Parkinson’s disease(PD)is the second most common neurodegenerative disorder.The progressive degeneration of dopamine(DA)producing neurons in the midbrain is the pathological hallmark,which leads to debilitating motor...Parkinson’s disease(PD)is the second most common neurodegenerative disorder.The progressive degeneration of dopamine(DA)producing neurons in the midbrain is the pathological hallmark,which leads to debilitating motor symptoms,including tremors,rigidity,and bradykinesia.Drug treatments,such as levodopa,provide symptomatic relief.However,they do not halt disease progression,and their effectiveness diminishes over time(reviewed in Poewe et al.,2017).展开更多
Type 2 diabetes mellitus has central complications:Diabetes,a metabolic disorder primarily characterized by hyperglycemia due to insufficient insulin secretion,or impaired insulin signaling,has significant central com...Type 2 diabetes mellitus has central complications:Diabetes,a metabolic disorder primarily characterized by hyperglycemia due to insufficient insulin secretion,or impaired insulin signaling,has significant central complications.Type 2 diabetes mellitus(T2DM),the most prevalent type of diabetes,affects more than 38 million individuals in the United States(approximately 1 in 10)and is defined by chronic hyperglycemia and insulin resistance,which refers to a reduced cellular response to insulin.展开更多
Early life stress correlates with a higher prevalence of neurological disorders,including autism,attention-deficit/hyperactivity disorder,schizophrenia,depression,and Parkinson's disease.These conditions,primarily...Early life stress correlates with a higher prevalence of neurological disorders,including autism,attention-deficit/hyperactivity disorder,schizophrenia,depression,and Parkinson's disease.These conditions,primarily involving abnormal development and damage of the dopaminergic system,pose significant public health challenges.Microglia,as the primary immune cells in the brain,are crucial in regulating neuronal circuit development and survival.From the embryonic stage to adulthood,microglia exhibit stage-specific gene expression profiles,transcriptome characteristics,and functional phenotypes,enhancing the susceptibility to early life stress.However,the role of microglia in mediating dopaminergic system disorders under early life stress conditions remains poorly understood.This review presents an up-to-date overview of preclinical studies elucidating the impact of early life stress on microglia,leading to dopaminergic system disorders,along with the underlying mechanisms and therapeutic potential for neurodegenerative and neurodevelopmental conditions.Impaired microglial activity damages dopaminergic neurons by diminishing neurotrophic support(e.g.,insulin-like growth factor-1)and hinders dopaminergic axon growth through defective phagocytosis and synaptic pruning.Furthermore,blunted microglial immunoreactivity suppresses striatal dopaminergic circuit development and reduces neuronal transmission.Furthermore,inflammation and oxidative stress induced by activated microglia can directly damage dopaminergic neurons,inhibiting dopamine synthesis,reuptake,and receptor activity.Enhanced microglial phagocytosis inhibits dopamine axon extension.These long-lasting effects of microglial perturbations may be driven by early life stress–induced epigenetic reprogramming of microglia.Indirectly,early life stress may influence microglial function through various pathways,such as astrocytic activation,the hypothalamic–pituitary–adrenal axis,the gut–brain axis,and maternal immune signaling.Finally,various therapeutic strategies and molecular mechanisms for targeting microglia to restore the dopaminergic system were summarized and discussed.These strategies include classical antidepressants and antipsychotics,antibiotics and anti-inflammatory agents,and herbal-derived medicine.Further investigations combining pharmacological interventions and genetic strategies are essential to elucidate the causal role of microglial phenotypic and functional perturbations in the dopaminergic system disrupted by early life stress.展开更多
Alzheimer's disease is a common neurodegenerative disorder in older adults.Despite its prevalence,its pathogenesis remains unclea r.In addition to the most widely accepted causes,which in clude excessive amyloid-b...Alzheimer's disease is a common neurodegenerative disorder in older adults.Despite its prevalence,its pathogenesis remains unclea r.In addition to the most widely accepted causes,which in clude excessive amyloid-beta aggregation,tau hyperphosphorylation,and deficiency of the neurotransmitter acetylcholine,numerous studies have shown that the dopaminergic system is also closely associated with the occurrence and development of this condition.Dopamine is a crucial catecholaminergic neurotransmitter in the human body.Dopamine-associated treatments,such as drugs that target dopamine receptor D and dopamine analogs,can improve cognitive function and alleviate psychiatric symptoms as well as ameliorate other clinical manifestations.Howeve r,therapeutics targeting the dopaminergic system are associated with various adverse reactions,such as addiction and exacerbation of cognitive impairment.This review summarizes the role of the dopaminergic system in the pathology of Alzheimer's disease,focusing on currently available dopamine-based therapies for this disorder and the common side effects associated with dopamine-related drugs.The aim of this review is to provide insights into the potential connections between the dopaminergic system and Alzheimer's disease,thus helping to clarify the mechanisms underlying the condition and exploring more effective therapeutic options.展开更多
Nowadays,presynaptic dopaminergic positron emission tomography,which assesses deficiencies in dopamine synthesis,storage,and transport,is widely utilized for early diagnosis and differential diagnosis of parkinsonism....Nowadays,presynaptic dopaminergic positron emission tomography,which assesses deficiencies in dopamine synthesis,storage,and transport,is widely utilized for early diagnosis and differential diagnosis of parkinsonism.This review provides a comprehensive summary of the latest developments in the application of presynaptic dopaminergic positron emission tomography imaging in disorders that manifest parkinsonism.We conducted a thorough literature search using reputable databases such as PubMed and Web of Science.Selection criteria involved identifying peer-reviewed articles published within the last 5 years,with emphasis on their relevance to clinical applications.The findings from these studies highlight that presynaptic dopaminergic positron emission tomography has demonstrated potential not only in diagnosing and differentiating various Parkinsonian conditions but also in assessing disease severity and predicting prognosis.Moreover,when employed in conjunction with other imaging modalities and advanced analytical methods,presynaptic dopaminergic positron emission tomography has been validated as a reliable in vivo biomarker.This validation extends to screening and exploring potential neuropathological mechanisms associated with dopaminergic depletion.In summary,the insights gained from interpreting these studies are crucial for enhancing the effectiveness of preclinical investigations and clinical trials,ultimately advancing toward the goals of neuroregeneration in parkinsonian disorders.展开更多
Despite decades of dedicated resea rch,Alzheimer's disease (AD) is an age-related and progressive neurodegenerative disorder for which the mechanisms of onset are sti unc ear.AD is cha racterized by featured histo...Despite decades of dedicated resea rch,Alzheimer's disease (AD) is an age-related and progressive neurodegenerative disorder for which the mechanisms of onset are sti unc ear.AD is cha racterized by featured histological alterations including amyloid-beta (AB) plaque deposition,accumulation of neurofibrillary to ngles of hyperphosphorylated-tau,and neuronal loss,accompanied by progressive cognitive decline and behavioral changes.展开更多
Dopamine,often termed the"feel-good"neurotransmitter,plays a crucial role in myriad physiological and psychological brain processes.While dopamine is primarily associated with pleasure,reward,and motivation,...Dopamine,often termed the"feel-good"neurotransmitter,plays a crucial role in myriad physiological and psychological brain processes.While dopamine is primarily associated with pleasure,reward,and motivation,its effects can be quite complex;and this complexity is further compounded when examining how dopamine functions in typical versus disease-affected neural circuits.In pa rticula r,epilepsy,characte rized by heightened brain excitability,is linked to cognitive dysfunction,and dopamine is implicated in elements of both its pathology and treatment.Neuroscience has been successful in describing the synaptic abnormalities believed to contribute to memory issues in epilepsy,aiding in the search for effective therapies for what persists as a major medical issue.展开更多
Dopamine(DA)is a vital neurotransmitter,and accurate detection of its concentration is critical for both clinical diagnos-tics and neuroscience research.Due to its electrochemical activity,DA is commonly detected usin...Dopamine(DA)is a vital neurotransmitter,and accurate detection of its concentration is critical for both clinical diagnos-tics and neuroscience research.Due to its electrochemical activity,DA is commonly detected using electrochemical methods,which are favored for their simplicity,fast response time,and suitability for in vivo analysis.In this work,a highly sensitive DA electrochemical sensor was developed using an Au@MoS_(2)composite,created by modifying molybdenum disulfide(MoS_(2))nanosheets with gold nanoparticles through HAuCl_(4) reduction,and it was aimed at enhancing DA adsorption and improving detection performance.Scanning Electron Microscopy(SEM),transmission electron microscopy(TEM),Energy Dispersive Spectroscopy(EDS),X-ray photoelectron spectroscopy(XPS)and X-ray Diffraction(XRD)confirmed the suc-cessful synthesis of Au@MoS_(2)and the uniform distribution of gold nanoparticles across the MoS_(2)nanosheets.Then,the electrochemical characterization demonstrated that the Au@MoS_(2)/GCE exhibited distinct oxidation peaks in a 10μmol·L^(-1)DA solution,with significantly enhanced electrochemical activity compared to both unmodified GCE and pristine MoS_(2).Furthermore,differential pulse voltammetry(DPV)further revealed a strong linear relationship between DA concentration and the current response in the range of 800 nmol·L^(-1)to 10μmol·L^(-1),with a low detection limit(LOD)of 78.9 nmol·L^(-1)(S/N=3).Additionally,the sensor showed excellent selectivity against other interfering substances.Moreover,the laser-induced Au@MoS_(2)(LIAu@MoS_(2)),with its abundance of negatively charged surface defects,enabled the ultra-sensitive detection of the ultra-low concentrations of DA.In conclusion,the successfully fabricated Au@MoS_(2)based sensor offers advantages such as low cost,ease of operation,and scalability,making it a promising candidate for biosensing applications due to its enhanced DA detection capabilities.展开更多
Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Cu...Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Currently,studies have reported increased oscillation power in cases of levodopa-induced dyskinesia.However,little is known about how the other electrophysiological parameters of gamma oscillations are altered in levodopa-induced dyskinesia.Furthermore,the role of the dopamine D3 receptor,which is implicated in levodopa-induced dyskinesia,in movement disorder-related changes in neural oscillations is unclear.We found that the cortico-striatal functional connectivity of beta oscillations was enhanced in a model of Parkinson’s disease.Furthermore,levodopa application enhanced cortical gamma oscillations in cortico-striatal projections and cortical gamma aperiodic components,as well as bidirectional primary motor cortex(M1)↔dorsolateral striatum gamma flow.Administration of PD128907(a selective dopamine D3 receptor agonist)induced dyskinesia and excessive gamma oscillations with a bidirectional M1↔dorsolateral striatum flow.However,administration of PG01037(a selective dopamine D3 receptor antagonist)attenuated dyskinesia,suppressed gamma oscillations and cortical gamma aperiodic components,and decreased gamma causality in the M1→dorsolateral striatum direction.These findings suggest that the dopamine D3 receptor plays a role in dyskinesia-related oscillatory activity,and that it has potential as a therapeutic target for levodopa-induced dyskinesia.展开更多
With the rapid development of flexible wearable electronic products,their application fields and demands are increasing,posing new challenges to flexible conductive materials.This paper selected flexible polydimethyls...With the rapid development of flexible wearable electronic products,their application fields and demands are increasing,posing new challenges to flexible conductive materials.This paper selected flexible polydimethylsiloxane(PDMS)as the substrate.In order to enhance the adhesion between the substrate and the metal coating,dopamine and silanization were used to co-modify its surface.A conductive layer of metallic copper is deposited on its surface using an inexpensive,easy-to-use electroless plating technique.By optimizing the process conditions,it is found that a uniform copper layer of about 0.6μm can be formed on the surface of the substrate by electroless plating at a constant temperature of 45℃ for 30 min with a conductivity of 5556 S/cm.The relative resistance changes under different deformation conditions,and the I-V curve of the LED circuit is not very different.Therefore,this paper prepared a flexible conductor with excellent electrical conductivity,high coating adhesion,and good electrical stability under large-scale deformation.展开更多
The complexity of living environment system demands higher requirements for the sensitivity and selectivity of the probe.Therefore,it is of great importance to develop a universal strategy for highperformance probe op...The complexity of living environment system demands higher requirements for the sensitivity and selectivity of the probe.Therefore,it is of great importance to develop a universal strategy for highperformance probe optimization.Herein,we propose a novel“Enrichment-enhanced Detection”strategy and use carbon dots-dopamine detection system as a representative model to evaluate its feasibility.The composite probe carbon dots (CDs)-encapsulated in glycol-chitosan (GC)(i.e.,CDs@GC) was obtained by simply mixing GC and CDs through noncovalent interactions,including electrostatic interactions and hydrogen bonding.Dopamine (DA) could be detected through internal filter effect (IFE)-induced quenching of CDs.In the case of CDs@GC,noncovalent interactions (electrostatic interactions) between GC and the formed quinone (oxide of DA) could selectively extract and enrich the local concentration of DA,thus effectively improving the sensitivity and selectivity of the sensing system.The nanosensor had a low detection limit of 3.7 nmol/L,which was a 12-fold sensitivity improvement compared to the bare CDs probes with similar fluorescent profiles,proving the feasibility of the“Enrichment-enhanced Detection”strategy.Further,to examine this theory in real case,we designed a highly portable sensing platform to realize visual determination of DA.Overall,our work introduces a new strategy for accurately detecting DA and provides valuable insights for the universal design and optimization of superior nanoprobes.展开更多
Computational approaches,encompassing both physics-based and machine learning(ML)methodologies,have gained substantial traction in drug repurposing efforts targeting specific therapeutic entities.The human dopamine(DA...Computational approaches,encompassing both physics-based and machine learning(ML)methodologies,have gained substantial traction in drug repurposing efforts targeting specific therapeutic entities.The human dopamine(DA)transporter(hDAT)is the primary therapeutic target of numerous psychiatric medications.However,traditional hDAT-targeting drugs,which interact with the primary binding site,encounter significant limitations,including addictive potential and stimulant effects.In this study,we propose an integrated workflow combining virtual screening based on weighted holistic atom localization and entity shape(WHALES)descriptors with in vitro experimental validation to repurpose novel hDAT-targeting drugs.Initially,WHALES descriptors facilitated a similarity search,employing four benztropine-like atypical inhibitors known to bind hDAT's allosteric site as templates.Consequently,from a compound library of 4,921 marketed and clinically tested drugs,we identified 27 candidate atypical inhibitors.Subsequently,ADMETlab was employed to predict the pharmacokinetic and toxicological properties of these candidates,while induced-fit docking(IFD)was performed to estimate their binding affinities.Six compounds were selected for in vitro assessments of neurotransmitter reuptake inhibitory activities.Among these,three exhibited significant inhibitory potency,with half maximal inhibitory concentration(IC_(50))values of 0.753μM,0.542μM,and 1.210μM,respectively.Finally,molecular dynamics(MD)simulations and end-point binding free energy analyses were conducted to elucidate and confirm the inhibitory mechanisms of the repurposed drugs against hDAT in its inward-open conformation.In conclusion,our study not only identifies promising active compounds as potential atypical inhibitors for novel therapeutic drug development targeting hDAT but also validates the effectiveness of our integrated computational and experimental workflow for drug repurposing.展开更多
Intraspecific conflict induced by the innate aggressiveness is one of the main reasons for the extremely low survival rate in mud crab Scylla paramamosain aquaculture,which have impeded the sustainable culture of the ...Intraspecific conflict induced by the innate aggressiveness is one of the main reasons for the extremely low survival rate in mud crab Scylla paramamosain aquaculture,which have impeded the sustainable culture of the species.In this study,we first classified and quantified the aggressive behavior,and established a crab aggressive behavior model,laying the foundation for subsequent research on evaluating combat intensity.The contents of 5-hydroxytryptamine(5-HT),dopamine(DA),and cAMP in the hemolymph of the mud crabs before and after fighting were measured by high-performance liquid chromatography-mass spectrometry(HPLC-MS),and the mud crabs exhibited a significant increase of 5-HT(P<0.05),while the DA and cAMP decreased significantly(P<0.05).In addition,we applied EthoVision to examine the changes of the crab behavior after DA administration.After 0.5 h of injection,the movement speed,distance,duration of aggressive behavior,and intensity of aggression in the high concentration DA group were significantly higher than those in the saline injection group and the untreated control group(P<0.05).The results of real-time quantitative polymerase chain reaction(qRT PCR)analysis showed that the expression of DA 1 in the thoracic ganglia of the mud crabs was significantly down-regulated in the DA injection group,and the aggressive behavior was weakened.Conversely,DA1 expression was up-regulated when aggressive behavior was strengthened.Besides,there were significant differences in the expression levels of receptor expression genes including 5-HT1,5-HT2,and crustacean hyperglycemic hormone(CHH)in different tissues,indicating that the alteration of aggressive behavior of the mud crab after injection with different concentrations of DA could be regulated by changes in the expression levels of corresponding receptor genes.Our results contribute to a deeper analysis of the aggressive behavior mechanism of the mud crabs and provide a theoretical basis for reducing fighting-related mortalities in aquaculture.展开更多
Dopamine β-monooxygenase N-terminal(DOMON)domain-containing genes are present across all taxa and are critical in cell signaling and redox transport.Despite their significance,these genes remain understudied in plant...Dopamine β-monooxygenase N-terminal(DOMON)domain-containing genes are present across all taxa and are critical in cell signaling and redox transport.Despite their significance,these genes remain understudied in plant species.In this study,we identified 15 DOMON genes in rice and analyzed their phylogenetic relationships,conserved motifs,and cis-regulatory elements.Phylogenetic analysis revealed distinct clustering of OsDOMON genes in rice and other monocots,compared with Arabidopsis thaliana.Promoter analysis showed a higher abundance of stress-related regulatory elements in Tetep,a well-known blast and abiotic stress-tolerant cultivar,compared with Nipponbare and HP2216.OsDOMON genes displayed differential expression under biotic stress(Magnaporthe oryzae infection)and abiotic stresses(drought,heat,and salinity)in contrasting cultivars.Tetep exhibited significantly higher expression levels of specific OsDOMON genes during early blast infection stages,particularly OsDOMON6.1 and OsDOMON9.2,suggesting their roles in cell wall fortification and reactive oxygen species signaling.Under abiotic stress,genes like OsDOMON3.3,OsDOMON8.1,and OsDOMON9.2 showed higher expression in Tetep,indicating their involvement in stress tolerance mechanisms.This study provides a foundation for future functional studies of OsDOMON genes,paving the way for developing rice cultivars resistant to biotic and abiotic stresses.展开更多
Additive Manufacturing(AM)can provide customized parts that conventional techniques fail to deliver.One important parameter in AM is the quality of the parts,as a result of the material extrusion 3D printing(3D-P)proc...Additive Manufacturing(AM)can provide customized parts that conventional techniques fail to deliver.One important parameter in AM is the quality of the parts,as a result of the material extrusion 3D printing(3D-P)procedure.This can be very important in defense-related applications,where optimum performance needs to be guaranteed.The quality of the Polyetherimide 3D-P specimens was examined by considering six control parameters,namely,infill percentage,layer height,deposition angle,travel speed,nozzle,and bed temperature.The quality indicators were the root mean square(Rq)and average(Ra)roughness,porosity,and the actual to nominal dimensional deviation.The examination was performed with optical profilometry,optical microscopy,and micro-computed tomography scanning.The Taguchi design of experiments was applied,with twenty-five runs,five levels for each control parameter,on five replicas.Two additional confirmation runs were conducted,to ensure reliability.Prediction equations were constructed to express the quality indicators in terms of the control parameters.Three modeling approaches were applied to the experimental data,to compare their efficiency,i.e.,Linear Regression Model(LRM),Reduced Quadratic Regression Model,and Quadratic Regression Model(QRM).QRM was the most accurate one,still the differences were not high even considering the simpler LRM model.展开更多
The present work primarily aims to explore the neuronal calcium(Ca^(2+)),IP_(3),and dopamine(DA)signaling systems through a feedback loop model.To date,there has been no exploration of this feedback model in fractiona...The present work primarily aims to explore the neuronal calcium(Ca^(2+)),IP_(3),and dopamine(DA)signaling systems through a feedback loop model.To date,there has been no exploration of this feedback model in fractional-order dynamical systems.This feedback loop model incorporates several crucial mechanisms like the buffering process,IP_(3)-receptor,ryanodine receptor,plasma membrane Ca^(2+)ATPase and sarcoplasmic/endoplasmic reticulum calcium ATPase(SERCA)pump,leak,sodium-calcium exchanger,voltage-gated Ca^(2+)channel,Orai channels,DA-dependent IP_(3)synthesis,and others.By incorporating these mechanisms,the model aims to provide a more comprehensive and realistic understanding of the system under investigation.The present model incorporates fractional-order dynamics along both spatial and temporal dimensions to examine the impacts of superdiffusion and memory showing Brownian motion of Ca^(2+),IP_(3),and DA signaling molecules.The bidirectional feedback between calcium and IP_(3)signaling systems,unidirectional feedback between calcium and dopamine signaling systems,and unidirectional feedback between IP_(3)and dopamine signaling systems have been incorporated into the present model.These feedback loops establish interactions among calcium,IP_(3),and dopamine signaling systems within neuronal cells.The numerical findings were obtained by using the Crank-Nicholson method with the Grunwald technique for fractional space derivatives and the L1method for fractional time derivatives in conjunction with the Gauss-Seidel Iterations.This research specifically investigates the implications of cell memory as well as superdiffusion on Ca^(2+),IP_(3),and DA dynamics in neuronal cells,which are interactive nonlinear systems.The superdiffusion process results in a reduction in Ca^(2+),IP_(3),and DA concentrations,while cellular memory leads to an increase in ion and molecule concentrations in neuronal cells during the initial time.The disruption of any given process can lead to imbalances in calcium,IP_(3),and DA systems,hence contributing to neurotoxicity and cellular demise.展开更多
Liver fibrosis remains a major global health challenge with limited therapeutic options.In their recent study,Wang et al report that levodopa,a dopamine precursor widely used in Parkinson’s disease,significantly atte...Liver fibrosis remains a major global health challenge with limited therapeutic options.In their recent study,Wang et al report that levodopa,a dopamine precursor widely used in Parkinson’s disease,significantly attenuates carbon tetrachloride-induced liver fibrosis in rats by enhancing dopamine receptor D1 expression and activating the Hippo signaling pathway,leading to phosphorylation and inactivation of yes-associated protein 1.This discovery links Gprotein-coupled receptor signaling to Hippo pathway regulation in hepatic fibrosis.The work highlights the dopamine receptor D1-Hippo/yes-associated protein 1 axis as a promising antifibrotic mechanism and introduces levodopa as a potential repurposing candidate for chronic liver disease.With its established safety and affordability,levodopa offers a rapidly translatable strategy that warrants validation in human tissues and diverse fibrosis models.Here,we place these findings in the broader context of G-protein-coupled receptor regulation of hepatic stellate cell activation,discuss translational opportunities for levodopa in liver fibrosis,and propose future directions to validate this pathway across disease models and clinical settings.展开更多
BACKGROUND Yes-associated protein 1(YAP1),a downstream transcriptional coactivator regulated by the Hippo signaling pathway,has been shown to be involved in liver fibrosis.YAP activity is modulated by G-protein couple...BACKGROUND Yes-associated protein 1(YAP1),a downstream transcriptional coactivator regulated by the Hippo signaling pathway,has been shown to be involved in liver fibrosis.YAP activity is modulated by G-protein coupled receptors,including Gαs-coupled protein dopamine receptor D1(DRD1).Levodopa,a dopamine precursor,activates DRD1 on cell surface,triggering its downstream signaling pathway.AIM To investigate the therapeutic effect of levodopa and the downstream mechanism on carbon tetrachloride(CCl_(4))-induced liver fibrosis,including liver DRD1 expression.METHODS SD rats were intraperitoneally injected with 40%CCl_(4)for 8 weeks to induce liver fibrosis,followed by treatment with varying doses of levodopa for 2 weeks.Serum aspartate aminotransferase(AST)and alanine aminotransferase(ALT)levels were measured,and liver pathology was assessed using hematoxylin and eosin and Masson's staining.Alpha-smooth muscle actin(α-SMA)content,along with the expressions of DRD1,YAP,and phosphorylated protein,was analyzed by Western blot,immunohistochemistry,and reverse transcription-quantitative real-time polymerase chain reaction.RESULTS Compared with the controls,levodopa-treated rats showed a decrease in the proportion of collagen in the liver and a recovery from liver fibrosis(P=0.0007).Western blot and immunohistochemistry indicated that DRD1 was upregulated in the fibrotic liver of rats treated with levodopa,showing an increase in DRD1 Level(P<0.0001).In addition,the upregulation of DRD1 activated the Hippo signaling pathway,manifested as increased YAP phosphorylation(P<0.05).CONCLUSION This was the first study to demonstrate that levodopa attenuates CCl_(4)-induced liver fibrosis by inhibiting the Hippo/YAP signaling pathways.展开更多
Hybrid antioxidants cinnamoyldopamine（2a）, p-coumaroyldopamine（2b）, caffeoyldopamine（2c）, feruloyldopamine（2d） and sinapoyldopamine（2e） were synthesized by conjugation of dopamine（DA） and hydroxycinnamic a...Hybrid antioxidants cinnamoyldopamine（2a）, p-coumaroyldopamine（2b）, caffeoyldopamine（2c）, feruloyldopamine（2d） and sinapoyldopamine（2e） were synthesized by conjugation of dopamine（DA） and hydroxycinnamic acids（HCAs）. The stabilities were studied in buffers at p H 1.3, p H 5.0, and p H 7.4 including the human plasma. All the compounds were found highly stable at acidic p H, but underwent hydrolysis at neutral p H. Furthermore, the hydrolysis proceeded much faster in plasma in the following order as indicated by half-life values（t1/2）, 2c（1.21 h）〈2e（1.52 h）〈2d（1.85 h）〈2b（3.38 h）〈2a（3.88 h）, correlating with the number of electron-donating groups. It has been proven by UV spectrum that 2c, 2d, and 2e displayed red shift of more than 50 nm as compared to 2a and 2b, because of the presence of OH and OCH3 groups. In addition, the compounds（2b–e） showed no cytotoxicity on normal HUVEC cells as DA, although 2a displayed a 16% inhibition of proliferation at 40 μM following 48 h incubation. Their free radical-scavenging activities were evaluated using ABTS^＊＋ and superoxide anion assays and the mechanisms were proposed. It was found that they all exhibited higher activities than trolox, a recognized antioxidant. Amazingly, in the case of the hybrids（2a–e）, their activity was higher than that of HCAs while lower or comparable to that of DA, suggesting that there may be a ＂saturation effect＂ with the hybrid molecules in the antioxidant activities.展开更多
Objective To investigate the influence of dopamine （DA） and DA receptor＇s antagonist on the transmission of noxious information in the central nervous system of normal rats or morphinistic rats. Methods The influen...Objective To investigate the influence of dopamine （DA） and DA receptor＇s antagonist on the transmission of noxious information in the central nervous system of normal rats or morphinistic rats. Methods The influence of DA on the electric activity of the pain-excited neuron （PEN） in the caudate nucleus （Cd） of normal rats or morphinistic rats was recorded after the sciatic nerve was noxiously stimulated. Results DA shortened the average latency of the evoked discharge of PEN in the Cd of normal rats, indicating that DA could increase the activity of PEN and pain sensitivity in normal rats. This effect could be inhibited by Droperidol. DA increased the average latency of the evoked discharge of PEN in the Cd of morphinistic rats, indicating that DA could inhibit the activity of PEN and pain sensitivity in morphinistic rats. Conclusion The responses to painful stimulation were completely opposite between normal rats and morphinistic rats after the intracerebroventricular injection of DA.展开更多
基金supported by the DGIST start-up funds from the Ministry of Science and ICT(2024010330)a National Research Foundation of Korea(NRF)grant funded by the Korea Government(MSIT)(No.RS-2024-00351442)(to TWK).
文摘Parkinson’s disease(PD)is the second most common neurodegenerative disorder.The progressive degeneration of dopamine(DA)producing neurons in the midbrain is the pathological hallmark,which leads to debilitating motor symptoms,including tremors,rigidity,and bradykinesia.Drug treatments,such as levodopa,provide symptomatic relief.However,they do not halt disease progression,and their effectiveness diminishes over time(reviewed in Poewe et al.,2017).
基金supported by grants from NIH T32(DK007260,to WC)the Steno North American Fellowship awarded by the Novo Nordisk Foundation(NNF23OC0087108,to WC)+6 种基金STI2030-Major Projects(2021ZD0202700,to HY)the National Natural Science Foundation of China(32241004,to HY)the Natural Science Foundation of Zhejiang Province of China(LR24C090001,to HY)Key R&D Program of Zhejiang Province(2024SSYS0017,to HY)CAMS Innovation Fund for Medical Sciences(2019-12M-5-057,to HY)Fundamental Research Funds for the Central Universities(226-2022-00193,to HY)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2023-PT310-01,to HY)。
文摘Type 2 diabetes mellitus has central complications:Diabetes,a metabolic disorder primarily characterized by hyperglycemia due to insufficient insulin secretion,or impaired insulin signaling,has significant central complications.Type 2 diabetes mellitus(T2DM),the most prevalent type of diabetes,affects more than 38 million individuals in the United States(approximately 1 in 10)and is defined by chronic hyperglycemia and insulin resistance,which refers to a reduced cellular response to insulin.
基金supported by the National Natural Science Foundation of China,Nos.82304990(to NY),81973748(to JC),82174278(to JC)the National Key R&D Program of China,No.2023YFE0209500(to JC)+4 种基金China Postdoctoral Science Foundation,No.2023M732380(to NY)Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine,No.202102010014(to JC)Huang Zhendong Research Fund for Traditional Chinese Medicine of Jinan University,No.201911(to JC)National Innovation and Entrepreneurship Training Program for Undergraduates in China,No.202310559128(to NY and QM)Innovation and Entrepreneurship Training Program for Undergraduates at Jinan University,Nos.CX24380,CX24381(both to NY and QM)。
文摘Early life stress correlates with a higher prevalence of neurological disorders,including autism,attention-deficit/hyperactivity disorder,schizophrenia,depression,and Parkinson's disease.These conditions,primarily involving abnormal development and damage of the dopaminergic system,pose significant public health challenges.Microglia,as the primary immune cells in the brain,are crucial in regulating neuronal circuit development and survival.From the embryonic stage to adulthood,microglia exhibit stage-specific gene expression profiles,transcriptome characteristics,and functional phenotypes,enhancing the susceptibility to early life stress.However,the role of microglia in mediating dopaminergic system disorders under early life stress conditions remains poorly understood.This review presents an up-to-date overview of preclinical studies elucidating the impact of early life stress on microglia,leading to dopaminergic system disorders,along with the underlying mechanisms and therapeutic potential for neurodegenerative and neurodevelopmental conditions.Impaired microglial activity damages dopaminergic neurons by diminishing neurotrophic support(e.g.,insulin-like growth factor-1)and hinders dopaminergic axon growth through defective phagocytosis and synaptic pruning.Furthermore,blunted microglial immunoreactivity suppresses striatal dopaminergic circuit development and reduces neuronal transmission.Furthermore,inflammation and oxidative stress induced by activated microglia can directly damage dopaminergic neurons,inhibiting dopamine synthesis,reuptake,and receptor activity.Enhanced microglial phagocytosis inhibits dopamine axon extension.These long-lasting effects of microglial perturbations may be driven by early life stress–induced epigenetic reprogramming of microglia.Indirectly,early life stress may influence microglial function through various pathways,such as astrocytic activation,the hypothalamic–pituitary–adrenal axis,the gut–brain axis,and maternal immune signaling.Finally,various therapeutic strategies and molecular mechanisms for targeting microglia to restore the dopaminergic system were summarized and discussed.These strategies include classical antidepressants and antipsychotics,antibiotics and anti-inflammatory agents,and herbal-derived medicine.Further investigations combining pharmacological interventions and genetic strategies are essential to elucidate the causal role of microglial phenotypic and functional perturbations in the dopaminergic system disrupted by early life stress.
文摘Alzheimer's disease is a common neurodegenerative disorder in older adults.Despite its prevalence,its pathogenesis remains unclea r.In addition to the most widely accepted causes,which in clude excessive amyloid-beta aggregation,tau hyperphosphorylation,and deficiency of the neurotransmitter acetylcholine,numerous studies have shown that the dopaminergic system is also closely associated with the occurrence and development of this condition.Dopamine is a crucial catecholaminergic neurotransmitter in the human body.Dopamine-associated treatments,such as drugs that target dopamine receptor D and dopamine analogs,can improve cognitive function and alleviate psychiatric symptoms as well as ameliorate other clinical manifestations.Howeve r,therapeutics targeting the dopaminergic system are associated with various adverse reactions,such as addiction and exacerbation of cognitive impairment.This review summarizes the role of the dopaminergic system in the pathology of Alzheimer's disease,focusing on currently available dopamine-based therapies for this disorder and the common side effects associated with dopamine-related drugs.The aim of this review is to provide insights into the potential connections between the dopaminergic system and Alzheimer's disease,thus helping to clarify the mechanisms underlying the condition and exploring more effective therapeutic options.
基金supported by the Research Project of the Shanghai Health Commission,No.2020YJZX0111(to CZ)the National Natural Science Foundation of China,Nos.82021002(to CZ),82272039(to CZ),82171252(to FL)+1 种基金a grant from the National Health Commission of People’s Republic of China(PRC),No.Pro20211231084249000238(to JW)Medical Innovation Research Project of Shanghai Science and Technology Commission,No.21Y11903300(to JG).
文摘Nowadays,presynaptic dopaminergic positron emission tomography,which assesses deficiencies in dopamine synthesis,storage,and transport,is widely utilized for early diagnosis and differential diagnosis of parkinsonism.This review provides a comprehensive summary of the latest developments in the application of presynaptic dopaminergic positron emission tomography imaging in disorders that manifest parkinsonism.We conducted a thorough literature search using reputable databases such as PubMed and Web of Science.Selection criteria involved identifying peer-reviewed articles published within the last 5 years,with emphasis on their relevance to clinical applications.The findings from these studies highlight that presynaptic dopaminergic positron emission tomography has demonstrated potential not only in diagnosing and differentiating various Parkinsonian conditions but also in assessing disease severity and predicting prognosis.Moreover,when employed in conjunction with other imaging modalities and advanced analytical methods,presynaptic dopaminergic positron emission tomography has been validated as a reliable in vivo biomarker.This validation extends to screening and exploring potential neuropathological mechanisms associated with dopaminergic depletion.In summary,the insights gained from interpreting these studies are crucial for enhancing the effectiveness of preclinical investigations and clinical trials,ultimately advancing toward the goals of neuroregeneration in parkinsonian disorders.
基金supported by an under-40 grant from the Italian Association for Alzheimer’s Research [AIRALZH AGYR2021]the Strategic University Projects–Young Researcher Independence grant [YRG2021] from the Università Campus Bio-Medico di Roma (Rome, Italy)(to LLB)+1 种基金Italian Ministry of Health [Research Grant:GR-2019-12370446]the American Alzheimer’s Association [AARG-22-922961](to PK)。
文摘Despite decades of dedicated resea rch,Alzheimer's disease (AD) is an age-related and progressive neurodegenerative disorder for which the mechanisms of onset are sti unc ear.AD is cha racterized by featured histological alterations including amyloid-beta (AB) plaque deposition,accumulation of neurofibrillary to ngles of hyperphosphorylated-tau,and neuronal loss,accompanied by progressive cognitive decline and behavioral changes.
文摘Dopamine,often termed the"feel-good"neurotransmitter,plays a crucial role in myriad physiological and psychological brain processes.While dopamine is primarily associated with pleasure,reward,and motivation,its effects can be quite complex;and this complexity is further compounded when examining how dopamine functions in typical versus disease-affected neural circuits.In pa rticula r,epilepsy,characte rized by heightened brain excitability,is linked to cognitive dysfunction,and dopamine is implicated in elements of both its pathology and treatment.Neuroscience has been successful in describing the synaptic abnormalities believed to contribute to memory issues in epilepsy,aiding in the search for effective therapies for what persists as a major medical issue.
基金supported by the Young Talent Innovation Team Support Project from Zhengzhou University(No.32213280)the scientific research program of innovation platform in State Tobacco Monopoly Administrationthe State Key Program of National Natural Science Foundation of China(Grant No.32130083).
文摘Dopamine(DA)is a vital neurotransmitter,and accurate detection of its concentration is critical for both clinical diagnos-tics and neuroscience research.Due to its electrochemical activity,DA is commonly detected using electrochemical methods,which are favored for their simplicity,fast response time,and suitability for in vivo analysis.In this work,a highly sensitive DA electrochemical sensor was developed using an Au@MoS_(2)composite,created by modifying molybdenum disulfide(MoS_(2))nanosheets with gold nanoparticles through HAuCl_(4) reduction,and it was aimed at enhancing DA adsorption and improving detection performance.Scanning Electron Microscopy(SEM),transmission electron microscopy(TEM),Energy Dispersive Spectroscopy(EDS),X-ray photoelectron spectroscopy(XPS)and X-ray Diffraction(XRD)confirmed the suc-cessful synthesis of Au@MoS_(2)and the uniform distribution of gold nanoparticles across the MoS_(2)nanosheets.Then,the electrochemical characterization demonstrated that the Au@MoS_(2)/GCE exhibited distinct oxidation peaks in a 10μmol·L^(-1)DA solution,with significantly enhanced electrochemical activity compared to both unmodified GCE and pristine MoS_(2).Furthermore,differential pulse voltammetry(DPV)further revealed a strong linear relationship between DA concentration and the current response in the range of 800 nmol·L^(-1)to 10μmol·L^(-1),with a low detection limit(LOD)of 78.9 nmol·L^(-1)(S/N=3).Additionally,the sensor showed excellent selectivity against other interfering substances.Moreover,the laser-induced Au@MoS_(2)(LIAu@MoS_(2)),with its abundance of negatively charged surface defects,enabled the ultra-sensitive detection of the ultra-low concentrations of DA.In conclusion,the successfully fabricated Au@MoS_(2)based sensor offers advantages such as low cost,ease of operation,and scalability,making it a promising candidate for biosensing applications due to its enhanced DA detection capabilities.
基金supported by the National Natural Science Foundation of China,No.82071254(to WZ).
文摘Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Currently,studies have reported increased oscillation power in cases of levodopa-induced dyskinesia.However,little is known about how the other electrophysiological parameters of gamma oscillations are altered in levodopa-induced dyskinesia.Furthermore,the role of the dopamine D3 receptor,which is implicated in levodopa-induced dyskinesia,in movement disorder-related changes in neural oscillations is unclear.We found that the cortico-striatal functional connectivity of beta oscillations was enhanced in a model of Parkinson’s disease.Furthermore,levodopa application enhanced cortical gamma oscillations in cortico-striatal projections and cortical gamma aperiodic components,as well as bidirectional primary motor cortex(M1)↔dorsolateral striatum gamma flow.Administration of PD128907(a selective dopamine D3 receptor agonist)induced dyskinesia and excessive gamma oscillations with a bidirectional M1↔dorsolateral striatum flow.However,administration of PG01037(a selective dopamine D3 receptor antagonist)attenuated dyskinesia,suppressed gamma oscillations and cortical gamma aperiodic components,and decreased gamma causality in the M1→dorsolateral striatum direction.These findings suggest that the dopamine D3 receptor plays a role in dyskinesia-related oscillatory activity,and that it has potential as a therapeutic target for levodopa-induced dyskinesia.
基金supported by the Natural Science Foundation of Hunan Province(Grant No.2021JJ40463).
文摘With the rapid development of flexible wearable electronic products,their application fields and demands are increasing,posing new challenges to flexible conductive materials.This paper selected flexible polydimethylsiloxane(PDMS)as the substrate.In order to enhance the adhesion between the substrate and the metal coating,dopamine and silanization were used to co-modify its surface.A conductive layer of metallic copper is deposited on its surface using an inexpensive,easy-to-use electroless plating technique.By optimizing the process conditions,it is found that a uniform copper layer of about 0.6μm can be formed on the surface of the substrate by electroless plating at a constant temperature of 45℃ for 30 min with a conductivity of 5556 S/cm.The relative resistance changes under different deformation conditions,and the I-V curve of the LED circuit is not very different.Therefore,this paper prepared a flexible conductor with excellent electrical conductivity,high coating adhesion,and good electrical stability under large-scale deformation.
基金the financial support from the National Natural Science Foundation of China(No.21904007)the Fundamental Research Funds for the Central Universities(China,No.2412022QD008)+1 种基金the Jilin Provincial Department of Education(China),the Key Laboratory of Nanobiosensing and Nanobioanalysis at Universities of Jilin Province(China)the Analysis and Testing Center of Northeast Normal University(China)。
文摘The complexity of living environment system demands higher requirements for the sensitivity and selectivity of the probe.Therefore,it is of great importance to develop a universal strategy for highperformance probe optimization.Herein,we propose a novel“Enrichment-enhanced Detection”strategy and use carbon dots-dopamine detection system as a representative model to evaluate its feasibility.The composite probe carbon dots (CDs)-encapsulated in glycol-chitosan (GC)(i.e.,CDs@GC) was obtained by simply mixing GC and CDs through noncovalent interactions,including electrostatic interactions and hydrogen bonding.Dopamine (DA) could be detected through internal filter effect (IFE)-induced quenching of CDs.In the case of CDs@GC,noncovalent interactions (electrostatic interactions) between GC and the formed quinone (oxide of DA) could selectively extract and enrich the local concentration of DA,thus effectively improving the sensitivity and selectivity of the sensing system.The nanosensor had a low detection limit of 3.7 nmol/L,which was a 12-fold sensitivity improvement compared to the bare CDs probes with similar fluorescent profiles,proving the feasibility of the“Enrichment-enhanced Detection”strategy.Further,to examine this theory in real case,we designed a highly portable sensing platform to realize visual determination of DA.Overall,our work introduces a new strategy for accurately detecting DA and provides valuable insights for the universal design and optimization of superior nanoprobes.
基金supported by the Natural Science Foundation of China(Grant No.:21505009)the Natural Science Foundation of Chongqing,China(Grant No.:2023NSCQ-MSX0140)the Open Project of Central Nervous System Drug Key Laboratory of Sichuan Province,China(Grant No.:230012-01SZ).
文摘Computational approaches,encompassing both physics-based and machine learning(ML)methodologies,have gained substantial traction in drug repurposing efforts targeting specific therapeutic entities.The human dopamine(DA)transporter(hDAT)is the primary therapeutic target of numerous psychiatric medications.However,traditional hDAT-targeting drugs,which interact with the primary binding site,encounter significant limitations,including addictive potential and stimulant effects.In this study,we propose an integrated workflow combining virtual screening based on weighted holistic atom localization and entity shape(WHALES)descriptors with in vitro experimental validation to repurpose novel hDAT-targeting drugs.Initially,WHALES descriptors facilitated a similarity search,employing four benztropine-like atypical inhibitors known to bind hDAT's allosteric site as templates.Consequently,from a compound library of 4,921 marketed and clinically tested drugs,we identified 27 candidate atypical inhibitors.Subsequently,ADMETlab was employed to predict the pharmacokinetic and toxicological properties of these candidates,while induced-fit docking(IFD)was performed to estimate their binding affinities.Six compounds were selected for in vitro assessments of neurotransmitter reuptake inhibitory activities.Among these,three exhibited significant inhibitory potency,with half maximal inhibitory concentration(IC_(50))values of 0.753μM,0.542μM,and 1.210μM,respectively.Finally,molecular dynamics(MD)simulations and end-point binding free energy analyses were conducted to elucidate and confirm the inhibitory mechanisms of the repurposed drugs against hDAT in its inward-open conformation.In conclusion,our study not only identifies promising active compounds as potential atypical inhibitors for novel therapeutic drug development targeting hDAT but also validates the effectiveness of our integrated computational and experimental workflow for drug repurposing.
基金Supported by the National Key R&D Program of China(No.2023YFD2401005)the Key R&D Program of Ningbo(No.2022Z059)the K.C.Wong Magna Fund of Ningbo University。
文摘Intraspecific conflict induced by the innate aggressiveness is one of the main reasons for the extremely low survival rate in mud crab Scylla paramamosain aquaculture,which have impeded the sustainable culture of the species.In this study,we first classified and quantified the aggressive behavior,and established a crab aggressive behavior model,laying the foundation for subsequent research on evaluating combat intensity.The contents of 5-hydroxytryptamine(5-HT),dopamine(DA),and cAMP in the hemolymph of the mud crabs before and after fighting were measured by high-performance liquid chromatography-mass spectrometry(HPLC-MS),and the mud crabs exhibited a significant increase of 5-HT(P<0.05),while the DA and cAMP decreased significantly(P<0.05).In addition,we applied EthoVision to examine the changes of the crab behavior after DA administration.After 0.5 h of injection,the movement speed,distance,duration of aggressive behavior,and intensity of aggression in the high concentration DA group were significantly higher than those in the saline injection group and the untreated control group(P<0.05).The results of real-time quantitative polymerase chain reaction(qRT PCR)analysis showed that the expression of DA 1 in the thoracic ganglia of the mud crabs was significantly down-regulated in the DA injection group,and the aggressive behavior was weakened.Conversely,DA1 expression was up-regulated when aggressive behavior was strengthened.Besides,there were significant differences in the expression levels of receptor expression genes including 5-HT1,5-HT2,and crustacean hyperglycemic hormone(CHH)in different tissues,indicating that the alteration of aggressive behavior of the mud crab after injection with different concentrations of DA could be regulated by changes in the expression levels of corresponding receptor genes.Our results contribute to a deeper analysis of the aggressive behavior mechanism of the mud crabs and provide a theoretical basis for reducing fighting-related mortalities in aquaculture.
基金supported by the Indian Council of Agricultural Research(ICAR)-Senior Research Fellowship from ICAR,India(Grant No.EDN/1/25/2015-Exam cell)ICAR-Centre for Agricultural Bioinformatics and National Institute for Plant Biotechnology,India(Grant No.1006456).
文摘Dopamine β-monooxygenase N-terminal(DOMON)domain-containing genes are present across all taxa and are critical in cell signaling and redox transport.Despite their significance,these genes remain understudied in plant species.In this study,we identified 15 DOMON genes in rice and analyzed their phylogenetic relationships,conserved motifs,and cis-regulatory elements.Phylogenetic analysis revealed distinct clustering of OsDOMON genes in rice and other monocots,compared with Arabidopsis thaliana.Promoter analysis showed a higher abundance of stress-related regulatory elements in Tetep,a well-known blast and abiotic stress-tolerant cultivar,compared with Nipponbare and HP2216.OsDOMON genes displayed differential expression under biotic stress(Magnaporthe oryzae infection)and abiotic stresses(drought,heat,and salinity)in contrasting cultivars.Tetep exhibited significantly higher expression levels of specific OsDOMON genes during early blast infection stages,particularly OsDOMON6.1 and OsDOMON9.2,suggesting their roles in cell wall fortification and reactive oxygen species signaling.Under abiotic stress,genes like OsDOMON3.3,OsDOMON8.1,and OsDOMON9.2 showed higher expression in Tetep,indicating their involvement in stress tolerance mechanisms.This study provides a foundation for future functional studies of OsDOMON genes,paving the way for developing rice cultivars resistant to biotic and abiotic stresses.
文摘Additive Manufacturing(AM)can provide customized parts that conventional techniques fail to deliver.One important parameter in AM is the quality of the parts,as a result of the material extrusion 3D printing(3D-P)procedure.This can be very important in defense-related applications,where optimum performance needs to be guaranteed.The quality of the Polyetherimide 3D-P specimens was examined by considering six control parameters,namely,infill percentage,layer height,deposition angle,travel speed,nozzle,and bed temperature.The quality indicators were the root mean square(Rq)and average(Ra)roughness,porosity,and the actual to nominal dimensional deviation.The examination was performed with optical profilometry,optical microscopy,and micro-computed tomography scanning.The Taguchi design of experiments was applied,with twenty-five runs,five levels for each control parameter,on five replicas.Two additional confirmation runs were conducted,to ensure reliability.Prediction equations were constructed to express the quality indicators in terms of the control parameters.Three modeling approaches were applied to the experimental data,to compare their efficiency,i.e.,Linear Regression Model(LRM),Reduced Quadratic Regression Model,and Quadratic Regression Model(QRM).QRM was the most accurate one,still the differences were not high even considering the simpler LRM model.
文摘The present work primarily aims to explore the neuronal calcium(Ca^(2+)),IP_(3),and dopamine(DA)signaling systems through a feedback loop model.To date,there has been no exploration of this feedback model in fractional-order dynamical systems.This feedback loop model incorporates several crucial mechanisms like the buffering process,IP_(3)-receptor,ryanodine receptor,plasma membrane Ca^(2+)ATPase and sarcoplasmic/endoplasmic reticulum calcium ATPase(SERCA)pump,leak,sodium-calcium exchanger,voltage-gated Ca^(2+)channel,Orai channels,DA-dependent IP_(3)synthesis,and others.By incorporating these mechanisms,the model aims to provide a more comprehensive and realistic understanding of the system under investigation.The present model incorporates fractional-order dynamics along both spatial and temporal dimensions to examine the impacts of superdiffusion and memory showing Brownian motion of Ca^(2+),IP_(3),and DA signaling molecules.The bidirectional feedback between calcium and IP_(3)signaling systems,unidirectional feedback between calcium and dopamine signaling systems,and unidirectional feedback between IP_(3)and dopamine signaling systems have been incorporated into the present model.These feedback loops establish interactions among calcium,IP_(3),and dopamine signaling systems within neuronal cells.The numerical findings were obtained by using the Crank-Nicholson method with the Grunwald technique for fractional space derivatives and the L1method for fractional time derivatives in conjunction with the Gauss-Seidel Iterations.This research specifically investigates the implications of cell memory as well as superdiffusion on Ca^(2+),IP_(3),and DA dynamics in neuronal cells,which are interactive nonlinear systems.The superdiffusion process results in a reduction in Ca^(2+),IP_(3),and DA concentrations,while cellular memory leads to an increase in ion and molecule concentrations in neuronal cells during the initial time.The disruption of any given process can lead to imbalances in calcium,IP_(3),and DA systems,hence contributing to neurotoxicity and cellular demise.
基金Supported by Open Project Fund of Henan Provincial Research Center for Precision Diagnosis and Treatment of Pulmonary Diseases Based on Multi-omics,No.DZXGCZXKF04.
文摘Liver fibrosis remains a major global health challenge with limited therapeutic options.In their recent study,Wang et al report that levodopa,a dopamine precursor widely used in Parkinson’s disease,significantly attenuates carbon tetrachloride-induced liver fibrosis in rats by enhancing dopamine receptor D1 expression and activating the Hippo signaling pathway,leading to phosphorylation and inactivation of yes-associated protein 1.This discovery links Gprotein-coupled receptor signaling to Hippo pathway regulation in hepatic fibrosis.The work highlights the dopamine receptor D1-Hippo/yes-associated protein 1 axis as a promising antifibrotic mechanism and introduces levodopa as a potential repurposing candidate for chronic liver disease.With its established safety and affordability,levodopa offers a rapidly translatable strategy that warrants validation in human tissues and diverse fibrosis models.Here,we place these findings in the broader context of G-protein-coupled receptor regulation of hepatic stellate cell activation,discuss translational opportunities for levodopa in liver fibrosis,and propose future directions to validate this pathway across disease models and clinical settings.
文摘BACKGROUND Yes-associated protein 1(YAP1),a downstream transcriptional coactivator regulated by the Hippo signaling pathway,has been shown to be involved in liver fibrosis.YAP activity is modulated by G-protein coupled receptors,including Gαs-coupled protein dopamine receptor D1(DRD1).Levodopa,a dopamine precursor,activates DRD1 on cell surface,triggering its downstream signaling pathway.AIM To investigate the therapeutic effect of levodopa and the downstream mechanism on carbon tetrachloride(CCl_(4))-induced liver fibrosis,including liver DRD1 expression.METHODS SD rats were intraperitoneally injected with 40%CCl_(4)for 8 weeks to induce liver fibrosis,followed by treatment with varying doses of levodopa for 2 weeks.Serum aspartate aminotransferase(AST)and alanine aminotransferase(ALT)levels were measured,and liver pathology was assessed using hematoxylin and eosin and Masson's staining.Alpha-smooth muscle actin(α-SMA)content,along with the expressions of DRD1,YAP,and phosphorylated protein,was analyzed by Western blot,immunohistochemistry,and reverse transcription-quantitative real-time polymerase chain reaction.RESULTS Compared with the controls,levodopa-treated rats showed a decrease in the proportion of collagen in the liver and a recovery from liver fibrosis(P=0.0007).Western blot and immunohistochemistry indicated that DRD1 was upregulated in the fibrotic liver of rats treated with levodopa,showing an increase in DRD1 Level(P<0.0001).In addition,the upregulation of DRD1 activated the Hippo signaling pathway,manifested as increased YAP phosphorylation(P<0.05).CONCLUSION This was the first study to demonstrate that levodopa attenuates CCl_(4)-induced liver fibrosis by inhibiting the Hippo/YAP signaling pathways.
基金The National Natural Science Foundation of China(Grant No.21302079)the Fundamental Research Funds for the Central Universities(Grant No.lzujbky-2014-151)
文摘Hybrid antioxidants cinnamoyldopamine（2a）, p-coumaroyldopamine（2b）, caffeoyldopamine（2c）, feruloyldopamine（2d） and sinapoyldopamine（2e） were synthesized by conjugation of dopamine（DA） and hydroxycinnamic acids（HCAs）. The stabilities were studied in buffers at p H 1.3, p H 5.0, and p H 7.4 including the human plasma. All the compounds were found highly stable at acidic p H, but underwent hydrolysis at neutral p H. Furthermore, the hydrolysis proceeded much faster in plasma in the following order as indicated by half-life values（t1/2）, 2c（1.21 h）〈2e（1.52 h）〈2d（1.85 h）〈2b（3.38 h）〈2a（3.88 h）, correlating with the number of electron-donating groups. It has been proven by UV spectrum that 2c, 2d, and 2e displayed red shift of more than 50 nm as compared to 2a and 2b, because of the presence of OH and OCH3 groups. In addition, the compounds（2b–e） showed no cytotoxicity on normal HUVEC cells as DA, although 2a displayed a 16% inhibition of proliferation at 40 μM following 48 h incubation. Their free radical-scavenging activities were evaluated using ABTS^＊＋ and superoxide anion assays and the mechanisms were proposed. It was found that they all exhibited higher activities than trolox, a recognized antioxidant. Amazingly, in the case of the hybrids（2a–e）, their activity was higher than that of HCAs while lower or comparable to that of DA, suggesting that there may be a ＂saturation effect＂ with the hybrid molecules in the antioxidant activities.
文摘Objective To investigate the influence of dopamine （DA） and DA receptor＇s antagonist on the transmission of noxious information in the central nervous system of normal rats or morphinistic rats. Methods The influence of DA on the electric activity of the pain-excited neuron （PEN） in the caudate nucleus （Cd） of normal rats or morphinistic rats was recorded after the sciatic nerve was noxiously stimulated. Results DA shortened the average latency of the evoked discharge of PEN in the Cd of normal rats, indicating that DA could increase the activity of PEN and pain sensitivity in normal rats. This effect could be inhibited by Droperidol. DA increased the average latency of the evoked discharge of PEN in the Cd of morphinistic rats, indicating that DA could inhibit the activity of PEN and pain sensitivity in morphinistic rats. Conclusion The responses to painful stimulation were completely opposite between normal rats and morphinistic rats after the intracerebroventricular injection of DA.
