RNA contains diverse post-transcriptional modifications,and its catabolic breakdown yields numerous modified nucleosides requiring correct processing,but the mechanisms remain unknown.Here,we demonstrate that three RN...RNA contains diverse post-transcriptional modifications,and its catabolic breakdown yields numerous modified nucleosides requiring correct processing,but the mechanisms remain unknown.Here,we demonstrate that three RNA-derived modified adenosines,N6-methyladenosine(m6A),N6,N6-dimethyladenosine(m6,6A),and N6-isopentenyladenosine(i6A),are sequentially metabolized into inosine monophosphate(IMP)to mitigate their intrinsic cytotoxicity.展开更多
An imbalance in adenosine-mediated signaling,particularly the increased A_(2A)R-mediated signaling,plays a role in the pathogenesis of Parkinson's disease.Existing therapeutic approaches fail to alter disease prog...An imbalance in adenosine-mediated signaling,particularly the increased A_(2A)R-mediated signaling,plays a role in the pathogenesis of Parkinson's disease.Existing therapeutic approaches fail to alter disease progression,demonstrating the need for novel approaches in PD.Repetitive transcranial magnetic stimulation is a non-invasive approach that has been shown to improve motor and non-motor symptoms of Parkinson's disease.However,the underlying mechanisms of the beneficial effects of repetitive transcranial magnetic stimulation remain unknown.The purpose of this study is to investigate the extent to which the beneficial effects of prolonged intermittent theta burst stimulation in the 6-hydroxydopamine model of experimental parkinsonism are based on modulation of adenosine-mediated signaling.Animals with unilateral 6-hydroxydopamine lesions underwent intermittent theta burst stimulation for 3 weeks and were tested for motor skills using the Rotarod test.Immunoblot,quantitative reverse transcription polymerase chain reaction,immunohistochemistry,and biochemical analysis of components of adenosine-mediated signaling were performed on the synaptosomal fraction of the lesioned caudate putamen.Prolonged intermittent theta burst stimulation improved motor symptoms in 6-hydroxydopamine-lesioned animals.A 6-hydroxydopamine lesion resulted in progressive loss of dopaminergic neurons in the caudate putamen.Treatment with intermittent theta burst stimulation began 7 days after the lesion,coinciding with the onset of motor symptoms.After treatment with prolonged intermittent theta burst stimulation,complete motor recovery was observed.This improvement was accompanied by downregulation of the e N/CD73-A_(2A)R pathway and a return to physiological levels of A_(1)R-adenosine deaminase 1 after 3 weeks of intermittent theta burst stimulation.Our results demonstrated that 6-hydroxydopamine-induced degeneration reduced the expression of A_(1)R and elevated the expression of A_(2A)R.Intermittent theta burst stimulation reversed these effects by restoring the abundances of A_(1)R and A_(2A)R to control levels.The shift in ARs expression likely restored the balance between dopamine-adenosine signaling,ultimately leading to the recovery of motor control.展开更多
The interaction between the gut microbiota and cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enh...The interaction between the gut microbiota and cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enhances communication along the gut–brain axis.The gut microbiota influences the cAMP-PKA signaling pathway through its metabolites,which activates the vagus nerve and modulates the immune and neuroendocrine systems.Conversely,alterations in the cAMP-PKA signaling pathway can affect the composition of the gut microbiota,creating a dynamic network of microbial-host interactions.This reciprocal regulation affects neurodevelopment,neurotransmitter control,and behavioral traits,thus playing a role in the modulation of neurological diseases.The coordinated activity of the gut microbiota and the cAMP-PKA signaling pathway regulates processes such as amyloid-β protein aggregation,mitochondrial dysfunction,abnormal energy metabolism,microglial activation,oxidative stress,and neurotransmitter release,which collectively influence the onset and progression of neurological diseases.This study explores the complex interplay between the gut microbiota and cAMP-PKA signaling pathway,along with its implications for potential therapeutic interventions in neurological diseases.Recent pharmacological research has shown that restoring the balance between gut flora and cAMP-PKA signaling pathway may improve outcomes in neurodegenerative diseases and emotional disorders.This can be achieved through various methods such as dietary modifications,probiotic supplements,Chinese herbal extracts,combinations of Chinese herbs,and innovative dosage forms.These findings suggest that regulating the gut microbiota and cAMP-PKA signaling pathway may provide valuable evidence for developing novel therapeutic approaches for neurodegenerative diseases.展开更多
BACKGROUND Although inflammatory diseases commonly affect the pleura and pleural space,their mechanisms of action remain unclear.The presence of several mediators emphasizes the concept of pleural inflammation.Adenosi...BACKGROUND Although inflammatory diseases commonly affect the pleura and pleural space,their mechanisms of action remain unclear.The presence of several mediators emphasizes the concept of pleural inflammation.Adenosine deaminase(ADA)is an inflammatory mediator detected at increased levels in the pleural fluid.AIM To determine the role of total pleural ADA(P-ADA)levels in the diagnosis of pleural inflammatory diseases.METHODS 157 patients with inflammatory pleural effusion(exudates,n=124,79%)and noninflammatory pleural effusion(transudates,n=33,21%)were included in this observational retrospective cohort study.The P-ADA assay was tested using a kinetic technique.The performance of the model was evaluated using the area under the receiver operating characteristic(ROC)curve(AUC).The ideal cutoff value for P-ADA in pleural inflammation was determined using the Youden index in the ROC curve.RESULTS The transudates included congestive heart failure(n=26),cirrhosis of the liver with ascites(n=3),chronic renal failure(n=3),and low total protein levels(n=1).The exudate cases included tuberculosis(n=44),adenocarcinoma(n=37),simple parapneumonic effusions(n=15),complicated parapneumonic effusions/empyema(n=8),lymphoma(n=7),and other diseases(n=13).The optimal cutoff value of P-ADA was≥9.00 U/L.The diagnostic parameters as sensitivity,specificity,positive and negative predictive values,positive and negative likelihood values,odds ratio,and accuracy were 77.69(95%CI:69.22-84.75);68.75(95%CI:49.99-83.88);90.38 and 44.90(95%CI:83.03-95.29;30.67-59.77);2.48 and 0.32(95%CI:2.21-11.2;0.27-0.51);7.65(95%CI:0.78-18.34),and 75.82(95%CI:68.24-82.37),respectively(χ^(2)=29.51,P=0.00001).An AUC value of 0.8107(95%CI:0.7174-0.8754;P=0.0000)was clinically useful.The Hosmer-Lemeshow test showed excellent discrimination.CONCLUSION P-ADA biomarker has high diagnostic performance for pleural inflammatory exudates.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
Pleural effusion,characterized by the accumulation of fluid in the pleural space,poses significant challenges in clinical practice,especially in determining whether it belongs to the inflammatory exudates or non-infla...Pleural effusion,characterized by the accumulation of fluid in the pleural space,poses significant challenges in clinical practice,especially in determining whether it belongs to the inflammatory exudates or non-inflammatory transudates.Adenosine deaminase(ADA),an enzyme primarily produced by immune cells,particularly lymphocytes,increase in response to inflammatory conditions,including tuberculosis and malignancies.Elevated ADA levels in pleural have been shown to correlate with inflammatory exudates,making it a valuable biomarker for dif-ferentiating between inflammatory and non-inflammatory effusions.Moreover,numerous studies have demonstrated the treatment function of ADA in inflammation-related pleural effusion syndrome.Recently,research has established the values for the implication of ADA in diagnosing and managing pleural disease.Based on these findings,ADA becomes a reliable,non-invasive marker for early diagnosis and the appropriate treatment for pleural inflammation,ultimately improving patient outcomes.展开更多
This editorial underscores the importance of Maranhão et al’s study,which investigates pleural adenosine deaminase(P-ADA)as a biomarker for inflammatory pleural effusions.Despite advances in imaging,distinguishi...This editorial underscores the importance of Maranhão et al’s study,which investigates pleural adenosine deaminase(P-ADA)as a biomarker for inflammatory pleural effusions.Despite advances in imaging,distinguishing between inflammatory and non-inflammatory causes of pleural effusion remains a diagnostic challenge.The authors conducted a rigorous retrospective cohort analysis of 157 patients(124 with inflammatory exudates and 33 with non-inflammatory transudates),establishing a robust cutoff value of P-ADA≥9.00 U/L for diagnosing inflammatory diseases using receiver operating characteristic curve analysis and internal statistical calibration.This is the first study to define a standardized PADA threshold in a Brazilian cohort,addressing previous inconsistencies in cutoff values.Furthermore,the authors delved into the pathophysiological mechanisms underlying elevated P-ADA,linking it to purinergic signaling pathways and immune cell activation,particularly emphasizing the role of ADA2 isoforms in macrophages and lymphocytes.Their findings support P-ADA as a non-invasive,cost-effective biomarker for early diagnosis,treatment stratification,and minimizing the need for invasive procedures such as thoracentesis.This has particular relevance in resource-limited settings,where streamlined diagnostics can reduce healthcare costs and improve patient outcomes.Future studies must prioritize global validation,explore the integration of adenosine deaminase with additional biomarkers(e.g.,interleukin 6,C-reactive protein),and support the development of point-of-care technologies.展开更多
Neuroinflammation,the inflammatory response of the central nervous system(CNS),is a common feature of many neurological disorders such as sepsis-associated encephalopathy(SAE),multiple sclerosis(MS),and Parkinson'...Neuroinflammation,the inflammatory response of the central nervous system(CNS),is a common feature of many neurological disorders such as sepsis-associated encephalopathy(SAE),multiple sclerosis(MS),and Parkinson's disease(PD).Prior studies identified cytokines(e.g.,tumor necrosis factor[TNF],interleukin[IL]-1,and IL-6)delivered by resident glial cells and brain-invading peripheral immune cells as the major contributor to neuroinflammation(Becher et al.,2017).In addition to pro-inflammatory cytokines,elevated levels of extracellular purine molecules such as adenosine triphosphate(ATP)and adenosine can be detected upon any pathological insults(e.g.,injury,ischemia,and hypoxia),contributing to the progression of neurological disorders(Borea et al.,2017).展开更多
Heart failure(HF)has emerged as one of the foremost global health threats due to its intricate pathophysiological mechanisms and multifactorial etiology.Adeno-sine triphosphate(ATP)-induced cell death represents a nov...Heart failure(HF)has emerged as one of the foremost global health threats due to its intricate pathophysiological mechanisms and multifactorial etiology.Adeno-sine triphosphate(ATP)-induced cell death represents a novel form of regulated cell deaths,marked by cellular energy depletion and metabolic dysregulation stemming from excessive ATP accumulation,identifying its uniqueness compared to other cell death processes modalities such as programmed cell death and necrosis.Growing evidence suggests that ATP-induced cell death(AICD)is predominantly governed by various biological pathways,including energy meta-bolism,redox homeostasis and intracellular calcium equilibrium.Recent research has shown that AICD is crucial in HF induced by pathological conditions like myocardial infarction,ischemia-reperfusion injury,and chemotherapy.Thus,it is essential to investigate the function of AICD in the pathogenesis of HF,as this may provide a foundation for the development of targeted therapies and novel treatment strategies.This review synthesizes current advancements in under-standing the link between AICD and HF,while further elucidating its invol-vement in cardiac remodeling and HF progression.展开更多
BACKGROUND Erianin is a natural bibenzyl compound extracted from Dendrobium chrysotoxum and is known for its anti-inflammatory and antioxidant properties.AIM To explore the possible therapeutic mechanisms of erianin a...BACKGROUND Erianin is a natural bibenzyl compound extracted from Dendrobium chrysotoxum and is known for its anti-inflammatory and antioxidant properties.AIM To explore the possible therapeutic mechanisms of erianin and determine if it can reduce cardiac damage in mice with type 2 diabetes.METHODS High-fat diet and intraperitoneal injections of streptozotocin were used to induce type 2 diabetes mellitus in C57BL/6 mice.Mice were divided into different groups including control,model,and treatment with various doses of erianin(10,20,and 40 mg/kg)as well as ML-385+erianin group.RESULTS Erianin reduced oxidative stress and inflammation and alleviated diabetic cardiomyopathy through the activation of the adenosine monophosphate-acti-vated protein kinase(AMPK)-nuclear factor erythroid 2-related factor 2(Nrf2)-heme oxygenase-1(HO-1)pathway.Treatments with erianin-M and erianin-H promoted weight stabilization and normalized fasting glucose levels relative to diabetic controls.Echocardiographic assessment demonstrated that erianin dose-dependently enhanced left ventricular systolic function(left ventricular ejection fraction,left ventricular fractional shortening)and mitigated ventricular remodeling(left ventricular internal diameter at end-diastole,left ventricular internal diameter at end-systole;P<0.05 vs model group).No significant differences were observed between the ML-385+erianin and placebo-treated groups.Histopathological examination through hematoxylin-eosin staining indicated that erianin ameliorated myocardial fiber fragmentation,structural disorganization,inflammatory cell infiltration,and cytolytic damage.Furthermore,it significantly reduced the serum levels of cardiac troponin I,creatine kinase,and its MB isoenzyme.However,the ML-385+erianin co-treatment failed to alleviate myocardial injury.Metabolic profiling revealed erianin-mediated improvements in glycemic regulation(glycated hemoglobin:P<0.001),plasma insulin homeostasis,and lipid metabolism(total cholesterol,triglycerides,low-density lipo-protein cholesterol reduction,and high-density lipoprotein cholesterol restoration;P<0.05 vs model group).Pro-inflammatory cytokines including tumor necrosis factor-α,interleukin(IL)-1β,and IL-6 were markedly suppressed in the erianin-M and erianin-H groups compared with the model group,whereas no significant differences were detected between the model and ML-385+erianin groups.Oxidative stress parameters showed decreased malondialdehyde levels accompanied by elevated superoxide dismutase and catalase activities in erianin-treated groups,with the most pronounced effects in the erianin-H group(P<0.05).Western blot analysis confirmed the significant upregulation of proteins associated with the AMPK/Nrf2/HO-1 pathway in erianin-M and erianin-H groups.These protective effects were abolished in the ML-385+erianin co-treatment group,which showed no statistical differences from the model group.CONCLUSION Erianin can effectively alleviate myocardial injury in type 2 diabetic mice by activating the AMPK-Nrf2-HO-1 pathway.展开更多
The tumor microenvironment(TME)is characterized by a symbiosis between cancer cells and the immune cells.The scarcity of oxygen generates hostility that forces cancer cells to alter their biological features in solid ...The tumor microenvironment(TME)is characterized by a symbiosis between cancer cells and the immune cells.The scarcity of oxygen generates hostility that forces cancer cells to alter their biological features in solid tumors.In response to low oxygen availability,the Hypoxia Inducible Factors(HIF-1/2/3α)act as metabolic mediators,producing extracellular metabolites in the tumor microenvironment that influence the immune cells.The modulation of lactate and adenosine on immune evasion has been widely described;however,under hypoxic conditions,it has been barely addressed.Evidence has demonstrated an interplay between cancer and the immune cells,and the present review explores thefindings that support HIFs bridging the gap between the rise of these metabolites and the immunosurveillance failure in a hypoxic context.Moreover,new insights based on systemic oxygen administration are discussed,which might counterbalance the effect mediated by lactate and adenosine,to recover anti-tumor immunity.Thus,the disruption of anti-tumor immunity has been the focus of recent research and this novel avenue opens therapeutic vulnerabilities that can be useful for cancer patients.展开更多
Expanding the specific surface area of substrates and carrying out precise surface engineering of imprinted nanocavities are crucial methods for enhancing the identification efficiency of molecularly imprinted polymer...Expanding the specific surface area of substrates and carrying out precise surface engineering of imprinted nanocavities are crucial methods for enhancing the identification efficiency of molecularly imprinted polymers(MIPs).To implement this synergistic strategy,bioinspired surface engineering was used to incorporate dual covalent receptors via precise post-imprinting modifications(PIMs)onto mesoporous silica nanosheets.The prepared sorbents(denoted as‘‘D-PMIPs”)were utilized to improve the specific identification of adenosine 5-monophosphate(AMP).Significantly,the mesoporous silica nanosheets possess a high surface area of approximately 498.73 m^(2)·g^(-1),which facilitates the formation of abundant specific recognition sites in the D-PMIPs.The dual covalent receptors are valuable for estab-lishing the spatial orientation and arrangement of AMP through multiple cooperative interactions.PIMs enable precise site-specific functionalization within the imprinted cavities,leading to the tailor-made formation of complementary binding sites.The maximum number of high-affinity binding sites(Nmax)of the D-PMIPs is 39.99 lmol·g^(-1),which is significantly higher than that of imprinted sorbents with a sin-gle receptor(i.e.,S-BMIPs or S-PMIPs).The kinetic data of the D-PMIPs can be effectively described by a pseudo-second-order model,indicating that the main binding mechanism involves synergistic chemisorption from boronate affinity and the pyrimidine base.This study suggests that using dual cova-lent receptors and PIMs is a reliable approach for creating imprinted sorbents with high selectivity,allow-ing for the controlled engineering of imprinted sites.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
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
During brain ischemia,excitotoxicity and peri-infarct depolarization injuries occur and cause cerebral tissue damage.Indeed,anoxic depolarization,consisting of massive neuronal depolarization due to the loss of membra...During brain ischemia,excitotoxicity and peri-infarct depolarization injuries occur and cause cerebral tissue damage.Indeed,anoxic depolarization,consisting of massive neuronal depolarization due to the loss of membrane ion gradients,occurs in vivo or in vitro during an energy failure.The neuromodulator adenosine is released in huge amounts during cerebral ischemia and exerts its effects by activating specific metabotropic receptors,namely:A_(1),A_(2A),A_(2B),and A_(3).The A_(2A)receptor subtype is highly expressed in striatal medium spiny neurons,which are particularly susceptible to ischemic damage.Evidence indicates that the A2Areceptors are upregulated in the rat striatum after stroke and the selective antagonist SCH58261 protects from exaggerated glutamate release within the first 4 hours from the insult and alleviates neurological impairment and histological injury in the following 24 hours.We recently added new knowledge to the mechanisms by which the adenosine A2Areceptor subtype participates in ischemia-induced neuronal death by performing patch-clamp recordings from medium spiny neurons in rat striatal brain slices exposed to oxygen and glucose deprivation.We demonstrated that the selective block of A2Areceptors by SCH58261 significantly reduced ionic imbalance and delayed the anoxic depolarization in medium spiny neurons during oxygen and glucose deprivation and that the mechanism involves voltage-gated K+channel modulation and a presynaptic inhibition of glutamate release by the A2Areceptor antagonist.The present review summarizes the latest findings in the literature about the possibility of developing selective ligands of A2Areceptors as advantageous therapeutic tools that may contribute to counteracting neurodegeneration after brain ischemia.展开更多
This review examined the critical role of adenosine signaling in modulating the behavior of tumor-associated macrophages(TAMs),a key determinant of the tumor microenvironment(TME).Adenosine is an immunosuppressive met...This review examined the critical role of adenosine signaling in modulating the behavior of tumor-associated macrophages(TAMs),a key determinant of the tumor microenvironment(TME).Adenosine is an immunosuppressive metabolite that is highly enriched in the TME due to elevated expression of adenosine triphosphatase(ATPase).Adenosine influences polarization of TAMs through A2A and A2B receptors,which drives a phenotype that supports tumor progression and immune evasion.The adenosine-mediated regulation of TAMs significantly suppresses the TME,dampening the efficacy of current immunotherapies.Targeting the adenosine pathway has shown potential in preclinical studies through reversal of the immunosuppressive microenvironment and antitumor immune response enhancement.Clinical trials are currently underway to determine the impact of A2A receptor antagonists,and CD39 and CD73 inhibition,enzymes that are pivotal in adenosine production,in various cancers.The current understanding of the CD39-CD73-adenosine axis in TAM regulation and the emerging strategies targeting adenosine signaling pathway for therapeutic intervention are the subjects of this review.The current clinical trials focusing on adenosine pathway inhibitors in combination with existing therapies to improve clinical outcomes are summarized and the need for continued research to refine these approaches for cancer treatment is emphasized.展开更多
BACKGROUND The biochemical phenomenon defined as poly adenosine diphosphate(ADP)-ribosylation(PARylation)is essential for the progression of pancreatic cancer.However,the excessive accumulation of poly ADP-ribose(PAR)...BACKGROUND The biochemical phenomenon defined as poly adenosine diphosphate(ADP)-ribosylation(PARylation)is essential for the progression of pancreatic cancer.However,the excessive accumulation of poly ADP-ribose(PAR)induces apoptosis-inducing factor(AIF)release from mitochondria and energy deprivation resulting in the caspase-independent death of cancer cells.AIM To investigate whether sustained calcium supply could induce an anticancer effect on pancreatic cancer by PAR accumulation.METHODS Two pancreatic cancer cell lines,AsPC-1 and CFPAC-1 were used for the study.Calcium influx and mitochondrial reactive oxygen species(ROS)were observed by fluorescence staining.Changes in enzyme levels,as well as PAR accumulation and energy metabolism,were measured using assay kits.AIF-dependent cell death was investigated followed by confirming in vivo anticancer effects by sustained calcium administration.RESULTS Mitochondrial ROS levels were elevated with increasing calcium influx into pancreatic cancer cells.Then,excess PAR accumulation,decreased PAR glycohydrolase and ADP-ribosyl hydrolase 3 levels,and energy deprivation were observed.In vitro and in vivo antitumor effects were confirmed to accompany elevated AIF levels.CONCLUSION This study visualized the potential anticancer effects of excessive PAR accumulation by sustained calcium supply on pancreatic cancer,however elucidating a clear mode of action remains a challenge,and it should be accompanied by further studies to assess its potential for clinical application.展开更多
The development of colorectal cancer(CRC)can result from changes in a variety of cellular systems within the tumor microenvironment.Particularly,it is primarily associated with genomic instability that is the gradual ...The development of colorectal cancer(CRC)can result from changes in a variety of cellular systems within the tumor microenvironment.Particularly,it is primarily associated with genomic instability that is the gradual accumulation of genetic and epigenetic changes consisting of a characteristic set of mutations crucial for pathways in CRC progression.Based on this background,the potential to focus on poly[adenosine diphosphate(ADP)-ribose]polymerase(PARP)-1 and poly-ADP ribosylation(PARylation)as the main causes of malignant formation of CRC may be considered.One of the important functions of PARP-1 and PARylation is its deoxyribonucleic acid(DNA)repair function,which plays a pivotal role in the DNA damage response and prevention of DNA damage maintaining the redox homeostasis involved in the regulation of oxidation and superoxide.PARP-1 and PARylation can also alter epigenetic markers and chromatin structure involved in transcriptional regulation for the oncogenes or tumor suppressor genes by remodeling histone and chromatin enzymes.Given the high importance of these processes in CRC,it can be considered that PARP-1 and PARylation are at the forefront of the pathological changes required for CRC progression.Therefore,this review addresses the current molecular biological features for understanding the multifactorial function of PARP-1 and PARylation in CRC related to the aforementioned roles;furthermore,it presents a summary of recent approaches with PARP-1 inhibition in non-clinical and clinical studies targeting CRC.This understanding could help embrace the importance of targeting PARP-1 and PARylation in the treatment of CRC,which may present the potential to identify various research topics that can be challenged both nonclinically and clinically.展开更多
AIM： To examine the effects of adenosine and A1 receptor activation on reperfusion-induced small intestinal injury. METHODS： Rats were randomized into groups with sham operation, ischemia and reperfusion, and system...AIM： To examine the effects of adenosine and A1 receptor activation on reperfusion-induced small intestinal injury. METHODS： Rats were randomized into groups with sham operation, ischemia and reperfusion, and systemic treatments with either adenosine or 2-chloro-N^6-cyclopentyladenosine, A1 receptor agonist or 8-cyclopentyl- 1,3-clipropylxanthine, A1 receptor antagonist, plus adenosine before ischemia. Following reperfusion, contractions of ileum segments in response to KCl, carbachol and substance P were recorded. Tissue myeloperoxidase,malondialdehyde, and reduced glutathione levels were measured. RESULTS： Ischemia significantly decreased both contraction and reduced glutathione level which were ameliorated by adenosine and agonist administration. Treatment also decreased neutrophil infiltration and membrane lipid peroxidation. Beneficial effects of adenosine were abolished by pretreatment with A1 receptor antagonist. CONCLUSION： The data suggest that adenosine and A1 receptor stimulation attenuate ischemic intestinal injury via decreasing oxidative stress, lowering neutrophil infiltration, and increasing reduced glutathione content.展开更多
文摘RNA contains diverse post-transcriptional modifications,and its catabolic breakdown yields numerous modified nucleosides requiring correct processing,but the mechanisms remain unknown.Here,we demonstrate that three RNA-derived modified adenosines,N6-methyladenosine(m6A),N6,N6-dimethyladenosine(m6,6A),and N6-isopentenyladenosine(i6A),are sequentially metabolized into inosine monophosphate(IMP)to mitigate their intrinsic cytotoxicity.
基金supported by a grant from Ministry of Science,Technological Development and Innovation,Serbia,No.451-03-68/2022-14/200178(to NN)University of Defence,No.MFVMA/02/22-24(to MN)。
文摘An imbalance in adenosine-mediated signaling,particularly the increased A_(2A)R-mediated signaling,plays a role in the pathogenesis of Parkinson's disease.Existing therapeutic approaches fail to alter disease progression,demonstrating the need for novel approaches in PD.Repetitive transcranial magnetic stimulation is a non-invasive approach that has been shown to improve motor and non-motor symptoms of Parkinson's disease.However,the underlying mechanisms of the beneficial effects of repetitive transcranial magnetic stimulation remain unknown.The purpose of this study is to investigate the extent to which the beneficial effects of prolonged intermittent theta burst stimulation in the 6-hydroxydopamine model of experimental parkinsonism are based on modulation of adenosine-mediated signaling.Animals with unilateral 6-hydroxydopamine lesions underwent intermittent theta burst stimulation for 3 weeks and were tested for motor skills using the Rotarod test.Immunoblot,quantitative reverse transcription polymerase chain reaction,immunohistochemistry,and biochemical analysis of components of adenosine-mediated signaling were performed on the synaptosomal fraction of the lesioned caudate putamen.Prolonged intermittent theta burst stimulation improved motor symptoms in 6-hydroxydopamine-lesioned animals.A 6-hydroxydopamine lesion resulted in progressive loss of dopaminergic neurons in the caudate putamen.Treatment with intermittent theta burst stimulation began 7 days after the lesion,coinciding with the onset of motor symptoms.After treatment with prolonged intermittent theta burst stimulation,complete motor recovery was observed.This improvement was accompanied by downregulation of the e N/CD73-A_(2A)R pathway and a return to physiological levels of A_(1)R-adenosine deaminase 1 after 3 weeks of intermittent theta burst stimulation.Our results demonstrated that 6-hydroxydopamine-induced degeneration reduced the expression of A_(1)R and elevated the expression of A_(2A)R.Intermittent theta burst stimulation reversed these effects by restoring the abundances of A_(1)R and A_(2A)R to control levels.The shift in ARs expression likely restored the balance between dopamine-adenosine signaling,ultimately leading to the recovery of motor control.
基金supported by the National Natural Science Foundation of China,No.82003965the Science and Technology Research Project of Sichuan Provincial Administration of Traditional Chinese Medicine,No.2024MS167(to LH)+2 种基金the Xinglin Scholar Program of Chengdu University of Traditional Chinese Medicine,No.QJRC2022033(to LH)the Improvement Plan for the'Xinglin Scholar'Scientific Research Talent Program at Chengdu University of Traditional Chinese Medicine,No.XKTD2023002(to LH)the 2023 National Project of the College Students'Innovation and Entrepreneurship Training Program at Chengdu University of Traditional Chinese Medicine,No.202310633028(to FD)。
文摘The interaction between the gut microbiota and cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enhances communication along the gut–brain axis.The gut microbiota influences the cAMP-PKA signaling pathway through its metabolites,which activates the vagus nerve and modulates the immune and neuroendocrine systems.Conversely,alterations in the cAMP-PKA signaling pathway can affect the composition of the gut microbiota,creating a dynamic network of microbial-host interactions.This reciprocal regulation affects neurodevelopment,neurotransmitter control,and behavioral traits,thus playing a role in the modulation of neurological diseases.The coordinated activity of the gut microbiota and the cAMP-PKA signaling pathway regulates processes such as amyloid-β protein aggregation,mitochondrial dysfunction,abnormal energy metabolism,microglial activation,oxidative stress,and neurotransmitter release,which collectively influence the onset and progression of neurological diseases.This study explores the complex interplay between the gut microbiota and cAMP-PKA signaling pathway,along with its implications for potential therapeutic interventions in neurological diseases.Recent pharmacological research has shown that restoring the balance between gut flora and cAMP-PKA signaling pathway may improve outcomes in neurodegenerative diseases and emotional disorders.This can be achieved through various methods such as dietary modifications,probiotic supplements,Chinese herbal extracts,combinations of Chinese herbs,and innovative dosage forms.These findings suggest that regulating the gut microbiota and cAMP-PKA signaling pathway may provide valuable evidence for developing novel therapeutic approaches for neurodegenerative diseases.
文摘BACKGROUND Although inflammatory diseases commonly affect the pleura and pleural space,their mechanisms of action remain unclear.The presence of several mediators emphasizes the concept of pleural inflammation.Adenosine deaminase(ADA)is an inflammatory mediator detected at increased levels in the pleural fluid.AIM To determine the role of total pleural ADA(P-ADA)levels in the diagnosis of pleural inflammatory diseases.METHODS 157 patients with inflammatory pleural effusion(exudates,n=124,79%)and noninflammatory pleural effusion(transudates,n=33,21%)were included in this observational retrospective cohort study.The P-ADA assay was tested using a kinetic technique.The performance of the model was evaluated using the area under the receiver operating characteristic(ROC)curve(AUC).The ideal cutoff value for P-ADA in pleural inflammation was determined using the Youden index in the ROC curve.RESULTS The transudates included congestive heart failure(n=26),cirrhosis of the liver with ascites(n=3),chronic renal failure(n=3),and low total protein levels(n=1).The exudate cases included tuberculosis(n=44),adenocarcinoma(n=37),simple parapneumonic effusions(n=15),complicated parapneumonic effusions/empyema(n=8),lymphoma(n=7),and other diseases(n=13).The optimal cutoff value of P-ADA was≥9.00 U/L.The diagnostic parameters as sensitivity,specificity,positive and negative predictive values,positive and negative likelihood values,odds ratio,and accuracy were 77.69(95%CI:69.22-84.75);68.75(95%CI:49.99-83.88);90.38 and 44.90(95%CI:83.03-95.29;30.67-59.77);2.48 and 0.32(95%CI:2.21-11.2;0.27-0.51);7.65(95%CI:0.78-18.34),and 75.82(95%CI:68.24-82.37),respectively(χ^(2)=29.51,P=0.00001).An AUC value of 0.8107(95%CI:0.7174-0.8754;P=0.0000)was clinically useful.The Hosmer-Lemeshow test showed excellent discrimination.CONCLUSION P-ADA biomarker has high diagnostic performance for pleural inflammatory exudates.
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.
文摘Pleural effusion,characterized by the accumulation of fluid in the pleural space,poses significant challenges in clinical practice,especially in determining whether it belongs to the inflammatory exudates or non-inflammatory transudates.Adenosine deaminase(ADA),an enzyme primarily produced by immune cells,particularly lymphocytes,increase in response to inflammatory conditions,including tuberculosis and malignancies.Elevated ADA levels in pleural have been shown to correlate with inflammatory exudates,making it a valuable biomarker for dif-ferentiating between inflammatory and non-inflammatory effusions.Moreover,numerous studies have demonstrated the treatment function of ADA in inflammation-related pleural effusion syndrome.Recently,research has established the values for the implication of ADA in diagnosing and managing pleural disease.Based on these findings,ADA becomes a reliable,non-invasive marker for early diagnosis and the appropriate treatment for pleural inflammation,ultimately improving patient outcomes.
文摘This editorial underscores the importance of Maranhão et al’s study,which investigates pleural adenosine deaminase(P-ADA)as a biomarker for inflammatory pleural effusions.Despite advances in imaging,distinguishing between inflammatory and non-inflammatory causes of pleural effusion remains a diagnostic challenge.The authors conducted a rigorous retrospective cohort analysis of 157 patients(124 with inflammatory exudates and 33 with non-inflammatory transudates),establishing a robust cutoff value of P-ADA≥9.00 U/L for diagnosing inflammatory diseases using receiver operating characteristic curve analysis and internal statistical calibration.This is the first study to define a standardized PADA threshold in a Brazilian cohort,addressing previous inconsistencies in cutoff values.Furthermore,the authors delved into the pathophysiological mechanisms underlying elevated P-ADA,linking it to purinergic signaling pathways and immune cell activation,particularly emphasizing the role of ADA2 isoforms in macrophages and lymphocytes.Their findings support P-ADA as a non-invasive,cost-effective biomarker for early diagnosis,treatment stratification,and minimizing the need for invasive procedures such as thoracentesis.This has particular relevance in resource-limited settings,where streamlined diagnostics can reduce healthcare costs and improve patient outcomes.Future studies must prioritize global validation,explore the integration of adenosine deaminase with additional biomarkers(e.g.,interleukin 6,C-reactive protein),and support the development of point-of-care technologies.
基金supported by grants from the Deutsche Forschungsgemeinschaft(HU 2614/1-1(Project No.462650276))the Fritz Thyssen Foundation(10.21.1.021MN)the Medical faculty of the University of Saarland(HOMFOR2016,HOMFORexzellent2017,HOMFOR2024 Anschubfinanzierung)to WH。
文摘Neuroinflammation,the inflammatory response of the central nervous system(CNS),is a common feature of many neurological disorders such as sepsis-associated encephalopathy(SAE),multiple sclerosis(MS),and Parkinson's disease(PD).Prior studies identified cytokines(e.g.,tumor necrosis factor[TNF],interleukin[IL]-1,and IL-6)delivered by resident glial cells and brain-invading peripheral immune cells as the major contributor to neuroinflammation(Becher et al.,2017).In addition to pro-inflammatory cytokines,elevated levels of extracellular purine molecules such as adenosine triphosphate(ATP)and adenosine can be detected upon any pathological insults(e.g.,injury,ischemia,and hypoxia),contributing to the progression of neurological disorders(Borea et al.,2017).
基金Supported by Science and Technology Department of Yunnan Province-Kunming Medical University,Kunming Medical Joint Special Project-Surface Project,No.202401AY070001-164Yunnan Provincial Clinical Research Center Cardiovascular Diseases-New Technology Research for Development Project for Diagnosis and Treatment Cardiovascular Diseases,No.202102AA310002the Key Technology Research and Device Development Project for Innovative Diagnosis and Treatment of Structural Heart Disease in the Southwest Plateau Region,No.202302AA310045.
文摘Heart failure(HF)has emerged as one of the foremost global health threats due to its intricate pathophysiological mechanisms and multifactorial etiology.Adeno-sine triphosphate(ATP)-induced cell death represents a novel form of regulated cell deaths,marked by cellular energy depletion and metabolic dysregulation stemming from excessive ATP accumulation,identifying its uniqueness compared to other cell death processes modalities such as programmed cell death and necrosis.Growing evidence suggests that ATP-induced cell death(AICD)is predominantly governed by various biological pathways,including energy meta-bolism,redox homeostasis and intracellular calcium equilibrium.Recent research has shown that AICD is crucial in HF induced by pathological conditions like myocardial infarction,ischemia-reperfusion injury,and chemotherapy.Thus,it is essential to investigate the function of AICD in the pathogenesis of HF,as this may provide a foundation for the development of targeted therapies and novel treatment strategies.This review synthesizes current advancements in under-standing the link between AICD and HF,while further elucidating its invol-vement in cardiac remodeling and HF progression.
文摘BACKGROUND Erianin is a natural bibenzyl compound extracted from Dendrobium chrysotoxum and is known for its anti-inflammatory and antioxidant properties.AIM To explore the possible therapeutic mechanisms of erianin and determine if it can reduce cardiac damage in mice with type 2 diabetes.METHODS High-fat diet and intraperitoneal injections of streptozotocin were used to induce type 2 diabetes mellitus in C57BL/6 mice.Mice were divided into different groups including control,model,and treatment with various doses of erianin(10,20,and 40 mg/kg)as well as ML-385+erianin group.RESULTS Erianin reduced oxidative stress and inflammation and alleviated diabetic cardiomyopathy through the activation of the adenosine monophosphate-acti-vated protein kinase(AMPK)-nuclear factor erythroid 2-related factor 2(Nrf2)-heme oxygenase-1(HO-1)pathway.Treatments with erianin-M and erianin-H promoted weight stabilization and normalized fasting glucose levels relative to diabetic controls.Echocardiographic assessment demonstrated that erianin dose-dependently enhanced left ventricular systolic function(left ventricular ejection fraction,left ventricular fractional shortening)and mitigated ventricular remodeling(left ventricular internal diameter at end-diastole,left ventricular internal diameter at end-systole;P<0.05 vs model group).No significant differences were observed between the ML-385+erianin and placebo-treated groups.Histopathological examination through hematoxylin-eosin staining indicated that erianin ameliorated myocardial fiber fragmentation,structural disorganization,inflammatory cell infiltration,and cytolytic damage.Furthermore,it significantly reduced the serum levels of cardiac troponin I,creatine kinase,and its MB isoenzyme.However,the ML-385+erianin co-treatment failed to alleviate myocardial injury.Metabolic profiling revealed erianin-mediated improvements in glycemic regulation(glycated hemoglobin:P<0.001),plasma insulin homeostasis,and lipid metabolism(total cholesterol,triglycerides,low-density lipo-protein cholesterol reduction,and high-density lipoprotein cholesterol restoration;P<0.05 vs model group).Pro-inflammatory cytokines including tumor necrosis factor-α,interleukin(IL)-1β,and IL-6 were markedly suppressed in the erianin-M and erianin-H groups compared with the model group,whereas no significant differences were detected between the model and ML-385+erianin groups.Oxidative stress parameters showed decreased malondialdehyde levels accompanied by elevated superoxide dismutase and catalase activities in erianin-treated groups,with the most pronounced effects in the erianin-H group(P<0.05).Western blot analysis confirmed the significant upregulation of proteins associated with the AMPK/Nrf2/HO-1 pathway in erianin-M and erianin-H groups.These protective effects were abolished in the ML-385+erianin co-treatment group,which showed no statistical differences from the model group.CONCLUSION Erianin can effectively alleviate myocardial injury in type 2 diabetic mice by activating the AMPK-Nrf2-HO-1 pathway.
文摘The tumor microenvironment(TME)is characterized by a symbiosis between cancer cells and the immune cells.The scarcity of oxygen generates hostility that forces cancer cells to alter their biological features in solid tumors.In response to low oxygen availability,the Hypoxia Inducible Factors(HIF-1/2/3α)act as metabolic mediators,producing extracellular metabolites in the tumor microenvironment that influence the immune cells.The modulation of lactate and adenosine on immune evasion has been widely described;however,under hypoxic conditions,it has been barely addressed.Evidence has demonstrated an interplay between cancer and the immune cells,and the present review explores thefindings that support HIFs bridging the gap between the rise of these metabolites and the immunosurveillance failure in a hypoxic context.Moreover,new insights based on systemic oxygen administration are discussed,which might counterbalance the effect mediated by lactate and adenosine,to recover anti-tumor immunity.Thus,the disruption of anti-tumor immunity has been the focus of recent research and this novel avenue opens therapeutic vulnerabilities that can be useful for cancer patients.
基金supported by the National Natural Science Foundation of China(22078132,22108103,and U22A20413)the Open Funding Project of the National Key Labora-tory of Biochemical Engineering(2021KF-02)+3 种基金China Postdoctoral Science Foundation(2021M691301)Jiangsu Key Research and Development Program(BE2022356)the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation(CPSF)(GZ20230989)Jiangsu Agricultural Independent Innovation Fund Project(CX(21)3079).
文摘Expanding the specific surface area of substrates and carrying out precise surface engineering of imprinted nanocavities are crucial methods for enhancing the identification efficiency of molecularly imprinted polymers(MIPs).To implement this synergistic strategy,bioinspired surface engineering was used to incorporate dual covalent receptors via precise post-imprinting modifications(PIMs)onto mesoporous silica nanosheets.The prepared sorbents(denoted as‘‘D-PMIPs”)were utilized to improve the specific identification of adenosine 5-monophosphate(AMP).Significantly,the mesoporous silica nanosheets possess a high surface area of approximately 498.73 m^(2)·g^(-1),which facilitates the formation of abundant specific recognition sites in the D-PMIPs.The dual covalent receptors are valuable for estab-lishing the spatial orientation and arrangement of AMP through multiple cooperative interactions.PIMs enable precise site-specific functionalization within the imprinted cavities,leading to the tailor-made formation of complementary binding sites.The maximum number of high-affinity binding sites(Nmax)of the D-PMIPs is 39.99 lmol·g^(-1),which is significantly higher than that of imprinted sorbents with a sin-gle receptor(i.e.,S-BMIPs or S-PMIPs).The kinetic data of the D-PMIPs can be effectively described by a pseudo-second-order model,indicating that the main binding mechanism involves synergistic chemisorption from boronate affinity and the pyrimidine base.This study suggests that using dual cova-lent receptors and PIMs is a reliable approach for creating imprinted sorbents with high selectivity,allow-ing for the controlled engineering of imprinted sites.
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supported by University of Florence RICATEN 2023 to EC.Grant/Award Numbers 58514_InternazionalizzazioneUniversity of Florence,to EC.Parkinson’s UK,Grant/Award Number:H-0902 to AJGWellcome Trust,Grant/Award Number:0926/Z/10/Z to AJG。
文摘During brain ischemia,excitotoxicity and peri-infarct depolarization injuries occur and cause cerebral tissue damage.Indeed,anoxic depolarization,consisting of massive neuronal depolarization due to the loss of membrane ion gradients,occurs in vivo or in vitro during an energy failure.The neuromodulator adenosine is released in huge amounts during cerebral ischemia and exerts its effects by activating specific metabotropic receptors,namely:A_(1),A_(2A),A_(2B),and A_(3).The A_(2A)receptor subtype is highly expressed in striatal medium spiny neurons,which are particularly susceptible to ischemic damage.Evidence indicates that the A2Areceptors are upregulated in the rat striatum after stroke and the selective antagonist SCH58261 protects from exaggerated glutamate release within the first 4 hours from the insult and alleviates neurological impairment and histological injury in the following 24 hours.We recently added new knowledge to the mechanisms by which the adenosine A2Areceptor subtype participates in ischemia-induced neuronal death by performing patch-clamp recordings from medium spiny neurons in rat striatal brain slices exposed to oxygen and glucose deprivation.We demonstrated that the selective block of A2Areceptors by SCH58261 significantly reduced ionic imbalance and delayed the anoxic depolarization in medium spiny neurons during oxygen and glucose deprivation and that the mechanism involves voltage-gated K+channel modulation and a presynaptic inhibition of glutamate release by the A2Areceptor antagonist.The present review summarizes the latest findings in the literature about the possibility of developing selective ligands of A2Areceptors as advantageous therapeutic tools that may contribute to counteracting neurodegeneration after brain ischemia.
基金supported by grants from the State’s Key Project of Research and Development Plan(Grant No.2021YFE0110600)the National Natural Science Foundation of China(Grant Nos.82072578 and 82350121)the Funding for Scientific Research and Innovation Team of The First Affiliated Hospital of Zhengzhou University(Grant No.ZYCXTD2023013)。
文摘This review examined the critical role of adenosine signaling in modulating the behavior of tumor-associated macrophages(TAMs),a key determinant of the tumor microenvironment(TME).Adenosine is an immunosuppressive metabolite that is highly enriched in the TME due to elevated expression of adenosine triphosphatase(ATPase).Adenosine influences polarization of TAMs through A2A and A2B receptors,which drives a phenotype that supports tumor progression and immune evasion.The adenosine-mediated regulation of TAMs significantly suppresses the TME,dampening the efficacy of current immunotherapies.Targeting the adenosine pathway has shown potential in preclinical studies through reversal of the immunosuppressive microenvironment and antitumor immune response enhancement.Clinical trials are currently underway to determine the impact of A2A receptor antagonists,and CD39 and CD73 inhibition,enzymes that are pivotal in adenosine production,in various cancers.The current understanding of the CD39-CD73-adenosine axis in TAM regulation and the emerging strategies targeting adenosine signaling pathway for therapeutic intervention are the subjects of this review.The current clinical trials focusing on adenosine pathway inhibitors in combination with existing therapies to improve clinical outcomes are summarized and the need for continued research to refine these approaches for cancer treatment is emphasized.
文摘BACKGROUND The biochemical phenomenon defined as poly adenosine diphosphate(ADP)-ribosylation(PARylation)is essential for the progression of pancreatic cancer.However,the excessive accumulation of poly ADP-ribose(PAR)induces apoptosis-inducing factor(AIF)release from mitochondria and energy deprivation resulting in the caspase-independent death of cancer cells.AIM To investigate whether sustained calcium supply could induce an anticancer effect on pancreatic cancer by PAR accumulation.METHODS Two pancreatic cancer cell lines,AsPC-1 and CFPAC-1 were used for the study.Calcium influx and mitochondrial reactive oxygen species(ROS)were observed by fluorescence staining.Changes in enzyme levels,as well as PAR accumulation and energy metabolism,were measured using assay kits.AIF-dependent cell death was investigated followed by confirming in vivo anticancer effects by sustained calcium administration.RESULTS Mitochondrial ROS levels were elevated with increasing calcium influx into pancreatic cancer cells.Then,excess PAR accumulation,decreased PAR glycohydrolase and ADP-ribosyl hydrolase 3 levels,and energy deprivation were observed.In vitro and in vivo antitumor effects were confirmed to accompany elevated AIF levels.CONCLUSION This study visualized the potential anticancer effects of excessive PAR accumulation by sustained calcium supply on pancreatic cancer,however elucidating a clear mode of action remains a challenge,and it should be accompanied by further studies to assess its potential for clinical application.
文摘The development of colorectal cancer(CRC)can result from changes in a variety of cellular systems within the tumor microenvironment.Particularly,it is primarily associated with genomic instability that is the gradual accumulation of genetic and epigenetic changes consisting of a characteristic set of mutations crucial for pathways in CRC progression.Based on this background,the potential to focus on poly[adenosine diphosphate(ADP)-ribose]polymerase(PARP)-1 and poly-ADP ribosylation(PARylation)as the main causes of malignant formation of CRC may be considered.One of the important functions of PARP-1 and PARylation is its deoxyribonucleic acid(DNA)repair function,which plays a pivotal role in the DNA damage response and prevention of DNA damage maintaining the redox homeostasis involved in the regulation of oxidation and superoxide.PARP-1 and PARylation can also alter epigenetic markers and chromatin structure involved in transcriptional regulation for the oncogenes or tumor suppressor genes by remodeling histone and chromatin enzymes.Given the high importance of these processes in CRC,it can be considered that PARP-1 and PARylation are at the forefront of the pathological changes required for CRC progression.Therefore,this review addresses the current molecular biological features for understanding the multifactorial function of PARP-1 and PARylation in CRC related to the aforementioned roles;furthermore,it presents a summary of recent approaches with PARP-1 inhibition in non-clinical and clinical studies targeting CRC.This understanding could help embrace the importance of targeting PARP-1 and PARylation in the treatment of CRC,which may present the potential to identify various research topics that can be challenged both nonclinically and clinically.
基金Zonguldak Karaelmas University Research Proje-cts Fund, No. 2003-01-09
文摘AIM： To examine the effects of adenosine and A1 receptor activation on reperfusion-induced small intestinal injury. METHODS： Rats were randomized into groups with sham operation, ischemia and reperfusion, and systemic treatments with either adenosine or 2-chloro-N^6-cyclopentyladenosine, A1 receptor agonist or 8-cyclopentyl- 1,3-clipropylxanthine, A1 receptor antagonist, plus adenosine before ischemia. Following reperfusion, contractions of ileum segments in response to KCl, carbachol and substance P were recorded. Tissue myeloperoxidase,malondialdehyde, and reduced glutathione levels were measured. RESULTS： Ischemia significantly decreased both contraction and reduced glutathione level which were ameliorated by adenosine and agonist administration. Treatment also decreased neutrophil infiltration and membrane lipid peroxidation. Beneficial effects of adenosine were abolished by pretreatment with A1 receptor antagonist. CONCLUSION： The data suggest that adenosine and A1 receptor stimulation attenuate ischemic intestinal injury via decreasing oxidative stress, lowering neutrophil infiltration, and increasing reduced glutathione content.
