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
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
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
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
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
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
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
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
Diabetic peripheral neuropathy(DPN)is a common complication of diabetes and is characterized by sensory and motor impairments resulting from neural injury.Schwann cells(SCs),which are important for peripheral nerve fu...Diabetic peripheral neuropathy(DPN)is a common complication of diabetes and is characterized by sensory and motor impairments resulting from neural injury.Schwann cells(SCs),which are important for peripheral nerve function,are compromised under hyperglycemic conditions,leading to impaired axonal re-generation and demyelination.Autophagy,a cellular degradation process,is essential for SC function and significantly influences DPN progression.This article highlights the significance of autophagy in SCs and its potential as a pharmacotherapeutic target in DPN.We discuss the mechanisms of autophagy in SCs,including the mammalian target of rapamycin,adenosine monophosphate-activated protein kinase,and phosphatase and tensin homolog-induced putative kinase/parkin pathways,and their dysregulation in DPN.This article also exa-mines various natural products and chemical agents that modulate autophagy and enhance the efficacy of DPN treatment.These agents target key signaling pathways,such as adenosine monophosphate-activated protein kinase/mam-malian target of rapamycin and demonstrate potential in promoting nerve re-generation and restoring SC function.The roles of exosomes,long non-coding RNA,and proteins in the regulation of autophagy have also been explored.In conclusion,targeting autophagy in SCs is a promising strategy for DPN treatment and offers new insights into therapeutic interventions.Further research is war-ranted to fully exploit these targets for clinical applications.展开更多
BACKGROUND Chemotherapy is an essential treatment for colorectal cancer(CRC)patients after surgery,but many patients do not benefit from chemotherapy because tumour heterogeneity results in varied responses.AIM To stu...BACKGROUND Chemotherapy is an essential treatment for colorectal cancer(CRC)patients after surgery,but many patients do not benefit from chemotherapy because tumour heterogeneity results in varied responses.AIM To study the effectiveness of in vitro chemosensitivity tests adenosine tripho-sphate-based tumour chemotherapy sensitivity test(ATP-TCA)for tailoring po-stoperative chemotherapy regimens for patients with CRC.METHODS Between January 2015 to December 2021,a total of 1549 CRC patients underwent surgery and in vitro chemosensitivity testing using ATP-TCA.A subset of 405 patients who met the survival assessment criteria were followed to collect data on overall survival(OS)and disease-free survival(DFS).Cox regression analysis revealed independent prognostic factors that affect OS and DFS for those re-ceiving oxaliplatin(L-OPH)and fluoropyrimidine-based regimens,aiding in the development of clinical predictive models.The relationships between the ATP-TCA results and clinical outcomes were analysed using the Kaplan-Meier method.RESULTS Tumour heterogeneity and resistance to multiple drugs were observed in 1549 patients.The sensitivity to 5-fluorouracil(5-FU)combined with L-OPH was tested among 1474 of these patients,yielding a sensitivity rate of 11.9%.ATP-TCA results were identified as an independent prognostic factor for DFS[P=0.002,hazard ratio(95%confidence interval):4.98(1.81-13.72)]in patients with resectable CRC.Compared with drug-resistant patients,sensitive CRC patients treated with 5-FU and L-OPH had significantly prolonged DFS(P=0.027).Further Kaplan-Meier analysis indicated that ATP-TCA sensitivity was significantly associated with improved OS(P=0.048)and DFS(P=0.003)in patients with stage III CRC.CONCLUSION The response of CRC patients to the combination regimen of 5-FU and L-OPH is heterogeneous.This study confirmed that the ATP-TCA is a valuable tool for predicting clinical outcomes,such as DFS,in patients with resectable CRC receiving chemotherapy.Although further validation with multicentre data is still necessary,these findings support that the ATP-TCA may function as a guiding tool for personalized chemotherapy administration,thereby optimizing treatment opportunities for patients.展开更多
BACKGROUND Metabolic dysregulation is considered a significant hallmark of hepatocellular carcinoma(HCC).SAC3 domain containing 1(SAC3D1)functions in the cell cycle,and its expression is upregulated in various cancers...BACKGROUND Metabolic dysregulation is considered a significant hallmark of hepatocellular carcinoma(HCC).SAC3 domain containing 1(SAC3D1)functions in the cell cycle,and its expression is upregulated in various cancers.It is known that metabolic changes occur at different stages of the cell cycle to maintain the biosynthesis and replication of both normal and cancer cells.Based on the role of SAC3D1 in mitosis,we hypothesize that abnormal expression of SAC3D1 may affect cellular metabolism.However,it remains unclear whether SAC3D1 mediates the progression of HCC by regulating metabolic reprogramming.AIM To comprehensively elucidate the impact and molecular mechanism of SAC3D1 on the progression of HCC by regulating the metabolic reprogramming.METHODS The constructed SAC3D1 overexpression and knockdown HCC cell lines were used for detecting cell proliferation,migration capabilities,as well as glycolysis and adenosine triphosphate(ATP)production rate assays.They were also employed for examining molecular markers associated with cell migration and glycolysis.The transcriptome sequencing data of cells have revealed the pathways potentially influenced by SAC3D1.The tail vein metastasis model and xenograft tumor experiments were utilized to demonstrate SAC3D1’s tumor-promoting effects in vivo.RESULTS SAC3D1 expression was upregulated and associated with poor prognosis in HCC patients.SAC3D1 enhanced the proliferation and migration abilities and reduced the population dependence of HCC cells in vitro and in vivo.The upregulation of SAC3D1 enhanced cellular glycolysis and ATP production.The cell transcriptome sequencing data revealed that SAC3D1 activated Wnt signaling pathway.SAC3D1 did not modulate the transcription ofβ-Catenin,while might inhibit its degradation.Further investigations indicated that the increase of SAC3D1 leads to moreβ-Catenin accumulating in the nucleus,facilitating the expression of c-Myc,one of the upstream regulatory factors of glycolysis.The iCRT3,an antagonist ofβ-Catenin,could counteract the increase of c-Myc induced by SAC3D1,while also downregulating the expression of glycolysis-related proteins.CONCLUSION This study found that SAC3D1 enhances HCC cell glycolysis and ATP production via theβ-Catenin/c-Myc signaling axis,thereby promoting the progression of HCC.展开更多
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
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
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
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 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 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 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.
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 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 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 Natural Science Foundation of Hunan Province,No.2023JJ60497Chinese Medicine Research Program of Hunan Province,No.2021169Xiangtan Medical Research Project Plan,No.2022-xtyx-34 and No.2022-xtyx-36.
文摘Diabetic peripheral neuropathy(DPN)is a common complication of diabetes and is characterized by sensory and motor impairments resulting from neural injury.Schwann cells(SCs),which are important for peripheral nerve function,are compromised under hyperglycemic conditions,leading to impaired axonal re-generation and demyelination.Autophagy,a cellular degradation process,is essential for SC function and significantly influences DPN progression.This article highlights the significance of autophagy in SCs and its potential as a pharmacotherapeutic target in DPN.We discuss the mechanisms of autophagy in SCs,including the mammalian target of rapamycin,adenosine monophosphate-activated protein kinase,and phosphatase and tensin homolog-induced putative kinase/parkin pathways,and their dysregulation in DPN.This article also exa-mines various natural products and chemical agents that modulate autophagy and enhance the efficacy of DPN treatment.These agents target key signaling pathways,such as adenosine monophosphate-activated protein kinase/mam-malian target of rapamycin and demonstrate potential in promoting nerve re-generation and restoring SC function.The roles of exosomes,long non-coding RNA,and proteins in the regulation of autophagy have also been explored.In conclusion,targeting autophagy in SCs is a promising strategy for DPN treatment and offers new insights into therapeutic interventions.Further research is war-ranted to fully exploit these targets for clinical applications.
基金Supported by the National Natural Science Foundation of China,No.U24A20765 and No.T2321005Jiangsu Provincial Science and Technology Plan Special Fund,No.BM2023003+5 种基金Jiangsu Provincial Medical Key Discipline,No.ZDXK202247the Priority Academic Program Development of the Jiangsu Higher Education InstitutesJiangsu Engineering Research Center on Drug Evaluation and Translation of Organoids/Organ Chip(2024)the Science and Technology Plan of Suzhou,No.SKYD2023183the Research Project Established by Chinese Pharmaceutical Association Hospital Pharmacy Department,No.CPA-Z05-ZC-2023002Gusu Health Talent Research Project,No.GSWS2022015.
文摘BACKGROUND Chemotherapy is an essential treatment for colorectal cancer(CRC)patients after surgery,but many patients do not benefit from chemotherapy because tumour heterogeneity results in varied responses.AIM To study the effectiveness of in vitro chemosensitivity tests adenosine tripho-sphate-based tumour chemotherapy sensitivity test(ATP-TCA)for tailoring po-stoperative chemotherapy regimens for patients with CRC.METHODS Between January 2015 to December 2021,a total of 1549 CRC patients underwent surgery and in vitro chemosensitivity testing using ATP-TCA.A subset of 405 patients who met the survival assessment criteria were followed to collect data on overall survival(OS)and disease-free survival(DFS).Cox regression analysis revealed independent prognostic factors that affect OS and DFS for those re-ceiving oxaliplatin(L-OPH)and fluoropyrimidine-based regimens,aiding in the development of clinical predictive models.The relationships between the ATP-TCA results and clinical outcomes were analysed using the Kaplan-Meier method.RESULTS Tumour heterogeneity and resistance to multiple drugs were observed in 1549 patients.The sensitivity to 5-fluorouracil(5-FU)combined with L-OPH was tested among 1474 of these patients,yielding a sensitivity rate of 11.9%.ATP-TCA results were identified as an independent prognostic factor for DFS[P=0.002,hazard ratio(95%confidence interval):4.98(1.81-13.72)]in patients with resectable CRC.Compared with drug-resistant patients,sensitive CRC patients treated with 5-FU and L-OPH had significantly prolonged DFS(P=0.027).Further Kaplan-Meier analysis indicated that ATP-TCA sensitivity was significantly associated with improved OS(P=0.048)and DFS(P=0.003)in patients with stage III CRC.CONCLUSION The response of CRC patients to the combination regimen of 5-FU and L-OPH is heterogeneous.This study confirmed that the ATP-TCA is a valuable tool for predicting clinical outcomes,such as DFS,in patients with resectable CRC receiving chemotherapy.Although further validation with multicentre data is still necessary,these findings support that the ATP-TCA may function as a guiding tool for personalized chemotherapy administration,thereby optimizing treatment opportunities for patients.
基金Supported by the Shanghai Yangpu District Science and Technology Commission,No.YPQ202303Shanghai Municipal Health Commission Clinical Research Special Project,No.202240122Shanghai Medical Innovation Research Special Project,No.22Y11908600.
文摘BACKGROUND Metabolic dysregulation is considered a significant hallmark of hepatocellular carcinoma(HCC).SAC3 domain containing 1(SAC3D1)functions in the cell cycle,and its expression is upregulated in various cancers.It is known that metabolic changes occur at different stages of the cell cycle to maintain the biosynthesis and replication of both normal and cancer cells.Based on the role of SAC3D1 in mitosis,we hypothesize that abnormal expression of SAC3D1 may affect cellular metabolism.However,it remains unclear whether SAC3D1 mediates the progression of HCC by regulating metabolic reprogramming.AIM To comprehensively elucidate the impact and molecular mechanism of SAC3D1 on the progression of HCC by regulating the metabolic reprogramming.METHODS The constructed SAC3D1 overexpression and knockdown HCC cell lines were used for detecting cell proliferation,migration capabilities,as well as glycolysis and adenosine triphosphate(ATP)production rate assays.They were also employed for examining molecular markers associated with cell migration and glycolysis.The transcriptome sequencing data of cells have revealed the pathways potentially influenced by SAC3D1.The tail vein metastasis model and xenograft tumor experiments were utilized to demonstrate SAC3D1’s tumor-promoting effects in vivo.RESULTS SAC3D1 expression was upregulated and associated with poor prognosis in HCC patients.SAC3D1 enhanced the proliferation and migration abilities and reduced the population dependence of HCC cells in vitro and in vivo.The upregulation of SAC3D1 enhanced cellular glycolysis and ATP production.The cell transcriptome sequencing data revealed that SAC3D1 activated Wnt signaling pathway.SAC3D1 did not modulate the transcription ofβ-Catenin,while might inhibit its degradation.Further investigations indicated that the increase of SAC3D1 leads to moreβ-Catenin accumulating in the nucleus,facilitating the expression of c-Myc,one of the upstream regulatory factors of glycolysis.The iCRT3,an antagonist ofβ-Catenin,could counteract the increase of c-Myc induced by SAC3D1,while also downregulating the expression of glycolysis-related proteins.CONCLUSION This study found that SAC3D1 enhances HCC cell glycolysis and ATP production via theβ-Catenin/c-Myc signaling axis,thereby promoting the progression of HCC.
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.
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.
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.
