Background:This study aimed to discover whether Cistanche tubulosa affects the AKT/CASP3 pathway by regulating m6A methylation,to exert a protective effect against peripheral nerve injury in a Parkinson's Disease(...Background:This study aimed to discover whether Cistanche tubulosa affects the AKT/CASP3 pathway by regulating m6A methylation,to exert a protective effect against peripheral nerve injury in a Parkinson's Disease(PD)mouse model.Methods:In this study,network pharmacology analysis and the molecular docking virtual screening technique was used to filter Acteoside(Act),a potential neuroprotective agent of active components in Cistanche tubulosa.A PD-related peripheral neuropathy mouse model was established by MPTP induction,followed by 21 days treatment of oral Act(25,50,and 100 mg kg^(−1)).Pole climbing,automatic avoidance ability and hot plate sensory tests were evaluated to determine behavioral changes caused by central and peripheral nerve injury.The pathological alterations of dorsal root ganglion tissue and the protein levels of IL-6,AKT,and CASP3 under Act intervention,as well as the dynamic changes of FTO,METTL3,and YTHDF2 which are closely related to m6A methylation,were comprehensively analyzed to observe the peripheral nerve protective efficacy of Act.Results:The results showed that peripheral neuropathy occurring with PD in the mouse model,which could be verified by behavioral tests and pathological histological changes.In addition to the previously established protective effect of Act on dopaminergic neurons in substantia nigra(SN),extensive follow-up studies demonstrated that Act effectively induced m6A methylation,which could further regulate the AKT/CASP3 pathway to play a therapeutic role.In this study,medium and high doses of Act played more obvious therapeutic roles.Conclusion:These findings suggest that Act may regulate the severity of peripheral nerve injury under the activation of the AKT/CASP3 signaling pathway by balancing the methylation level of m6A.These results provide a theoretical basis and experimental evidence for further research on the protective effect of Cistanche tubulosa on both the central and peripheral nerves in the treatment of PD.展开更多
Allatostatins （ASTs）, a family of insect neuropeptide, can inhibit juvenile hormone （JH） biosynthesis by the corpora allata （CA） in Diploptera punctata, and therefore be regarded as potential leads for the disco...Allatostatins （ASTs）, a family of insect neuropeptide, can inhibit juvenile hormone （JH） biosynthesis by the corpora allata （CA） in Diploptera punctata, and therefore be regarded as potential leads for the discovery of new insect growth regulators （1GRs）. But several shortcomings, such as their sensitivity to peptidases and high cost, impeded their practical application in pest management. In order to discover new IGRs, one AST analog B1 possessing non-peptide group was discovered with high ability to inhibit JH biosynthesis in vitro （IC50： 0.09 μmol/L） in our previous studies. In the present work, two series of B1 analogs with different substituents on the N-terminus region were designed and synthesized. The result suggested that benzene showed better activity than other heterocycles, and the para-substitution on the benzene was beneficial for activity. Moreover, analogs with logP value over 2.0 exhibited good activity, which indicated the hydrophobicity is important to the bioactivity. Three dimension quantitative structure-activity relationship （3D-QSAR） studies were performed to highlight the structural require- ments of ASTanalogs, which demonstrated introduction of bulkier substituents on the N-terminus would increase the activity. Analog Ⅱ12 （IC50： 0.08 μmol/L） exhibited similar inhibitory activity to the lead B1, but its synthetic route was simpler than B1. Therefore, Ⅱ12 could be used as a new lead compound for the discovery eco-friendly IGRs.展开更多
In this study, we conducted a clinical analysis of lymphocyte subtypes in 268 patients with Parkinson＇s disease （PD） to assess their clinical impact as a potential marker of advanced PD in Chinese patients. The par...In this study, we conducted a clinical analysis of lymphocyte subtypes in 268 patients with Parkinson＇s disease （PD） to assess their clinical impact as a potential marker of advanced PD in Chinese patients. The participants comprised 268 sporadic PD patients and 268 healthy controls. The numbers of natural killer （NK） cells and CD3＋, CD3＋CD4＋, CD3＋CD8＋, and CD19＋ lympho- cytes from peripheral blood were determined by immunos- taining and flow cytometric analysis and the percentages of these CD＋ T cells were calculated. The ratio of regulatory T （Treg）/helper T 17 （Thl7） lymphocytes from 64 PD patients and 46 controls was determined by flow cytometric analysis. The results showed that the percentage of NK cells was higher in advanced PD patients than in controls （22.92% ± 10.08% versus 19.76% ±10.09%, P= 0.006）, while CD3＋ T cells are decreased （62.93% ±9.27% versus 65.75% ± 9.13%, P = 0.005）. The percentage of CD19＋ B cells in male patients was lower （P = 0.021） than in female patients, whereas NK cells were increased （P 〈 0.0001）. The scores on the Unified Parkinson＇s Disease Rating Scale （UPDRS） and the Non-Motor Symptoms Scale in late-onset PD patients were significantly higher than those in earlyonset patients （P = 0.024 and P = 0.007, respectively）. The percentage of CD19＋ B cells in patients with UPDRS scores 〉24 was lower than in those with scores 〈24 （10.17% ± 4.19% versus 12.22% ± 5.39%, P = 0.009）. In addition, the Treg/Th17 ratio in female patients was higher than that in female controls （13.88 ± 6.32 versus 9.94 ±4.06, P = 0.042）. These results suggest that the percentages of NK cells, CD3＋ T cells, and CD19＋ B cells along with the Treg/Th17 ratio in peripheral blood may be used to predict the risk of PD in Chinese individuals and provide fresh avenues for novel diagnostic biomarkers and therapeutic designs.展开更多
Previous studies suggest that the reduction of SMAD3(mothers against decapentaplegic homolog 3)has a great impact on tumor development,but its exact pathological function remains unclear.In this study,we found that th...Previous studies suggest that the reduction of SMAD3(mothers against decapentaplegic homolog 3)has a great impact on tumor development,but its exact pathological function remains unclear.In this study,we found that the protein level of SMAD3 was greatly reduced in human-grade IV glioblastoma tissues,in which LAMP2A(lysosome-associated membrane protein type 2A)was significantly up-regulated.LAMP2A is a key ratelimiting protein of chaperone-mediated autophagy(CMA),a lysosome pathway of protein degradation that is activated in glioma.We carefully analyzed the amino-acid sequence of SMAD3 and found that it contained a pentapeptide motif biochemically related to KFERQ,which has been proposed to be a targeting sequence for CMA.In vitro,we confirmed that SMAD3 was degraded in either serum-free or KFERQ motif deleted condition,which was regulated by LAMP2A and interacted with HSC70(heat shock cognate 71 kDa protein).Using isolated lysosomes,amino-acid residues 75 and 128 of SMAD3 were found to be of importance for this process,which affected the CMA pathway in which SMAD3 was involved.Similarly,down-regulating SMAD3 or up-regulating LAMP2A in cultured glioma cells enhanced their proliferation and invasion.Taken together,these results suggest that excessive activation of CMA regulates glioma cell growth by promoting the degradation of SMAD3.Therefore,targeting the SMAD3-LAMP2Amediated CMA-lysosome pathway may be a promising approach in anti-cancer therapy.展开更多
Objective:Oncocardiology is increasingly hot research field/topic in the clinical management of cancer with anti-angiogenic therapy of vascular endothelial growth factor(VEGF)that may cause cardiovascular toxicity,suc...Objective:Oncocardiology is increasingly hot research field/topic in the clinical management of cancer with anti-angiogenic therapy of vascular endothelial growth factor(VEGF)that may cause cardiovascular toxicity,such as hypertension via vascular dysfunction and attenuation of eNOS/NO signaling in the baroreflex afferent pathway.The aim of the current study was to evaluate the potential roles of VEGF/VEGF receptors(VEGFRs)expressed in the baroreflex afferent pathway in autonomic control of blood pressure(BP)regulation.Methods:The distribution and expression of VEGF/VEGFRs were detected in the nodose ganglia(NG)and nucleus of tractus solitary(NTS)using immunostaining and molecular approaches.The direct role of VEGF was tested by NG microinjection under physiological and hypertensive conditions.Results:Immunostaining data showed that either VEGF or VEGFR2/VEGFR3 was clearly detected in the NG and NTS of adult male rats.Microinjection of VEGF directly into the NG reduced the mean blood pressure(MBP)dose-dependently,which was less dramatic in renovascular hypertension(RVH)rats,suggesting the VEGF-mediated depressor response by direct activation of the 1st-order baroreceptor neurons in the NG under both normal and disease conditions.Notably,this reduced depressor response in RVH rats was directly caused by the downregulation of VEGFR2,which compensated the up regulation of VEGF/VEGFR3 in the NG during the development of hypertension.Conclusion:It demonstrated for the first time that the BP-lowering property of VEGF/VEGFRs signaling via the activation of baroreflex afferent function may be a common target/pathway leading to BP dysregulation in anti-angiogenic therapy.展开更多
Parkinson’s disease(PD)is referring to the multi-systemicα-synucleinopathy with Lewy bodies deposited in midbrain.In ageing,the environmental and genetic factors work together and overactive major histocompatibility...Parkinson’s disease(PD)is referring to the multi-systemicα-synucleinopathy with Lewy bodies deposited in midbrain.In ageing,the environmental and genetic factors work together and overactive major histocompatibility complex pathway to regulate immune reactions in central nerve system which resulting in neural degeneration,especially in dopaminergic neurons.As a series of biomarkers,the human leukocyte antigen genes with its related proteomics play cortical roles on the antigen presentation of major histocompatibility complex molecules to stimulate the differentiation of T lymphocytes and i-proteasome activities under their immune response to the PD-related environmental alteration and genetic variation.Furthermore,dopaminergic drugs change the biological characteristic of T lymphatic cells,affect theα-synuclein presentation pathway,and inhibit T lymphatic cells to release cytotoxicity in PD development.Taking together,the serum inflammatory factors and blood T cells are involved in the immune dysregulation of PD and inspected as the potential clinic biomarkers for PD prediction.展开更多
Loss of sweat glands(SwGs)commonly associated with extensive skin defects is a leading cause of hyperthermia and heat stroke.In vivo tissue engineering possesses the potential to take use of the body natural ability t...Loss of sweat glands(SwGs)commonly associated with extensive skin defects is a leading cause of hyperthermia and heat stroke.In vivo tissue engineering possesses the potential to take use of the body natural ability to regenerate SwGs,making it more conducive to clinical translation.Despite recent advances in regenerative medicine,reconstructing SwG tissue with the same structure and function as native tissue remains challenging.Elucidating the SwG generation mechanism and developing biomaterials for in vivo tissue engineering is essential for understanding and developing in vivo SwG regenerative strategies.Here,we outline the cell biology associated with functional wound healing and the characteristics of bioactive materials.We critically summarize the recent progress in bioactive material-based cell modulation approaches for in vivo SwG regeneration,including the recruitment of endogenous cells to the skin lesion for SwG regeneration and in vivo cellular reprogramming for SwG regeneration.We discussed the re-establishment of microenvironment via bioactive material-mediated regulators.Besides,we offer promising perspectives for directing in situ SwG regeneration via bioactive material-based cell-free strategy,which is a simple and effective approach to regenerate SwG tissue with both fidelity of structure and function.Finally,we discuss the opportunities and challenges of in vivo SwG regeneration in detail.The molecular mechanisms and cell fate modulation of in vivo SwG regeneration will provide further insights into the regeneration of patient-specific SwGs and the development of potential intervention strategies for gland-derived diseases.展开更多
Background Seed amplification assays(SAA)enable the amplification of pathological misfolded proteins,includ‑ingα-synuclein(αSyn),in both tissue homogenates and body fluids of Parkinson’s disease(PD)patients.SAA inv...Background Seed amplification assays(SAA)enable the amplification of pathological misfolded proteins,includ‑ingα-synuclein(αSyn),in both tissue homogenates and body fluids of Parkinson’s disease(PD)patients.SAA involves repeated cycles of shaking or sonication coupled with incubation periods.However,this amplification scheme has limitations in tracking protein propagation due to repeated fragmentation.Methods We introduced a modified form of SAA,known as Quiescent SAA(QSAA),and evaluated biopsy and autopsy samples from individuals clinically diagnosed with PD and those without synucleinopathies(control group).Brain biopsy samples were obtained from 14 PD patients and 6 controls without synucleinopathies.Addition‑ally,skin samples were collected from 214 PD patients and 208 control subjects.Data were analyzed from April 2019 to May 2023.Results QSAA successfully amplifiedαSyn aggregates in brain tissue sections from mice inoculated with pre-formed fibrils.In the skin samples from 214 PD cases and 208 non-PD cases,QSAA demonstrated high sensitivity(90.2%)and specificity(91.4%)in differentiating between PD and non-PD cases.Notably,moreαSyn aggregates were detected by QSAA compared to immunofluorescence with the pS129-αSyn antibody in consecutive slices of both brain and skin samples.Conclusion We introduced the new QSAA method tailored for in situ amplification ofαSyn aggregates in brain and skin samples while maintaining tissue integrity,providing a streamlined approach to diagnosing PD with individual variability.The integration of seeding activities with the location of deposition ofαSyn seeds advances our understanding of the mechanism underlyingαSyn misfolding in PD.展开更多
The spectrum of synucleinopathies,including Parkinson’s disease(PD),multiple system atrophy(MSA),and dementia with Lewy bodies(DLB),is characterized byα-synuclein(αSyn)pathology,which serves as the definitive diagn...The spectrum of synucleinopathies,including Parkinson’s disease(PD),multiple system atrophy(MSA),and dementia with Lewy bodies(DLB),is characterized byα-synuclein(αSyn)pathology,which serves as the definitive diagnostic marker.However,current diagnostic methods primarily rely on motor symptoms that manifest years after the initial neuropathological changes,thereby delaying potential treatment.The symptomatic overlap between PD and MSA further complicates the diagnosis,highlighting the need for precise and differential diagnostic methods for these overlapping neurodegenerative diseases.αSyn misfolding and aggregation occur before clinical symptoms appear,suggesting that detection of pathologicalαSyn could enable early molecular diagnosis of synucleinopathies.Recent advances in seed amplification assay(SAA)offer a tool for detecting neurodegenerative diseases by identifyingαSyn misfolding in fluid and tissue samples,even at preclinical stages.Extensive research has validated the effectiveness and reproducibility of SAAs for diagnosing synucleinopathies,with ongoing efforts focusing on optimizing conditions for detecting pathologicalαSyn in more accessible samples and identifying specificαSyn species to differentiate between various synucleinopathies.This review offers a thorough overview of SAA technology,exploring its applications for diagnosing synucleinopathies,addressing the current challenges,and outlining future directions for its clinical use.展开更多
To the Editor:Obstructive sleep apnea(OSA)is one of the common sleep disorders in Parkinson’s disease(PD)that is often associated with sleep fragmentation and intermittent hypoxemia.[1]Clinically,it has been observed...To the Editor:Obstructive sleep apnea(OSA)is one of the common sleep disorders in Parkinson’s disease(PD)that is often associated with sleep fragmentation and intermittent hypoxemia.[1]Clinically,it has been observed that symptoms of OSA significantly overlap with both motor and non-motor symptoms of PD.However,the effect of OSA on the clinical symptoms of PD and the underlying mechanisms are still not well understood.OSA has been observed to induce sleep fragmentation and alterations in microscopic sleep architecture detected by electroencephalogram(EEG).展开更多
基金Xinjiang Uygur Autonomous Region Science and Technology Department-Tianshan Innovation Team Program Project,Grant/Award Number:2023D14006Xinjiang Uygur Autonomous Region Science and Technology Department-Natural Science Foundation,Grant/Award Number:2023D01C115。
文摘Background:This study aimed to discover whether Cistanche tubulosa affects the AKT/CASP3 pathway by regulating m6A methylation,to exert a protective effect against peripheral nerve injury in a Parkinson's Disease(PD)mouse model.Methods:In this study,network pharmacology analysis and the molecular docking virtual screening technique was used to filter Acteoside(Act),a potential neuroprotective agent of active components in Cistanche tubulosa.A PD-related peripheral neuropathy mouse model was established by MPTP induction,followed by 21 days treatment of oral Act(25,50,and 100 mg kg^(−1)).Pole climbing,automatic avoidance ability and hot plate sensory tests were evaluated to determine behavioral changes caused by central and peripheral nerve injury.The pathological alterations of dorsal root ganglion tissue and the protein levels of IL-6,AKT,and CASP3 under Act intervention,as well as the dynamic changes of FTO,METTL3,and YTHDF2 which are closely related to m6A methylation,were comprehensively analyzed to observe the peripheral nerve protective efficacy of Act.Results:The results showed that peripheral neuropathy occurring with PD in the mouse model,which could be verified by behavioral tests and pathological histological changes.In addition to the previously established protective effect of Act on dopaminergic neurons in substantia nigra(SN),extensive follow-up studies demonstrated that Act effectively induced m6A methylation,which could further regulate the AKT/CASP3 pathway to play a therapeutic role.In this study,medium and high doses of Act played more obvious therapeutic roles.Conclusion:These findings suggest that Act may regulate the severity of peripheral nerve injury under the activation of the AKT/CASP3 signaling pathway by balancing the methylation level of m6A.These results provide a theoretical basis and experimental evidence for further research on the protective effect of Cistanche tubulosa on both the central and peripheral nerves in the treatment of PD.
基金financially supported by the National Natural Science Foundation of China(No.21372257)the grants from the National Key Research and Development Plan(No.2017YFD0200504)
文摘Allatostatins （ASTs）, a family of insect neuropeptide, can inhibit juvenile hormone （JH） biosynthesis by the corpora allata （CA） in Diploptera punctata, and therefore be regarded as potential leads for the discovery of new insect growth regulators （1GRs）. But several shortcomings, such as their sensitivity to peptidases and high cost, impeded their practical application in pest management. In order to discover new IGRs, one AST analog B1 possessing non-peptide group was discovered with high ability to inhibit JH biosynthesis in vitro （IC50： 0.09 μmol/L） in our previous studies. In the present work, two series of B1 analogs with different substituents on the N-terminus region were designed and synthesized. The result suggested that benzene showed better activity than other heterocycles, and the para-substitution on the benzene was beneficial for activity. Moreover, analogs with logP value over 2.0 exhibited good activity, which indicated the hydrophobicity is important to the bioactivity. Three dimension quantitative structure-activity relationship （3D-QSAR） studies were performed to highlight the structural require- ments of ASTanalogs, which demonstrated introduction of bulkier substituents on the N-terminus would increase the activity. Analog Ⅱ12 （IC50： 0.08 μmol/L） exhibited similar inhibitory activity to the lead B1, but its synthetic route was simpler than B1. Therefore, Ⅱ12 could be used as a new lead compound for the discovery eco-friendly IGRs.
基金supported by the National Key R&D Program of China (2016YFC1306600)the National Natural Science Foundation of China (81471292, U1603281, U1503222, 81430021)+2 种基金the Science Foundation of Guangdong Province, China (2015A030311021)a Technology Project of Guangzhou Municipality, China (201504281820463)a Science and Technology Planning Project of Guangdong Province, China (2016A050502025)
文摘In this study, we conducted a clinical analysis of lymphocyte subtypes in 268 patients with Parkinson＇s disease （PD） to assess their clinical impact as a potential marker of advanced PD in Chinese patients. The participants comprised 268 sporadic PD patients and 268 healthy controls. The numbers of natural killer （NK） cells and CD3＋, CD3＋CD4＋, CD3＋CD8＋, and CD19＋ lympho- cytes from peripheral blood were determined by immunos- taining and flow cytometric analysis and the percentages of these CD＋ T cells were calculated. The ratio of regulatory T （Treg）/helper T 17 （Thl7） lymphocytes from 64 PD patients and 46 controls was determined by flow cytometric analysis. The results showed that the percentage of NK cells was higher in advanced PD patients than in controls （22.92% ± 10.08% versus 19.76% ±10.09%, P= 0.006）, while CD3＋ T cells are decreased （62.93% ±9.27% versus 65.75% ± 9.13%, P = 0.005）. The percentage of CD19＋ B cells in male patients was lower （P = 0.021） than in female patients, whereas NK cells were increased （P 〈 0.0001）. The scores on the Unified Parkinson＇s Disease Rating Scale （UPDRS） and the Non-Motor Symptoms Scale in late-onset PD patients were significantly higher than those in earlyonset patients （P = 0.024 and P = 0.007, respectively）. The percentage of CD19＋ B cells in patients with UPDRS scores 〉24 was lower than in those with scores 〈24 （10.17% ± 4.19% versus 12.22% ± 5.39%, P = 0.009）. In addition, the Treg/Th17 ratio in female patients was higher than that in female controls （13.88 ± 6.32 versus 9.94 ±4.06, P = 0.042）. These results suggest that the percentages of NK cells, CD3＋ T cells, and CD19＋ B cells along with the Treg/Th17 ratio in peripheral blood may be used to predict the risk of PD in Chinese individuals and provide fresh avenues for novel diagnostic biomarkers and therapeutic designs.
基金supported by the National Key R&D Program of China(2016YFC1306601 and 2017YFC1306002)the National Natural Science Foundation of China(82071416,81870992,81870856,U1603281,81903958,81901282,and 82004459)+3 种基金the Natural Science Foundation of Guangdong Province(2020A1515010986,2019A1515011189,and 2018A030310521)a Science and Technol-ogy Planning Project of Guangdong Province(A2018315)a Tech-nology Project of Guangzhou(2018-1202-SF-0019 and 2019ZD09)and a China Postdoctoral Science Foundation Grant(2019M662873)。
文摘Previous studies suggest that the reduction of SMAD3(mothers against decapentaplegic homolog 3)has a great impact on tumor development,but its exact pathological function remains unclear.In this study,we found that the protein level of SMAD3 was greatly reduced in human-grade IV glioblastoma tissues,in which LAMP2A(lysosome-associated membrane protein type 2A)was significantly up-regulated.LAMP2A is a key ratelimiting protein of chaperone-mediated autophagy(CMA),a lysosome pathway of protein degradation that is activated in glioma.We carefully analyzed the amino-acid sequence of SMAD3 and found that it contained a pentapeptide motif biochemically related to KFERQ,which has been proposed to be a targeting sequence for CMA.In vitro,we confirmed that SMAD3 was degraded in either serum-free or KFERQ motif deleted condition,which was regulated by LAMP2A and interacted with HSC70(heat shock cognate 71 kDa protein).Using isolated lysosomes,amino-acid residues 75 and 128 of SMAD3 were found to be of importance for this process,which affected the CMA pathway in which SMAD3 was involved.Similarly,down-regulating SMAD3 or up-regulating LAMP2A in cultured glioma cells enhanced their proliferation and invasion.Taken together,these results suggest that excessive activation of CMA regulates glioma cell growth by promoting the degradation of SMAD3.Therefore,targeting the SMAD3-LAMP2Amediated CMA-lysosome pathway may be a promising approach in anti-cancer therapy.
基金supported by the National Natural Science Foundation of China(31171122,81573431,81971326 for B.-y.,Li).
文摘Objective:Oncocardiology is increasingly hot research field/topic in the clinical management of cancer with anti-angiogenic therapy of vascular endothelial growth factor(VEGF)that may cause cardiovascular toxicity,such as hypertension via vascular dysfunction and attenuation of eNOS/NO signaling in the baroreflex afferent pathway.The aim of the current study was to evaluate the potential roles of VEGF/VEGF receptors(VEGFRs)expressed in the baroreflex afferent pathway in autonomic control of blood pressure(BP)regulation.Methods:The distribution and expression of VEGF/VEGFRs were detected in the nodose ganglia(NG)and nucleus of tractus solitary(NTS)using immunostaining and molecular approaches.The direct role of VEGF was tested by NG microinjection under physiological and hypertensive conditions.Results:Immunostaining data showed that either VEGF or VEGFR2/VEGFR3 was clearly detected in the NG and NTS of adult male rats.Microinjection of VEGF directly into the NG reduced the mean blood pressure(MBP)dose-dependently,which was less dramatic in renovascular hypertension(RVH)rats,suggesting the VEGF-mediated depressor response by direct activation of the 1st-order baroreceptor neurons in the NG under both normal and disease conditions.Notably,this reduced depressor response in RVH rats was directly caused by the downregulation of VEGFR2,which compensated the up regulation of VEGF/VEGFR3 in the NG during the development of hypertension.Conclusion:It demonstrated for the first time that the BP-lowering property of VEGF/VEGFRs signaling via the activation of baroreflex afferent function may be a common target/pathway leading to BP dysregulation in anti-angiogenic therapy.
基金This review was supported by research grants from the State Key Development Program for Basic Research of China(2011CB510000)the National Natural Science Foundation of China(81271428,81471292,U1503222 and 81430021)+2 种基金the keypoint Science Foundation of Guangdong of China(2015A030311021)a grant supported by technology project of Guangzhou(201604020152)a grant supported by assisting research project of science and technology for Xinjiang(201591160).
文摘Parkinson’s disease(PD)is referring to the multi-systemicα-synucleinopathy with Lewy bodies deposited in midbrain.In ageing,the environmental and genetic factors work together and overactive major histocompatibility complex pathway to regulate immune reactions in central nerve system which resulting in neural degeneration,especially in dopaminergic neurons.As a series of biomarkers,the human leukocyte antigen genes with its related proteomics play cortical roles on the antigen presentation of major histocompatibility complex molecules to stimulate the differentiation of T lymphocytes and i-proteasome activities under their immune response to the PD-related environmental alteration and genetic variation.Furthermore,dopaminergic drugs change the biological characteristic of T lymphatic cells,affect theα-synuclein presentation pathway,and inhibit T lymphatic cells to release cytotoxicity in PD development.Taking together,the serum inflammatory factors and blood T cells are involved in the immune dysregulation of PD and inspected as the potential clinic biomarkers for PD prediction.
基金supported in part by the National Nature Science Foundation of China[92268206,81830064]the CAMS Innovation Fund for Medical Sciences[CIFMS,2019-I2M-5-059]+2 种基金the Military Medical Research Projects[145AKJ260015000X,2022-JCJQ-ZB-09600,2020-JCJQ-ZD-256-021]the Military Medical Research and Development Projects[AWS17J005,2019-126]the Specific Research Fund of The Innovation Platform for Academicians of Hainan Province[YSPTZX202317].
文摘Loss of sweat glands(SwGs)commonly associated with extensive skin defects is a leading cause of hyperthermia and heat stroke.In vivo tissue engineering possesses the potential to take use of the body natural ability to regenerate SwGs,making it more conducive to clinical translation.Despite recent advances in regenerative medicine,reconstructing SwG tissue with the same structure and function as native tissue remains challenging.Elucidating the SwG generation mechanism and developing biomaterials for in vivo tissue engineering is essential for understanding and developing in vivo SwG regenerative strategies.Here,we outline the cell biology associated with functional wound healing and the characteristics of bioactive materials.We critically summarize the recent progress in bioactive material-based cell modulation approaches for in vivo SwG regeneration,including the recruitment of endogenous cells to the skin lesion for SwG regeneration and in vivo cellular reprogramming for SwG regeneration.We discussed the re-establishment of microenvironment via bioactive material-mediated regulators.Besides,we offer promising perspectives for directing in situ SwG regeneration via bioactive material-based cell-free strategy,which is a simple and effective approach to regenerate SwG tissue with both fidelity of structure and function.Finally,we discuss the opportunities and challenges of in vivo SwG regeneration in detail.The molecular mechanisms and cell fate modulation of in vivo SwG regeneration will provide further insights into the regeneration of patient-specific SwGs and the development of potential intervention strategies for gland-derived diseases.
基金supported by National Natural Science Foundation of China(81870856,81870992,82071416,82071417,82188101,32171236)Central Government Guiding Local Science and Technology Development Projects(ZYYD2022C17)+4 种基金Key Research and Development Program of Guangzhou(2023B03J0631)Municipal University(Faculty)Joint Funding Project(202102010010)Municipal and University(Institute)Jointly Funded Project for Basic and Applied Basic Research(202201020472)Guangdong Basic and Applied Basic Research Foundation(2021B1515140026,2022B1515230004)the Science and Technology Commission of Shanghai Municipality(STCSM)(20XD1425000,2019SHZDZX02 and 22JC1410400).
文摘Background Seed amplification assays(SAA)enable the amplification of pathological misfolded proteins,includ‑ingα-synuclein(αSyn),in both tissue homogenates and body fluids of Parkinson’s disease(PD)patients.SAA involves repeated cycles of shaking or sonication coupled with incubation periods.However,this amplification scheme has limitations in tracking protein propagation due to repeated fragmentation.Methods We introduced a modified form of SAA,known as Quiescent SAA(QSAA),and evaluated biopsy and autopsy samples from individuals clinically diagnosed with PD and those without synucleinopathies(control group).Brain biopsy samples were obtained from 14 PD patients and 6 controls without synucleinopathies.Addition‑ally,skin samples were collected from 214 PD patients and 208 control subjects.Data were analyzed from April 2019 to May 2023.Results QSAA successfully amplifiedαSyn aggregates in brain tissue sections from mice inoculated with pre-formed fibrils.In the skin samples from 214 PD cases and 208 non-PD cases,QSAA demonstrated high sensitivity(90.2%)and specificity(91.4%)in differentiating between PD and non-PD cases.Notably,moreαSyn aggregates were detected by QSAA compared to immunofluorescence with the pS129-αSyn antibody in consecutive slices of both brain and skin samples.Conclusion We introduced the new QSAA method tailored for in situ amplification ofαSyn aggregates in brain and skin samples while maintaining tissue integrity,providing a streamlined approach to diagnosing PD with individual variability.The integration of seeding activities with the location of deposition ofαSyn seeds advances our understanding of the mechanism underlyingαSyn misfolding in PD.
基金supported by the National Natural Science Foundation of China(81870856,81870992,82071416)the Central Government Guiding Local Science and Technology Development Projects(ZYYD2022C17)+5 种基金the Key Research and Development Program of Guangzhou(2023B03J0631)the Municipal University(Faculty)Joint Funding Project(202102010010)the Guangdong Basic and Applied Basic Research Foundation(2022B1515230004)the Guangzhou Science and Technology Bureau 2024 Basic Research Program Municipal University(Institute)Joint Funding“Dengfeng Hospital”(2023A03J01331)the Guangzhou Science and Technology Bureau Municipal University(Institute)Joint Funding Project Basic and Applied Basic Research Project(202201020397)the Second Affiliated Hospital of Xinjiang Medical University,the State Key Laboratory of Pathogenesis,Prevention and Treatment of High Incidence Diseases in Central Asia(SKL-HIDCA-2022-NKX1).
文摘The spectrum of synucleinopathies,including Parkinson’s disease(PD),multiple system atrophy(MSA),and dementia with Lewy bodies(DLB),is characterized byα-synuclein(αSyn)pathology,which serves as the definitive diagnostic marker.However,current diagnostic methods primarily rely on motor symptoms that manifest years after the initial neuropathological changes,thereby delaying potential treatment.The symptomatic overlap between PD and MSA further complicates the diagnosis,highlighting the need for precise and differential diagnostic methods for these overlapping neurodegenerative diseases.αSyn misfolding and aggregation occur before clinical symptoms appear,suggesting that detection of pathologicalαSyn could enable early molecular diagnosis of synucleinopathies.Recent advances in seed amplification assay(SAA)offer a tool for detecting neurodegenerative diseases by identifyingαSyn misfolding in fluid and tissue samples,even at preclinical stages.Extensive research has validated the effectiveness and reproducibility of SAAs for diagnosing synucleinopathies,with ongoing efforts focusing on optimizing conditions for detecting pathologicalαSyn in more accessible samples and identifying specificαSyn species to differentiate between various synucleinopathies.This review offers a thorough overview of SAA technology,exploring its applications for diagnosing synucleinopathies,addressing the current challenges,and outlining future directions for its clinical use.
基金supported by grants from the National Key R&D Program of China(No.2017YFC 0909100)Jiangsu Provincial Medical Key Discipline(No.ZDXK202217)+5 种基金Suzhou Technology Development Programme(No.SLT201924 and SKJY2021090)Discipline Construction Program of the Second Affiliated Hospital of Soochow University(No.XKTJ XK202001)Science and Technology Innovation Project of Xiongan New Area(No.2023XAGG0073)Jiangsu Provincial Medical Key Discipline(No.ZDXK202217)Suzhou Key Laboratory(No.SZS2023015)the National Key R&D Program of China(No.2022YFC2503904).
文摘To the Editor:Obstructive sleep apnea(OSA)is one of the common sleep disorders in Parkinson’s disease(PD)that is often associated with sleep fragmentation and intermittent hypoxemia.[1]Clinically,it has been observed that symptoms of OSA significantly overlap with both motor and non-motor symptoms of PD.However,the effect of OSA on the clinical symptoms of PD and the underlying mechanisms are still not well understood.OSA has been observed to induce sleep fragmentation and alterations in microscopic sleep architecture detected by electroencephalogram(EEG).
