common metabolic product in organism,is not only importance to provide energy in various cellular activities but also is widely explored in the bio-inspired synthetic supramolecular area which becomes a fascinating topic with the rapid development of biology,chemistry and materials science.In this review,the recent advances about ATP interacted with functional small organic compounds and metal coordinated complexes are summarized.The design principles,its function as an active supramolecular matrix,the associated non-covalent binding modes and assembly induced properties including the optical properties,morphologies are presented in details.Besides,their applications for metal ion detecting,enzyme activity monitoring and drug delivery are described due to their excellently dynamic assembly properties,adjustability,and response to stimuli.Finally,an overview of the existing challenges and future prospects of ATP-induced supramolecular systems are also discussed.
文摘A distinctive feature of phosphates is their special and significant ability to form inorganic polymeric compounds---condensed phosphates, which are destined to play a considerable role in our ＂high-tech＂ society in the future. Numerous olygophosphates, polyphosphates, double condensed phosphates and cyclophosphates with diverse formula, such as double tetra-, octa- and dodecaphosphates were obtained and described by us last years. The offered data are the outcomes of our scientific researches： of synthesis, analysis, and estimation of results in correlation with new achievements in inorganic polymer＇s chemistry. Many double condensed compounds, containing monovalent metals are obtained by us during systematic investigation of polycomponent systems, containing mono- and trivalent metals at temperature range 100-600 ~C. Synthesised condensed phosphates, in fact--inorganic polymers were examined in detail by chemical and thermogravimetric analysis, most compounds were examined by paper chromatography and the structures are determined by X-ray structural techniques/diffraction analysis. During our fundamental researches numerous new （about 70） unknown until now condensed phosphates have been obtained. Dependency of composition VS temperature and molar ratio, reliance of structure from duration of synthesis and radius of the ions are revealed.
文摘Spermatozoa are highly specialized cells. Adenosine triphosphate （ATP）, which provides the energy for supporting the key functions of the spermatozoa, is formed by 2 metabolic pathways, namely glycolysis and oxidative phosphorylation （OXPHOS）. It is produced in the mitochondria through OXPHOS as well as in the head and principal piece of the flagellum through glycolysis. However, there is a great discrepancy as to which method of ATP production is primarily utilized by the spermatozoa for successful fertilization. Mitochondrial respiration is considered to be a more efficient metabolic process for ATP synthesis in comparison to glycolysis. However, studies have shown that the diffusion potential of ATP from the mitochondria to the distal end of the flagellum is not sufficient to support sperm motility, suggesting that glycolysis in the tail region is the preferred pathway for energy production. It is suggested by many investigators that although glycolysis forms the major source of ATP along the flagellum, energy required for sperm motility is mainly produced during mitochondrial respiration. Nevertheless, some studies have shown that when glycolysis is inhibited, proper functioning and motility of spermatozoa remains intact although it is unclear whether such motility can be sustained for prolonged periods of time, or is sufficiently vigorous to achieve optimal fertilization. The purpose of this article is to provide an overview of mammalian sperm energy metabolism and identify the preferred metabolic pathway for ATP generation which forms the basis of energy Droduction in human spermatozoa during fertilization.
基金the Research Funds for Jiangsu Province Key Research and Development Plan (Grant No. BE2016750)Research Funds for Military Family Planning (Grant No. 16JS012)+5 种基金Six Talent Peaks Project in Jiangsu Province (Grant No. 2017-WSW-033)Chinese Medical Association Special Fund for Clinical Medical Research (Grant No. 17020350704)Foundation for Key Medical Talents in Jiangsu Province (Grant No. ZDRCA2016096)Natural Science Foundation of Jiangsu Province (Grant No. BK20170620)China Postdoctoral Science Foundation (Grant No. 2017M613434)National Natural Science Foundation of China (Grant No. 81701431 and 81701440).
文摘Vitamin D deficiency is a common health issue around the world. We therefore evaluated the associations of semen quality with both serum and seminal plasma vitamin D levels and studied the mechanisms underlying these by incubating spermatozoa with 1,25(OH)2D in vitro. Two hun dred and twenty-two men were in eluded in our study. Vitamin D was detected using an electrochemilumi nesce nee method. Spermatozoa used for in vitro experiments were isolated by density gradient centrifugation. Positive relationships of serum 25(OH)D with semen volume and seminal plasma fructose were identified. Seminal plasma 25(OH)D level showed no relationship with serum 25(OH)D level, while it was inversely associated with sperm concentration and positively correlated with semen volume and sperm kinetic values. In vitro, sperm kinetic parameters in creased after in cubation with 1,25(OH)2D, especially upon in cubation for 30 min with it at a concen tration of 0.1 nmol l-1. Under these in cubation conditions, the upward migratio n of spermatozoa in creased remarkably with increasing ade nosine triphosphate (ATP) con centratio n. The concentrati on of cyclic ade nosine mono phosphate (cAMP) and the activity of protei n kinase A (PKA) were both elevated, and the PKA inhibitor, N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H89) reversed the in crease of ATP producti on. The conce ntrations of cytoplasmic calcium ions and n icotinamide adenine dinucleotide (NADH) were both enhanced, while mitochondrial calcium uniporter (MCU) inhibitor, Ruthenium 360 (Ru360) did not reverse the increase of ATP production. Therefore, seminal plasma vitamin D may be invoIved in regulating sperm motility, and 1,25(OH)2D may enhance sperm motility by promoting the synthesis of ATP both through the cAMP/PKA pathway and the in crease in in tracellular calcium ions.
