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
AIM:To examine the ocular toxicity linked to sildenafilusage and the possible protective benefits of adenosinetriphosphate(ATP)against this toxicity in rats.METHODS:Twenty-four male albino Wistar-type ratswere divided...AIM:To examine the ocular toxicity linked to sildenafilusage and the possible protective benefits of adenosinetriphosphate(ATP)against this toxicity in rats.METHODS:Twenty-four male albino Wistar-type ratswere divided into four equal groups(n=6/group)as follows:healthy group(HG),ATP-only group(ATPG),sildenafil-onlygroup(SILG),and ATP+sildenafil group(ATP+SLD).ATPG andATP+SLD groups were injected intraperitoneally with ATP(4 mg/kg),while SILG and HG groups were injected withsaline(0.9%NaCl)by the same route as a solvent.One hourafter the administration of ATP and solvent,sildenafil(10 m g/k g)was administered orally to the SILG andATP+SLD groups.This procedure was repeated once a dayfor 4wk.The animals were then sacrificed,eyeballs wereremoved and oxidant and antioxidant parameters weremeasured biochemically.Additionally,the ocular tissueswere evaluated histopathologically.RESULTS:Sildenafil increased oxidant(malondialdehyde)levels and decreased antioxidant levels(total glutathione,superoxide dismutase,catalase)in rat ocular tissues andcaused severe oxidative stress.In addition,sildenafil hasbeen shown histopathologically to cause oxidative damagein retinal layers.ATP treatment suppressed oxidative stressand attenuated histopathological damage in the retinal layers.CONCLUSION:ATP protects retinal tissue againstsildenafil-induced ocular oxidative damage in rats andmay contribute to the development of novel approaches toprevent or treat this damage.展开更多
Cholelithiasis has a complex pathogenesis,necessitating better therapeutic and preventive strategies.We recently read with interest Wang et al’s study on lysine acetyltransferase 2A(KAT2A)-mediated adenosine monophos...Cholelithiasis has a complex pathogenesis,necessitating better therapeutic and preventive strategies.We recently read with interest Wang et al’s study on lysine acetyltransferase 2A(KAT2A)-mediated adenosine monophosphate-activated protein kinase(AMPK)succinylation in cholelithiasis.Using mouse models and gallbladder mucosal epithelial cells,they found that KAT2A inhibits gallstones through AMPK K170 succinylation,thereby activating the AMPK/silent information regulator 1 pathway to reduce inflammation and pyroptosis.This study is the first to connect lysine succinylation with cholelithiasis,offering new insights and identifying succinylation as a potential therapeutic target.Future research should confirm these findings using patient samples,investigate other posttranslational modifications,and use structural biology to clarify succinylationinduced conformational changes,thereby bridging basic research to clinical applications.展开更多
Sporadic or late-onset Alzheimer’s disease(LOAD)occurs in 1 of 10 people over 65 years of age and comprises 95%of all AD patients.Unlike early-onset AD,which is caused by defined single gene mutations,the mechanisms ...Sporadic or late-onset Alzheimer’s disease(LOAD)occurs in 1 of 10 people over 65 years of age and comprises 95%of all AD patients.Unlike early-onset AD,which is caused by defined single gene mutations,the mechanisms and events underlying risk for LOAD are not fully understood and no substantial disease-modifying interventions are currently available.Age is the most prominent risk factor for LOAD,and interacting age-related and LOAD-associated factors contribute to its pathogenesis.Among these factors are changes in bioenergetic cell functions,which metabolize substrates and produce energy stored in adenosine triphosphate.展开更多
Hemorrhagic shock(HS)is a leading cause of death worldwide,particularly within the first 24 h post-injury.Current treatments are limited,especially in low-resource settings.Therapeutic hypothermia(TH)offers potential ...Hemorrhagic shock(HS)is a leading cause of death worldwide,particularly within the first 24 h post-injury.Current treatments are limited,especially in low-resource settings.Therapeutic hypothermia(TH)offers potential benefits by reducing metabolic demands and protecting organs,but its application in HS is challenged by cooling difficulties and side effects.This study introduces a novel nasal gel formulation of N6-cyclohexyladenosine(CHA),an adenosine A1 receptor agonist,designed to enhance brain delivery while minimizing peripheral side effects.In a mouse model of HS,administration of CHA nasal gel significantly improved survival rates,reduced metabolic rates,and protected major organs without worsening coagulopathy.Metabolomics analysis revealed a shift towards fatty acid oxidation and increased antioxidant capacity.These findings demonstrate that CHA nasal gel effectively induces TH,offering a safe and innovative treatment strategy for HS,particularly in resource-limited environments.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
Growing evidence suggests that exercise can provide neuroprotection by improving mitochondrial quality control(MQC)on the aged brain.Adenosine 5′-monophosphate(AMP)-activated protein kinase(AMPK)signaling responsiven...Growing evidence suggests that exercise can provide neuroprotection by improving mitochondrial quality control(MQC)on the aged brain.Adenosine 5′-monophosphate(AMP)-activated protein kinase(AMPK)signaling responsiveness declines with aging.However,whether AMPK plays a role in the exercise-mediated improvement of memory and MQC in the aged hippocampus remains to be established.5-Aminoimidazole 4-carboxamide ribonucleoside(AICAR),a pharmacological agonist of AMPK,has been proposed to be an exercise mimetic recently.However,it has not been clarified whether AICAR could mimic the effects of exercise on the aged hippocampus through improvement of MQC.In this study,AICAR(AMPK agonist)and Compound C(AMPK inhibitor)were used to investigate if AMPK plays a key role in exercise-induced improvement of MQC and if AICAR could act as an exercise mimetic through improvement of MQC in aged hippocampus.Both exercise and AICAR improved the memory of aged mice and increased AMPK phosphorylation in the aged hippocampus.Exercise,but not AICAR,improved mitochondrial respiratory function in the aged hippocampus and increased the microtubule associated protein 1 light chain 3(LC3)-II/LC3-I ratio and the protein expression of LC3-II and autophagy related protein 7(ATG7)in the lysate of whole hippocampal tissue.Both exercise and AICAR increased the ratio of LC3-II/LC3-I and the protein expression of LC3-II in the mitochondrial fractions of the hippocampus.Regarding mitochondrial dynamics,neither exercise training nor AICAR changed the protein level of mitofusin 2(Mfn2).Exercise,but not AICAR,increased the protein level of dynamin-related protein 1(Drp1).Furthermore,both exercise training and AICAR increased the protein level of peroxisome proliferator-activated receptorγcoactivator 1α(PGC-1α),a modulator of mitochondrial biogenesis.Compound C abolished the exercise-induced effects on memory in aged mice,AMPK phosphorylation,autophagy,mitophagy,and mitochondrial fission in the aged hippocampus.However,Compound C did not reverse the exercise-induced increase in PGC-1αprotein levels in the aged hippocampus.Our data provide evidence that AMPK plays an important role in the exercise-induced improvement of memory and MQC in the hippocampus of aged mice.Importantly,we demonstrated for the first time that AICAR could partially mimetic the beneficial effects of endurance exercise on memory and MQC in the hippocampus of aged mice,and thus may be a promising exercise mimetic for counteracting brain aging.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
Studies have shown that chitosan protects against neurodegenerative diseases. However, the precise mechanism remains poorly understood. In this study, we administered chitosan intragastrically to an MPTP-induced mouse...Studies have shown that chitosan protects against neurodegenerative diseases. However, the precise mechanism remains poorly understood. In this study, we administered chitosan intragastrically to an MPTP-induced mouse model of Parkinson's disease and found that it effectively reduced dopamine neuron injury, neurotransmitter dopamine release, and motor symptoms. These neuroprotective effects of chitosan were related to bacterial metabolites, specifically shortchain fatty acids, and chitosan administration altered intestinal microbial diversity and decreased short-chain fatty acid production in the gut. Furthermore, chitosan effectively reduced damage to the intestinal barrier and the blood–brain barrier. Finally, we demonstrated that chitosan improved intestinal barrier function and alleviated inflammation in both the peripheral nervous system and the central nervous system by reducing acetate levels. Based on these findings, we suggest a molecular mechanism by which chitosan decreases inflammation through reducing acetate levels and repairing the intestinal and blood–brain barriers, thereby alleviating symptoms of Parkinson's disease.展开更多
Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell,influencing behaviors from food choices to emotional memories.These receptors also contribute to our perception of flavor...Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell,influencing behaviors from food choices to emotional memories.These receptors also contribute to our perception of flavor and have potential applications in medical diagnostics and environmental monitoring.The ability of the olfactory system to regenerate its sensory neurons provides a unique model to study neural regeneration,a phenomenon largely absent in the central nervous system.Insights gained from how olfactory neurons continuously replace themselves and reestablish functional connections can provide strategies to promote similar regenerative processes in the central nervous system,where damage often results in permanent deficits.Understanding the molecular and cellular mechanisms underpinning olfactory neuron regeneration could pave the way for developing therapeutic approaches to treat spinal co rd injuries and neurodegenerative diseases like Alzheimer's disease.Olfa ctory receptors are found in almost any cell of eve ry orga n/tissue of the mammalian body.This ectopic expression provides insights into the chemical structures that can activate olfactory receptors.In addition to odors,olfactory receptors in ectopic expression may respond to endogenous compounds and molecules produced by mucosal colonizing microbiota.The analysis of the function of olfactory receptors in ectopic expression provides valuable information on the signaling pathway engaged upon receptor activation and the receptor's role in proliferation and cell differentiation mechanisms.This review explo res the ectopic expression of olfa ctory receptors and the role they may play in neural regeneration within the central nervous system,with particular attention to compounds that can activate these receptors to initiate regenerative processes.Evidence suggests that olfactory receptors could serve as potential therapeutic targets for enhancing neural repair and recovery following central nervous system injuries.展开更多
During the development of the nervous system,there is an overproduction of neurons and synapses.Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their el...During the development of the nervous system,there is an overproduction of neurons and synapses.Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their elimination or strengthening.We have extensively studied the involvement of the brain-derived neurotrophic factor-Tropomyosin-related kinase B receptor neurotrophic retrograde pathway,at the neuromuscular junction,in the axonal development and synapse elimination process versus the synapse consolidation.The purpose of this review is to describe the neurotrophic influence on developmental synapse elimination,in relation to other molecular pathways that we and others have found to regulate this process.In particular,we summarize our published results based on transmitter release analysis and axonal counts to show the different involvement of the presynaptic acetylcholine muscarinic autoreceptors,coupled to downstream serine-threonine protein kinases A and C(PKA and PKC)and voltage-gated calcium channels,at different nerve endings in developmental competition.The dynamic changes that occur simultaneously in several nerve terminals and synapses converge across a postsynaptic site,influence each other,and require careful studies to individualize the mechanisms of specific endings.We describe an activity-dependent balance(related to the extent of transmitter release)between the presynaptic muscarinic subtypes and the neurotrophin-mediated TrkB/p75NTR pathways that can influence the timing and fate of the competitive interactions between the different axon terminals.The downstream displacement of the PKA/PKC activity ratio to lower values,both in competing nerve terminals and at postsynaptic sites,plays a relevant role in controlling the elimination of supernumerary synapses.Finally,calcium entry through L-and P/Q-subtypes of voltage-gated calcium channels(both channels are present,together with the N-type channel in developing nerve terminals)contributes to reduce transmitter release and promote withdrawal of the most unfavorable nerve terminals during elimination(the weakest in acetylcholine release and those that have already become silent).The main findings contribute to a better understanding of punishment-rewarding interactions between nerve endings during development.Identifying the molecular targets and signaling pathways that allow synapse consolidation or withdrawal of synapses in different situations is important for potential therapies in neurodegenerative diseases.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
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
Interferon regulatory factor 7 plays a crucial role in the innate immune response.However,whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown.Here we report...Interferon regulatory factor 7 plays a crucial role in the innate immune response.However,whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown.Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease and co-localizes with microglial cells.Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype.In addition,si RNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase,tumor necrosis factorα,CD16,CD32,and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1.Taken together,our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase-stimulator of interferon genes-interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson's disease.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 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
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
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
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
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.
文摘AIM:To examine the ocular toxicity linked to sildenafilusage and the possible protective benefits of adenosinetriphosphate(ATP)against this toxicity in rats.METHODS:Twenty-four male albino Wistar-type ratswere divided into four equal groups(n=6/group)as follows:healthy group(HG),ATP-only group(ATPG),sildenafil-onlygroup(SILG),and ATP+sildenafil group(ATP+SLD).ATPG andATP+SLD groups were injected intraperitoneally with ATP(4 mg/kg),while SILG and HG groups were injected withsaline(0.9%NaCl)by the same route as a solvent.One hourafter the administration of ATP and solvent,sildenafil(10 m g/k g)was administered orally to the SILG andATP+SLD groups.This procedure was repeated once a dayfor 4wk.The animals were then sacrificed,eyeballs wereremoved and oxidant and antioxidant parameters weremeasured biochemically.Additionally,the ocular tissueswere evaluated histopathologically.RESULTS:Sildenafil increased oxidant(malondialdehyde)levels and decreased antioxidant levels(total glutathione,superoxide dismutase,catalase)in rat ocular tissues andcaused severe oxidative stress.In addition,sildenafil hasbeen shown histopathologically to cause oxidative damagein retinal layers.ATP treatment suppressed oxidative stressand attenuated histopathological damage in the retinal layers.CONCLUSION:ATP protects retinal tissue againstsildenafil-induced ocular oxidative damage in rats andmay contribute to the development of novel approaches toprevent or treat this damage.
基金Supported by Wenzhou Science and Technology Bureau,No.Y20240207.
文摘Cholelithiasis has a complex pathogenesis,necessitating better therapeutic and preventive strategies.We recently read with interest Wang et al’s study on lysine acetyltransferase 2A(KAT2A)-mediated adenosine monophosphate-activated protein kinase(AMPK)succinylation in cholelithiasis.Using mouse models and gallbladder mucosal epithelial cells,they found that KAT2A inhibits gallstones through AMPK K170 succinylation,thereby activating the AMPK/silent information regulator 1 pathway to reduce inflammation and pyroptosis.This study is the first to connect lysine succinylation with cholelithiasis,offering new insights and identifying succinylation as a potential therapeutic target.Future research should confirm these findings using patient samples,investigate other posttranslational modifications,and use structural biology to clarify succinylationinduced conformational changes,thereby bridging basic research to clinical applications.
文摘Sporadic or late-onset Alzheimer’s disease(LOAD)occurs in 1 of 10 people over 65 years of age and comprises 95%of all AD patients.Unlike early-onset AD,which is caused by defined single gene mutations,the mechanisms and events underlying risk for LOAD are not fully understood and no substantial disease-modifying interventions are currently available.Age is the most prominent risk factor for LOAD,and interacting age-related and LOAD-associated factors contribute to its pathogenesis.Among these factors are changes in bioenergetic cell functions,which metabolize substrates and produce energy stored in adenosine triphosphate.
基金supported by grants from the National Natural Science Foundation of China(No.81981340417 to LiSu)Natural Science Foundation of Jiangsu Province Outstanding Youth Fund(No.BK20240134 to Yuanqing Gao).
文摘Hemorrhagic shock(HS)is a leading cause of death worldwide,particularly within the first 24 h post-injury.Current treatments are limited,especially in low-resource settings.Therapeutic hypothermia(TH)offers potential benefits by reducing metabolic demands and protecting organs,but its application in HS is challenged by cooling difficulties and side effects.This study introduces a novel nasal gel formulation of N6-cyclohexyladenosine(CHA),an adenosine A1 receptor agonist,designed to enhance brain delivery while minimizing peripheral side effects.In a mouse model of HS,administration of CHA nasal gel significantly improved survival rates,reduced metabolic rates,and protected major organs without worsening coagulopathy.Metabolomics analysis revealed a shift towards fatty acid oxidation and increased antioxidant capacity.These findings demonstrate that CHA nasal gel effectively induces TH,offering a safe and innovative treatment strategy for HS,particularly in resource-limited environments.
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 grants from the National Natural Science Foundation of China(81301128,81771500,82202789,82205065)the 2022 Suzhou Health Youth Backbone Talent“National Tutorial System”Training Project(Qngg2022024)+2 种基金the Science and Technology Project of Suzhou City of China(SKJYD2021195)the Science,Technology and Innovation Commission of Shenzhen(JCYJ20220530165211026)the Postgraduate Research and Practice Innovation Program in Jiangsu Province(KYCX22_3157,KYCX24_3371,YCX25_3517).
文摘Growing evidence suggests that exercise can provide neuroprotection by improving mitochondrial quality control(MQC)on the aged brain.Adenosine 5′-monophosphate(AMP)-activated protein kinase(AMPK)signaling responsiveness declines with aging.However,whether AMPK plays a role in the exercise-mediated improvement of memory and MQC in the aged hippocampus remains to be established.5-Aminoimidazole 4-carboxamide ribonucleoside(AICAR),a pharmacological agonist of AMPK,has been proposed to be an exercise mimetic recently.However,it has not been clarified whether AICAR could mimic the effects of exercise on the aged hippocampus through improvement of MQC.In this study,AICAR(AMPK agonist)and Compound C(AMPK inhibitor)were used to investigate if AMPK plays a key role in exercise-induced improvement of MQC and if AICAR could act as an exercise mimetic through improvement of MQC in aged hippocampus.Both exercise and AICAR improved the memory of aged mice and increased AMPK phosphorylation in the aged hippocampus.Exercise,but not AICAR,improved mitochondrial respiratory function in the aged hippocampus and increased the microtubule associated protein 1 light chain 3(LC3)-II/LC3-I ratio and the protein expression of LC3-II and autophagy related protein 7(ATG7)in the lysate of whole hippocampal tissue.Both exercise and AICAR increased the ratio of LC3-II/LC3-I and the protein expression of LC3-II in the mitochondrial fractions of the hippocampus.Regarding mitochondrial dynamics,neither exercise training nor AICAR changed the protein level of mitofusin 2(Mfn2).Exercise,but not AICAR,increased the protein level of dynamin-related protein 1(Drp1).Furthermore,both exercise training and AICAR increased the protein level of peroxisome proliferator-activated receptorγcoactivator 1α(PGC-1α),a modulator of mitochondrial biogenesis.Compound C abolished the exercise-induced effects on memory in aged mice,AMPK phosphorylation,autophagy,mitophagy,and mitochondrial fission in the aged hippocampus.However,Compound C did not reverse the exercise-induced increase in PGC-1αprotein levels in the aged hippocampus.Our data provide evidence that AMPK plays an important role in the exercise-induced improvement of memory and MQC in the hippocampus of aged mice.Importantly,we demonstrated for the first time that AICAR could partially mimetic the beneficial effects of endurance exercise on memory and MQC in the hippocampus of aged mice,and thus may be a promising exercise mimetic for counteracting brain aging.
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 Natural Science Foundation of China,Nos. 32260196 (to JY), 81860646 (to ZY) and 31860274 (to JY)a grant from Yunnan Department of Science and Technology,Nos. 202101AT070251 (to JY), 202201AS070084 (to ZY), 202301AY070001-239 (to JY), 202101AZ070001-012, and 2019FI016 (to ZY)。
文摘Studies have shown that chitosan protects against neurodegenerative diseases. However, the precise mechanism remains poorly understood. In this study, we administered chitosan intragastrically to an MPTP-induced mouse model of Parkinson's disease and found that it effectively reduced dopamine neuron injury, neurotransmitter dopamine release, and motor symptoms. These neuroprotective effects of chitosan were related to bacterial metabolites, specifically shortchain fatty acids, and chitosan administration altered intestinal microbial diversity and decreased short-chain fatty acid production in the gut. Furthermore, chitosan effectively reduced damage to the intestinal barrier and the blood–brain barrier. Finally, we demonstrated that chitosan improved intestinal barrier function and alleviated inflammation in both the peripheral nervous system and the central nervous system by reducing acetate levels. Based on these findings, we suggest a molecular mechanism by which chitosan decreases inflammation through reducing acetate levels and repairing the intestinal and blood–brain barriers, thereby alleviating symptoms of Parkinson's disease.
文摘Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell,influencing behaviors from food choices to emotional memories.These receptors also contribute to our perception of flavor and have potential applications in medical diagnostics and environmental monitoring.The ability of the olfactory system to regenerate its sensory neurons provides a unique model to study neural regeneration,a phenomenon largely absent in the central nervous system.Insights gained from how olfactory neurons continuously replace themselves and reestablish functional connections can provide strategies to promote similar regenerative processes in the central nervous system,where damage often results in permanent deficits.Understanding the molecular and cellular mechanisms underpinning olfactory neuron regeneration could pave the way for developing therapeutic approaches to treat spinal co rd injuries and neurodegenerative diseases like Alzheimer's disease.Olfa ctory receptors are found in almost any cell of eve ry orga n/tissue of the mammalian body.This ectopic expression provides insights into the chemical structures that can activate olfactory receptors.In addition to odors,olfactory receptors in ectopic expression may respond to endogenous compounds and molecules produced by mucosal colonizing microbiota.The analysis of the function of olfactory receptors in ectopic expression provides valuable information on the signaling pathway engaged upon receptor activation and the receptor's role in proliferation and cell differentiation mechanisms.This review explo res the ectopic expression of olfa ctory receptors and the role they may play in neural regeneration within the central nervous system,with particular attention to compounds that can activate these receptors to initiate regenerative processes.Evidence suggests that olfactory receptors could serve as potential therapeutic targets for enhancing neural repair and recovery following central nervous system injuries.
基金supported by Catalan Government,Nos.2014SGR344(to JT),2017SGR704(to JT),2021SGR01214(to MAL)MCIN/AEI/10.13039/501100011033/by“ERDF A way of making Europe,”Nos.SAF2015-67143(to JT),PID2019-106332GB-I00(to JT and MAL)and PID2022-141252NB-I00(to MAL).
文摘During the development of the nervous system,there is an overproduction of neurons and synapses.Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their elimination or strengthening.We have extensively studied the involvement of the brain-derived neurotrophic factor-Tropomyosin-related kinase B receptor neurotrophic retrograde pathway,at the neuromuscular junction,in the axonal development and synapse elimination process versus the synapse consolidation.The purpose of this review is to describe the neurotrophic influence on developmental synapse elimination,in relation to other molecular pathways that we and others have found to regulate this process.In particular,we summarize our published results based on transmitter release analysis and axonal counts to show the different involvement of the presynaptic acetylcholine muscarinic autoreceptors,coupled to downstream serine-threonine protein kinases A and C(PKA and PKC)and voltage-gated calcium channels,at different nerve endings in developmental competition.The dynamic changes that occur simultaneously in several nerve terminals and synapses converge across a postsynaptic site,influence each other,and require careful studies to individualize the mechanisms of specific endings.We describe an activity-dependent balance(related to the extent of transmitter release)between the presynaptic muscarinic subtypes and the neurotrophin-mediated TrkB/p75NTR pathways that can influence the timing and fate of the competitive interactions between the different axon terminals.The downstream displacement of the PKA/PKC activity ratio to lower values,both in competing nerve terminals and at postsynaptic sites,plays a relevant role in controlling the elimination of supernumerary synapses.Finally,calcium entry through L-and P/Q-subtypes of voltage-gated calcium channels(both channels are present,together with the N-type channel in developing nerve terminals)contributes to reduce transmitter release and promote withdrawal of the most unfavorable nerve terminals during elimination(the weakest in acetylcholine release and those that have already become silent).The main findings contribute to a better understanding of punishment-rewarding interactions between nerve endings during development.Identifying the molecular targets and signaling pathways that allow synapse consolidation or withdrawal of synapses in different situations is important for potential therapies in neurodegenerative diseases.
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.
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.
基金supported by the National Natural Science Foundation of China,Nos.82171429,81771384a grant from Wuxi Municipal Health Commission,No.1286010241190480(all to YS)。
文摘Interferon regulatory factor 7 plays a crucial role in the innate immune response.However,whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown.Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease and co-localizes with microglial cells.Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype.In addition,si RNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase,tumor necrosis factorα,CD16,CD32,and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1.Taken together,our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase-stimulator of interferon genes-interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson's disease.
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 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.
