Objective To analyze the epidemiological characteristics and epidemic situation of children with Kashin-Beck disease(KBD)in China,and provide the basis for formulating prevention and control measures.Methods Fixed-poi...Objective To analyze the epidemiological characteristics and epidemic situation of children with Kashin-Beck disease(KBD)in China,and provide the basis for formulating prevention and control measures.Methods Fixed-point monitoring,moving-point monitoring,and full coverage of monitoring were promoted successively from 1990 to 2023.Some children(7-12 years old)underwent clinical and right-hand X-ray examinations every year.According to the KBD diagnosis criteria,clinical and X-ray assessments were used to confirm the diagnosis.Results In 1990,the national KBD detectable rate was 21.01%.X-ray detection decreased to below 10%in 2003 and below 5%in 2007.Between 2010 and 2018,the prevalence of KBD in children was less than 0.4%,which fluctuated at a low level,and has decreased to 0%since 2019.Spatial epidemiological analysis indicated a spatial clustering of adult patients prevalence rate in the KBD areas.Conclusion The evaluation results of the elimination of KBD in China over the last 5 years showed that all villages in the monitored areas have reached the elimination standard.While the adult KBD patients still need for policy consideration and care.展开更多
This study aimed to evaluate the sensitivity and specificity of the new clinical diagnostic and classification criteria for Kashin-Beck disease （KBD） using six clinical markers： flexion of the distal part of finger...This study aimed to evaluate the sensitivity and specificity of the new clinical diagnostic and classification criteria for Kashin-Beck disease （KBD） using six clinical markers： flexion of the distal part of fingers, deformed fingers, enlarged finger joints, shortened fingers, squat down, and dwarfism. One-third of the total population in Linyou County was sampled by stratified random sampling.展开更多
To understand how differentially methylated genes（DMGs）might affect the pathogenesis of Kashin-Beck disease（KBD）.Genome-wide methylation profiling of whole blood from 12matched KBD and controls pairs was performed...To understand how differentially methylated genes（DMGs）might affect the pathogenesis of Kashin-Beck disease（KBD）.Genome-wide methylation profiling of whole blood from 12matched KBD and controls pairs was performed using a high-resolution Infinium 450 K methylation array.In total,97 CpG sites were differentially展开更多
Objective：To identify the in vitro effects of sodium hyaluronate（HA） on the proliferation and the apoptosis of chondrocytes from patients with Kashin-Beck disease（KBD） and osteoarthritis（OA）. Methods：Samples o...Objective：To identify the in vitro effects of sodium hyaluronate（HA） on the proliferation and the apoptosis of chondrocytes from patients with Kashin-Beck disease（KBD） and osteoarthritis（OA）. Methods：Samples of articular cartilages from KBD and OA patients, as well as healthy volunteers（6 subjects in each of the 3 groups） were dissected, digested with collagenase and the cells cultured in monolayers. Chondrocytes from each sample were assigned to an untreated group and two HA-treated groups： H0（no HA）, H100（HA, 0.1 g/L） and H500（HA, 0.5 g/L）. The first passage chondrocytes were used to observe proliferation using the MTT assay, and apoptosis by flow cytometry through Annexin V/PI staining. Results：HA promoted proliferation of chondrocytes in all the three groups, and.in KBD and OA groups, for cells cultured for 4 and 6 days, H500 significantly promoted the cell proliferation. The apoptotic rates of both KBD and OA group chondrocytes were in the order H500 〈 HA100 〈 H0. Conclusion：Sodium hyaluronate administration has a dosedependent in vitro effect to promote proliferation and inhibit apoptosis of chondrocytes from patients with KBD and OA.展开更多
To evaluate the efficacy of changing grains on the prevention and treatment of Kashin-Beck Disease （KBD） in children, community-based trials were acquired from seven electronic databases （up to July 2014）. As a re...To evaluate the efficacy of changing grains on the prevention and treatment of Kashin-Beck Disease （KBD） in children, community-based trials were acquired from seven electronic databases （up to July 2014）. As a result, the methodological quality of the six trials that have been included into our analysis was low. The pooled ORs favoring the prevention and treatment effects of changing grains were 0.15 （95% CI： 0.03-0.70） and 2.13 （95% CI： 1.44-3.16） respectively by meta-analysis. Subgroup analysis demonstrated the pooled OR favoring treatment effect of exchanging grains rather than drying grains both compared with endemic grains. The results showed that changing grains had obvious effects on the prevention and treatment of KBD in children. However, the evidences were limited by the potential biases and confounders. Large and well-designed trials are still needed.展开更多
Objective To explore potential serum biomarkers of children with Kashin-Beck Disease(KBD)and the metabolic pathways to which the biomarkers belong.Methods A two-stage metabolomic study was employed.The discovery cohor...Objective To explore potential serum biomarkers of children with Kashin-Beck Disease(KBD)and the metabolic pathways to which the biomarkers belong.Methods A two-stage metabolomic study was employed.The discovery cohort included 56 patients,51 internal controls,and 50 external controls.The metabolites were determined by HPLC-(Q-TOF)-MS and confirmed by Human Metabolome Databases(HMDB)and Metlin databases.MetaboAnalyst 3.0 and the Kyoto Encyclopedia of Genes and Genomes(KEGG)database were used to analyze the metabolic pathways of the candidate metabolites.The use of HPLC-(Q-TRAP)-MS enabled quantitative detection of the target metabolites which were chosen using the discovery study and verified in another independent verification cohort of 31 patients,41 internal controls,and 50 external controls.Results Eight candidate metabolites were identified out in the discovery study,namely kynurenic acid,N-α-acetylarginine,6-hydroxymelatonin,sphinganine,ceramide,sphingosine-1 P,spermidine,and glycine.These metabolites exist in sphingolipid,glutathione,and tryptophan metabolic pathways.In the second-stage study,five candidate metabolites were validated,including kynurenic acid,N-α-acetylarginine,sphinganine,spermidine,and sphingosine-1 P.Except for spermidine,all substances exhibited low expression in the case group compared with the external control group,and the difference in levels of sphinganine,spermidine,and sphingosine-1 P was statistically significant.Conclusion The direction of change of levels of sphinganine,spermidine,and sphingosine-1 P in the two-stage study cohorts was completely consistent,and the differences were statistically significant.Therefore,these substances can be used as potential biomarkers of KBD.Furthermore,these results raise the possibility that sphingolipid metabolic pathways may be closely related to KBD.展开更多
Objective This study was designed to determine the methylation profile of four CpGs and the genotypes of two CpG-SNPs located in promoter region of DIO2 in patients with Kashin-Beck disease(KBD).We also analyzed the i...Objective This study was designed to determine the methylation profile of four CpGs and the genotypes of two CpG-SNPs located in promoter region of DIO2 in patients with Kashin-Beck disease(KBD).We also analyzed the interaction between the CpGs methylations and CpG-SNPs.Methods Whole blood specimens were collected from 16 KBD patients and 16 healthy subjects.Four CpGs and two CpG-SNPs in the promoter regions of DIO2 were detected using matrix-assisted laser desorption ionization time of flight mass spectrometry(MALDI-TOF-MS).The CpGs methylation levels were compared between samples from KBD patients and healthy subjects.The methylation levels were also analyzed in KBD patients with different CpG-SNP genotypes.Results The mRNA expression of DIO2 in whole blood of KBD patients was significnatly lower than in healthy controls(P<0.05).The methylation levels of DIO2-1_CpG_3 in KBD patients were significantly higher than those in healthy controls(P<0.05).The methylation levels of four CpGs were not significantly different between KBD patients and healthy controls.The methylation level of DIO2-1_CpG_3 in the promoter region of DIO2 in KBD patients with GA/AA genotype was significantly higher than that of KBD patients with GG genotype(P<0.05).Conclusion The methylation level of DIO2 increases in KBD patients.Similar trends exist in KBD carriers of variant genotypes of CpG-SNPs DIO2 rs955849187.展开更多
Objective To investigate the relationship between erythrocyte immune function and selenium (Se) level. Methods Forty-nine Kashin-Beck patients in endemic area aged 13-16 years were divided into two groups and were ora...Objective To investigate the relationship between erythrocyte immune function and selenium (Se) level. Methods Forty-nine Kashin-Beck patients in endemic area aged 13-16 years were divided into two groups and were orally given either selenized yeast or sodium selenite to provide 200 μ g selenium per day for 12 weeks. Erythrocyte selenium level, glutathione peroxidase activity, the rosette formation rates of red blood cells complement receptor typeⅠ(CR1), the immune function of red blood cells, and circulating immune complexes(CIC) were determined. Results After supplementing with selenium for 12 weeks, erythrocyte selenium level, glutathione peroxidase activity, the rosette formation rates of red blood cells CR1 were significantly increased. But the difference in rosette formation rates of IC and CIC content was not significant between before and after Se supplementation. Conclusion The increase of the immune function of the erythrocyte by selenium-supplement may be one of the effective mechanisms for the prevention of Kashin-Beck disease.展开更多
This study aimed to investigate the effect of hyaluronic acid(HA)on the expression of heat-shock protein 70(HSP70)in chondrocytes isolated from patients with osteoarthritis(OA)and Kashin-Beck disease(KBD).The chondroc...This study aimed to investigate the effect of hyaluronic acid(HA)on the expression of heat-shock protein 70(HSP70)in chondrocytes isolated from patients with osteoarthritis(OA)and Kashin-Beck disease(KBD).The chondrocytes were collected from OA and KBD patients,and chondrocytes isolated from patients of accident injuries were used as the control.The chondrocytes were treated with HA at different doses.HSP70 expression in chondrocytes at both mRNA and protein levels was tested by PCR and Western blot analysis.Compared with control,both mRNA and protein levels of HSP70 were higher in chondrocytes from KBD and OA.However,HA at the dose of 500μg/mL significantly inhibited HSP70 expression levels in both KBD and OA groups(P<0.05).In conclusion,HSP70 is highly expressed in chondrocytes of patients of OA and KBD.HA intervention inhibits the upregulation of HSP70 in chondrocytes of OA and KBD patients and could be a promising agent for treatment of OA and KBD.展开更多
Kashin-Beck disease(KBD)is an endemic osteoarthropathy.Its distribution region covers a long and narrow belt on the Pacific side and belongs to continental climate with short summer,long frost period,and large tempera...Kashin-Beck disease(KBD)is an endemic osteoarthropathy.Its distribution region covers a long and narrow belt on the Pacific side and belongs to continental climate with short summer,long frost period,and large temperature differences between day and night.In particular,KBD patients are typically scattered in the rural areas with seasonal features such as cold winters and rainy autumns.Etiological studies have demonstrated that the carrier of pathogenic factors is the grains produced in endemic areas.Risk factors for KBD include fungal contamination of grains due to poor storage conditions associated with cold weather.The epidemiological characteristics of KBD include agricultural area,early age of onset,gender equality,family aggregation,regional differences,and annual fluctuations.A series of preventive measures have been successfully taken in the past decades.National surveillance data indicate that the annual incidence of KBD is gradually declining.展开更多
Objective The occurrence characteristic of Kashin Beck Disease (KBD) in pedigrees ascertained on the basis of one proband was estimated. Methods A total of 255 individuals in 40 pedigrees were collected from areas ...Objective The occurrence characteristic of Kashin Beck Disease (KBD) in pedigrees ascertained on the basis of one proband was estimated. Methods A total of 255 individuals in 40 pedigrees were collected from areas in the Shaanxi Province. Results ① Parents and siblings of index cases have a 3-4 times higher risk than a random unrelated individual. The odds ratio for disease is higher in mothers than in fathers of index cases; ② Prevalence in relatives of index cases (K r= 59.2% ) greatly exceeds population prevalence (K= 17.5% ); ③ K r increases with sibship size; ④ There is no significant difference of K r for male and female siblings of index cases. Also, population prevalence is not sex specific. Conclusion In conjunction with environmental agents, genetics may play an important role in KBD etiology.展开更多
Objective To oberve the change in blood glutathione peroxidase (GSH-Px) protein levels of residents in the low-selenium (Se) area by contrasting the blood GSH-Px protein level of the children in the Keshan disease are...Objective To oberve the change in blood glutathione peroxidase (GSH-Px) protein levels of residents in the low-selenium (Se) area by contrasting the blood GSH-Px protein level of the children in the Keshan disease area with those in the Kashin-Beck disease and non-endemic areas. Methods GSH-Px protein levels were measured by enzyme-linked immunosorbent assays (ELISA). The Se content and GSH-Px activity were assayed by the 2,3-diaminonaphthalene spectrofluorimetric method and glutathione reductase-coupled method respectively. Results ①The blood Se content and GSH-Px protein level of children in Keshan disease area (Moding) were significantly lower than those in Xi’an non-endemic area, however, there was no significant difference when compared with the low-Se non-endemic area; ②The blood Se content, GSH-Px activity and GSH-Px protein level of children in the Kashin-Beck disease area (Yulin) were significantly lower than those of children in two non-endemic areas and in the Keshan disease area; ③The blood Se content and GSH-Px activity were positively correlated to the GSH-Px protein level respectively. Conclusion These results indicate that the blood GSH-Px protein level is decreased in the low-Se residents. The Se status not only affects the GSH-Px activity but also regulate the GSH-Px protein level.展开更多
Alzheimer's disease is a common neurodegenerative disorder in older adults.Despite its prevalence,its pathogenesis remains unclea r.In addition to the most widely accepted causes,which in clude excessive amyloid-b...Alzheimer's disease is a common neurodegenerative disorder in older adults.Despite its prevalence,its pathogenesis remains unclea r.In addition to the most widely accepted causes,which in clude excessive amyloid-beta aggregation,tau hyperphosphorylation,and deficiency of the neurotransmitter acetylcholine,numerous studies have shown that the dopaminergic system is also closely associated with the occurrence and development of this condition.Dopamine is a crucial catecholaminergic neurotransmitter in the human body.Dopamine-associated treatments,such as drugs that target dopamine receptor D and dopamine analogs,can improve cognitive function and alleviate psychiatric symptoms as well as ameliorate other clinical manifestations.Howeve r,therapeutics targeting the dopaminergic system are associated with various adverse reactions,such as addiction and exacerbation of cognitive impairment.This review summarizes the role of the dopaminergic system in the pathology of Alzheimer's disease,focusing on currently available dopamine-based therapies for this disorder and the common side effects associated with dopamine-related drugs.The aim of this review is to provide insights into the potential connections between the dopaminergic system and Alzheimer's disease,thus helping to clarify the mechanisms underlying the condition and exploring more effective therapeutic options.展开更多
Meningeal lymphatic vessels form a relationship between the nervous system and periphery, which is relevant in both health and disease. Meningeal lymphatic vessels not only play a key role in the drainage of brain met...Meningeal lymphatic vessels form a relationship between the nervous system and periphery, which is relevant in both health and disease. Meningeal lymphatic vessels not only play a key role in the drainage of brain metabolites but also contribute to antigen delivery and immune cell activation. The advent of novel genomic technologies has enabled rapid progress in the characterization of myeloid and lymphoid cells and their interactions with meningeal lymphatic vessels within the central nervous system. In this review, we provide an overview of the multifaceted roles of meningeal lymphatic vessels within the context of the central nervous system immune network, highlighting recent discoveries on the immunological niche provided by meningeal lymphatic vessels. Furthermore, we delve into the mechanisms of crosstalk between meningeal lymphatic vessels and immune cells in the central nervous system under both homeostatic conditions and neurodegenerative diseases, discussing how these interactions shape the pathological outcomes. Regulation of meningeal lymphatic vessel function and structure can influence lymphatic drainage, cerebrospinal fluid-borne immune modulators, and immune cell populations in aging and neurodegenerative disorders, thereby playing a key role in shaping meningeal and brain parenchyma immunity.展开更多
Heat shock protein family B(small)member 8(HSPB8)is a 22 kDa ubiquitously expressed protein belonging to the family of small heat shock proteins.HSPB8 is involved in various cellular mechanisms mainly related to prote...Heat shock protein family B(small)member 8(HSPB8)is a 22 kDa ubiquitously expressed protein belonging to the family of small heat shock proteins.HSPB8 is involved in various cellular mechanisms mainly related to proteotoxic stress response and in other processes such as inflammation,cell division,and migration.HSPB8 binds misfolded clients to prevent their aggregation by assisting protein refolding or degradation through chaperone-assisted selective autophagy.In line with this function,the pro-degradative activity of HSPB8 has been found protective in several neurodegenerative and neuromuscular diseases characterized by protein misfolding and aggregation.In cancer,HSPB8 has a dual role being capable of exerting either a pro-or an anti-tumoral activity depending on the pathways and factors expressed by the model of cancer under investigation.Moreover,HSPB8 exerts a protective function in different diseases by modulating the inflammatory response,which characterizes not only neurodegenerative diseases,but also other chronic or acute conditions affecting the nervous system,such as multiple sclerosis and intracerebellar hemorrhage.Of note,HSPB8 modulation may represent a therapeutic approach in other neurological conditions that develop as a secondary consequence of other diseases.This is the case of cognitive impairment related to diabetes mellitus,in which HSPB8 exerts a protective activity by assuring mitochondrial homeostasis.This review aims to summarize the diverse and multiple functions of HSPB8 in different pathological conditions,focusing on the beneficial effects of its modulation.Drug-based and alternative therapeutic approaches targeting HSPB8 and its regulated pathways will be discussed,emphasizing how new strategies for cell and tissue-specific delivery represent an avenue to advance in disease treatments.展开更多
Copper,one of the most prolific transition metals in the body,is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations.Copper homeostasis is...Copper,one of the most prolific transition metals in the body,is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations.Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins,including copper transporters(CTR1 and CTR2),the two copper ion transporters the Cu-transporting ATPase 1(ATP7A)and Cu-transporting beta(ATP7B),and the three copper chaperones ATOX1,CCS,and COX17.Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue.Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins,including ceruloplasmin and metallothionein,is involved in the pathogenesis of neurodegenerative disorders.However,the exact mechanisms underlying these processes are not known.Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress.Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction.Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation,with elevated levels activating several critical inflammatory pathways.Additionally,copper can bind aberrantly to several neuronal proteins,including alphasynuclein,tau,superoxide dismutase 1,and huntingtin,thereby inducing neurotoxicity and ultimately cell death.This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases,with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis.By synthesizing the current findings on the functions of copper in oxidative stress,neuroinflammation,mitochondrial dysfunction,and protein misfolding,we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders,such as Wilson's disease,Menkes'disease,Alzheimer's disease,Parkinson's disease,amyotrophic lateral sclerosis,Huntington's disease,and multiple sclerosis.Potential clinically significant therapeutic targets,including superoxide dismutase 1,D-penicillamine,and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline,along with their associated therapeutic agents,are further discussed.Ultimately,we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.展开更多
Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela ...Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation of tau protein, an endogenous microtubule-associated protein that protects the integrity of neuronal cytoskeletons. Tau hyperphosphorylation results in protein misfolding and subsequent accumulation of tau tangles forming neurotoxic aggregates. These misfolded proteins are characteristic of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease and can lead to downstream neuroinflammatory processes, including assembly and activation of the inflammasome complex. Inflammasomes refer to a family of multimeric protein units that, upon activation, release a cascade of signaling molecules resulting in caspase-induced cell death and inflammation mediated by the release of interleukin-1β cytokine. One specific inflammasome, the NOD-like receptor protein 3, has been proposed to be a key regulator of tau phosphorylation where it has been shown that prolonged NOD-like receptor protein 3 activation acts as a causal factor in pathological tau accumulation and spreading. This review begins by describing the epidemiology and pathophysiology of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease. Next, we highlight neuroinflammation as an overriding theme and discuss the role of the NOD-like receptor protein 3 inflammasome in the formation of tau deposits and how such tauopathic entities spread throughout the brain. We then propose a novel framework linking traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease as inflammasomedependent pathologies that exist along a temporal continuum. Finally, we discuss potential therapeutic targets that may intercept this pathway and ultimately minimize long-term neurological decline.展开更多
Neurodegenerative diseases cause great medical and economic burdens for both patients and society;however, the complex molecular mechanisms thereof are not yet well understood. With the development of high-coverage se...Neurodegenerative diseases cause great medical and economic burdens for both patients and society;however, the complex molecular mechanisms thereof are not yet well understood. With the development of high-coverage sequencing technology, researchers have started to notice that genomic repeat regions, previously neglected in search of disease culprits, are active contributors to multiple neurodegenerative diseases. In this review, we describe the association between repeat element variants and multiple degenerative diseases through genome-wide association studies and targeted sequencing. We discuss the identification of disease-relevant repeat element variants, further powered by the advancement of long-read sequencing technologies and their related tools, and summarize recent findings in the molecular mechanisms of repeat element variants in brain degeneration, such as those causing transcriptional silencing or RNA-mediated gain of toxic function. Furthermore, we describe how in silico predictions using innovative computational models, such as deep learning language models, could enhance and accelerate our understanding of the functional impact of repeat element variants. Finally, we discuss future directions to advance current findings for a better understanding of neurodegenerative diseases and the clinical applications of genomic repeat elements.展开更多
Pyrroloquinoline quinone is a quinone described as a cofactor for many bacterial dehydrogenases and is reported to exert an effect on metabolism in mammalian cells/tissues.Pyrroloquinoline quinone is present in the di...Pyrroloquinoline quinone is a quinone described as a cofactor for many bacterial dehydrogenases and is reported to exert an effect on metabolism in mammalian cells/tissues.Pyrroloquinoline quinone is present in the diet being available in foodstuffs,conferring the potential of this compound to be supplemented by dietary administration.Pyrroloquinoline quinone’s nutritional role in mammalian health is supported by the extensive deficits in reproduction,growth,and immunity resulting from the dietary absence of pyrroloquinoline quinone,and as such,pyrroloquinoline quinone has been considered as a“new vitamin.”Although the classification of pyrroloquinoline quinone as a vitamin needs to be properly established,the wide range of benefits for health provided has been reported in many studies.In this respect,pyrroloquinoline quinone seems to be particularly involved in regulating cell signaling pathways that promote metabolic and mitochondrial processes in many experimental contexts,thus dictating the rationale to consider pyrroloquinoline quinone as a vital compound for mammalian life.Through the regulation of different metabolic mechanisms,pyrroloquinoline quinone may improve clinical deficits where dysfunctional metabolism and mitochondrial activity contribute to induce cell damage and death.Pyrroloquinoline quinone has been demonstrated to have neuroprotective properties in different experimental models of neurodegeneration,although the link between pyrroloquinoline quinone-promoted metabolism and improved neuronal viability in some of such contexts is still to be fully elucidated.Here,we review the general properties of pyrroloquinoline quinone and its capacity to modulate metabolic and mitochondrial mechanisms in physiological contexts.In addition,we analyze the neuroprotective properties of pyrroloquinoline quinone in different neurodegenerative conditions and consider future perspectives for pyrroloquinoline quinone’s potential in health and disease.展开更多
基金supported by the Central government subsidies to local public health special funds,National Key Research and Development Program of China[2022YFC2503101]Basic Research and Development Funds for Heilongjiang Province-affiliated Universities[2023-KYYWF-0272].
文摘Objective To analyze the epidemiological characteristics and epidemic situation of children with Kashin-Beck disease(KBD)in China,and provide the basis for formulating prevention and control measures.Methods Fixed-point monitoring,moving-point monitoring,and full coverage of monitoring were promoted successively from 1990 to 2023.Some children(7-12 years old)underwent clinical and right-hand X-ray examinations every year.According to the KBD diagnosis criteria,clinical and X-ray assessments were used to confirm the diagnosis.Results In 1990,the national KBD detectable rate was 21.01%.X-ray detection decreased to below 10%in 2003 and below 5%in 2007.Between 2010 and 2018,the prevalence of KBD in children was less than 0.4%,which fluctuated at a low level,and has decreased to 0%since 2019.Spatial epidemiological analysis indicated a spatial clustering of adult patients prevalence rate in the KBD areas.Conclusion The evaluation results of the elimination of KBD in China over the last 5 years showed that all villages in the monitored areas have reached the elimination standard.While the adult KBD patients still need for policy consideration and care.
基金supported by the National Natural Scientific Foundation of China(81472924,81620108026)the Fundamental Research Funds for the Central Universities in 2015
文摘This study aimed to evaluate the sensitivity and specificity of the new clinical diagnostic and classification criteria for Kashin-Beck disease （KBD） using six clinical markers： flexion of the distal part of fingers, deformed fingers, enlarged finger joints, shortened fingers, squat down, and dwarfism. One-third of the total population in Linyou County was sampled by stratified random sampling.
基金supported by grants from the National Natural Science Foundation of China(No.81273007)
文摘To understand how differentially methylated genes（DMGs）might affect the pathogenesis of Kashin-Beck disease（KBD）.Genome-wide methylation profiling of whole blood from 12matched KBD and controls pairs was performed using a high-resolution Infinium 450 K methylation array.In total,97 CpG sites were differentially
基金supported by the Ministry of Science and Technology(2006 DFA33610)the Natural Scientific Fund of China(30630058)the International Co-operative Fund in Shaanxi(2005KW-13)
文摘Objective：To identify the in vitro effects of sodium hyaluronate（HA） on the proliferation and the apoptosis of chondrocytes from patients with Kashin-Beck disease（KBD） and osteoarthritis（OA）. Methods：Samples of articular cartilages from KBD and OA patients, as well as healthy volunteers（6 subjects in each of the 3 groups） were dissected, digested with collagenase and the cells cultured in monolayers. Chondrocytes from each sample were assigned to an untreated group and two HA-treated groups： H0（no HA）, H100（HA, 0.1 g/L） and H500（HA, 0.5 g/L）. The first passage chondrocytes were used to observe proliferation using the MTT assay, and apoptosis by flow cytometry through Annexin V/PI staining. Results：HA promoted proliferation of chondrocytes in all the three groups, and.in KBD and OA groups, for cells cultured for 4 and 6 days, H500 significantly promoted the cell proliferation. The apoptotic rates of both KBD and OA group chondrocytes were in the order H500 〈 HA100 〈 H0. Conclusion：Sodium hyaluronate administration has a dosedependent in vitro effect to promote proliferation and inhibit apoptosis of chondrocytes from patients with KBD and OA.
基金supported by the National Natural Scientific Foundation of China(No.81402639,81472924,81101337)
文摘To evaluate the efficacy of changing grains on the prevention and treatment of Kashin-Beck Disease （KBD） in children, community-based trials were acquired from seven electronic databases （up to July 2014）. As a result, the methodological quality of the six trials that have been included into our analysis was low. The pooled ORs favoring the prevention and treatment effects of changing grains were 0.15 （95% CI： 0.03-0.70） and 2.13 （95% CI： 1.44-3.16） respectively by meta-analysis. Subgroup analysis demonstrated the pooled OR favoring treatment effect of exchanging grains rather than drying grains both compared with endemic grains. The results showed that changing grains had obvious effects on the prevention and treatment of KBD in children. However, the evidences were limited by the potential biases and confounders. Large and well-designed trials are still needed.
基金supported by the National Natural Science Foundation[NO.81372937]。
文摘Objective To explore potential serum biomarkers of children with Kashin-Beck Disease(KBD)and the metabolic pathways to which the biomarkers belong.Methods A two-stage metabolomic study was employed.The discovery cohort included 56 patients,51 internal controls,and 50 external controls.The metabolites were determined by HPLC-(Q-TOF)-MS and confirmed by Human Metabolome Databases(HMDB)and Metlin databases.MetaboAnalyst 3.0 and the Kyoto Encyclopedia of Genes and Genomes(KEGG)database were used to analyze the metabolic pathways of the candidate metabolites.The use of HPLC-(Q-TRAP)-MS enabled quantitative detection of the target metabolites which were chosen using the discovery study and verified in another independent verification cohort of 31 patients,41 internal controls,and 50 external controls.Results Eight candidate metabolites were identified out in the discovery study,namely kynurenic acid,N-α-acetylarginine,6-hydroxymelatonin,sphinganine,ceramide,sphingosine-1 P,spermidine,and glycine.These metabolites exist in sphingolipid,glutathione,and tryptophan metabolic pathways.In the second-stage study,five candidate metabolites were validated,including kynurenic acid,N-α-acetylarginine,sphinganine,spermidine,and sphingosine-1 P.Except for spermidine,all substances exhibited low expression in the case group compared with the external control group,and the difference in levels of sphinganine,spermidine,and sphingosine-1 P was statistically significant.Conclusion The direction of change of levels of sphinganine,spermidine,and sphingosine-1 P in the two-stage study cohorts was completely consistent,and the differences were statistically significant.Therefore,these substances can be used as potential biomarkers of KBD.Furthermore,these results raise the possibility that sphingolipid metabolic pathways may be closely related to KBD.
基金supported by the National Natural Science Foundation of China(82073494)Key Re-search and Development Program of Shaanxi Prov-ince(2020SF-076)+1 种基金Special R&D Program Proj-ect of Chinese Academy of Se-enriched Industry(2020FXZX0501)the Subject Innovation Team of Shaanxi University of Chinese Medicine(132041933).
文摘Objective This study was designed to determine the methylation profile of four CpGs and the genotypes of two CpG-SNPs located in promoter region of DIO2 in patients with Kashin-Beck disease(KBD).We also analyzed the interaction between the CpGs methylations and CpG-SNPs.Methods Whole blood specimens were collected from 16 KBD patients and 16 healthy subjects.Four CpGs and two CpG-SNPs in the promoter regions of DIO2 were detected using matrix-assisted laser desorption ionization time of flight mass spectrometry(MALDI-TOF-MS).The CpGs methylation levels were compared between samples from KBD patients and healthy subjects.The methylation levels were also analyzed in KBD patients with different CpG-SNP genotypes.Results The mRNA expression of DIO2 in whole blood of KBD patients was significnatly lower than in healthy controls(P<0.05).The methylation levels of DIO2-1_CpG_3 in KBD patients were significantly higher than those in healthy controls(P<0.05).The methylation levels of four CpGs were not significantly different between KBD patients and healthy controls.The methylation level of DIO2-1_CpG_3 in the promoter region of DIO2 in KBD patients with GA/AA genotype was significantly higher than that of KBD patients with GG genotype(P<0.05).Conclusion The methylation level of DIO2 increases in KBD patients.Similar trends exist in KBD carriers of variant genotypes of CpG-SNPs DIO2 rs955849187.
文摘Objective To investigate the relationship between erythrocyte immune function and selenium (Se) level. Methods Forty-nine Kashin-Beck patients in endemic area aged 13-16 years were divided into two groups and were orally given either selenized yeast or sodium selenite to provide 200 μ g selenium per day for 12 weeks. Erythrocyte selenium level, glutathione peroxidase activity, the rosette formation rates of red blood cells complement receptor typeⅠ(CR1), the immune function of red blood cells, and circulating immune complexes(CIC) were determined. Results After supplementing with selenium for 12 weeks, erythrocyte selenium level, glutathione peroxidase activity, the rosette formation rates of red blood cells CR1 were significantly increased. But the difference in rosette formation rates of IC and CIC content was not significant between before and after Se supplementation. Conclusion The increase of the immune function of the erythrocyte by selenium-supplement may be one of the effective mechanisms for the prevention of Kashin-Beck disease.
基金Supported by Project of Science and Technology of Social Development in Shaanxi Province(No.2013SF2-10)Shaanxi Science&Technology Coordination&Innovation Project(No.2015KTCQ03-01).
文摘This study aimed to investigate the effect of hyaluronic acid(HA)on the expression of heat-shock protein 70(HSP70)in chondrocytes isolated from patients with osteoarthritis(OA)and Kashin-Beck disease(KBD).The chondrocytes were collected from OA and KBD patients,and chondrocytes isolated from patients of accident injuries were used as the control.The chondrocytes were treated with HA at different doses.HSP70 expression in chondrocytes at both mRNA and protein levels was tested by PCR and Western blot analysis.Compared with control,both mRNA and protein levels of HSP70 were higher in chondrocytes from KBD and OA.However,HA at the dose of 500μg/mL significantly inhibited HSP70 expression levels in both KBD and OA groups(P<0.05).In conclusion,HSP70 is highly expressed in chondrocytes of patients of OA and KBD.HA intervention inhibits the upregulation of HSP70 in chondrocytes of OA and KBD patients and could be a promising agent for treatment of OA and KBD.
文摘Kashin-Beck disease(KBD)is an endemic osteoarthropathy.Its distribution region covers a long and narrow belt on the Pacific side and belongs to continental climate with short summer,long frost period,and large temperature differences between day and night.In particular,KBD patients are typically scattered in the rural areas with seasonal features such as cold winters and rainy autumns.Etiological studies have demonstrated that the carrier of pathogenic factors is the grains produced in endemic areas.Risk factors for KBD include fungal contamination of grains due to poor storage conditions associated with cold weather.The epidemiological characteristics of KBD include agricultural area,early age of onset,gender equality,family aggregation,regional differences,and annual fluctuations.A series of preventive measures have been successfully taken in the past decades.National surveillance data indicate that the annual incidence of KBD is gradually declining.
文摘Objective The occurrence characteristic of Kashin Beck Disease (KBD) in pedigrees ascertained on the basis of one proband was estimated. Methods A total of 255 individuals in 40 pedigrees were collected from areas in the Shaanxi Province. Results ① Parents and siblings of index cases have a 3-4 times higher risk than a random unrelated individual. The odds ratio for disease is higher in mothers than in fathers of index cases; ② Prevalence in relatives of index cases (K r= 59.2% ) greatly exceeds population prevalence (K= 17.5% ); ③ K r increases with sibship size; ④ There is no significant difference of K r for male and female siblings of index cases. Also, population prevalence is not sex specific. Conclusion In conjunction with environmental agents, genetics may play an important role in KBD etiology.
文摘Objective To oberve the change in blood glutathione peroxidase (GSH-Px) protein levels of residents in the low-selenium (Se) area by contrasting the blood GSH-Px protein level of the children in the Keshan disease area with those in the Kashin-Beck disease and non-endemic areas. Methods GSH-Px protein levels were measured by enzyme-linked immunosorbent assays (ELISA). The Se content and GSH-Px activity were assayed by the 2,3-diaminonaphthalene spectrofluorimetric method and glutathione reductase-coupled method respectively. Results ①The blood Se content and GSH-Px protein level of children in Keshan disease area (Moding) were significantly lower than those in Xi’an non-endemic area, however, there was no significant difference when compared with the low-Se non-endemic area; ②The blood Se content, GSH-Px activity and GSH-Px protein level of children in the Kashin-Beck disease area (Yulin) were significantly lower than those of children in two non-endemic areas and in the Keshan disease area; ③The blood Se content and GSH-Px activity were positively correlated to the GSH-Px protein level respectively. Conclusion These results indicate that the blood GSH-Px protein level is decreased in the low-Se residents. The Se status not only affects the GSH-Px activity but also regulate the GSH-Px protein level.
文摘Alzheimer's disease is a common neurodegenerative disorder in older adults.Despite its prevalence,its pathogenesis remains unclea r.In addition to the most widely accepted causes,which in clude excessive amyloid-beta aggregation,tau hyperphosphorylation,and deficiency of the neurotransmitter acetylcholine,numerous studies have shown that the dopaminergic system is also closely associated with the occurrence and development of this condition.Dopamine is a crucial catecholaminergic neurotransmitter in the human body.Dopamine-associated treatments,such as drugs that target dopamine receptor D and dopamine analogs,can improve cognitive function and alleviate psychiatric symptoms as well as ameliorate other clinical manifestations.Howeve r,therapeutics targeting the dopaminergic system are associated with various adverse reactions,such as addiction and exacerbation of cognitive impairment.This review summarizes the role of the dopaminergic system in the pathology of Alzheimer's disease,focusing on currently available dopamine-based therapies for this disorder and the common side effects associated with dopamine-related drugs.The aim of this review is to provide insights into the potential connections between the dopaminergic system and Alzheimer's disease,thus helping to clarify the mechanisms underlying the condition and exploring more effective therapeutic options.
基金supported by the National Natural Science Foundation of China, No.82274616the Key Laboratory Project for General Universities in Guangdong Province, No.2019KSYS005Guangdong Province Science and Technology Plan International Cooperation Project, No.2020A0505100052 (all to QW)。
文摘Meningeal lymphatic vessels form a relationship between the nervous system and periphery, which is relevant in both health and disease. Meningeal lymphatic vessels not only play a key role in the drainage of brain metabolites but also contribute to antigen delivery and immune cell activation. The advent of novel genomic technologies has enabled rapid progress in the characterization of myeloid and lymphoid cells and their interactions with meningeal lymphatic vessels within the central nervous system. In this review, we provide an overview of the multifaceted roles of meningeal lymphatic vessels within the context of the central nervous system immune network, highlighting recent discoveries on the immunological niche provided by meningeal lymphatic vessels. Furthermore, we delve into the mechanisms of crosstalk between meningeal lymphatic vessels and immune cells in the central nervous system under both homeostatic conditions and neurodegenerative diseases, discussing how these interactions shape the pathological outcomes. Regulation of meningeal lymphatic vessel function and structure can influence lymphatic drainage, cerebrospinal fluid-borne immune modulators, and immune cell populations in aging and neurodegenerative disorders, thereby playing a key role in shaping meningeal and brain parenchyma immunity.
基金supported by:Fondazione Telethon-Italy(No.GGP19128 to AP)Fondazione Cariplo-Italy(No.2021-1544 to RC)+14 种基金Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica(AriSLA)-Italy(No.MLOpathy to APTarget-RAN to AP)Association Française contre les Myopathies-France(AFM Telethon No.23236 to AP)Kennedy’s Disease Association-USA(2018 grant to RC2020 grant to MG)Ministero dell’Universitàe della Ricerca(MIUR)-Italy(PRIN-Progetti di ricerca di interesse nazionale(No.2017F2A2C5 to APNo.2022EFLFL8 to APNo.2020PBS5MJ to VCNo.2022KSJZF5 to VC)PRIN-Progetti di ricerca di interesse nazionale-bando 2022,PNRR finanziato dall’Unione europea-Next Generation EU,componente M4C2,investimento 1.1(No.P2022B5J32 to RC and No.P20225R4Y5 to VC)CN3:RNA-Codice Proposta:CN_00000041Tematica Sviluppo di terapia genica e farmaci con tecnologia a RNA(Centro Nazionale di Ricerca-CN3 National Center for Gene Therapy and Drugs based on RNA Technology to AP)Progetto Dipartimenti di Eccellenza(to DiSFeB)Ministero della Salute,Agenzia Italiana del Farmaco(AIFA)-Italy(Co_ALS to AP)Universitàdegli Studi di Milano(piano di sviluppo della ricerca(PSR)UNIMI-linea B(to RC and BT).
文摘Heat shock protein family B(small)member 8(HSPB8)is a 22 kDa ubiquitously expressed protein belonging to the family of small heat shock proteins.HSPB8 is involved in various cellular mechanisms mainly related to proteotoxic stress response and in other processes such as inflammation,cell division,and migration.HSPB8 binds misfolded clients to prevent their aggregation by assisting protein refolding or degradation through chaperone-assisted selective autophagy.In line with this function,the pro-degradative activity of HSPB8 has been found protective in several neurodegenerative and neuromuscular diseases characterized by protein misfolding and aggregation.In cancer,HSPB8 has a dual role being capable of exerting either a pro-or an anti-tumoral activity depending on the pathways and factors expressed by the model of cancer under investigation.Moreover,HSPB8 exerts a protective function in different diseases by modulating the inflammatory response,which characterizes not only neurodegenerative diseases,but also other chronic or acute conditions affecting the nervous system,such as multiple sclerosis and intracerebellar hemorrhage.Of note,HSPB8 modulation may represent a therapeutic approach in other neurological conditions that develop as a secondary consequence of other diseases.This is the case of cognitive impairment related to diabetes mellitus,in which HSPB8 exerts a protective activity by assuring mitochondrial homeostasis.This review aims to summarize the diverse and multiple functions of HSPB8 in different pathological conditions,focusing on the beneficial effects of its modulation.Drug-based and alternative therapeutic approaches targeting HSPB8 and its regulated pathways will be discussed,emphasizing how new strategies for cell and tissue-specific delivery represent an avenue to advance in disease treatments.
基金supported by the Notional Natural Science Foundation of Chino,No.82160690Colloborotive Innovation Center of Chinese Ministry of Education,No.2020-39Science and Technology Foundation of Guizhou Province,No.ZK[2021]-014(all to FZ)。
文摘Copper,one of the most prolific transition metals in the body,is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations.Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins,including copper transporters(CTR1 and CTR2),the two copper ion transporters the Cu-transporting ATPase 1(ATP7A)and Cu-transporting beta(ATP7B),and the three copper chaperones ATOX1,CCS,and COX17.Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue.Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins,including ceruloplasmin and metallothionein,is involved in the pathogenesis of neurodegenerative disorders.However,the exact mechanisms underlying these processes are not known.Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress.Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction.Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation,with elevated levels activating several critical inflammatory pathways.Additionally,copper can bind aberrantly to several neuronal proteins,including alphasynuclein,tau,superoxide dismutase 1,and huntingtin,thereby inducing neurotoxicity and ultimately cell death.This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases,with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis.By synthesizing the current findings on the functions of copper in oxidative stress,neuroinflammation,mitochondrial dysfunction,and protein misfolding,we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders,such as Wilson's disease,Menkes'disease,Alzheimer's disease,Parkinson's disease,amyotrophic lateral sclerosis,Huntington's disease,and multiple sclerosis.Potential clinically significant therapeutic targets,including superoxide dismutase 1,D-penicillamine,and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline,along with their associated therapeutic agents,are further discussed.Ultimately,we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.
文摘Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation of tau protein, an endogenous microtubule-associated protein that protects the integrity of neuronal cytoskeletons. Tau hyperphosphorylation results in protein misfolding and subsequent accumulation of tau tangles forming neurotoxic aggregates. These misfolded proteins are characteristic of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease and can lead to downstream neuroinflammatory processes, including assembly and activation of the inflammasome complex. Inflammasomes refer to a family of multimeric protein units that, upon activation, release a cascade of signaling molecules resulting in caspase-induced cell death and inflammation mediated by the release of interleukin-1β cytokine. One specific inflammasome, the NOD-like receptor protein 3, has been proposed to be a key regulator of tau phosphorylation where it has been shown that prolonged NOD-like receptor protein 3 activation acts as a causal factor in pathological tau accumulation and spreading. This review begins by describing the epidemiology and pathophysiology of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease. Next, we highlight neuroinflammation as an overriding theme and discuss the role of the NOD-like receptor protein 3 inflammasome in the formation of tau deposits and how such tauopathic entities spread throughout the brain. We then propose a novel framework linking traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease as inflammasomedependent pathologies that exist along a temporal continuum. Finally, we discuss potential therapeutic targets that may intercept this pathway and ultimately minimize long-term neurological decline.
基金supported by the National Natural Science Foundation of China, No.61932008Natural Science Foundation of Shanghai, No.21ZR1403200 (both to JC)。
文摘Neurodegenerative diseases cause great medical and economic burdens for both patients and society;however, the complex molecular mechanisms thereof are not yet well understood. With the development of high-coverage sequencing technology, researchers have started to notice that genomic repeat regions, previously neglected in search of disease culprits, are active contributors to multiple neurodegenerative diseases. In this review, we describe the association between repeat element variants and multiple degenerative diseases through genome-wide association studies and targeted sequencing. We discuss the identification of disease-relevant repeat element variants, further powered by the advancement of long-read sequencing technologies and their related tools, and summarize recent findings in the molecular mechanisms of repeat element variants in brain degeneration, such as those causing transcriptional silencing or RNA-mediated gain of toxic function. Furthermore, we describe how in silico predictions using innovative computational models, such as deep learning language models, could enhance and accelerate our understanding of the functional impact of repeat element variants. Finally, we discuss future directions to advance current findings for a better understanding of neurodegenerative diseases and the clinical applications of genomic repeat elements.
基金supported by Karolinska Institutet in the form of a Board of Research Faculty Funded Career Positionby St.Erik Eye Hospital philanthropic donationsVetenskapsrådet 2022-00799.
文摘Pyrroloquinoline quinone is a quinone described as a cofactor for many bacterial dehydrogenases and is reported to exert an effect on metabolism in mammalian cells/tissues.Pyrroloquinoline quinone is present in the diet being available in foodstuffs,conferring the potential of this compound to be supplemented by dietary administration.Pyrroloquinoline quinone’s nutritional role in mammalian health is supported by the extensive deficits in reproduction,growth,and immunity resulting from the dietary absence of pyrroloquinoline quinone,and as such,pyrroloquinoline quinone has been considered as a“new vitamin.”Although the classification of pyrroloquinoline quinone as a vitamin needs to be properly established,the wide range of benefits for health provided has been reported in many studies.In this respect,pyrroloquinoline quinone seems to be particularly involved in regulating cell signaling pathways that promote metabolic and mitochondrial processes in many experimental contexts,thus dictating the rationale to consider pyrroloquinoline quinone as a vital compound for mammalian life.Through the regulation of different metabolic mechanisms,pyrroloquinoline quinone may improve clinical deficits where dysfunctional metabolism and mitochondrial activity contribute to induce cell damage and death.Pyrroloquinoline quinone has been demonstrated to have neuroprotective properties in different experimental models of neurodegeneration,although the link between pyrroloquinoline quinone-promoted metabolism and improved neuronal viability in some of such contexts is still to be fully elucidated.Here,we review the general properties of pyrroloquinoline quinone and its capacity to modulate metabolic and mitochondrial mechanisms in physiological contexts.In addition,we analyze the neuroprotective properties of pyrroloquinoline quinone in different neurodegenerative conditions and consider future perspectives for pyrroloquinoline quinone’s potential in health and disease.
