Parkinson’s disease is a neurodegenerative disease characterized by motor and gastrointestinal dysfunction.Gastrointestinal dysfunction can precede the onset of motor symptoms by several years.Gut microbiota dysbiosi...Parkinson’s disease is a neurodegenerative disease characterized by motor and gastrointestinal dysfunction.Gastrointestinal dysfunction can precede the onset of motor symptoms by several years.Gut microbiota dysbiosis is involved in the pathogenesis of Parkinson’s disease,whether it plays a causal role in motor dysfunction,and the mechanism underlying this potential effect,remain unknown.CCAAT/enhancer binding proteinβ/asparagine endopeptidase(C/EBPβ/AEP)signaling,activated by bacterial endotoxin,can promoteα-synuclein transcription,thereby contributing to Parkinson’s disease pathology.In this study,we aimed to investigate the role of the gut microbiota in C/EBPβ/AEP signaling,α-synuclein-related pathology,and motor symptoms using a rotenone-induced mouse model of Parkinson’s disease combined with antibiotic-induced microbiome depletion and fecal microbiota transplantation.We found that rotenone administration resulted in gut microbiota dysbiosis and perturbation of the intestinal barrier,as well as activation of the C/EBP/AEP pathway,α-synuclein aggregation,and tyrosine hydroxylase-positive neuron loss in the substantia nigra in mice with motor deficits.However,treatment with rotenone did not have any of these adverse effects in mice whose gut microbiota was depleted by pretreatment with antibiotics.Importantly,we found that transplanting gut microbiota derived from mice treated with rotenone induced motor deficits,intestinal inflammation,and endotoxemia.Transplantation of fecal microbiota from healthy control mice alleviated rotenone-induced motor deficits,intestinal inflammation,endotoxemia,and intestinal barrier impairment.These results highlight the vital role that gut microbiota dysbiosis plays in inducing motor deficits,C/EBPβ/AEP signaling activation,andα-synuclein-related pathology in a rotenone-induced mouse model of Parkinson’s disease.Additionally,our findings suggest that supplementing with healthy microbiota may be a safe and effective treatment that could help ameliorate the progression of motor deficits in patients with Parkinson’s disease.展开更多
The endoplasmic reticulum,a key cellular organelle,regulates a wide variety of cellular activities.Endoplasmic reticulum autophagy,one of the quality control systems of the endoplasmic reticulum,plays a pivotal role i...The endoplasmic reticulum,a key cellular organelle,regulates a wide variety of cellular activities.Endoplasmic reticulum autophagy,one of the quality control systems of the endoplasmic reticulum,plays a pivotal role in maintaining endoplasmic reticulum homeostasis by controlling endoplasmic reticulum turnover,remodeling,and proteostasis.In this review,we briefly describe the endoplasmic reticulum quality control system,and subsequently focus on the role of endoplasmic reticulum autophagy,emphasizing the spatial and temporal mechanisms underlying the regulation of endoplasmic reticulum autophagy according to cellular requirements.We also summarize the evidence relating to how defective or abnormal endoplasmic reticulum autophagy contributes to the pathogenesis of neurodegenerative diseases.In summary,this review highlights the mechanisms associated with the regulation of endoplasmic reticulum autophagy and how they influence the pathophysiology of degenerative nerve disorders.This review would help researchers to understand the roles and regulatory mechanisms of endoplasmic reticulum-phagy in neurodegenerative disorders.展开更多
Stem cell transplantation has brought new hope for the treatment of neurological diseases.The key to stem cell therapy lies in inducing the specific differentiation of stem cells into nerve cells.Because the different...Stem cell transplantation has brought new hope for the treatment of neurological diseases.The key to stem cell therapy lies in inducing the specific differentiation of stem cells into nerve cells.Because the differentiation of stem cells in vitro and in vivo is affected by multiple factors,the final differentiation outcome is strongly associated with the microenvironment in which the stem cells are located.Accordingly,the optimal microenvironment for inducing stem cell differentiation is a hot topic.EGb761 is extracted from the leaves of the Ginkgo biloba tree.It is used worldwide and is becoming one of the focuses of stem cell research.Studies have shown that EGb761 can antagonize oxygen free radicals,stabilize cell membranes,promote neurogenesis and synaptogenesis,increase the level of brain-derived neurotrophic factors,and replicate the environment required during the differentiation of stem cells into nerve cells.This offers the possibility of using EGb761 to induce the differentiation of stem cells,facilitating stem cell transplantation.To provide a comprehensive reference for the future application of EGb761 in stem cell therapy,we reviewed studies investigating the influence of EGb761 on stem cells.These started with the composition and neuropharmacology of EGb761,and eventually led to the finding that EGb761 and some of its important components play important roles in the differentiation of stem cells and the protection of a beneficial microenvironment for stem cell transplantation.展开更多
Autophagy has been shown to play an important role in Parkinson’s disease.We hypothesized that skin-derived precursor cells exhibit neuroprotective effects in Parkinson’s disease through affecting autophagy.In this ...Autophagy has been shown to play an important role in Parkinson’s disease.We hypothesized that skin-derived precursor cells exhibit neuroprotective effects in Parkinson’s disease through affecting autophagy.In this study,6-hydroxydopamine-damaged SH-SY5Y cells were pretreated with a culture medium containing skin-derived precursors differentiated into Schwann cells(SKP-SCs).The results showed that the SKP-SC culture medium remarkably enhanced the activity of SH-SY5Y cells damaged by 6-hydroxydopamine,reduced excessive autophagy,increased tyrosine hydroxylase expression,reducedα-synuclein expression,reduced the autophagosome number,and activated the PI3K/AKT/mTOR pathway.Autophagy activator rapamycin inhibited the effects of SKP-SCs,and autophagy inhibitor 3-methyladenine had the opposite effect.These findings confirm that SKP-SCs modulate the PI3K/AKT/mTOR pathway to inhibit autophagy,thereby exhibiting a neuroprotective effect in a cellular model of Parkinson’s disease.This study was approved by the Animal Ethics Committee of Laboratory Animal Center of Nantong University(approval No.S20181009-205)on October 9,2018.展开更多
Microglia are the main non-neuronal cells in the central nervous system that have important roles in brain development and functional connectivity of neural circuits.In brain physiology,highly dynamic microglial proce...Microglia are the main non-neuronal cells in the central nervous system that have important roles in brain development and functional connectivity of neural circuits.In brain physiology,highly dynamic microglial processes are facilitated to sense the surrounding environment and stimuli.Once the brain switches its functional states,microglia are recruited to specific sites to exert their immune functions,including the release of cytokines and phagocytosis of cellular debris.The crosstalk of microglia between neurons,neural stem cells,endothelial cells,oligodendrocytes,and astrocytes contributes to their functions in synapse pruning,neurogenesis,vascularization,myelination,and blood-brain barrier permeability.In this review,we highlight the neuron-derived“find-me,”“eat-me,”and“don't eat-me”molecular signals that drive microglia in response to changes in neuronal activity for synapse refinement during brain development.This review reveals the molecular mechanism of neuron-microglia interaction in synaptic pruning and presents novel ideas for the synaptic pruning of microglia in disease,thereby providing important clues for discovery of target drugs and development of nervous system disease treatment methods targeting synaptic dysfunction.展开更多
Adhesion G protein-coupled receptors(aGPCRs)are the second largest diverse group within the GPCR superfamily,which play critical roles in many physiological and patho-logical processes through cell-cell and cell-extra...Adhesion G protein-coupled receptors(aGPCRs)are the second largest diverse group within the GPCR superfamily,which play critical roles in many physiological and patho-logical processes through cell-cell and cell-extracellular matrix interactions.The adhesion GPCR Adgrg6,also known as GPR126,is one of the better-characterized aGPCRs.GPR126 was previously found to have critical developmental roles in Schwann cell maturation and its mediated myelination in the peripheral nervous system in both zebrafish and mammals.Current studies have extended our understanding of GPR126-mediated roles during develop-ment and in human diseases.In this review,we highlighted these recent advances in GPR126 in expression profile,molecular structure,ligand-receptor interactions,and associated physiological and pathological functions in development and diseases.展开更多
Background China is one of the countries with the highest burden of stroke.Implementing multidimensional management guidelines will help clinicians practise evidence-based care,improve patient outcomes and alleviate s...Background China is one of the countries with the highest burden of stroke.Implementing multidimensional management guidelines will help clinicians practise evidence-based care,improve patient outcomes and alleviate societal burdens.This update of the 2019 edition will provide the latest comprehensive recommendations for the diagnosis and treatment of ischaemic cerebrovascular diseases.Methods We conducted a comprehensive search on MEDLINE(via PubMed)up to 31 August 2023.The writing team established the recommendations through multiple rounds of online and offline discussions.Each recommendation was graded using the evidence grading algorithm developed by the Chinese Stroke Association(CSA).The draft was reviewed and finalised by the CSA Stroke Guidelines Writing Committee.Results This update included revisions of 15 existing recommendations and 136 new recommendations in the following areas of stroke care:emergency assessment and diagnosis of ischaemic cerebrovascular disease,acute-phase reperfusion therapy,evaluation of underlying mechanisms,antithrombotic therapy,prevention and treatment of complications,and risk factor management.Conclusions This guideline updated the recommendations for the clinical management of ischaemic cerebrovascular disease from 2019.展开更多
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. It is a complex syndrome with heterogeneous aetiologies, pathogenesis and manifestations. Patients with PD may...Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. It is a complex syndrome with heterogeneous aetiologies, pathogenesis and manifestations. Patients with PD may present with motor symptoms and various non-motor symptoms (NMSs). NMSs have been reported in almost every diagnosed case of PD and usually precede motor symptoms. Multiple factors have been proved to be associated with the occurrence of NMSs in PD, among which genetic differentiation is a featured one. With the development of sequencing techniques, an increasing number of NMS-related genetic factors have been identified. This article reviews some of the latest discoveries in this regard.展开更多
Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-associated death worldwide.Angiogenesis,the process of formation of new blood vessels,is required for cancer cells to obtain nutrients and oxygen.HCC ...Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-associated death worldwide.Angiogenesis,the process of formation of new blood vessels,is required for cancer cells to obtain nutrients and oxygen.HCC is a typical hypervascular solid tumor with an aberrant vascular network and angiogenesis that contribute to its growth,progression,invasion,and metastasis.Current anti-angiogenic therapies target mainly tyrosine kinases,vascular endothelial growth factor receptor(VEGFR),and plateletderived growth factor receptor(PDGFR),and are considered effective strategies for HCC,particularly advanced HCC.However,because the survival benefits conferred by these anti-angiogenic therapies are modest,new anti-angiogenic targets must be identified.Several recent studies have determined the underlying molecular mechanisms,including pro-angiogenic factors secreted by HCC cells,the tumor microenvironment,and cancer stem cells.In this review,we summarize the roles of pro-angiogenic factors;the involvement of endothelial cells,hepatic stellate cells,tumor-associated macrophages,and tumor-associated neutrophils present in the tumor microenvironment;and the regulatory influence of cancer stem cells on angiogenesis in HCC.Furthermore,we discuss some of the clinically approved anti-angiogenic therapies and potential novel therapeutic targets for angiogenesis in HCC.A better understanding of the mechanisms underlying angiogenesis may lead to the development of more optimized anti-angiogenic treatment modalities for HCC.展开更多
Parkinson’s disease(PD)is a complicated neurodegenerative disease,characterized by the accumulation ofα-synuclein(α-syn)in Lewy bodies and neurites,and massive loss of midbrain dopamine neurons.Increasing evidence ...Parkinson’s disease(PD)is a complicated neurodegenerative disease,characterized by the accumulation ofα-synuclein(α-syn)in Lewy bodies and neurites,and massive loss of midbrain dopamine neurons.Increasing evidence suggests that gut microbiota and microbial metabolites are involved in the development of PD.Among these,short-chain fatty acids(SCFAs),the most abundant microbial metabolites,have been proven to play a key role in brain-gut communication.In this review,we analyze the role of SCFAs in the pathology of PD from multiple dimensions and summarize the alterations of SCFAs in PD patients as well as their correlation with motor and non-motor symptoms.Future research should focus on further elucidating the role of SCFAs in neuroinflammation,as well as developing novel strategies employing SCFAs and their derivatives to treat PD.展开更多
Background:Studies suggest seasonal fluctuations of symptoms in Parkinson’s disease(PD)patients in Western countries.However,the association between seasonal change and variation in nonmotor symptoms(NMS)in Chinese P...Background:Studies suggest seasonal fluctuations of symptoms in Parkinson’s disease(PD)patients in Western countries.However,the association between seasonal change and variation in nonmotor symptoms(NMS)in Chinese PD patients is unclear.Here,we studied whether there is a change rule with annual cycle with severity of NMS for patients with PD in Southeast China.Methods:We studied 1005 PD patients between April 2008 and October 2020.Patients were classified into four seasons according to the 24 Chinese solar terms,based on assessment date.We compared comprehensive NMS scales and polysomnography parameters among groups and conducted further analysis of disease severity.Results:Among the 1005 patients studied,the mean age was 64.2±9.7 years and 569(56.6%)of them were men.Relative to the summer group,patients assessed during winter had higher Scales for Outcomes in Parkinson’s disease-Autonomic Dysfunction(SCOPA-AUT)scores(P=0.045).The sleep efficiency factor scores of Pittsburgh Sleep Quality Index in patients were higher during spring than summer(P=0.009).Among patients who completed polysomnography during the same period(n=135),compared with summer follow-ups,we observed a higher percentage of NREMS1 in winter and spring follow-ups(P=0.042,P=0.011),a higher NREMS1 time in spring follow-ups(P=0.0024),a lower NREMS2 time in winter follow-ups(P=0.007),and a higher percentage of phasic rapid eye movement(REM)-sleep without atonia in autumn and winter follow-ups(P=0.026 and P=0.020,respectively).In a subset of patients with PD and REM sleep behavior disorder(RBD;n=182),those visited during winter had higher scores for RBD questionnaire-Hong Kong and its factor 1(dream-related sub-score)than those visited during summer(P=0.034,P=0.020).We observed similar findings for SCOPA-AUT and sleep efficiency factor scores in early stage patients in subgroup analysis.Conclusions:PD patients assessed for follow-up during summer showed less severe symptoms of autonomic dysfunction and RBD symptoms than those assessed in winter,and less sleep disturbance than those in spring and winter,suggesting that seasonal change and NMS fluctuation are related,especially in patients with early stage PD.展开更多
Alzheimer’s disease(AD)is a neurodegenerative disease that currently cannot be cured by any drug or intervention,due to its complicated pathogenesis.Current animal and cellular models of AD are unable to meet researc...Alzheimer’s disease(AD)is a neurodegenerative disease that currently cannot be cured by any drug or intervention,due to its complicated pathogenesis.Current animal and cellular models of AD are unable to meet research needs for AD.However,recent three-dimensional(3D)cerebral organoid models derived from human stem cells have provided a new tool to study molecular mechanisms and pharmaceutical developments of AD.In this review,we discuss the advantages and key limitations of the AD cerebral organoid system in comparison to the commonly used AD models,and propose possible solutions,in order to improve their application in AD research.Ethical concerns associated with human cerebral organoids are also discussed.We also summarize future directions of studies that will improve the cerebral organoid system to better model the pathological events observed in AD brains.展开更多
Owing to the promising therapeutic effect and one-time treatment advantage, gene therapy may completely change the management of eye diseases, especially retinal diseases. Adeno-associated virus (AAV) is considered on...Owing to the promising therapeutic effect and one-time treatment advantage, gene therapy may completely change the management of eye diseases, especially retinal diseases. Adeno-associated virus (AAV) is considered one of the most promising viral gene delivery tools because it can infect various types of tissues and is considered as a relatively safe gene delivery vector. The eye is one of the most popular organs for gene therapy, since its limited volume is suitable for small doses of AAV stably transduction. Recently, an increasing number of clinical trials of AAV-mediated gene therapy are underway. This review summarizes the biological functions of AAV and its application in the treatment of various ocular diseases, as well as the characteristics of different AAV delivery routes in clinical applications. Here, the latest research progresses in AAV-mediated gene editing and silencing strategies to modify that the genetic ocular diseases are systematically outlined, especially by base editing and prime editing. We discuss the progress of AAV in ocular optogenetic therapy. We also summarize the application of AAV-mediated gene therapy in animal models and the difficulties in its clinical transformation.展开更多
Background：Rapid eye movement （REM） sleep behavior disorder （RBD） and obstructive sleep apnea （OSA） are the most common sleep disorders in Parkinson’s disease （PD）. The aim of this study was to identify whet...Background：Rapid eye movement （REM） sleep behavior disorder （RBD） and obstructive sleep apnea （OSA） are the most common sleep disorders in Parkinson’s disease （PD）. The aim of this study was to identify whether RBD could alleviate OSA severity in PD patients and its effect on cognitive impairment.Methods：From February 2014 to May 2017, we recruited 174 PD patients from the Second Affiliated Hospital of Soochow University, all of whom underwent polysomnography （PSG）. We collected clinical data, PSG results, and compared information between patients with and without RBD or OSA by analysis of covariance. We also investigated the effect of these sleep disorders on cognitive impairment using linear regression.Results：We grouped participants as follows： PD only （n = 53）, PD ＋ OSA （n = 29）, PD ＋ RBD （n = 61）, and PD ＋ RBD ＋ OSA （n = 31）. Minimum oxygen saturation （SaO2） during whole sleep and in REM sleep was higher in PD ＋ RBD ＋ OSA patients than that in PD ＋ OSA patients. PD ＋ RBD patients had worse Mini-Mental Status Examination and Montreal Cognitive Assessment （MoCA） scores than those in the PD group （P 〈 0.001）, especially in visuospatial/executive, attention, and memory functions. The PD ＋ OSA group performed worse than the PD group in the delayed recall domain. After adjusting for age, sex, body mass index, education, disease severity, and other sleep disorders, MoCA was negatively associated with OSA （β = ？0.736, P = 0.043） and RBD （β = ？2.575, P 〈 0.001）. The severity of RBD （tonic/phasic electromyography activity） and OSA （apnea-hypopnea index/oxygen desaturation index/minimum SaO2） were also associated with MoCA. The adjusted β values of RBD-related parameters were higher than that for OSA.Conclusions：We found that RBD alleviated OSA severity; however, RBD and OSA together exacerbated PD cognitive impairment. Further studies are needed to evaluate whether OSA treatment can improve cognition in PD.展开更多
Objective：Excessive daytime sleepiness （EDS） is one of the most common sleep abnormalities in patients with Parkinson’s disease （PD）, yet its multifactorial etiology complicates its treatment. This review summar...Objective：Excessive daytime sleepiness （EDS） is one of the most common sleep abnormalities in patients with Parkinson’s disease （PD）, yet its multifactorial etiology complicates its treatment. This review summarized recent studies on the epidemiology, etiology, clinical implications, associated features, and evaluation of EDS in PD. The efficacy of pharmacologic and non-pharmacologic treatments for EDS in PD was also reviewed.Data Sources：English language articles indexed in PubMed and Cochrane databases and Chinese-language papers indexed in Wanfang and National Knowledge Infrastructure databases that were published between January 1987 and November 2017 were located using the following search terms： ＂sleepiness＂ , ＂sleep and Parkinson’s disease＂ , and ＂Parkinson’s disease and treatment＂ .Study Selection：Original research articles and critical reviews related to EDS in PD were selected.Results：EDS is a major health hazard and is associated with many motor and nonmotor symptoms of PD. Its causes are multifactorial. There are few specific guidelines for the treatment of EDS in PD. It is first necessary to identify and treat any possible factors causing EDS. Recent studies showed that some nonpharmacologic （i.e., cognitive behavioral therapy, light therapy, and repetitive transcranial magnetic stimulation） and pharmacologic （i.e., modafinil, methylphenidate, caffeine, istradefylline, sodium oxybate, and atomoxetine） treatments may be effective in treating EDS in PD.Conclusions：EDS is common in the PD population and can have an immensely negative impact on quality of life. Its causes are multifactorial, which complicates its treatment. Further investigations are required to determine the safety and efficacy of potential therapies and to develop novel treatment approaches for EDS in PD.展开更多
Background： Parkinson＇s disease （PD） patients with long-term levodopa （L-DOPA） treatment are suffering from severe circadian dysfunction. However, it is hard to distinguish that the circadian disturbance in pati...Background： Parkinson＇s disease （PD） patients with long-term levodopa （L-DOPA） treatment are suffering from severe circadian dysfunction. However, it is hard to distinguish that the circadian disturbance in patients is due to the disease progression itself, or is affected by L-DOPA replacement therapy. This study was to investigate the role of L-DOPA on the circadian dysfunction in a rat model of PD. Methods： The rat model of PD was constructed by a bilateral striatal injection with 6-hydroxydopamine （6-OHDA）, followed by administration of saline or 25 mg/kg L-DOPA for 21 consecutive days. Rotarod test, footprint test, and open-field test were carried out to evaluate the motor function. Striatum, suprachiasmatic nucleus （SCN）, liver, and plasma were collected at 6：00, 12：00, 18：00, and 24：00. Quantitative real-time polymerase chain reaction was used to examine the expression of clock genes. Enzyme-linked immunosorbent assay was used to determine the secretion level of cortisol and melatonin. High-performance liquid chromatography was used to measure the neurotransmitters. Analysis of variance was used for data analysis. Results： L-DOPA alleviated the motor deficits induced by 6-OHDA lesions in the footprint and open-field test （P 〈 0.01, P 〈 0.001, respectively）. After L-DOPA treatment, Bmall decreased in the SCN compared with 6-OHDA group at 12：00 （P 〈 0.01） and 24：00 （P 〈 0.001 ）. In the striatum, the expression ofBmall, Rorα was lower than that in the 6-OHDA group at 18：00 （P 〈 0.05） and L-DOPA seemed to delay the peak of Per2 to 24：00. In liver, L-DOPA did not affect the rhythmicity and expression of these clock genes （P 〉 0.05）. In addition, the cortisol secretion was increased （P 〉 0.05）, but melatonin was further inhibited after L-DOPA treatment at 6：00 （P 〈 0.01）. Conclusions： In the circadian system of advanced PD rat models, circadian dysfunction is not only contributed by the degeneration of the disease itself but also long-term L-DOPA therapy may further aggravate it.展开更多
To the Editor:Alterations of circadian rhythms seem to be the casual contribution to sleep disturbances,depression,and other non-motor symptoms in Parkinson's disease(PD).[1,2]By restoring the circadian rhythm,bri...To the Editor:Alterations of circadian rhythms seem to be the casual contribution to sleep disturbances,depression,and other non-motor symptoms in Parkinson's disease(PD).[1,2]By restoring the circadian rhythm,bright light therapy(BLT)might be a potentially new treatment option for PD.However,no studies have conclusively demonstrated the effects of BLT on the non-motor symptoms in PD.展开更多
Stroke is the leading cause of disability and mortality worldwide.More than half of stroke patients have sleep disorders,including sleep breathing disorders,non-apnea sleep disturbances,and circadian rhythm disruption...Stroke is the leading cause of disability and mortality worldwide.More than half of stroke patients have sleep disorders,including sleep breathing disorders,non-apnea sleep disturbances,and circadian rhythm disruption.Therefore,sleep disturbances,particularly obstructive sleep apnea(OSA),have long been speculated as new preventive and therapeutic targets for stroke.Whether the specific roles of the above sleep disorders in stroke outcome or the efficacy of OSA treatment with continuous positive airway pressure(CPAP)therapy to prevent cerebrovascular events remains uncertain yet.It is noteworthy that there are important limitations among these studies.Here,we briefly reviewed representative studies and subsequently addressed the opportunities mainly for clinical research.The main recommendations are outlined at the end.展开更多
Dear Editor,R-spondin3(RSPO3)is essential for vascular development and angiogenesis.Analyzing RSPO3-knockout embryos revealed severe vascular defects in the placenta(Aoki et al.2007).In both Xenopus and murine embryos...Dear Editor,R-spondin3(RSPO3)is essential for vascular development and angiogenesis.Analyzing RSPO3-knockout embryos revealed severe vascular defects in the placenta(Aoki et al.2007).In both Xenopus and murine embryos,RSPO3 KO led to significant vascular defects(Kazanskaya et al.2008)and embryonic death(Kazanskaya et al.2008).In the placenta,RSPO3 could promote vascular endothelial growth factor(VEGF)expression(Kazanskaya et al.2008).RSPO3 is a ligand of low-density lipoprotein receptor-related protein 6(LRP6)and leucine-rich repeat G protein-coupled receptor 4(LGR4)to form a multiple ligands-receptors-cluster with Wnt and frizzled(FzD),thereby activating and amplifying downstreamβ-catenin signaling(in and Yoon 2012;Tocci et al.2020).展开更多
Circadian rhythm is manifested by the behavioral and physiological changes from day to night, which is controlled by the pacemaker and its regulator. The former is located at the suprachiasmatic nuclei （SCN） in the ...Circadian rhythm is manifested by the behavioral and physiological changes from day to night, which is controlled by the pacemaker and its regulator. The former is located at the suprachiasmatic nuclei （SCN） in the anterior hypothalamus, while the latter is composed of clock genes present in all tissues. Circadian desynchronization influences normal patterns of day-night rhythms such as sleep and alertness cycles, rest and activity cycles. Parkinson＇s disease （PD） exhibits diurnal fluctuations. Circadian dysfunction has been observed in PD patients and animal models, which may result in negative conse- quences to the homeostasis and even exacerbate the disease progression. Therefore, circadian therapies, including light stimulation, physical activity, dietary and social schedules, may be helpful for PD patients. However, the cellular and molecular mechanisms that underlie the circadian dysfunction in PD remain elusive. Further research on circadian patterns is needed. This article summarizes the existing research on the circadian rhythms in PD, focusing on the clinical symptom variations, molecular changes, as well as the available treatment options.展开更多
基金supported by Jiangsu Provincial Medical Key Discipline,No.ZDXK202217(to CFL)Jiangsu Planned Projects for Postdoctoral Research Funds,No.1601056C(to SL).
文摘Parkinson’s disease is a neurodegenerative disease characterized by motor and gastrointestinal dysfunction.Gastrointestinal dysfunction can precede the onset of motor symptoms by several years.Gut microbiota dysbiosis is involved in the pathogenesis of Parkinson’s disease,whether it plays a causal role in motor dysfunction,and the mechanism underlying this potential effect,remain unknown.CCAAT/enhancer binding proteinβ/asparagine endopeptidase(C/EBPβ/AEP)signaling,activated by bacterial endotoxin,can promoteα-synuclein transcription,thereby contributing to Parkinson’s disease pathology.In this study,we aimed to investigate the role of the gut microbiota in C/EBPβ/AEP signaling,α-synuclein-related pathology,and motor symptoms using a rotenone-induced mouse model of Parkinson’s disease combined with antibiotic-induced microbiome depletion and fecal microbiota transplantation.We found that rotenone administration resulted in gut microbiota dysbiosis and perturbation of the intestinal barrier,as well as activation of the C/EBP/AEP pathway,α-synuclein aggregation,and tyrosine hydroxylase-positive neuron loss in the substantia nigra in mice with motor deficits.However,treatment with rotenone did not have any of these adverse effects in mice whose gut microbiota was depleted by pretreatment with antibiotics.Importantly,we found that transplanting gut microbiota derived from mice treated with rotenone induced motor deficits,intestinal inflammation,and endotoxemia.Transplantation of fecal microbiota from healthy control mice alleviated rotenone-induced motor deficits,intestinal inflammation,endotoxemia,and intestinal barrier impairment.These results highlight the vital role that gut microbiota dysbiosis plays in inducing motor deficits,C/EBPβ/AEP signaling activation,andα-synuclein-related pathology in a rotenone-induced mouse model of Parkinson’s disease.Additionally,our findings suggest that supplementing with healthy microbiota may be a safe and effective treatment that could help ameliorate the progression of motor deficits in patients with Parkinson’s disease.
基金supported by the National Natural Science Foundation of China,Nos.92049120 and 81870897STI2030-Major Projects,No.2021ZD0204001+6 种基金Guangdong Key Project for Development of New Tools for the Diagnosis and Treatment of Autism,No.2018B030335001the Natural Science Foundation of Jiangsu Province,No.BK20181436the National Major Scientific and Technological Special Project for Significant New Drug Development,No.2019ZX09301102the Discipline Construction Program of the Second Affiliated Hospital of Soochow University,No.XKTJ-TD202003Sino-German Cooperation Mobility Programme,No.M-0679the Science and Technology Project of Suzhou,No.SKY2022161Research Project of Neurological Diseases of the Second Affiliated Hospital of Soochow University Medical Center,No.ND2023A01(all to QHM)。
文摘The endoplasmic reticulum,a key cellular organelle,regulates a wide variety of cellular activities.Endoplasmic reticulum autophagy,one of the quality control systems of the endoplasmic reticulum,plays a pivotal role in maintaining endoplasmic reticulum homeostasis by controlling endoplasmic reticulum turnover,remodeling,and proteostasis.In this review,we briefly describe the endoplasmic reticulum quality control system,and subsequently focus on the role of endoplasmic reticulum autophagy,emphasizing the spatial and temporal mechanisms underlying the regulation of endoplasmic reticulum autophagy according to cellular requirements.We also summarize the evidence relating to how defective or abnormal endoplasmic reticulum autophagy contributes to the pathogenesis of neurodegenerative diseases.In summary,this review highlights the mechanisms associated with the regulation of endoplasmic reticulum autophagy and how they influence the pathophysiology of degenerative nerve disorders.This review would help researchers to understand the roles and regulatory mechanisms of endoplasmic reticulum-phagy in neurodegenerative disorders.
基金funded by the National Natural Science Foundation of China,No.81501185(to CR)the Key Research&Development Project of Shandong Province of China,No.2017GSF218043(to CR)the Science and Technology Planning Project of Yantai of China,No.2016WS017(to LNG),2017WS105(to HL)
文摘Stem cell transplantation has brought new hope for the treatment of neurological diseases.The key to stem cell therapy lies in inducing the specific differentiation of stem cells into nerve cells.Because the differentiation of stem cells in vitro and in vivo is affected by multiple factors,the final differentiation outcome is strongly associated with the microenvironment in which the stem cells are located.Accordingly,the optimal microenvironment for inducing stem cell differentiation is a hot topic.EGb761 is extracted from the leaves of the Ginkgo biloba tree.It is used worldwide and is becoming one of the focuses of stem cell research.Studies have shown that EGb761 can antagonize oxygen free radicals,stabilize cell membranes,promote neurogenesis and synaptogenesis,increase the level of brain-derived neurotrophic factors,and replicate the environment required during the differentiation of stem cells into nerve cells.This offers the possibility of using EGb761 to induce the differentiation of stem cells,facilitating stem cell transplantation.To provide a comprehensive reference for the future application of EGb761 in stem cell therapy,we reviewed studies investigating the influence of EGb761 on stem cells.These started with the composition and neuropharmacology of EGb761,and eventually led to the finding that EGb761 and some of its important components play important roles in the differentiation of stem cells and the protection of a beneficial microenvironment for stem cell transplantation.
基金Technology Project of Nantong of China,Nos.JC2020052(to XSG),JCZ19087(to XSG)the National Natural Science Foundation of China,Nos.81873742(to KFK),81901195(to JBS),81502867(to TX),82073627(to TX).
文摘Autophagy has been shown to play an important role in Parkinson’s disease.We hypothesized that skin-derived precursor cells exhibit neuroprotective effects in Parkinson’s disease through affecting autophagy.In this study,6-hydroxydopamine-damaged SH-SY5Y cells were pretreated with a culture medium containing skin-derived precursors differentiated into Schwann cells(SKP-SCs).The results showed that the SKP-SC culture medium remarkably enhanced the activity of SH-SY5Y cells damaged by 6-hydroxydopamine,reduced excessive autophagy,increased tyrosine hydroxylase expression,reducedα-synuclein expression,reduced the autophagosome number,and activated the PI3K/AKT/mTOR pathway.Autophagy activator rapamycin inhibited the effects of SKP-SCs,and autophagy inhibitor 3-methyladenine had the opposite effect.These findings confirm that SKP-SCs modulate the PI3K/AKT/mTOR pathway to inhibit autophagy,thereby exhibiting a neuroprotective effect in a cellular model of Parkinson’s disease.This study was approved by the Animal Ethics Committee of Laboratory Animal Center of Nantong University(approval No.S20181009-205)on October 9,2018.
基金supported by the National Natural Science Foundation of ChinaNo.32200778(to QC)+5 种基金the Natural Science Foundation of Jiangsu ProvinceNo.BK20220494(to QC)Suzhou Medical and Health Technology Innovation ProjectNo.SKY2022107(to QC)a grant from the Clinical Research Center of Neurological Disease in The Second Affiliated Hospital of Soochow UniversityNos.ND2022A04(to QC)and ND2023B06(to JS)。
文摘Microglia are the main non-neuronal cells in the central nervous system that have important roles in brain development and functional connectivity of neural circuits.In brain physiology,highly dynamic microglial processes are facilitated to sense the surrounding environment and stimuli.Once the brain switches its functional states,microglia are recruited to specific sites to exert their immune functions,including the release of cytokines and phagocytosis of cellular debris.The crosstalk of microglia between neurons,neural stem cells,endothelial cells,oligodendrocytes,and astrocytes contributes to their functions in synapse pruning,neurogenesis,vascularization,myelination,and blood-brain barrier permeability.In this review,we highlight the neuron-derived“find-me,”“eat-me,”and“don't eat-me”molecular signals that drive microglia in response to changes in neuronal activity for synapse refinement during brain development.This review reveals the molecular mechanism of neuron-microglia interaction in synaptic pruning and presents novel ideas for the synaptic pruning of microglia in disease,thereby providing important clues for discovery of target drugs and development of nervous system disease treatment methods targeting synaptic dysfunction.
基金supported by the National Natural Science Foundation of China(No.32200778)the Natural Science Foundation of Jiangsu Province,China(No.BK20220494)+3 种基金Suzhou Medical and Health Technology Innovation Project(China)(No.SKY2022107)startup fund of Soochow University(China)(No.NH21500221,NH21500122)the Clinical Research Center of Neurological Disease in The Second Affiliated Hospital of Soochow University,China(No.ND2022A04 to Qifei Cong)the Nantong Municipal Health and Family Planning Commission(China)(No.QA2021017 to Xin Chu).
文摘Adhesion G protein-coupled receptors(aGPCRs)are the second largest diverse group within the GPCR superfamily,which play critical roles in many physiological and patho-logical processes through cell-cell and cell-extracellular matrix interactions.The adhesion GPCR Adgrg6,also known as GPR126,is one of the better-characterized aGPCRs.GPR126 was previously found to have critical developmental roles in Schwann cell maturation and its mediated myelination in the peripheral nervous system in both zebrafish and mammals.Current studies have extended our understanding of GPR126-mediated roles during develop-ment and in human diseases.In this review,we highlighted these recent advances in GPR126 in expression profile,molecular structure,ligand-receptor interactions,and associated physiological and pathological functions in development and diseases.
基金This research received specific funding from the Chinese Stroke Association.
文摘Background China is one of the countries with the highest burden of stroke.Implementing multidimensional management guidelines will help clinicians practise evidence-based care,improve patient outcomes and alleviate societal burdens.This update of the 2019 edition will provide the latest comprehensive recommendations for the diagnosis and treatment of ischaemic cerebrovascular diseases.Methods We conducted a comprehensive search on MEDLINE(via PubMed)up to 31 August 2023.The writing team established the recommendations through multiple rounds of online and offline discussions.Each recommendation was graded using the evidence grading algorithm developed by the Chinese Stroke Association(CSA).The draft was reviewed and finalised by the CSA Stroke Guidelines Writing Committee.Results This update included revisions of 15 existing recommendations and 136 new recommendations in the following areas of stroke care:emergency assessment and diagnosis of ischaemic cerebrovascular disease,acute-phase reperfusion therapy,evaluation of underlying mechanisms,antithrombotic therapy,prevention and treatment of complications,and risk factor management.Conclusions This guideline updated the recommendations for the clinical management of ischaemic cerebrovascular disease from 2019.
文摘Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. It is a complex syndrome with heterogeneous aetiologies, pathogenesis and manifestations. Patients with PD may present with motor symptoms and various non-motor symptoms (NMSs). NMSs have been reported in almost every diagnosed case of PD and usually precede motor symptoms. Multiple factors have been proved to be associated with the occurrence of NMSs in PD, among which genetic differentiation is a featured one. With the development of sequencing techniques, an increasing number of NMS-related genetic factors have been identified. This article reviews some of the latest discoveries in this regard.
基金supported by the National Key Research and Development Program of China(Grant No.2020YFA0803700)the National Natural Science Foundation of China(Grant Nos.91639108,81770272,and 81970425)+1 种基金the Beijing Natural Science Foundation(Grant No.7212044)the Beijing Hospital Authority Youth Program(Grant No.QML20190306)。
文摘Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-associated death worldwide.Angiogenesis,the process of formation of new blood vessels,is required for cancer cells to obtain nutrients and oxygen.HCC is a typical hypervascular solid tumor with an aberrant vascular network and angiogenesis that contribute to its growth,progression,invasion,and metastasis.Current anti-angiogenic therapies target mainly tyrosine kinases,vascular endothelial growth factor receptor(VEGFR),and plateletderived growth factor receptor(PDGFR),and are considered effective strategies for HCC,particularly advanced HCC.However,because the survival benefits conferred by these anti-angiogenic therapies are modest,new anti-angiogenic targets must be identified.Several recent studies have determined the underlying molecular mechanisms,including pro-angiogenic factors secreted by HCC cells,the tumor microenvironment,and cancer stem cells.In this review,we summarize the roles of pro-angiogenic factors;the involvement of endothelial cells,hepatic stellate cells,tumor-associated macrophages,and tumor-associated neutrophils present in the tumor microenvironment;and the regulatory influence of cancer stem cells on angiogenesis in HCC.Furthermore,we discuss some of the clinically approved anti-angiogenic therapies and potential novel therapeutic targets for angiogenesis in HCC.A better understanding of the mechanisms underlying angiogenesis may lead to the development of more optimized anti-angiogenic treatment modalities for HCC.
基金supported by the Jiangsu Provincial Key R&D Program(BE2018658)Jiangsu Provincial Medical Key Discipline(ZDXK202217)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD).
文摘Parkinson’s disease(PD)is a complicated neurodegenerative disease,characterized by the accumulation ofα-synuclein(α-syn)in Lewy bodies and neurites,and massive loss of midbrain dopamine neurons.Increasing evidence suggests that gut microbiota and microbial metabolites are involved in the development of PD.Among these,short-chain fatty acids(SCFAs),the most abundant microbial metabolites,have been proven to play a key role in brain-gut communication.In this review,we analyze the role of SCFAs in the pathology of PD from multiple dimensions and summarize the alterations of SCFAs in PD patients as well as their correlation with motor and non-motor symptoms.Future research should focus on further elucidating the role of SCFAs in neuroinflammation,as well as developing novel strategies employing SCFAs and their derivatives to treat PD.
基金supported by grants from the Jiangsu Provincial Medical Key Discipline Project(ZDXKB2016022)Suzhou Clinical Research Center of Neurological Disease(Szzx201503)+2 种基金Suzhou Science and Technology Project(SYS2020130)Chinese Sleep Research Society Hansoh Project(2019HSA03)Discipline Construction Program of the Second Affiliated Hospital of Soochow University(XKTJ-TD202003).
文摘Background:Studies suggest seasonal fluctuations of symptoms in Parkinson’s disease(PD)patients in Western countries.However,the association between seasonal change and variation in nonmotor symptoms(NMS)in Chinese PD patients is unclear.Here,we studied whether there is a change rule with annual cycle with severity of NMS for patients with PD in Southeast China.Methods:We studied 1005 PD patients between April 2008 and October 2020.Patients were classified into four seasons according to the 24 Chinese solar terms,based on assessment date.We compared comprehensive NMS scales and polysomnography parameters among groups and conducted further analysis of disease severity.Results:Among the 1005 patients studied,the mean age was 64.2±9.7 years and 569(56.6%)of them were men.Relative to the summer group,patients assessed during winter had higher Scales for Outcomes in Parkinson’s disease-Autonomic Dysfunction(SCOPA-AUT)scores(P=0.045).The sleep efficiency factor scores of Pittsburgh Sleep Quality Index in patients were higher during spring than summer(P=0.009).Among patients who completed polysomnography during the same period(n=135),compared with summer follow-ups,we observed a higher percentage of NREMS1 in winter and spring follow-ups(P=0.042,P=0.011),a higher NREMS1 time in spring follow-ups(P=0.0024),a lower NREMS2 time in winter follow-ups(P=0.007),and a higher percentage of phasic rapid eye movement(REM)-sleep without atonia in autumn and winter follow-ups(P=0.026 and P=0.020,respectively).In a subset of patients with PD and REM sleep behavior disorder(RBD;n=182),those visited during winter had higher scores for RBD questionnaire-Hong Kong and its factor 1(dream-related sub-score)than those visited during summer(P=0.034,P=0.020).We observed similar findings for SCOPA-AUT and sleep efficiency factor scores in early stage patients in subgroup analysis.Conclusions:PD patients assessed for follow-up during summer showed less severe symptoms of autonomic dysfunction and RBD symptoms than those assessed in winter,and less sleep disturbance than those in spring and winter,suggesting that seasonal change and NMS fluctuation are related,especially in patients with early stage PD.
基金This review was supported in part by grants from the Key R&D Program of Ningxia(2018BFG02005 to J.L.,2021BEG03100 to Y.Y.)the National Natural Science Foundation of China(82060792 and 81660645 to Y.Y.,81660673 to J.L.)+2 种基金the Natural Science Foundation of Ningxia(2020AAC03133 to Y.Y.,2021AAC03143 to J.L.)the Fourth Batch of Ningxia Youth Talents Supporting Program(TJGC2019091 to J.L.,TJGC2019100 to Y.Y.)the National College Students Innovation and Entrepreneurship Training Program(S202010752039 to F-C.B.).
文摘Alzheimer’s disease(AD)is a neurodegenerative disease that currently cannot be cured by any drug or intervention,due to its complicated pathogenesis.Current animal and cellular models of AD are unable to meet research needs for AD.However,recent three-dimensional(3D)cerebral organoid models derived from human stem cells have provided a new tool to study molecular mechanisms and pharmaceutical developments of AD.In this review,we discuss the advantages and key limitations of the AD cerebral organoid system in comparison to the commonly used AD models,and propose possible solutions,in order to improve their application in AD research.Ethical concerns associated with human cerebral organoids are also discussed.We also summarize future directions of studies that will improve the cerebral organoid system to better model the pathological events observed in AD brains.
基金the National Natural Science Foundation of China(82200961)the National Basic Science Center Program of China(82388101)+2 种基金the Science and Technology Commission of Shanghai(20DZ2270800)Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology(2022SKLEKFKT004)the China Postdoctoral Science Foundation(2022M720091).
文摘Owing to the promising therapeutic effect and one-time treatment advantage, gene therapy may completely change the management of eye diseases, especially retinal diseases. Adeno-associated virus (AAV) is considered one of the most promising viral gene delivery tools because it can infect various types of tissues and is considered as a relatively safe gene delivery vector. The eye is one of the most popular organs for gene therapy, since its limited volume is suitable for small doses of AAV stably transduction. Recently, an increasing number of clinical trials of AAV-mediated gene therapy are underway. This review summarizes the biological functions of AAV and its application in the treatment of various ocular diseases, as well as the characteristics of different AAV delivery routes in clinical applications. Here, the latest research progresses in AAV-mediated gene editing and silencing strategies to modify that the genetic ocular diseases are systematically outlined, especially by base editing and prime editing. We discuss the progress of AAV in ocular optogenetic therapy. We also summarize the application of AAV-mediated gene therapy in animal models and the difficulties in its clinical transformation.
文摘Background：Rapid eye movement （REM） sleep behavior disorder （RBD） and obstructive sleep apnea （OSA） are the most common sleep disorders in Parkinson’s disease （PD）. The aim of this study was to identify whether RBD could alleviate OSA severity in PD patients and its effect on cognitive impairment.Methods：From February 2014 to May 2017, we recruited 174 PD patients from the Second Affiliated Hospital of Soochow University, all of whom underwent polysomnography （PSG）. We collected clinical data, PSG results, and compared information between patients with and without RBD or OSA by analysis of covariance. We also investigated the effect of these sleep disorders on cognitive impairment using linear regression.Results：We grouped participants as follows： PD only （n = 53）, PD ＋ OSA （n = 29）, PD ＋ RBD （n = 61）, and PD ＋ RBD ＋ OSA （n = 31）. Minimum oxygen saturation （SaO2） during whole sleep and in REM sleep was higher in PD ＋ RBD ＋ OSA patients than that in PD ＋ OSA patients. PD ＋ RBD patients had worse Mini-Mental Status Examination and Montreal Cognitive Assessment （MoCA） scores than those in the PD group （P 〈 0.001）, especially in visuospatial/executive, attention, and memory functions. The PD ＋ OSA group performed worse than the PD group in the delayed recall domain. After adjusting for age, sex, body mass index, education, disease severity, and other sleep disorders, MoCA was negatively associated with OSA （β = ？0.736, P = 0.043） and RBD （β = ？2.575, P 〈 0.001）. The severity of RBD （tonic/phasic electromyography activity） and OSA （apnea-hypopnea index/oxygen desaturation index/minimum SaO2） were also associated with MoCA. The adjusted β values of RBD-related parameters were higher than that for OSA.Conclusions：We found that RBD alleviated OSA severity; however, RBD and OSA together exacerbated PD cognitive impairment. Further studies are needed to evaluate whether OSA treatment can improve cognition in PD.
文摘Objective：Excessive daytime sleepiness （EDS） is one of the most common sleep abnormalities in patients with Parkinson’s disease （PD）, yet its multifactorial etiology complicates its treatment. This review summarized recent studies on the epidemiology, etiology, clinical implications, associated features, and evaluation of EDS in PD. The efficacy of pharmacologic and non-pharmacologic treatments for EDS in PD was also reviewed.Data Sources：English language articles indexed in PubMed and Cochrane databases and Chinese-language papers indexed in Wanfang and National Knowledge Infrastructure databases that were published between January 1987 and November 2017 were located using the following search terms： ＂sleepiness＂ , ＂sleep and Parkinson’s disease＂ , and ＂Parkinson’s disease and treatment＂ .Study Selection：Original research articles and critical reviews related to EDS in PD were selected.Results：EDS is a major health hazard and is associated with many motor and nonmotor symptoms of PD. Its causes are multifactorial. There are few specific guidelines for the treatment of EDS in PD. It is first necessary to identify and treat any possible factors causing EDS. Recent studies showed that some nonpharmacologic （i.e., cognitive behavioral therapy, light therapy, and repetitive transcranial magnetic stimulation） and pharmacologic （i.e., modafinil, methylphenidate, caffeine, istradefylline, sodium oxybate, and atomoxetine） treatments may be effective in treating EDS in PD.Conclusions：EDS is common in the PD population and can have an immensely negative impact on quality of life. Its causes are multifactorial, which complicates its treatment. Further investigations are required to determine the safety and efficacy of potential therapies and to develop novel treatment approaches for EDS in PD.
基金This work was supported by grants from the National Natural Science Foundation of China （No. 91649114）,Jiangsu Provincial Special Program of Medical Science （No. BL2014042）, the Plans for Graduate Research and Innovation in Colleges and Universities of Jiangsu Province （No. KYZZ15_0334）, and Suzhou Clinical Research Center of Neurological Disease （No. Szzx201503）. This was also partly supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions and Jiangsu Provincial Medical Key Discipline Project.
文摘Background： Parkinson＇s disease （PD） patients with long-term levodopa （L-DOPA） treatment are suffering from severe circadian dysfunction. However, it is hard to distinguish that the circadian disturbance in patients is due to the disease progression itself, or is affected by L-DOPA replacement therapy. This study was to investigate the role of L-DOPA on the circadian dysfunction in a rat model of PD. Methods： The rat model of PD was constructed by a bilateral striatal injection with 6-hydroxydopamine （6-OHDA）, followed by administration of saline or 25 mg/kg L-DOPA for 21 consecutive days. Rotarod test, footprint test, and open-field test were carried out to evaluate the motor function. Striatum, suprachiasmatic nucleus （SCN）, liver, and plasma were collected at 6：00, 12：00, 18：00, and 24：00. Quantitative real-time polymerase chain reaction was used to examine the expression of clock genes. Enzyme-linked immunosorbent assay was used to determine the secretion level of cortisol and melatonin. High-performance liquid chromatography was used to measure the neurotransmitters. Analysis of variance was used for data analysis. Results： L-DOPA alleviated the motor deficits induced by 6-OHDA lesions in the footprint and open-field test （P 〈 0.01, P 〈 0.001, respectively）. After L-DOPA treatment, Bmall decreased in the SCN compared with 6-OHDA group at 12：00 （P 〈 0.01） and 24：00 （P 〈 0.001 ）. In the striatum, the expression ofBmall, Rorα was lower than that in the 6-OHDA group at 18：00 （P 〈 0.05） and L-DOPA seemed to delay the peak of Per2 to 24：00. In liver, L-DOPA did not affect the rhythmicity and expression of these clock genes （P 〉 0.05）. In addition, the cortisol secretion was increased （P 〉 0.05）, but melatonin was further inhibited after L-DOPA treatment at 6：00 （P 〈 0.01）. Conclusions： In the circadian system of advanced PD rat models, circadian dysfunction is not only contributed by the degeneration of the disease itself but also long-term L-DOPA therapy may further aggravate it.
基金This work was supported by grants from the Jiangsu Provincial Key R&D Program(No.BE2018658)the Jiangsu Provincial Medical Key Discipline Project(No.ZDXKB2016022)+2 种基金Discipline Construction Program of the Second Affiliated Hospital Soochow University(No.XKTJ-XK202001)the National Natural Science Foundation of China(No.81801253)the Natural Science Foundation of Jiangsu Province(BK 20180214).
文摘To the Editor:Alterations of circadian rhythms seem to be the casual contribution to sleep disturbances,depression,and other non-motor symptoms in Parkinson's disease(PD).[1,2]By restoring the circadian rhythm,bright light therapy(BLT)might be a potentially new treatment option for PD.However,no studies have conclusively demonstrated the effects of BLT on the non-motor symptoms in PD.
基金Jiangsu Provincial Medical Key Discipline Project(No.ZDXKB2016022)Suzhou Clinical Research Center of Neurological Disease(No.Szzx201503)Discipline Construction Program of the Second Affiliated Hospital Soochow University(No.XKTJ-XK202001)。
文摘Stroke is the leading cause of disability and mortality worldwide.More than half of stroke patients have sleep disorders,including sleep breathing disorders,non-apnea sleep disturbances,and circadian rhythm disruption.Therefore,sleep disturbances,particularly obstructive sleep apnea(OSA),have long been speculated as new preventive and therapeutic targets for stroke.Whether the specific roles of the above sleep disorders in stroke outcome or the efficacy of OSA treatment with continuous positive airway pressure(CPAP)therapy to prevent cerebrovascular events remains uncertain yet.It is noteworthy that there are important limitations among these studies.Here,we briefly reviewed representative studies and subsequently addressed the opportunities mainly for clinical research.The main recommendations are outlined at the end.
基金supported by Key Research and Development Program of Jiangsu Province(No.BE2019652)National Natural Science Foundation of China(81922025,81974388,82171461,81771457).
文摘Dear Editor,R-spondin3(RSPO3)is essential for vascular development and angiogenesis.Analyzing RSPO3-knockout embryos revealed severe vascular defects in the placenta(Aoki et al.2007).In both Xenopus and murine embryos,RSPO3 KO led to significant vascular defects(Kazanskaya et al.2008)and embryonic death(Kazanskaya et al.2008).In the placenta,RSPO3 could promote vascular endothelial growth factor(VEGF)expression(Kazanskaya et al.2008).RSPO3 is a ligand of low-density lipoprotein receptor-related protein 6(LRP6)and leucine-rich repeat G protein-coupled receptor 4(LGR4)to form a multiple ligands-receptors-cluster with Wnt and frizzled(FzD),thereby activating and amplifying downstreamβ-catenin signaling(in and Yoon 2012;Tocci et al.2020).
基金supported by the National Natural Science Foundation of China(81471299)Jiangsu Provincial Special Program of Medical Science(BL2014042)+4 种基金Suzhou Clinical Key Disease Diagnosis and Treatment Technology Foundation(LCZX201304)the Plans for Graduate Research and Innovation in Colleges and Universities of Jiangsu Province,China(KYZZ15_0334)Suzhou Medical Key Discipline Projectthe Priority Academic Program Development of Jiangsu Higher Education Institutions,China(PAPD)Suzhou Clinical Research Center of Neurological Disease(Szzx201503)
文摘Circadian rhythm is manifested by the behavioral and physiological changes from day to night, which is controlled by the pacemaker and its regulator. The former is located at the suprachiasmatic nuclei （SCN） in the anterior hypothalamus, while the latter is composed of clock genes present in all tissues. Circadian desynchronization influences normal patterns of day-night rhythms such as sleep and alertness cycles, rest and activity cycles. Parkinson＇s disease （PD） exhibits diurnal fluctuations. Circadian dysfunction has been observed in PD patients and animal models, which may result in negative conse- quences to the homeostasis and even exacerbate the disease progression. Therefore, circadian therapies, including light stimulation, physical activity, dietary and social schedules, may be helpful for PD patients. However, the cellular and molecular mechanisms that underlie the circadian dysfunction in PD remain elusive. Further research on circadian patterns is needed. This article summarizes the existing research on the circadian rhythms in PD, focusing on the clinical symptom variations, molecular changes, as well as the available treatment options.
