Background The association of E670G polymorphism in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene and serum lipid profiles is inconsistent in dif- ferent ethnic groups.Bai Ku Yao is a special subgroup...Background The association of E670G polymorphism in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene and serum lipid profiles is inconsistent in dif- ferent ethnic groups.Bai Ku Yao is a special subgroup of the Yao minority in China.The present study was undertaken association of PCSK9 E670G polymorphism and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations.Methods A total of 649 subjects of Bai Ku Yao and 646 participants of Han Chinese were randomly selected from our previous stratified randomized cluster samples.Genotyping of the PCSK9 E670G polymorphism was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis,and then confirmed by direct sequencing. Results The levels of serum total cholesterol(TC),high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C) and apolipoprotein(Apo) AI were lower in Bai Ku Yao than in Han(P【0.01 for all).The frequency of A and G alleles was 98.00%and 2.00%in Bai Ku Yao,and 95.20%and 4.80%in Han(P【0.01);respectively. The frequency of AA,AG and GG genotypes was 95.99%,4.01%and 0%in Bai Ku Yao,and 91.02%, 8.36%and 0.62%in Han(P【0.01);respectively.There were also significant differences in the genotypic and allelic frequencies between n and the ratio of ApoAI to ApoB in Han Chinese but not in Bai Ku Yao were different between the AA and AG/GG genotypes(P【0.05 for all).The G allele carriers had higher serum HDL-C and higher ApoAI to ApoB ratio than the G allele noncarriers.When serum lipid parameters in Han were analyzed according to sex,the G allele carriers had higher serum HDL and ApoAI levels in males (P【0.05),and lower ApoB level and higher ApoAI to ApoB ratio in females(P【0.05 for all).Multiple linear regression analysis showed that serum HDL-C levels were correlated with genotypes in both ethnic groups(P【0.05 each).Serum lipid parameters were also correlated with sex,age,body massindex,alcohol consumption,cigarette smoking,and blood pressure in both ethnic groups(P【0.05-0.001).Conclusions These results suggest that the PCSK9 E670G polymorphism is mainly associated with some serum lipid parameters in the Han population,both gender show different relations to different serum lipid parameters.The G allele carriers might have higher serum lipid profiles than the G allele noncarriers. ormal LDL-C(≤3.20 mmol/L) and high LDL-C subgroups (】 3.20 mmol/L,P【0.01;respectively) in Bai Ku Yao, and between normal ApoB(≤1.14 g/L) and high ApoB subgroups(】 1.14 g/L,P 【 0.01;respectively) in Han.展开更多
Objective： To facilitate manipulation of gene expression in different host cells, we used pEGFP-N1 as backbone to construct a versatile vector that can drive foreign gene expression in prokaryotic and eukaryotic cell...Objective： To facilitate manipulation of gene expression in different host cells, we used pEGFP-N1 as backbone to construct a versatile vector that can drive foreign gene expression in prokaryotic and eukaryotic cells. Methods： A cloning and expression vector, pEGFP-NI-lac, was constructed by inserting the prokaryotic lac promoter of pUC 19 into the eukaryotic expression vector, pEGFP-N1, between the eukaryotic PCMV promoter and enhanced green fluorescent protein （EGFP） open reading frames. To assess the function of pEGFP-NI-lac, the nucleotide sequence encoding the hepatitis C virus （HCV） core protein was cloned into the multiple cloning sites. Western blotting analysis was used to detect the expression of the HCV core protein in Escherichia coli DH5a and HepG2 cells. Results： Restriction enzyme digestion and sequence analysis indicated that pEGFP-NI-lac was successfully constructed and the HCV core gene was cloned into this vector. The Western blotting results showed that pEGFP-NI-lac promoted expression of HCV core gene in prokaryotic E. coli DH5a and eukaryotic HepG2 cells. Conclusion： The pEGFP-NI-lac vector has been successfully constructed and functions in both prokaryotic and eukaryotic cells. The EGFP reporter can be used as an insert-inactivation marker for clone selection or as an expression tag. This vector can be used for cloning and expression of genes in both prokaryotic and eukaryotic cells, making gene cloning, expression and functional studies convenient as well as time- and labor-efficient展开更多
Background:Microarray analysis is a popular tool to investigate the function of genes that are responsi-ble for the phenotype of the disease.Keloid is a intricate lesion which is probably modulated by interplay of man...Background:Microarray analysis is a popular tool to investigate the function of genes that are responsi-ble for the phenotype of the disease.Keloid is a intricate lesion which is probably modulated by interplay of manygenes.We ventured to study the differences of gene expressions between keloids and normal skins with the aid ofcDNA microarray in order to explore the molecular mechanism underlying keloid formation.Methods:The PCRproducts of 8400 human genes were spotted on a chip in array.The DNAs were t...展开更多
Schizophrenia is a complex psychiatric disorder marked by positive and negative symptoms,leading to mood disturbances,cognitive impairments,and social withdrawal.While anti-psychotic medications remain the cornerstone...Schizophrenia is a complex psychiatric disorder marked by positive and negative symptoms,leading to mood disturbances,cognitive impairments,and social withdrawal.While anti-psychotic medications remain the cornerstone of treatment,they often fail to fully address certain symptoms.Additionally,treatment-resistant schizophrenia,affecting 30%-40%of patients,remains a substantial clinical challenge.Positive,negative symptoms and cognitive impairments have been linked to disruptions in the glutamatergic,serotonin,GABAergic,and muscarinic pathways in the brain.Recent advances using genome-wide association study and other approaches have uncovered a significant number of new schizophrenia risk genes that uncovered new,and reinforced prior,concepts on the genetic and neurological underpinnings of schizophrenia,including abnormalities in synaptic function,immune processes,and lipid metabolism.Concurrently,new therapeutics targeting different modalities,which are expected to address some of the limitations of anti-psychotic drugs currently being offered to patients,are currently being evaluated.Collectively,these efforts provide new momentum for the next phase of schizophrenia research and treatment.展开更多
Regulatory T cells,a subset of CD4^(+)T cells,play a critical role in maintaining immune tolerance and tissue homeostasis due to their potent immunosuppressive properties.Recent advances in research have highlighted t...Regulatory T cells,a subset of CD4^(+)T cells,play a critical role in maintaining immune tolerance and tissue homeostasis due to their potent immunosuppressive properties.Recent advances in research have highlighted the important therapeutic potential of Tregs in neurological diseases and tissue repair,emphasizing their multifaceted roles in immune regulation.This review aims to summarize and analyze the mechanisms of action and therapeutic potential of Tregs in relation to neurological diseases and neural regeneration.Beyond their classical immune-regulatory functions,emerging evidence points to non-immune mechanisms of regulatory T cells,particularly their interactions with stem cells and other non-immune cells.These interactions contribute to optimizing the repair microenvironment and promoting tissue repair and nerve regeneration,positioning non-immune pathways as a promising direction for future research.By modulating immune and non-immune cells,including neurons and glia within neural tissues,Tregs have demonstrated remarkable efficacy in enhancing regeneration in the central and peripheral nervous systems.Preclinical studies have revealed that Treg cells interact with neurons,glial cells,and other neural components to mitigate inflammatory damage and support functional recovery.Current mechanistic studies show that Tregs can significantly promote neural repair and functional recovery by regulating inflammatory responses and the local immune microenvironment.However,research on the mechanistic roles of regulatory T cells in other diseases remains limited,highlighting substantial gaps and opportunities for exploration in this field.Laboratory and clinical studies have further advanced the application of regulatory T cells.Technical advances have enabled efficient isolation,ex vivo expansion and functionalization,and adoptive transfer of regulatory T cells,with efficacy validated in animal models.Innovative strategies,including gene editing,cell-free technologies,biomaterial-based recruitment,and in situ delivery have expanded the therapeutic potential of regulatory T cells.Gene editing enables precise functional optimization,while biomaterial and in situ delivery technologies enhance their accumulation and efficacy at target sites.These advancements not only improve the immune-regulatory capacity of regulatory T cells but also significantly enhance their role in tissue repair.By leveraging the pivotal and diverse functions of Tregs in immune modulation and tissue repair,regulatory T cells–based therapies may lead to transformative breakthroughs in the treatment of neurological diseases.展开更多
The human retina,a complex and highly specialized structure,includes multiple cell types that work synergistically to generate and transmit visual signals.However,genetic predisposition or age-related degeneration can...The human retina,a complex and highly specialized structure,includes multiple cell types that work synergistically to generate and transmit visual signals.However,genetic predisposition or age-related degeneration can lead to retinal damage that severely impairs vision or causes blindness.Treatment options for retinal diseases are limited,and there is an urgent need for innovative therapeutic strategies.Cell and gene therapies are promising because of the efficacy of delivery systems that transport therapeutic genes to targeted retinal cells.Gene delivery systems hold great promise for treating retinal diseases by enabling the targeted delivery of therapeutic genes to affected cells or by converting endogenous cells into functional ones to facilitate nerve regeneration,potentially restoring vision.This review focuses on two principal categories of gene delivery vectors used in the treatment of retinal diseases:viral and non-viral systems.Viral vectors,including lentiviruses and adeno-associated viruses,exploit the innate ability of viruses to infiltrate cells,which is followed by the introduction of therapeutic genetic material into target cells for gene correction.Lentiviruses can accommodate exogenous genes up to 8 kb in length,but their mechanism of integration into the host genome presents insertion mutation risks.Conversely,adeno-associated viruses are safer,as they exist as episomes in the nucleus,yet their limited packaging capacity constrains their application to a narrower spectrum of diseases,which necessitates the exploration of alternative delivery methods.In parallel,progress has also occurred in the development of novel non-viral delivery systems,particularly those based on liposomal technology.Manipulation of the ratios of hydrophilic and hydrophobic molecules within liposomes and the development of new lipid formulations have led to the creation of advanced non-viral vectors.These innovative systems include solid lipid nanoparticles,polymer nanoparticles,dendrimers,polymeric micelles,and polymeric nanoparticles.Compared with their viral counterparts,non-viral delivery systems offer markedly enhanced loading capacities that enable the direct delivery of nucleic acids,mRNA,or protein molecules into cells.This bypasses the need for DNA transcription and processing,which significantly enhances therapeutic efficiency.Nevertheless,the immunogenic potential and accumulation toxicity associated with non-viral particulate systems necessitates continued optimization to reduce adverse effects in vivo.This review explores the various delivery systems for retinal therapies and retinal nerve regeneration,and details the characteristics,advantages,limitations,and clinical applications of each vector type.By systematically outlining these factors,our goal is to guide the selection of the optimal delivery tool for a specific retinal disease,which will enhance treatment efficacy and improve patient outcomes while paving the way for more effective and targeted therapeutic interventions.展开更多
AIM:To identify key genes and inflammatory signaling pathways involved in the anti-inflammatory effects of Hedysarum polybotrys polysaccharide(HPS)in a rat model of endotoxin-induced uveitis(EIU).METHODS:EIU was induc...AIM:To identify key genes and inflammatory signaling pathways involved in the anti-inflammatory effects of Hedysarum polybotrys polysaccharide(HPS)in a rat model of endotoxin-induced uveitis(EIU).METHODS:EIU was induced in Wistar rats through subcutaneous injection of lipopolysaccharide(LPS,200μg)and the rats were then randomly assigned to EIU group(n=5)and the HPS intervention group(n=5).HPS(400 mg/kg,intraperitoneally)or its carrier was administered 24h and 1h prior to EIU induction.Eyes were examined and enucleated 24h post-induction,and total RNA was extracted from the iris-ciliary body.Gene expression microarrays were used to identify differentially expressed genes(DEGs),followed by bioinformatics analyses,including gene ontology(GO)and pathway analysis.Key findings were not experimentally validated at the mRNA or protein level.RESULTS:A total of 322 DEGs were identified,comprising 254 mRNA and 68 lncRNA genes.GO analysis revealed significant functional categories,including response to LPS.Pathway analysis identified key signaling pathways involved in uveitis,such as cytokine-cytokine receptor interactions.Notably,16 mRNA and 7 lncRNA DEGs emerged as central nodes in the gene correlation network.CONCLUSION:HPS exerts its anti-inflammatory effects through coordinated signaling pathways,offering insights into potential therapeutic targets for managing uveitis.展开更多
BACKGROUND Crohn’s disease(CD)is a chronic inflammatory bowel disease with unknown etiology.Inflammatory chemical mediators synthesized from arachidonic acid,an n-6 polyunsaturated fatty acid(PUFA),have been shown to...BACKGROUND Crohn’s disease(CD)is a chronic inflammatory bowel disease with unknown etiology.Inflammatory chemical mediators synthesized from arachidonic acid,an n-6 polyunsaturated fatty acid(PUFA),have been shown to activate CD.Additionally,n-3 PUFAs are metabolized by the same enzyme as n-6 PUFAs and known to inhibit the arachidonic acid cascade.Our previous study noted that the presence of erythrocyte membrane fatty acids is a characteristic finding in Japanese CD patients.It was thus speculated that FADS2 gene polymorphisms,which induce PUFA metabolizing enzymes,are involved in the pathogenesis of CD,though no such relationship was found.AIM To investigate the relationship of FADS2 polymorphisms with serum and erythrocyte membrane fatty acid composition ratios,and disease activity.METHODS Using previously reported findings regarding FADS2 genetic polymorphisms,the records of 52 CD patients undergoing treatment at Jikei University Kashiwa Hospital were analyzed.Mutations noted were divided into three groups;wild-type(GG),heterozygous mutants(GA),and homozygous(AA),with the activities of delta-6 and delta-5 desaturases compared using redefined d6d index(rd.d6di)and d5d index(d5di).Additionally,comparisons of serum and erythrocyte membranes for fatty acid composition,and also gene polymorphisms and CD activity index(CDAI)were performed.RESULTS The presence of the rs174538 mutation in FADS2 resulted in reduction of only rd.d6di in the erythrocyte membrane(P<0.01).In contrast,that mutation was found to be associated with d5di induced by FADS1 in serum(P=0.019)as well as the erythrocyte membrane(P<0.0001),and also with reduction in the fatty acid composition of arachidonic acid in both serum(P<0.0001)and the erythrocyte membrane(P<0.01).Regarding disease activity,a positive correlation of CDAI score with rd.d6di in both serum(P<0.05)and the erythrocyte membrane(P<0.05)was found only in the rs174538 wild-type group.In contrast,there was no correction between CDAI and d5di in either serum or erythrocyte membrane samples.CONCLUSION The rs174538 mutation alters the fatty acid profile through strong linkage to the FADS1 gene.In wild-type individuals,rd.d6di was positively correlated with CDAI,suggesting predictive utility of disease severity.展开更多
Neurodevelopmental and neurodegenerative illnesses constitute a global health issue and a foremost economic burden since they are a large cause of incapacity and death worldwide.Altogether,the burden of neurological d...Neurodevelopmental and neurodegenerative illnesses constitute a global health issue and a foremost economic burden since they are a large cause of incapacity and death worldwide.Altogether,the burden of neurological disorders has increased considerably over the past 30 years because of population aging.Overall,neurological diseases significantly impair cognitive and motor functions and their incidence will increase as societies age and the world's population continues to grow.Autism spectrum disorder,motor neuron disease,encephalopathy,epilepsy,stroke,ataxia,Alzheimer's disease,amyotrophic lateral sclerosis,Huntington's disease,and Parkinson's disease represent a non-exhaustive list of neurological illnesses.These affections are due to perturbations in cellular homeostasis leading to the progressive injury and death of neurons in the nervous system.Among the common features of neurological handicaps,we find protein aggregation,oxidative stress,neuroinflammation,and mitochondrial impairment in the target tissues,e.g.,the brain,cerebellum,and spinal cord.The high energy requirements of neurons and their inability to produce sufficient adenosine triphosphate by glycolysis,are responsible for their dependence on functional mitochondria for their integrity.Reactive oxygen species,produced along with the respiration process within mitochondria,can lead to oxidative stress,which compromises neuronal survival.Besides having an essential role in energy production and oxidative stress,mitochondria are indispensable for an array of cellular processes,such as amino acid metabolism,iron-sulfur cluster biosynthesis,calcium homeostasis,intrinsic programmed cell death(apoptosis),and intraorganellar signaling.Despite the progress made in the last decades in the understanding of a growing number of genetic and molecular causes of central nervous diseases,therapies that are effective to diminish or halt neuronal dysfunction/death are rare.Given the genetic complexity responsible for neurological disorders,the development of neuroprotective strategies seeking to preserve mitochondrial homeostasis is a realistic challenge to lastingly diminish the harmful evolution of these pathologies and so to recover quality of life.A promising candidate is the neuroglobin,a globin superfamily member of 151 amino acids,which is found at high levels in the brain,the eye,and the cerebellum.The protein,which localizes to mitochondria,is involved in electron transfer,oxygen storage and defence against oxidative stress;hence,possessing neuroprotective properties.This review surveys up-to-date knowledge and emphasizes on existing investigations regarding neuroglobin physiological functions,which remain since its discovery in 2000 under intense debate and the possibility of using neuroglobin either by gene therapy or its direct delivery into the brain to treat neurological disorders.展开更多
Background:Tandem gene repeats naturally occur as important genomic features and determine many traits in living organisms,like human diseases and microbial productivities of target bioproducts.Methods:Here,we develop...Background:Tandem gene repeats naturally occur as important genomic features and determine many traits in living organisms,like human diseases and microbial productivities of target bioproducts.Methods:Here,we developed a bacterial type-II toxin-antitoxin-mediated method to manipulate genomic integration of tandem gene repeats in Saccharomyces cerevisiae and further visualised the evolutionary trajectories of gene repeats.We designed a tri-vector system to introduce toxin-antitoxin-driven gene amplification modules.Results:This system delivered multi-copy gene integration in the form of tandem gene repeats spontaneously and independently from toxin-antitoxin-mediated selection.Inducing the toxin(RelE)expressing via a copper(II)-inducible CUP1 promoter successfully drove the in-situ gene amplification of the antitoxin(RelB)module,resulting in~40 copies of a green fluorescence reporter gene per copy of genome.Copy-number changes,copy-number increase and copy-number decrease,and stable maintenance were visualised using the green fluorescence protein and blue chromoprotein AeBlue as reporters.Copy-number increases happened spontaneously and independent on a selection pressure.Increased copy number was quickly enriched through toxin-antitoxin-mediated selection.Conclusion:In summary,the bacterial toxin-antitoxin systems provide a flexible mechanism to manipulate gene copy number in eukaryotic cells and can be exploited for synthetic biology and metabolic engineering applications.展开更多
BACKGROUND Well-differentiated small bowel mesenteric liposarcoma(LPS)is rare,with high malignancy,poor prognosis,and high preponderance to local recurrence.CASE SUMMARY Here we described a 71-year-old male,who compla...BACKGROUND Well-differentiated small bowel mesenteric liposarcoma(LPS)is rare,with high malignancy,poor prognosis,and high preponderance to local recurrence.CASE SUMMARY Here we described a 71-year-old male,who complains of persistent abdominal distension for a month.The clinical manifestation is a huge abdominal mass occupying almost the entire abdomen.Physical examination indicated palpable massive mass in the abdomen,hard texture,indefinable boundary,poor mobility.The abdominal enhanced computed tomography at another hospital scan showed multiple abdominal masses originating from the small bowel mesentery.Abdominal and pelvic magnetic resonance imaging at our hospital showed multiple masses in the abdominal and pelvic cavities,indicating that the tumor originated from the mesentery or peritoneum.Results of exploratory laparotomy indicated that the tremendous mass primarily results from the mesentery of the small intestine,occupying the entire abdominal cavity in a polymorphic and lobulated shape.The patient underwent complete surgical resection of the tumor,and the weight of the tumor was approximately 11 kg.The histopathological examination of the resected specimens confirmed the diagnosis of well-differentiated LPS of the small bowel mesentery.CONCLUSION Completed surgical resection was cornerstone,and histopathological and molecular confirmations were crucial.The necessity of adjuvant therapy should be phrased as a potential consideration to improve patient’s survival time.展开更多
The etiopathogenesis of gastrointestinal diseases is varied in nature.Various etiogenic factors described are infective,inflammatory,viral,bacterial,parasitic,dietary and lifestyle change.Rare causative agents are imm...The etiopathogenesis of gastrointestinal diseases is varied in nature.Various etiogenic factors described are infective,inflammatory,viral,bacterial,parasitic,dietary and lifestyle change.Rare causative agents are immunological,and others associated as idiopathic,are undiagnosed by all possible means.Some of the rare diseases are congenital in nature,passing from the parent to the child.Many of the undiagnosed diseases are now being diagnosed as genetic and the genes have been implicated as a causative agent.There is a search for newer treatments for such diseases,which is called genomic medicine.Genomic medicine is an emerging medical discipline that involves the use of genomic information about an individual.This is used both for diagnostic as well as therapeutic decisions to improve the current health domain and pave the way for policymakers for its clinical use.In the developing era of precision medicine,genomics,epigenomics,environmental exposure,and other data would be used to more accurately guide individual diagnosis and treatment.Genomic medicine is already making an impact in the fields of oncology,pharmacology,rare,infectious and many undiagnosed diseases.It is beginning to fuel new approaches in certain medical specialties.Oncology is at the leading edge of incorporating genomics,as diagnostics for genetic and genomic markers are increasingly included in cancer screening,and to guide tailored treatment strategies.Genetics and genetic medicine have been reported to play a role in gastroenterology in several ways,including genetic testing(hereditary pancreatitis and hereditary gastrointestinal cancer syndromes).Genetic testing can also help subtype diseases,such as classifying pancreatitis as idiopathic or hereditary.Gene therapy is a promising approach for treating gastrointestinal diseases that are not effectively treated by conventional pharmaceuticals and surgeries.Gene therapy strategies include gene addition,gene editing,messenger RNA therapy,and gene silencing.Understanding genetic determinants,advances in genetics,have led to a better understanding of the genetic factors that contribute to human disease.Family-member risk stratification and genetic diagnosis can help identify family members who are at risk,which can lead to preventive treatments,lifestyle recommendations,and routine follow ups.Selecting target genes helps identify the gene targets associated with each gastrointestinal disease.Common gastrointestinal diseases associated with genetic abnormalities include-inflammatory bowel disease,gastroesophageal reflux disease,non-alcoholic fatty liver disease,and irritable bowel syndrome.With advancing tools and technology,research in the search of newer and individualized treatment,genes and genetic medicines are expected to play a significant role in human health and gastroenterology.展开更多
Background:Receptor-interacting protein kinases(RIPKs)regulate cell death,inflammation,and immune responses,yet their roles in cancer are not fully understood.This study investigates the expression,genomic alterations...Background:Receptor-interacting protein kinases(RIPKs)regulate cell death,inflammation,and immune responses,yet their roles in cancer are not fully understood.This study investigates the expression,genomic alterations,and functional implications of RIPK family members across various cancers.Methods:We collected multi-omics data from The Cancer Genome Atlas and other public databases,including gene expression,copy number variation(CNV),mutation,methylation,tumor mutation burden(TMB),and microsatellite instability(MSI).Differential expression and survival analyses were performed using DESeq2 and Cox proportional hazards models.CNV and mutation data were analyzed with GISTIC2 and Mutect2,and methylation data with the ChAMP package.Correlations with TMB and MSI were assessed using Pearson coefficients,and gene set enrichment analysis was conducted with the MSigDB Hallmark gene sets.Results:RIPK family members show significant differential expression in various cancers,with RIPK1 and RIPK4 frequently altered.Survival analysis reveals heterogeneous impacts on overall survival.CNV and mutation analyses identify high alteration frequencies for RIPK2 and RIPK7,affecting gene expression.RIPK1 and RIPK7 are hypermethylated in several cancers,inversely correlating with RIPK3 expression.RIPK1,RIPK2,RIPK5,RIPK6,and RIPK7 correlate positively with TMB,while RIPK3 shows negative correlations in some cancers.MSI analysis indicates associations with DNA mismatch repair.G ene set enrichment analysis highlights immune-related pathway enrichment for RIPK1,RIPK2,RIPK3,and RIPK6,and cell proliferation and DNA repair pathways for RIPK4 and RIPK5.RIPK family members showed heterogeneous alterations across cancers:for example,RIPK7 was mutated in up to~15%of u terine c orpus e ndometrial c arcinoma and l ung s quamous c ell c arcinoma cases,and RIPK1 and RIPK7 exhibited frequent promoter hypermethylation in multiple tumor types.Several genes displayed context-dependent associations with overall survival and with TMB/MSI.Conclusion:This pan-cancer analysis of the RIPK family reveals their diverse roles and potential as biomarkers and therapeutic targets.The findings emphasize the importance of RIPK genes in tumorigenesis and suggest context-dependent functions across cancer types.Further studies are needed to explore their mechanisms in cancer development and clinical applications.展开更多
Ischemic stroke is a serious medical event that cannot be predicted in advance and can have longlasting effects on patients,families,and communities.A deeper understanding of the changes in gene expression and the fun...Ischemic stroke is a serious medical event that cannot be predicted in advance and can have longlasting effects on patients,families,and communities.A deeper understanding of the changes in gene expression and the fundamental molecular mechanisms involved could help address this critical issue.In recent years,research into regulatory long non-coding(lnc)RNAs,a diverse group of RNA molecules with regulatory functions,has emerged as a promising direction in the study of cerebral infarction.This review paper aims to provide a comprehensive exploration of the roles of regulatory lncRNAs in cerebral infarction,as well as potential strategies for their application in clinical settings.LncRNAs have the potential to act as“sponges”that attract specific microRNAs,thereby regulating the expression of microRNA target genes.These interactions influence various aspects of ischemic stroke,including reperfusion-induced damage,cell death,immune responses,autophagy,angiogenesis,and the generation of reactive oxygen species.We highlight several regulatory lncRNAs that have been utilized in animal model treatments,including lncRNA NKILA,lncRNA Meg8,and lncRNA H19.Additionally,we discuss lncRNAs that have been used as biomarkers for the diagnosis and prognosis of cerebral infarction,such as lncRNA FOXO3,lncRNA XIST,and lncRNA RMST.The lncRNAs hold potential for genetic-level treatments in patients.However,numerous challenges,including inefficiency,low targeting accuracy,and side effects observed in preliminary studies,indicate the need for thorough investigation.The application of lncRNAs in ischemic stroke presents challenges that require careful and extensive validation.展开更多
In this work,ofloxacin(OFL),a kind of frequently detected antibiotic in groundwater,was selected to explore its impact(at ng/L-μg/L-level)on denitrification performance in an autotrophic denitrification system driven...In this work,ofloxacin(OFL),a kind of frequently detected antibiotic in groundwater,was selected to explore its impact(at ng/L-μg/L-level)on denitrification performance in an autotrophic denitrification system driven by pyrite/sulfur(FeS2/S0).Results showed that OFL restrained nitrate removal efficiency,and the inhibition degree was positively related to the concentration of OFL.After being exposed to increased OFL(200 ng/L-100μg/L)for 69 days,higher inhibition of electron transport activity(ETSA),enzyme activities of nitrate reductase(NAR),and nitrite reductase(NIR)were acquired.Meanwhile,the extracellular protein(PN)content of sludge samples was remarkably stimulated by OFL to resist the augmented toxicity.OFL contributed to increased microbial diversity and sulfur/sulfide oxidation functional genes in ng/L-level bioreactors,whereas led to a decline inμg/L level experiments.With OFL at concentrations of 200 ng/L and 100μg/L,the whole expression of 10 key denitrification functional genes was depressed,and the higher the OFL concentration,the lower the expression level.However,no significant proliferation of antibiotic resistance genes(ARGs)either in 200 ng/L-OFL or 100μg/L-OFL groups was observed.Two-factor correlation analysis results indicated that Thiobacillus,Anaerolineae,Anaerolineales,and Nitrospirae might be the main hosts of existing ARGs in this system.展开更多
Complex genetic relationships between neurodegenerative disorders and neuropsychiatric symptoms have been shown, suggesting shared pathogenic mechanisms and emphasizing the potential for developing common therapeutic ...Complex genetic relationships between neurodegenerative disorders and neuropsychiatric symptoms have been shown, suggesting shared pathogenic mechanisms and emphasizing the potential for developing common therapeutic targets. Apolipoprotein E(APOE) genotypes and their corresponding protein(Apo E) isoforms may influence the biophysical properties of the cell membrane lipid bilayer. However, the role of APOE in central nervous system pathophysiology extended beyond its lipid transport function. In the present review article, we analyzed the links existing between APOE genotypes and the neurobiology of neuropsychiatric symptoms in neurodegenerative and vascular diseases. APOE genotypes(APOE ε2, APOE ε3, and APOE ε4) were implicated in common mechanisms underlying a wide spectrum of neurodegenerative diseases, including sporadic Alzheimer's disease, synucleinopathies such as Parkinson's disease and Lewy body disease, stroke, and traumatic brain injury. These shared pathways often involved neuroinflammation, abnormal protein accumulation, or responses to acute detrimental events. Across these conditions, APOE variants are believed to contribute to the modulation of inflammatory responses, the regulation of amyloid and tau pathology, as well as the clearance of proteins such as α-synuclein. The bidirectional interactions among Apo E, amyloid and mitochondrial metabolism, immunomodulatory effects, neuronal repair, and remodeling underscored the complexity of Apo E's role in neuropsychiatric symptoms associated with these conditions since from early phases of cognitive impairment such as mild cognitive impairment and mild behavioral impairment. Besides Apo E-specific isoforms' link to increased neuropsychiatric symptoms in Alzheimer's disease(depression, psychosis, aberrant motor behaviors, and anxiety, not apathy), the APOE ε4 genotype was also considered a significant genetic risk factor for Lewy body disease and its worse cognitive outcomes. Conversely, the APOE ε2 variant has been observed not to exert a protective effect equally in all neurodegenerative diseases. Specifically, in Lewy body disease, this variant may delay disease onset, paralleling its protective role in Alzheimer's disease, although its role in frontotemporal dementia is uncertain. The APOE ε4 genotype has been associated with adverse cognitive outcomes across other various neurodegenerative conditions. In Parkinson's disease, the APOE ε4 allele significantly impacted cognitive performance, increasing the risk of developing dementia, even in cases of pure synucleinopathies with minimal co-pathology from Alzheimer's disease. Similarly, in traumatic brain injury, recovery rates varied, with APOE ε4 carriers demonstrating a greater risk of poor long-term cognitive outcomes and elevated levels of neuropsychiatric symptoms. Furthermore, APOE ε4 influenced the age of onset and severity of stroke, as well as the likelihood of developing stroke-associated dementia, potentially due to its role in compromising endothelial integrity and promoting blood–brain barrier dysfunction.展开更多
AAV-PHP.eB is an artificial adeno-associated virus(AAV)that crosses the blood-brain barrier and targets neurons more efficiently than other AAVs when administered systematically.While AAV-PHP.eB has been used in vario...AAV-PHP.eB is an artificial adeno-associated virus(AAV)that crosses the blood-brain barrier and targets neurons more efficiently than other AAVs when administered systematically.While AAV-PHP.eB has been used in various disease models,its cellular tropism in cerebrovascular diseases remains unclear.In the present study,we aimed to elucidate the tropism of AAV-PHP.eB for different cell types in the brain in a mouse model of ischemic stroke and evaluate its effectiveness in mediating basic fibroblast growth factor(bFGF)gene therapy.Mice were injected intravenously with AAV-PHP.eB either 14 days prior to(pre-stroke)or 1 day following(post-stroke)transient middle cerebral artery occlusion.Notably,we observed a shift in tropism from neurons to endothelial cells with post-stroke administration of AAV-PHP.eB-mNeonGreen(mNG).This endothelial cell tropism correlated strongly with expression of the endothelial membrane receptor lymphocyte antigen 6 family member A(Ly6A).Furthermore,AAV-PHP.eB-mediated overexpression of bFGF markedly improved neurobehavioral outcomes and promoted long-term neurogenesis and angiogenesis post-ischemic stroke.Our findings underscore the significance of considering potential tropism shifts when utilizing AAV-PHP.eB-mediated gene therapy in neurological diseases and suggest a promising new strategy for bFGF gene therapy in stroke treatment.展开更多
Parkinson’s disease is a common neurodegenerative disease with movement disorders associated with the intracytoplasmic deposition of aggregate proteins such asα-synuclein in neurons.As one of the major intracellular...Parkinson’s disease is a common neurodegenerative disease with movement disorders associated with the intracytoplasmic deposition of aggregate proteins such asα-synuclein in neurons.As one of the major intracellular degradation pathways,the autophagy-lysosome pathway plays an important role in eliminating these proteins.Accumulating evidence has shown that upregulation of the autophagy-lysosome pathway may contribute to the clearance ofα-synuclein aggregates and protect against degeneration of dopaminergic neurons in Parkinson’s disease.Moreover,multiple genes associated with the pathogenesis of Parkinson’s disease are intimately linked to alterations in the autophagy-lysosome pathway.Thus,this pathway appears to be a promising therapeutic target for treatment of Parkinson’s disease.In this review,we briefly introduce the machinery of autophagy.Then,we provide a description of the effects of Parkinson’s disease–related genes on the autophagy-lysosome pathway.Finally,we highlight the potential chemical and genetic therapeutic strategies targeting the autophagy–lysosome pathway and their applications in Parkinson’s disease.展开更多
Nerve regeneration following traumatic peripheral nerve injuries and neuropathies is a complex process modulated by diverse factors and intricate molecular mechanisms.Past studies have focused on factors that stimulat...Nerve regeneration following traumatic peripheral nerve injuries and neuropathies is a complex process modulated by diverse factors and intricate molecular mechanisms.Past studies have focused on factors that stimulate axonal outgrowth and myelin regeneration.However,recent studies have highlighted the pivotal role of autophagy in peripheral nerve regeneration,particularly in the context of traumatic injuries.Consequently,autophagy-targeting modulation has emerged as a promising therapeutic approach to enhancing peripheral nerve regeneration.Our current understanding suggests that activating autophagy facilitates the rapid clearance of damaged axons and myelin sheaths,thereby enhancing neuronal survival and mitigating injury-induced oxidative stress and inflammation.These actions collectively contribute to creating a favorable microenvironment for structural and functional nerve regeneration.A range of autophagyinducing drugs and interventions have demonstrated beneficial effects in alleviating peripheral neuropathy and promoting nerve regeneration in preclinical models of traumatic peripheral nerve injuries.This review delves into the regulation of autophagy in cell types involved in peripheral nerve regeneration,summarizing the potential drugs and interventions that can be harnessed to promote this process.We hope that our review will offer novel insights and perspectives on the exploitation of autophagy pathways in the treatment of peripheral nerve injuries and neuropathies.展开更多
文摘Background The association of E670G polymorphism in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene and serum lipid profiles is inconsistent in dif- ferent ethnic groups.Bai Ku Yao is a special subgroup of the Yao minority in China.The present study was undertaken association of PCSK9 E670G polymorphism and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations.Methods A total of 649 subjects of Bai Ku Yao and 646 participants of Han Chinese were randomly selected from our previous stratified randomized cluster samples.Genotyping of the PCSK9 E670G polymorphism was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis,and then confirmed by direct sequencing. Results The levels of serum total cholesterol(TC),high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C) and apolipoprotein(Apo) AI were lower in Bai Ku Yao than in Han(P【0.01 for all).The frequency of A and G alleles was 98.00%and 2.00%in Bai Ku Yao,and 95.20%and 4.80%in Han(P【0.01);respectively. The frequency of AA,AG and GG genotypes was 95.99%,4.01%and 0%in Bai Ku Yao,and 91.02%, 8.36%and 0.62%in Han(P【0.01);respectively.There were also significant differences in the genotypic and allelic frequencies between n and the ratio of ApoAI to ApoB in Han Chinese but not in Bai Ku Yao were different between the AA and AG/GG genotypes(P【0.05 for all).The G allele carriers had higher serum HDL-C and higher ApoAI to ApoB ratio than the G allele noncarriers.When serum lipid parameters in Han were analyzed according to sex,the G allele carriers had higher serum HDL and ApoAI levels in males (P【0.05),and lower ApoB level and higher ApoAI to ApoB ratio in females(P【0.05 for all).Multiple linear regression analysis showed that serum HDL-C levels were correlated with genotypes in both ethnic groups(P【0.05 each).Serum lipid parameters were also correlated with sex,age,body massindex,alcohol consumption,cigarette smoking,and blood pressure in both ethnic groups(P【0.05-0.001).Conclusions These results suggest that the PCSK9 E670G polymorphism is mainly associated with some serum lipid parameters in the Han population,both gender show different relations to different serum lipid parameters.The G allele carriers might have higher serum lipid profiles than the G allele noncarriers. ormal LDL-C(≤3.20 mmol/L) and high LDL-C subgroups (】 3.20 mmol/L,P【0.01;respectively) in Bai Ku Yao, and between normal ApoB(≤1.14 g/L) and high ApoB subgroups(】 1.14 g/L,P 【 0.01;respectively) in Han.
基金Supported by the National High Technology Research and Development Program of China (863 Program, 2009AA02Z111)the National Natural Science Foundation of China (30872223)the Funds of the State Key Laboratory of Pathogen and Biosecurity
文摘Objective： To facilitate manipulation of gene expression in different host cells, we used pEGFP-N1 as backbone to construct a versatile vector that can drive foreign gene expression in prokaryotic and eukaryotic cells. Methods： A cloning and expression vector, pEGFP-NI-lac, was constructed by inserting the prokaryotic lac promoter of pUC 19 into the eukaryotic expression vector, pEGFP-N1, between the eukaryotic PCMV promoter and enhanced green fluorescent protein （EGFP） open reading frames. To assess the function of pEGFP-NI-lac, the nucleotide sequence encoding the hepatitis C virus （HCV） core protein was cloned into the multiple cloning sites. Western blotting analysis was used to detect the expression of the HCV core protein in Escherichia coli DH5a and HepG2 cells. Results： Restriction enzyme digestion and sequence analysis indicated that pEGFP-NI-lac was successfully constructed and the HCV core gene was cloned into this vector. The Western blotting results showed that pEGFP-NI-lac promoted expression of HCV core gene in prokaryotic E. coli DH5a and eukaryotic HepG2 cells. Conclusion： The pEGFP-NI-lac vector has been successfully constructed and functions in both prokaryotic and eukaryotic cells. The EGFP reporter can be used as an insert-inactivation marker for clone selection or as an expression tag. This vector can be used for cloning and expression of genes in both prokaryotic and eukaryotic cells, making gene cloning, expression and functional studies convenient as well as time- and labor-efficient
文摘Background:Microarray analysis is a popular tool to investigate the function of genes that are responsi-ble for the phenotype of the disease.Keloid is a intricate lesion which is probably modulated by interplay of manygenes.We ventured to study the differences of gene expressions between keloids and normal skins with the aid ofcDNA microarray in order to explore the molecular mechanism underlying keloid formation.Methods:The PCRproducts of 8400 human genes were spotted on a chip in array.The DNAs were t...
基金supported by the Ministry of Health National Medical Research Council (to JL)the National University of Singapore (to JJEC)
文摘Schizophrenia is a complex psychiatric disorder marked by positive and negative symptoms,leading to mood disturbances,cognitive impairments,and social withdrawal.While anti-psychotic medications remain the cornerstone of treatment,they often fail to fully address certain symptoms.Additionally,treatment-resistant schizophrenia,affecting 30%-40%of patients,remains a substantial clinical challenge.Positive,negative symptoms and cognitive impairments have been linked to disruptions in the glutamatergic,serotonin,GABAergic,and muscarinic pathways in the brain.Recent advances using genome-wide association study and other approaches have uncovered a significant number of new schizophrenia risk genes that uncovered new,and reinforced prior,concepts on the genetic and neurological underpinnings of schizophrenia,including abnormalities in synaptic function,immune processes,and lipid metabolism.Concurrently,new therapeutics targeting different modalities,which are expected to address some of the limitations of anti-psychotic drugs currently being offered to patients,are currently being evaluated.Collectively,these efforts provide new momentum for the next phase of schizophrenia research and treatment.
基金supported by the National Natural Science Foundation of China,Nos.32271389,31900987(both to PY)the Natural Science Foundation of Jiangsu Province,No.BK20230608(to JJ)。
文摘Regulatory T cells,a subset of CD4^(+)T cells,play a critical role in maintaining immune tolerance and tissue homeostasis due to their potent immunosuppressive properties.Recent advances in research have highlighted the important therapeutic potential of Tregs in neurological diseases and tissue repair,emphasizing their multifaceted roles in immune regulation.This review aims to summarize and analyze the mechanisms of action and therapeutic potential of Tregs in relation to neurological diseases and neural regeneration.Beyond their classical immune-regulatory functions,emerging evidence points to non-immune mechanisms of regulatory T cells,particularly their interactions with stem cells and other non-immune cells.These interactions contribute to optimizing the repair microenvironment and promoting tissue repair and nerve regeneration,positioning non-immune pathways as a promising direction for future research.By modulating immune and non-immune cells,including neurons and glia within neural tissues,Tregs have demonstrated remarkable efficacy in enhancing regeneration in the central and peripheral nervous systems.Preclinical studies have revealed that Treg cells interact with neurons,glial cells,and other neural components to mitigate inflammatory damage and support functional recovery.Current mechanistic studies show that Tregs can significantly promote neural repair and functional recovery by regulating inflammatory responses and the local immune microenvironment.However,research on the mechanistic roles of regulatory T cells in other diseases remains limited,highlighting substantial gaps and opportunities for exploration in this field.Laboratory and clinical studies have further advanced the application of regulatory T cells.Technical advances have enabled efficient isolation,ex vivo expansion and functionalization,and adoptive transfer of regulatory T cells,with efficacy validated in animal models.Innovative strategies,including gene editing,cell-free technologies,biomaterial-based recruitment,and in situ delivery have expanded the therapeutic potential of regulatory T cells.Gene editing enables precise functional optimization,while biomaterial and in situ delivery technologies enhance their accumulation and efficacy at target sites.These advancements not only improve the immune-regulatory capacity of regulatory T cells but also significantly enhance their role in tissue repair.By leveraging the pivotal and diverse functions of Tregs in immune modulation and tissue repair,regulatory T cells–based therapies may lead to transformative breakthroughs in the treatment of neurological diseases.
基金Hongguang Wu,Both authors contributed equally to this work and share first authorshipLing Dong,Both authors contributed equally to this work and share first authorship。
文摘The human retina,a complex and highly specialized structure,includes multiple cell types that work synergistically to generate and transmit visual signals.However,genetic predisposition or age-related degeneration can lead to retinal damage that severely impairs vision or causes blindness.Treatment options for retinal diseases are limited,and there is an urgent need for innovative therapeutic strategies.Cell and gene therapies are promising because of the efficacy of delivery systems that transport therapeutic genes to targeted retinal cells.Gene delivery systems hold great promise for treating retinal diseases by enabling the targeted delivery of therapeutic genes to affected cells or by converting endogenous cells into functional ones to facilitate nerve regeneration,potentially restoring vision.This review focuses on two principal categories of gene delivery vectors used in the treatment of retinal diseases:viral and non-viral systems.Viral vectors,including lentiviruses and adeno-associated viruses,exploit the innate ability of viruses to infiltrate cells,which is followed by the introduction of therapeutic genetic material into target cells for gene correction.Lentiviruses can accommodate exogenous genes up to 8 kb in length,but their mechanism of integration into the host genome presents insertion mutation risks.Conversely,adeno-associated viruses are safer,as they exist as episomes in the nucleus,yet their limited packaging capacity constrains their application to a narrower spectrum of diseases,which necessitates the exploration of alternative delivery methods.In parallel,progress has also occurred in the development of novel non-viral delivery systems,particularly those based on liposomal technology.Manipulation of the ratios of hydrophilic and hydrophobic molecules within liposomes and the development of new lipid formulations have led to the creation of advanced non-viral vectors.These innovative systems include solid lipid nanoparticles,polymer nanoparticles,dendrimers,polymeric micelles,and polymeric nanoparticles.Compared with their viral counterparts,non-viral delivery systems offer markedly enhanced loading capacities that enable the direct delivery of nucleic acids,mRNA,or protein molecules into cells.This bypasses the need for DNA transcription and processing,which significantly enhances therapeutic efficiency.Nevertheless,the immunogenic potential and accumulation toxicity associated with non-viral particulate systems necessitates continued optimization to reduce adverse effects in vivo.This review explores the various delivery systems for retinal therapies and retinal nerve regeneration,and details the characteristics,advantages,limitations,and clinical applications of each vector type.By systematically outlining these factors,our goal is to guide the selection of the optimal delivery tool for a specific retinal disease,which will enhance treatment efficacy and improve patient outcomes while paving the way for more effective and targeted therapeutic interventions.
基金Supported by the National Natural Science Fundation of China(No.82101107No.81471575).
文摘AIM:To identify key genes and inflammatory signaling pathways involved in the anti-inflammatory effects of Hedysarum polybotrys polysaccharide(HPS)in a rat model of endotoxin-induced uveitis(EIU).METHODS:EIU was induced in Wistar rats through subcutaneous injection of lipopolysaccharide(LPS,200μg)and the rats were then randomly assigned to EIU group(n=5)and the HPS intervention group(n=5).HPS(400 mg/kg,intraperitoneally)or its carrier was administered 24h and 1h prior to EIU induction.Eyes were examined and enucleated 24h post-induction,and total RNA was extracted from the iris-ciliary body.Gene expression microarrays were used to identify differentially expressed genes(DEGs),followed by bioinformatics analyses,including gene ontology(GO)and pathway analysis.Key findings were not experimentally validated at the mRNA or protein level.RESULTS:A total of 322 DEGs were identified,comprising 254 mRNA and 68 lncRNA genes.GO analysis revealed significant functional categories,including response to LPS.Pathway analysis identified key signaling pathways involved in uveitis,such as cytokine-cytokine receptor interactions.Notably,16 mRNA and 7 lncRNA DEGs emerged as central nodes in the gene correlation network.CONCLUSION:HPS exerts its anti-inflammatory effects through coordinated signaling pathways,offering insights into potential therapeutic targets for managing uveitis.
文摘BACKGROUND Crohn’s disease(CD)is a chronic inflammatory bowel disease with unknown etiology.Inflammatory chemical mediators synthesized from arachidonic acid,an n-6 polyunsaturated fatty acid(PUFA),have been shown to activate CD.Additionally,n-3 PUFAs are metabolized by the same enzyme as n-6 PUFAs and known to inhibit the arachidonic acid cascade.Our previous study noted that the presence of erythrocyte membrane fatty acids is a characteristic finding in Japanese CD patients.It was thus speculated that FADS2 gene polymorphisms,which induce PUFA metabolizing enzymes,are involved in the pathogenesis of CD,though no such relationship was found.AIM To investigate the relationship of FADS2 polymorphisms with serum and erythrocyte membrane fatty acid composition ratios,and disease activity.METHODS Using previously reported findings regarding FADS2 genetic polymorphisms,the records of 52 CD patients undergoing treatment at Jikei University Kashiwa Hospital were analyzed.Mutations noted were divided into three groups;wild-type(GG),heterozygous mutants(GA),and homozygous(AA),with the activities of delta-6 and delta-5 desaturases compared using redefined d6d index(rd.d6di)and d5d index(d5di).Additionally,comparisons of serum and erythrocyte membranes for fatty acid composition,and also gene polymorphisms and CD activity index(CDAI)were performed.RESULTS The presence of the rs174538 mutation in FADS2 resulted in reduction of only rd.d6di in the erythrocyte membrane(P<0.01).In contrast,that mutation was found to be associated with d5di induced by FADS1 in serum(P=0.019)as well as the erythrocyte membrane(P<0.0001),and also with reduction in the fatty acid composition of arachidonic acid in both serum(P<0.0001)and the erythrocyte membrane(P<0.01).Regarding disease activity,a positive correlation of CDAI score with rd.d6di in both serum(P<0.05)and the erythrocyte membrane(P<0.05)was found only in the rs174538 wild-type group.In contrast,there was no correction between CDAI and d5di in either serum or erythrocyte membrane samples.CONCLUSION The rs174538 mutation alters the fatty acid profile through strong linkage to the FADS1 gene.In wild-type individuals,rd.d6di was positively correlated with CDAI,suggesting predictive utility of disease severity.
基金supported by AFM-Telethon grants N°21704 and 23264,Universite Paris Cite(Paris)the National Institute of Health and Medical Research(INSERM)+3 种基金the National Center for Scientific Research(CNRS)the French Association Connaître les Syndromes Cerebelleux(CSC)(to MCD)GV/2021/188 granted from Conselleria of Innovation,Universities,28 Science and Society digital of the Community of Valencia(Spain)(to ITC)Subprograma Atraccion de Talento-Contratos Postdoctorales de la Universitat de Valencia(to IMY).
文摘Neurodevelopmental and neurodegenerative illnesses constitute a global health issue and a foremost economic burden since they are a large cause of incapacity and death worldwide.Altogether,the burden of neurological disorders has increased considerably over the past 30 years because of population aging.Overall,neurological diseases significantly impair cognitive and motor functions and their incidence will increase as societies age and the world's population continues to grow.Autism spectrum disorder,motor neuron disease,encephalopathy,epilepsy,stroke,ataxia,Alzheimer's disease,amyotrophic lateral sclerosis,Huntington's disease,and Parkinson's disease represent a non-exhaustive list of neurological illnesses.These affections are due to perturbations in cellular homeostasis leading to the progressive injury and death of neurons in the nervous system.Among the common features of neurological handicaps,we find protein aggregation,oxidative stress,neuroinflammation,and mitochondrial impairment in the target tissues,e.g.,the brain,cerebellum,and spinal cord.The high energy requirements of neurons and their inability to produce sufficient adenosine triphosphate by glycolysis,are responsible for their dependence on functional mitochondria for their integrity.Reactive oxygen species,produced along with the respiration process within mitochondria,can lead to oxidative stress,which compromises neuronal survival.Besides having an essential role in energy production and oxidative stress,mitochondria are indispensable for an array of cellular processes,such as amino acid metabolism,iron-sulfur cluster biosynthesis,calcium homeostasis,intrinsic programmed cell death(apoptosis),and intraorganellar signaling.Despite the progress made in the last decades in the understanding of a growing number of genetic and molecular causes of central nervous diseases,therapies that are effective to diminish or halt neuronal dysfunction/death are rare.Given the genetic complexity responsible for neurological disorders,the development of neuroprotective strategies seeking to preserve mitochondrial homeostasis is a realistic challenge to lastingly diminish the harmful evolution of these pathologies and so to recover quality of life.A promising candidate is the neuroglobin,a globin superfamily member of 151 amino acids,which is found at high levels in the brain,the eye,and the cerebellum.The protein,which localizes to mitochondria,is involved in electron transfer,oxygen storage and defence against oxidative stress;hence,possessing neuroprotective properties.This review surveys up-to-date knowledge and emphasizes on existing investigations regarding neuroglobin physiological functions,which remain since its discovery in 2000 under intense debate and the possibility of using neuroglobin either by gene therapy or its direct delivery into the brain to treat neurological disorders.
基金supported partially by the Australian Government through the Australian Research Council Centres of Excellence funding scheme(project CE200100029)。
文摘Background:Tandem gene repeats naturally occur as important genomic features and determine many traits in living organisms,like human diseases and microbial productivities of target bioproducts.Methods:Here,we developed a bacterial type-II toxin-antitoxin-mediated method to manipulate genomic integration of tandem gene repeats in Saccharomyces cerevisiae and further visualised the evolutionary trajectories of gene repeats.We designed a tri-vector system to introduce toxin-antitoxin-driven gene amplification modules.Results:This system delivered multi-copy gene integration in the form of tandem gene repeats spontaneously and independently from toxin-antitoxin-mediated selection.Inducing the toxin(RelE)expressing via a copper(II)-inducible CUP1 promoter successfully drove the in-situ gene amplification of the antitoxin(RelB)module,resulting in~40 copies of a green fluorescence reporter gene per copy of genome.Copy-number changes,copy-number increase and copy-number decrease,and stable maintenance were visualised using the green fluorescence protein and blue chromoprotein AeBlue as reporters.Copy-number increases happened spontaneously and independent on a selection pressure.Increased copy number was quickly enriched through toxin-antitoxin-mediated selection.Conclusion:In summary,the bacterial toxin-antitoxin systems provide a flexible mechanism to manipulate gene copy number in eukaryotic cells and can be exploited for synthetic biology and metabolic engineering applications.
文摘BACKGROUND Well-differentiated small bowel mesenteric liposarcoma(LPS)is rare,with high malignancy,poor prognosis,and high preponderance to local recurrence.CASE SUMMARY Here we described a 71-year-old male,who complains of persistent abdominal distension for a month.The clinical manifestation is a huge abdominal mass occupying almost the entire abdomen.Physical examination indicated palpable massive mass in the abdomen,hard texture,indefinable boundary,poor mobility.The abdominal enhanced computed tomography at another hospital scan showed multiple abdominal masses originating from the small bowel mesentery.Abdominal and pelvic magnetic resonance imaging at our hospital showed multiple masses in the abdominal and pelvic cavities,indicating that the tumor originated from the mesentery or peritoneum.Results of exploratory laparotomy indicated that the tremendous mass primarily results from the mesentery of the small intestine,occupying the entire abdominal cavity in a polymorphic and lobulated shape.The patient underwent complete surgical resection of the tumor,and the weight of the tumor was approximately 11 kg.The histopathological examination of the resected specimens confirmed the diagnosis of well-differentiated LPS of the small bowel mesentery.CONCLUSION Completed surgical resection was cornerstone,and histopathological and molecular confirmations were crucial.The necessity of adjuvant therapy should be phrased as a potential consideration to improve patient’s survival time.
文摘The etiopathogenesis of gastrointestinal diseases is varied in nature.Various etiogenic factors described are infective,inflammatory,viral,bacterial,parasitic,dietary and lifestyle change.Rare causative agents are immunological,and others associated as idiopathic,are undiagnosed by all possible means.Some of the rare diseases are congenital in nature,passing from the parent to the child.Many of the undiagnosed diseases are now being diagnosed as genetic and the genes have been implicated as a causative agent.There is a search for newer treatments for such diseases,which is called genomic medicine.Genomic medicine is an emerging medical discipline that involves the use of genomic information about an individual.This is used both for diagnostic as well as therapeutic decisions to improve the current health domain and pave the way for policymakers for its clinical use.In the developing era of precision medicine,genomics,epigenomics,environmental exposure,and other data would be used to more accurately guide individual diagnosis and treatment.Genomic medicine is already making an impact in the fields of oncology,pharmacology,rare,infectious and many undiagnosed diseases.It is beginning to fuel new approaches in certain medical specialties.Oncology is at the leading edge of incorporating genomics,as diagnostics for genetic and genomic markers are increasingly included in cancer screening,and to guide tailored treatment strategies.Genetics and genetic medicine have been reported to play a role in gastroenterology in several ways,including genetic testing(hereditary pancreatitis and hereditary gastrointestinal cancer syndromes).Genetic testing can also help subtype diseases,such as classifying pancreatitis as idiopathic or hereditary.Gene therapy is a promising approach for treating gastrointestinal diseases that are not effectively treated by conventional pharmaceuticals and surgeries.Gene therapy strategies include gene addition,gene editing,messenger RNA therapy,and gene silencing.Understanding genetic determinants,advances in genetics,have led to a better understanding of the genetic factors that contribute to human disease.Family-member risk stratification and genetic diagnosis can help identify family members who are at risk,which can lead to preventive treatments,lifestyle recommendations,and routine follow ups.Selecting target genes helps identify the gene targets associated with each gastrointestinal disease.Common gastrointestinal diseases associated with genetic abnormalities include-inflammatory bowel disease,gastroesophageal reflux disease,non-alcoholic fatty liver disease,and irritable bowel syndrome.With advancing tools and technology,research in the search of newer and individualized treatment,genes and genetic medicines are expected to play a significant role in human health and gastroenterology.
基金supported by grants from the Tianjin Health Technology Project(Grant no.2022QN106).
文摘Background:Receptor-interacting protein kinases(RIPKs)regulate cell death,inflammation,and immune responses,yet their roles in cancer are not fully understood.This study investigates the expression,genomic alterations,and functional implications of RIPK family members across various cancers.Methods:We collected multi-omics data from The Cancer Genome Atlas and other public databases,including gene expression,copy number variation(CNV),mutation,methylation,tumor mutation burden(TMB),and microsatellite instability(MSI).Differential expression and survival analyses were performed using DESeq2 and Cox proportional hazards models.CNV and mutation data were analyzed with GISTIC2 and Mutect2,and methylation data with the ChAMP package.Correlations with TMB and MSI were assessed using Pearson coefficients,and gene set enrichment analysis was conducted with the MSigDB Hallmark gene sets.Results:RIPK family members show significant differential expression in various cancers,with RIPK1 and RIPK4 frequently altered.Survival analysis reveals heterogeneous impacts on overall survival.CNV and mutation analyses identify high alteration frequencies for RIPK2 and RIPK7,affecting gene expression.RIPK1 and RIPK7 are hypermethylated in several cancers,inversely correlating with RIPK3 expression.RIPK1,RIPK2,RIPK5,RIPK6,and RIPK7 correlate positively with TMB,while RIPK3 shows negative correlations in some cancers.MSI analysis indicates associations with DNA mismatch repair.G ene set enrichment analysis highlights immune-related pathway enrichment for RIPK1,RIPK2,RIPK3,and RIPK6,and cell proliferation and DNA repair pathways for RIPK4 and RIPK5.RIPK family members showed heterogeneous alterations across cancers:for example,RIPK7 was mutated in up to~15%of u terine c orpus e ndometrial c arcinoma and l ung s quamous c ell c arcinoma cases,and RIPK1 and RIPK7 exhibited frequent promoter hypermethylation in multiple tumor types.Several genes displayed context-dependent associations with overall survival and with TMB/MSI.Conclusion:This pan-cancer analysis of the RIPK family reveals their diverse roles and potential as biomarkers and therapeutic targets.The findings emphasize the importance of RIPK genes in tumorigenesis and suggest context-dependent functions across cancer types.Further studies are needed to explore their mechanisms in cancer development and clinical applications.
基金supported by the China Postdoctoral Science Foundation,No.2022M712689the Natural Science Foundation of the Jiangsu Higher Education Institutions of China,No.22KJB1800029+1 种基金The University Student Innovation Project of Yangzhou University,No.XCX20240856The Jiangsu Provincial Science and Technology Talent Project,No.FZ20240964(all to TX).
文摘Ischemic stroke is a serious medical event that cannot be predicted in advance and can have longlasting effects on patients,families,and communities.A deeper understanding of the changes in gene expression and the fundamental molecular mechanisms involved could help address this critical issue.In recent years,research into regulatory long non-coding(lnc)RNAs,a diverse group of RNA molecules with regulatory functions,has emerged as a promising direction in the study of cerebral infarction.This review paper aims to provide a comprehensive exploration of the roles of regulatory lncRNAs in cerebral infarction,as well as potential strategies for their application in clinical settings.LncRNAs have the potential to act as“sponges”that attract specific microRNAs,thereby regulating the expression of microRNA target genes.These interactions influence various aspects of ischemic stroke,including reperfusion-induced damage,cell death,immune responses,autophagy,angiogenesis,and the generation of reactive oxygen species.We highlight several regulatory lncRNAs that have been utilized in animal model treatments,including lncRNA NKILA,lncRNA Meg8,and lncRNA H19.Additionally,we discuss lncRNAs that have been used as biomarkers for the diagnosis and prognosis of cerebral infarction,such as lncRNA FOXO3,lncRNA XIST,and lncRNA RMST.The lncRNAs hold potential for genetic-level treatments in patients.However,numerous challenges,including inefficiency,low targeting accuracy,and side effects observed in preliminary studies,indicate the need for thorough investigation.The application of lncRNAs in ischemic stroke presents challenges that require careful and extensive validation.
基金supported by the National Natural Science Foundation of China(No.42377083)the Natural Science Foundation of Sichuan Province,China(No.2025 ZNSFSC0433).
文摘In this work,ofloxacin(OFL),a kind of frequently detected antibiotic in groundwater,was selected to explore its impact(at ng/L-μg/L-level)on denitrification performance in an autotrophic denitrification system driven by pyrite/sulfur(FeS2/S0).Results showed that OFL restrained nitrate removal efficiency,and the inhibition degree was positively related to the concentration of OFL.After being exposed to increased OFL(200 ng/L-100μg/L)for 69 days,higher inhibition of electron transport activity(ETSA),enzyme activities of nitrate reductase(NAR),and nitrite reductase(NIR)were acquired.Meanwhile,the extracellular protein(PN)content of sludge samples was remarkably stimulated by OFL to resist the augmented toxicity.OFL contributed to increased microbial diversity and sulfur/sulfide oxidation functional genes in ng/L-level bioreactors,whereas led to a decline inμg/L level experiments.With OFL at concentrations of 200 ng/L and 100μg/L,the whole expression of 10 key denitrification functional genes was depressed,and the higher the OFL concentration,the lower the expression level.However,no significant proliferation of antibiotic resistance genes(ARGs)either in 200 ng/L-OFL or 100μg/L-OFL groups was observed.Two-factor correlation analysis results indicated that Thiobacillus,Anaerolineae,Anaerolineales,and Nitrospirae might be the main hosts of existing ARGs in this system.
文摘Complex genetic relationships between neurodegenerative disorders and neuropsychiatric symptoms have been shown, suggesting shared pathogenic mechanisms and emphasizing the potential for developing common therapeutic targets. Apolipoprotein E(APOE) genotypes and their corresponding protein(Apo E) isoforms may influence the biophysical properties of the cell membrane lipid bilayer. However, the role of APOE in central nervous system pathophysiology extended beyond its lipid transport function. In the present review article, we analyzed the links existing between APOE genotypes and the neurobiology of neuropsychiatric symptoms in neurodegenerative and vascular diseases. APOE genotypes(APOE ε2, APOE ε3, and APOE ε4) were implicated in common mechanisms underlying a wide spectrum of neurodegenerative diseases, including sporadic Alzheimer's disease, synucleinopathies such as Parkinson's disease and Lewy body disease, stroke, and traumatic brain injury. These shared pathways often involved neuroinflammation, abnormal protein accumulation, or responses to acute detrimental events. Across these conditions, APOE variants are believed to contribute to the modulation of inflammatory responses, the regulation of amyloid and tau pathology, as well as the clearance of proteins such as α-synuclein. The bidirectional interactions among Apo E, amyloid and mitochondrial metabolism, immunomodulatory effects, neuronal repair, and remodeling underscored the complexity of Apo E's role in neuropsychiatric symptoms associated with these conditions since from early phases of cognitive impairment such as mild cognitive impairment and mild behavioral impairment. Besides Apo E-specific isoforms' link to increased neuropsychiatric symptoms in Alzheimer's disease(depression, psychosis, aberrant motor behaviors, and anxiety, not apathy), the APOE ε4 genotype was also considered a significant genetic risk factor for Lewy body disease and its worse cognitive outcomes. Conversely, the APOE ε2 variant has been observed not to exert a protective effect equally in all neurodegenerative diseases. Specifically, in Lewy body disease, this variant may delay disease onset, paralleling its protective role in Alzheimer's disease, although its role in frontotemporal dementia is uncertain. The APOE ε4 genotype has been associated with adverse cognitive outcomes across other various neurodegenerative conditions. In Parkinson's disease, the APOE ε4 allele significantly impacted cognitive performance, increasing the risk of developing dementia, even in cases of pure synucleinopathies with minimal co-pathology from Alzheimer's disease. Similarly, in traumatic brain injury, recovery rates varied, with APOE ε4 carriers demonstrating a greater risk of poor long-term cognitive outcomes and elevated levels of neuropsychiatric symptoms. Furthermore, APOE ε4 influenced the age of onset and severity of stroke, as well as the likelihood of developing stroke-associated dementia, potentially due to its role in compromising endothelial integrity and promoting blood–brain barrier dysfunction.
基金supported by the National Natural Science Foundation of China,Nos.81870921(to YW),81974179(to ZZ),82271320(to ZZ),82071284(to YT)National Key R&D Program of China,No.2022YFA1603600(to ZZ),2019YFA0112000(to YT)+1 种基金Scientific Research and Innovation Program of Shanghai Education Commission,No.2019-01-07-00-02-E00064(to GYY)Scientific and Technological Innovation Act Program of Shanghai Science and Technology Commission,No.20JC1411900(to GYY).
文摘AAV-PHP.eB is an artificial adeno-associated virus(AAV)that crosses the blood-brain barrier and targets neurons more efficiently than other AAVs when administered systematically.While AAV-PHP.eB has been used in various disease models,its cellular tropism in cerebrovascular diseases remains unclear.In the present study,we aimed to elucidate the tropism of AAV-PHP.eB for different cell types in the brain in a mouse model of ischemic stroke and evaluate its effectiveness in mediating basic fibroblast growth factor(bFGF)gene therapy.Mice were injected intravenously with AAV-PHP.eB either 14 days prior to(pre-stroke)or 1 day following(post-stroke)transient middle cerebral artery occlusion.Notably,we observed a shift in tropism from neurons to endothelial cells with post-stroke administration of AAV-PHP.eB-mNeonGreen(mNG).This endothelial cell tropism correlated strongly with expression of the endothelial membrane receptor lymphocyte antigen 6 family member A(Ly6A).Furthermore,AAV-PHP.eB-mediated overexpression of bFGF markedly improved neurobehavioral outcomes and promoted long-term neurogenesis and angiogenesis post-ischemic stroke.Our findings underscore the significance of considering potential tropism shifts when utilizing AAV-PHP.eB-mediated gene therapy in neurological diseases and suggest a promising new strategy for bFGF gene therapy in stroke treatment.
基金supported by the National Natural Science Foundation of China,No.82101340(to FJ).
文摘Parkinson’s disease is a common neurodegenerative disease with movement disorders associated with the intracytoplasmic deposition of aggregate proteins such asα-synuclein in neurons.As one of the major intracellular degradation pathways,the autophagy-lysosome pathway plays an important role in eliminating these proteins.Accumulating evidence has shown that upregulation of the autophagy-lysosome pathway may contribute to the clearance ofα-synuclein aggregates and protect against degeneration of dopaminergic neurons in Parkinson’s disease.Moreover,multiple genes associated with the pathogenesis of Parkinson’s disease are intimately linked to alterations in the autophagy-lysosome pathway.Thus,this pathway appears to be a promising therapeutic target for treatment of Parkinson’s disease.In this review,we briefly introduce the machinery of autophagy.Then,we provide a description of the effects of Parkinson’s disease–related genes on the autophagy-lysosome pathway.Finally,we highlight the potential chemical and genetic therapeutic strategies targeting the autophagy–lysosome pathway and their applications in Parkinson’s disease.
基金supported by the National Natural Science Foundation of China,Nos.82271411(to RG),51803072(to WLiu)grants from the Department of Finance of Jilin Province,Nos.2022SCZ25(to RG),2022SCZ10(to WLiu),2021SCZ07(to RG)+2 种基金Jilin Provincial Science and Technology Program,No.YDZJ202201ZYTS038(to WLiu)The Youth Support Programmed Project of China-Japan Union Hospital of Jilin University,No.2022qnpy11(to WLuo)The Project of China-Japan Union Hospital of Jilin University,No.XHQMX20233(to RG)。
文摘Nerve regeneration following traumatic peripheral nerve injuries and neuropathies is a complex process modulated by diverse factors and intricate molecular mechanisms.Past studies have focused on factors that stimulate axonal outgrowth and myelin regeneration.However,recent studies have highlighted the pivotal role of autophagy in peripheral nerve regeneration,particularly in the context of traumatic injuries.Consequently,autophagy-targeting modulation has emerged as a promising therapeutic approach to enhancing peripheral nerve regeneration.Our current understanding suggests that activating autophagy facilitates the rapid clearance of damaged axons and myelin sheaths,thereby enhancing neuronal survival and mitigating injury-induced oxidative stress and inflammation.These actions collectively contribute to creating a favorable microenvironment for structural and functional nerve regeneration.A range of autophagyinducing drugs and interventions have demonstrated beneficial effects in alleviating peripheral neuropathy and promoting nerve regeneration in preclinical models of traumatic peripheral nerve injuries.This review delves into the regulation of autophagy in cell types involved in peripheral nerve regeneration,summarizing the potential drugs and interventions that can be harnessed to promote this process.We hope that our review will offer novel insights and perspectives on the exploitation of autophagy pathways in the treatment of peripheral nerve injuries and neuropathies.
