The rapid expansion of urbanization has led to widespread exposure of wild birds to intensive light at night(LAN).While previous studies have established LAN-induced cognitive impairment in birds,the underlying neurob...The rapid expansion of urbanization has led to widespread exposure of wild birds to intensive light at night(LAN).While previous studies have established LAN-induced cognitive impairment in birds,the underlying neurobiological mechanisms remain poorly understood.We hypothesized that LAN exposure impaired cognitive function of birds potentially through neurodegeneration,metabolic dysregulation and neuroinflammatory responses in the telencephalon.Using Zebra Finches(Taeniopygia guttata)as an avian model,under 16L:8D photoperiods,we compared associative learning and memory abilities and neurobiological parameters between experimental groups exposed to dim light at night(LAN)versus nocturnal darkness(CTR).Compared to the CTR birds,the LAN-exposed birds exhibited significantly lower learning and memory performances,reduced neuron density and simplified dendritic morphology in the telencephalons.The key energy metabolic substrates(cholic acid,CTP,D-mannose-6-phosphate)and neuroprotective agents(trehalose,menaquinone,L-gulono-1,4-lactone)in the telencephalons of LAN-exposed birds showed depletion,while oxidative stress markers(methionine sulfoxide)and inflammatory mediators(cis-gondoic acid)exhibited elevation.The neurotransmitter dopamine and histamine metabolic pathway were disrupted in the LAN-exposed birds.The microglias were activated with pro-inflammatory IL-1βand IL-6 levels increasing and anti-inflammatory IL-10 decreasing in the telencephalons of the LAN-exposed birds.These findings indicate a potential mechanistic pathway whereby dim light exposure at night can induce neuroinflammation through oxidative stress-mediated microglial activation,energy metabolism and neurotransmitter homeostasis disruption,ultimately leading to neurodegeneration in the telencephalons of birds.展开更多
BACKGROUND Synthetic messenger RNA(mRNA)vaccines have raised concerns regarding prolonged spike protein expression,immune activation,and potential off-target effects.AIM To investigate transcriptomic alterations in in...BACKGROUND Synthetic messenger RNA(mRNA)vaccines have raised concerns regarding prolonged spike protein expression,immune activation,and potential off-target effects.AIM To investigate transcriptomic alterations in individuals with new-onset adverse events or cancer following mRNA coronavirus disease 2019 vaccination.METHODS Bulk RNA sequencing was performed on peripheral blood from two patient groups:(1)Individuals with new-onset nonmalignant adverse events;and(2)Individuals newly diagnosed with cancer post-vaccination.A control group of normal individuals was used for comparison.Differential gene expression was analyzed using DESeq2,and Gene Set Enrichment Analysis was conducted using the MSigDB database and custom gene sets.RESULTS Both vaccine patient groups displayed widespread transcriptional dysregulation.In the nonmalignant adverse event group,hallmark enrichments included mitochondrial dysfunction,proteasome-mediated stress,transcriptomic instability,and systemic inflammation.The cancer group exhibited additional hallmarks of genomic instability and epigenetic reprogramming.Nonsense-mediated decay,ribosomal stress,and myelocytomatosis oncogene activation were prominent in both groups,while immune signaling via toll-like receptors and type I interferons was particularly elevated in cancer patients.The observed transcriptomic profiles indicate cellular stress responses,mitochondrial dysfunction,and immune dysregulation following exposure to mRNA vaccines,potentially in susceptible individuals.CONCLUSION Shared and distinct molecular signatures in both cohorts demonstrate underlying mechanisms contributing to postvaccine symptomatology and complications,including oncogenesis and or progression of malignant disease.These findings underscore the need for a deeper investigation into the long-term safety of mRNA vaccines and host response variability.展开更多
Diabetic osteoporosis(DOP)is a common complication in diabetes,driven by hyperglycemia-induced metabolic disturbances,chronic inflammation,and oxi-dative stress.This review describes the critical role of iron metaboli...Diabetic osteoporosis(DOP)is a common complication in diabetes,driven by hyperglycemia-induced metabolic disturbances,chronic inflammation,and oxi-dative stress.This review describes the critical role of iron metabolism dysregu-lation in DOP pathogenesis,focusing on ferroptosis,a novel iron-dependent cell death pathway characterized by lipid peroxidation and reactive oxygen species(ROS)overproduction.Diabetic conditions exacerbate iron overload,impairing osteoblast function and enhancing osteoclast activity,while triggering ferroptosis in bone cells.Ferroptosis not only accelerates osteoblast apoptosis but also amplifies osteoclast-mediated bone resorption,synergistically promoting bone loss.Furthermore,chronic inflammation and oxidative stress disrupt the balance between bone formation and resorption,with elevated pro-inflammatory cyto-kines(e.g.,tumor necrosis factor-α,interleukin-6)and ROS exacerbating cellular dysfunction.Therapeutic strategies targeting iron metabolism(e.g.,deferoxamine)and ferroptosis inhibition(e.g.,nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway activation,antioxidants like melatonin)demonstrate potential to mitigate DOP progression.Future research should prioritize personalized interventions,clinical trials of iron chelators and antioxidants,and mechanistic studies to refine therapeutic approaches.This review provides a comprehensive framework for understanding DOP pathogenesis and highlights innovative strategies to improve bone health in diabetic patients.展开更多
To the editor:Non-suicidal self-injury(NSSI)is an array of directly prepense or repetitive self-harm behaviours without suicidal intent.Individuals engage in self-injurious behaviours to reduce negative mental and cog...To the editor:Non-suicidal self-injury(NSSI)is an array of directly prepense or repetitive self-harm behaviours without suicidal intent.Individuals engage in self-injurious behaviours to reduce negative mental and cognitive states or evoke positive emotions.展开更多
Polytrauma with significant bone and volumetric muscle loss presents substantial clinical challenges.Although immune responses significantly influence fracture healing post-polytrauma,the cellular and molecular underp...Polytrauma with significant bone and volumetric muscle loss presents substantial clinical challenges.Although immune responses significantly influence fracture healing post-polytrauma,the cellular and molecular underpinnings of polytrauma-induced immune dysregulation require further investigation.While previous studies examined either injury site tissue or systemic tissue(peripheral blood),our study uniquely investigated both systemic and local immune cells at the same time to better understand polytrauma-induced immune dysregulation and associated impaired bone healing.Using single-cell RNA sequencing(scRNA-seq)in a rat polytrauma model,we analyzed blood,bone marrow,and the local defect soft tissue to identify potential cellular and molecular targets involved in immune dysregulation.We identified a trauma-associated immunosuppressive myeloid(TIM)cell population that drives systemic immune dysregulation,immunosuppression,and potentially impaired bone healing.We found CD1d as a global marker for TIM cells in polytrauma.展开更多
During the development and progression of severe acute pancreatitis(SAP) ,conspicuous immune dysregulation develops,which is mainly manifested as excessive immune response in the early stage and immunosuppression in t...During the development and progression of severe acute pancreatitis(SAP) ,conspicuous immune dysregulation develops,which is mainly manifested as excessive immune response in the early stage and immunosuppression in the late stage. This process involves complex changes in a variety of immune molecules and cells,such as cytokines,complements,lymphocytes,and leukocytes. With the gradual deepening of studies on the development and progression of SAP,the role of immune dysregulation in the pathogenesis of SAP has attracted more and more attention. In this article,we review the advances in research on the immune dysregulation in SAP and the immunotherapy of this disease through exploring the formation of excessive immune response and immune suppression as well as their mutual transformation.展开更多
Epstein-Barr virus(EBV)-associated gastric carcinoma(EBVaGC)comprises nearly 10%of gastric carcinoma cases worldwide.Recently,it was recognised to have unique clinicopathologic characteristics,including male predomina...Epstein-Barr virus(EBV)-associated gastric carcinoma(EBVaGC)comprises nearly 10%of gastric carcinoma cases worldwide.Recently,it was recognised to have unique clinicopathologic characteristics,including male predominance,lower rates of lymph node involvement,and better prognosis.EBVaGC is further characterised by abnormal hypermethylation of tumour suppressor gene promoter regions,causing down-regulation of their expression.In the present review,we critically discuss the role of EBV in gastric carcinogenesis,summarising the role of viral proteins and microRNAs with respect to aberrant methylation in EBVaGC.Given the role of epigenetic dysregulation in tumourigenesis,epigenetic modifiers may represent a novel therapeutic strategy.展开更多
Parkinson’s disease(PD)is the second most common neurodegenerative disease,which manifests with both motor and non-motor symptoms.Circadian rhythm dysregulation,as one of the most challenging non-motor features of PD...Parkinson’s disease(PD)is the second most common neurodegenerative disease,which manifests with both motor and non-motor symptoms.Circadian rhythm dysregulation,as one of the most challenging non-motor features of PD,usually appears long before obvious motor symptoms.Moreover,the dysregulated circadian rhythm has recently been reported to play pivotal roles in PD pathogenesis,and it has emerged as a hot topic in PD research.In this review,we briefly introduce the circadian rhythm and circadian rhythm-related genes,and then summarize recent research progress on the altered circadian rhythm in PD,ranging from clinical features to the possible causes of PD-related circadian disorders.We believe that future comprehensive studies on the topic may not only help us to explore the mechanisms of PD,but also shed light on the better management of PD.展开更多
The present study was designed to evaluate the hepatoprotective and antioxidant potentials of silibinin(SBN)against N-nitrosodimethylamine(DMN)-induced toxic insults in the rat liver.The liver damage was induced in Wi...The present study was designed to evaluate the hepatoprotective and antioxidant potentials of silibinin(SBN)against N-nitrosodimethylamine(DMN)-induced toxic insults in the rat liver.The liver damage was induced in Wistar albino rats by repeated administration of DMN(10 mg·kg-1 b.w.,i.p.)on 3 consecutive days per week for 3 weeks.SBN(100 mg·kg-1 b.w.,p.o.)was given daily to the DMN treated rats for two weeks.The marker enzymes of liver toxicity and second-line enzymic and non-enzymic antioxidants were evaluated in serum and liver tissues before and after SBN treatment.Histopathology of the liver was evaluated by H & E staining.The DMN treatment produced a progressive increase in all the serum marker enzymes(AST,ALT,ALP,LDH,and γ-GT),peaking on Day 21.This treatment produced highly significant decreases in all the second-line antioxidant parameters(GSH,GST,GR,GPx,and vitamins C and E).The SBN treatment significantly reversed the DMN-induced damages,towards normalcy.Histopathological studies confirmed the development of liver toxicity in DMN-treated rats,which was reversed by SBN treatment in corroboration with the aforementioned biochemical results,indicating the hepatoprotective and antioxidant properties of SBN.In conclusion,the DMN-induced degenerative changes in the liver were alleviated by SBN treatment and this protective ability may be attributed to its antioxidant,free radical scavenging,and membrane stabilizing properties.展开更多
This case report describes a woman aged approximately 50 years who has suffered from balance dysregulation and dizziness for more than 10 years. Although the subject underwent several examinations to confirm the etiol...This case report describes a woman aged approximately 50 years who has suffered from balance dysregulation and dizziness for more than 10 years. Although the subject underwent several examinations to confirm the etiology of her symptoms, the root cause remained unknown. The symptoms were thought to be caused by electromagnetic wave hypersensitivity because the subject experienced uneasiness and dizziness when a cell phone was held close to her body. A cell phone was used to diagnose the collection of harmful electromagnetic waves, and an amalgam filling was determined to be the cause. The amalgam filling was removed under strict protection, and the subject’s symptoms completely disappeared soon after the filling was removed.展开更多
Gastric cancer(GC) is one of the most common cancers in the world and a significant threat to the health of patients, especially those from China and Japan. The prognosis for patients with late stage GC receiving the ...Gastric cancer(GC) is one of the most common cancers in the world and a significant threat to the health of patients, especially those from China and Japan. The prognosis for patients with late stage GC receiving the standard of care treatment, including surgery, chemotherapy and radiotherapy, remains poor. Developing novel treatment strategies, identifying new molecules for targeted therapy, and devising screening techniques to detect this cancer in its early stages are needed for GC patients. The discovery of non-coding RNAs(nc RNAs), primarily micro RNAs(mi RNAs) and long non-coding RNAs(lnc RNAs), helped to elucidate the mechanisms of tumorigenesis, diagnosis and treatment of GC. Recently, significant research has been conducted on non-coding RNAs and how the regulatory dysfunction of these RNAs impacts the tumorigenesis of GC. In this study, we review papers published in the last five years concerning the dysregulation of noncoding RNAs, especially mi RNAs and lnc RNAs, in GC. We summarize instances of aberrant expression of the ncR NAs in GC and their effect on survival-related events, including cell cycle regulation, AKT signaling, apoptosis and drug resistance. Additionally, we evaluate how nc RNA dysregulation affects the metastatic process, including the epithelial-mesenchymal transition, stem cells, transcription factor activity, and oncogene and tumor suppressor expression. Lastly, we determine how ncR NAs affect angiogenesis in the microenvironment of GC. We further discuss the use of ncR NAs as potential biomarkers for use in clinical screening, early diagnosis and prognosis of GC. At present, no ideal ncR NAs have been identified as targets for the treatment of GC.展开更多
Ca^2＋ dysregulation is an early event observed in Alzheimer＇s disease（AD） patients preceding the presence of its clinical symptoms.Dysregulation of neuronalCa^2＋ will cause synaptic loss and neuronal death,eventu...Ca^2＋ dysregulation is an early event observed in Alzheimer＇s disease（AD） patients preceding the presence of its clinical symptoms.Dysregulation of neuronalCa^2＋ will cause synaptic loss and neuronal death,eventually leading to memory impairments and cognitive decline.Treatments targetingCa^2＋ signaling pathways are potential therapeutic strategies against AD.The complicated interactions make it challenging and expensive to study the underlying mechanisms as to how Ca^2＋ signaling contributes to the pathogenesis of AD.Computational modeling offers new opportunities to study the signaling pathway and test proposed mechanisms.In this mini-review,we present some computational approaches that have been used to study Ca^2＋ dysregulation of AD by simulating Ca^2＋signaling at various levels.We also pointed out the future directions that computational modeling can be done in studying the Ca^2＋ dysregulation in AD.展开更多
BACKGROUND Immune dysregulation,polyendocrinopthy,enteropathy,X-linked(IPEX)syndrome is a rare X-linked recessive disease caused by mutations in the forkhead box protein 3(FOXP3)gene,which is a master transcriptional ...BACKGROUND Immune dysregulation,polyendocrinopthy,enteropathy,X-linked(IPEX)syndrome is a rare X-linked recessive disease caused by mutations in the forkhead box protein 3(FOXP3)gene,which is a master transcriptional regulator for the development and function of CD4+CD25+regulatory T(Treg)cells.The dysfunction of these cells leads to multiple system autoimmune diseases.We present a case of IPEX due to a mutation not reported in the literature before.CASE SUMMARY We report a male patient with IPEX syndrome who presented with refractory diarrhea and malabsorption leading to failure to thrive,as well as with hypothyroidism and nephrotic syndrome.Laboratory investigation showed increased total IgE and Treg cells,decreased free triiodothyronine(FT3)and free thyroxine(FT4),and proteinuria.Multiple dietary and supportive treatments were introduced but did not improve the diarrhea during his hospital stay.Ultimately,whole exome sequencing revealed that the patient was hemizygous for the exon 5,c.542G>A(p.Ser181Asn)mutation of the FOXP3 gene,which has not been previously reported.The patient remains on prednisone and euthyrox while awaiting hematopoietic stem cell transplantation at the time of the compilation of this case report.CONCLUSION We report a novel FOXP3 gene mutation involved in IPEX.A high level of suspicion should be maintained in an early-onset refractory diarrhea patient.展开更多
Cell phone and personal computer users have increased considerably in recent years, particularly in more developed countries. These devices have facilitated communication on a global scale. However, there have been a ...Cell phone and personal computer users have increased considerably in recent years, particularly in more developed countries. These devices have facilitated communication on a global scale. However, there have been a number of reports of abnormalities occurring in the body due to the electromagnetic waves emitted by such electronic devices. The long lists of both general and severe symptoms, including headaches, fatigue, tinnitus, dizziness, memory loss, irregular heartbeat, and whole-body skin symptoms, have been reported that are apparently associated with the condition of electromagnetic hypersensitivity. In dentistry, titanium dental implants may be commonly associated with antenna-like activity, but the underlying mechanism remains unknown. In the current case studies, balance difficulties were found to occur when the patients had titanium dental implants. These implants seemed to be acting as antennae and collecting harmful electromagnetic waves. Further studies are required to confirm this hypothesis.展开更多
BACKGROUND High risk of alcohol and drug use disorders in people with attentiondeficit/hyperactivity disorder(ADHD)calls for exploratory research of relationships with clinical features of ADHD.AIM To estimate prevale...BACKGROUND High risk of alcohol and drug use disorders in people with attentiondeficit/hyperactivity disorder(ADHD)calls for exploratory research of relationships with clinical features of ADHD.AIM To estimate prevalence of alcohol/drug use disorders and associations with ADHD symptom severity and emotional dysregulation,in adults with ADHD.METHODS This observational cross-sectional clinical study consisted of patients admitted to a private psychiatric outpatient clinic in Oslo,Norway(2014-2018).Five-hundred and fifty-eight eligible patients diagnosed with ADHD(Diagnostic and Statistical Manual of Mental Disorders,Fifth Edition(DSM-5)criteria)agreed to participate.Alcohol and drug use disorders were diagnosed using the Mini International Neuropsychiatric Interview(MINI).Dependence and abuse were merged into“use”disorder as in MINI version 7.0/DSM-5.Questions were related both to lifetime and the past 12-mo.ADHD severity was assessed by the Adult ADHD Self Report Scale(ASRS).Subdivisions of the ASRS questionnaire as inattentive items and hyperactive/impulsivity items were recorded separately.Emotional dysregulation was assessed by the eight-item version of Barkley’s Current Behavior Scale-Self Report.RESULTS The 12-mo prevalence was 5.3%for alcohol use disorder and 13.7%for drug use disorder.The lifetime prevalence was 12.0%for alcohol use disorder and 27.7%for drug use disorder.Men had higher rates of both alcohol use disorder and drug use disorder compared to women.The prevalence of drug use disorder was more than twice that of alcohol use disorder for both sexes.The drugs most participants reported having used were(in descending order):Amphetamine(19.1%),cannabis(17.1%),cocaine or ecstasy(7.4%),benzodiazepines(7.4%),and heroin or other opioids(2.9%).Lifetime drug use disorder was significantly associated with both hyperactivity-impulsivity symptoms and emotional dysregulation symptom severity.Lifetime alcohol use disorder,on the other hand,was not significantly associated with ADHD symptoms or emotional dysregulation when adjusted for gender and age.CONCLUSION Patients with ADHD have a high lifetime prevalence of drug use disorder,which is associated with higher levels of hyperactivity-impulsivity symptoms and emotional dysregulation.展开更多
Background: Central or hypothalamic hypogonadism as an initial manifestation of Shapiro Syndrome has not been described in the literature. Herein, we report first case in which initial presentation of central hypogona...Background: Central or hypothalamic hypogonadism as an initial manifestation of Shapiro Syndrome has not been described in the literature. Herein, we report first case in which initial presentation of central hypogonadism led to a confirmed diagnosis of Shapiro Syndrome during a casual evaluation of hypothalamic pituitary anatomy with MRI of brain. Case presentation: 53 year old Caucasian man was documented to manifest Central or hypogonadotropic hypogonadism following evaluation of excessive sweating episodes, lack of libido and erectile dysfunction for a duration of several years. Brain MRI performed for assessment of the etiology documented no pituitary abnormality. Instead agenesis of Corpus Callosum was noted. The subject had been hospitalized on many occasions at this and several other medical centers with hypothermia or hyperthermia without a documentation of a definite cause. Therefore, the diagnosis of Shapiro Syndrome was made. Conclusion: This report is the first documentation of subject manifesting central, more likely to be hypothalamic rather than hypogonadotropic hypogonadism in conjunction with Shapiro Syndrome.展开更多
AIM To explore novel therapeutic target of cisplatin resistance in human gastric cancer.METHODS The sensitivity of SGC7901 cells and cisplatin-resistant SGC7901 cells(SGC7901/DDP) for cisplatin were detected by 3-(4,5...AIM To explore novel therapeutic target of cisplatin resistance in human gastric cancer.METHODS The sensitivity of SGC7901 cells and cisplatin-resistant SGC7901 cells(SGC7901/DDP) for cisplatin were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay. High-quality total RNA which isolated from SGC7901/DDP cells and SGC7901 cells were used for mR NA microarray analysis. Results were analyzed bioinformatically to predict their roles in the development of cisplatin resistance and the expression of 13 dysregulated mR NAs we selected were validated by quantitative real-time polymerase chain reaction(qR T-PCR). RESULTS SGC7901/DDP cells highly resistant to cisplatin demonstrated by MTT assay. A total of 1308 m RNAs(578 upregulated and 730 downregulated) were differentially expressed(fold change ≥ 2 and P-value < 0.05) in the SGC7901/DDP cells compared with SGC7901 cells. The expression of mR NAs detected by q RT-PCR were consistent with the microarray results. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway and protein-protein interaction analysis demonstrated that the differentially expressed mR NAs were enriched in PI3K-Akt, Notch, MAPK, ErbB, Jak-STAT, NF-kappa B signaling pathways which may be involved in cisplatin resistance. Several genes such as PDE3 B, VEGFC, IGFBP3, TLR4, HIPK2 and EGF may associated with drug resistance of gastric cancer cells to cisplatin.CONCLUSION Exploration of those altered mR NAs may provide more promising strategy in diagnosis and therapy for gastric cancer with cisplatin resistance.展开更多
Lung cancer is the leading cause of cancer-related mortality globally,including small-cell lung cancer and non-small-cell lung cancer.As the most prevalent histological subtype of non-small-cell lung cancer,lung adeno...Lung cancer is the leading cause of cancer-related mortality globally,including small-cell lung cancer and non-small-cell lung cancer.As the most prevalent histological subtype of non-small-cell lung cancer,lung adenocarcinoma(LUAD)accounts for approximately 40%of all lung cancer cases.1 Due to the heterogeneity of LUAD,accurate categorization is required to create a treatment plan for LUAD patients,while the existing paradigm does not adequately capture the enormously heterogeneous characteristics of LUAD.The rise of epigenetics has brought new perspectives for tumor heterogeneity exploration.Epigenetic modifications,such as aberrant DNA methylation and microRNA(miRNA),are essential in controlling gene expression,heterogeneity,and clinical implication.2 Meanwhile,epigenetic disruptions contribute to lung cancer tumorigenesis,the generation of a malignant phenotype and aggression,and chemoresistance,which could serve as credible biomarkers for lung cancer molecular categorization,early diagnosis,prognosis classification,and treatment efficacy prediction.3 Through integrative clustering of the gene expression profiles regulated by epigenetics,we determined and validated four lung adenocarcinoma epigenetic subtypes(LAESs)with distinct prognoses and biological peculiarities from four independent multi-center lung adenocarcinoma cohorts.展开更多
基金supported by grants from Key laboratory of Ecology and Environment in Minority Area,National Ethnic Affairs Commission(KLEEMA202207)。
文摘The rapid expansion of urbanization has led to widespread exposure of wild birds to intensive light at night(LAN).While previous studies have established LAN-induced cognitive impairment in birds,the underlying neurobiological mechanisms remain poorly understood.We hypothesized that LAN exposure impaired cognitive function of birds potentially through neurodegeneration,metabolic dysregulation and neuroinflammatory responses in the telencephalon.Using Zebra Finches(Taeniopygia guttata)as an avian model,under 16L:8D photoperiods,we compared associative learning and memory abilities and neurobiological parameters between experimental groups exposed to dim light at night(LAN)versus nocturnal darkness(CTR).Compared to the CTR birds,the LAN-exposed birds exhibited significantly lower learning and memory performances,reduced neuron density and simplified dendritic morphology in the telencephalons.The key energy metabolic substrates(cholic acid,CTP,D-mannose-6-phosphate)and neuroprotective agents(trehalose,menaquinone,L-gulono-1,4-lactone)in the telencephalons of LAN-exposed birds showed depletion,while oxidative stress markers(methionine sulfoxide)and inflammatory mediators(cis-gondoic acid)exhibited elevation.The neurotransmitter dopamine and histamine metabolic pathway were disrupted in the LAN-exposed birds.The microglias were activated with pro-inflammatory IL-1βand IL-6 levels increasing and anti-inflammatory IL-10 decreasing in the telencephalons of the LAN-exposed birds.These findings indicate a potential mechanistic pathway whereby dim light exposure at night can induce neuroinflammation through oxidative stress-mediated microglial activation,energy metabolism and neurotransmitter homeostasis disruption,ultimately leading to neurodegeneration in the telencephalons of birds.
文摘BACKGROUND Synthetic messenger RNA(mRNA)vaccines have raised concerns regarding prolonged spike protein expression,immune activation,and potential off-target effects.AIM To investigate transcriptomic alterations in individuals with new-onset adverse events or cancer following mRNA coronavirus disease 2019 vaccination.METHODS Bulk RNA sequencing was performed on peripheral blood from two patient groups:(1)Individuals with new-onset nonmalignant adverse events;and(2)Individuals newly diagnosed with cancer post-vaccination.A control group of normal individuals was used for comparison.Differential gene expression was analyzed using DESeq2,and Gene Set Enrichment Analysis was conducted using the MSigDB database and custom gene sets.RESULTS Both vaccine patient groups displayed widespread transcriptional dysregulation.In the nonmalignant adverse event group,hallmark enrichments included mitochondrial dysfunction,proteasome-mediated stress,transcriptomic instability,and systemic inflammation.The cancer group exhibited additional hallmarks of genomic instability and epigenetic reprogramming.Nonsense-mediated decay,ribosomal stress,and myelocytomatosis oncogene activation were prominent in both groups,while immune signaling via toll-like receptors and type I interferons was particularly elevated in cancer patients.The observed transcriptomic profiles indicate cellular stress responses,mitochondrial dysfunction,and immune dysregulation following exposure to mRNA vaccines,potentially in susceptible individuals.CONCLUSION Shared and distinct molecular signatures in both cohorts demonstrate underlying mechanisms contributing to postvaccine symptomatology and complications,including oncogenesis and or progression of malignant disease.These findings underscore the need for a deeper investigation into the long-term safety of mRNA vaccines and host response variability.
基金Supported by Henan Province Key Research and Development Program,No.231111311000Henan Provincial Science and Technology Research Project,No.232102310411+2 种基金Henan Province Medical Science and Technology Key Project,No.LHGJ20220566 and No.LHGJ20240365Henan Province Medical Education Research Project,No.WJLX2023079Zhengzhou Medical and Health Technology Innovation Guidance Program,No.2024YLZDJH022.
文摘Diabetic osteoporosis(DOP)is a common complication in diabetes,driven by hyperglycemia-induced metabolic disturbances,chronic inflammation,and oxi-dative stress.This review describes the critical role of iron metabolism dysregu-lation in DOP pathogenesis,focusing on ferroptosis,a novel iron-dependent cell death pathway characterized by lipid peroxidation and reactive oxygen species(ROS)overproduction.Diabetic conditions exacerbate iron overload,impairing osteoblast function and enhancing osteoclast activity,while triggering ferroptosis in bone cells.Ferroptosis not only accelerates osteoblast apoptosis but also amplifies osteoclast-mediated bone resorption,synergistically promoting bone loss.Furthermore,chronic inflammation and oxidative stress disrupt the balance between bone formation and resorption,with elevated pro-inflammatory cyto-kines(e.g.,tumor necrosis factor-α,interleukin-6)and ROS exacerbating cellular dysfunction.Therapeutic strategies targeting iron metabolism(e.g.,deferoxamine)and ferroptosis inhibition(e.g.,nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway activation,antioxidants like melatonin)demonstrate potential to mitigate DOP progression.Future research should prioritize personalized interventions,clinical trials of iron chelators and antioxidants,and mechanistic studies to refine therapeutic approaches.This review provides a comprehensive framework for understanding DOP pathogenesis and highlights innovative strategies to improve bone health in diabetic patients.
基金supported by the National Natural Science Foundation of China(No.82300114)the Natural Science Foundation of Hubei Province General Program(No.2023AFB684)the Natural Science Foundation of Hubei Province Youth Program(No.2022CFB671).
文摘Objective Sepsis-induced acute lung injury(ALI)poses a critical challenge in critical care,yet its immunoregulatory mechanisms remain poorly defined.This study aimed to delineate immune dysregulation networks and identify therapeutic targets through multiomics data integration.Methods Transcriptomic datasets(GSE40180 and GSE165226)were analyzed through a multiphase bioinformatics workflow,including gene set enrichment analysis(GSEA),immune cell deconvolution(CIBERSORT),differential gene expression profiling(|log2FC|>1.5,P.adj<0.05),and pathway annotation(GO/KEGG).Protein–protein interaction(PPI)networks were constructed to identify hub genes.Experimental validation was done using a murine cecal ligation and puncture(CLP)model with histopathological lung injury scoring and RT-qPCR-based hub gene verification.Results Integrated analysis revealed 26 consensus biological processes(24 upregulated,2 downregulated)dominated by innate immune activation.CIBERSORT revealed significant infiltration of M1 macrophages,neutrophils,activated dendritic cells(DCs),and activated natural killer(NK)cells in septic lungs,which was concurrent with Th17/naive CD8+T-cell dysregulation.Among the 58 differentially expressed genes(DEG),7 hub genes(Cxcl1,Cxcl2,Ccl3,Cd14,Saa3,Timp1,and Socs3)were significantly correlated with immune cell dynamics.CLP modeling confirmed severe alveolar damage(lung injury score:8.11±1.17 vs.1.97±0.29;P<0.0001)and upregulated hub gene expression(all P<0.01)in septic lungs,with hub gene expression levels strongly correlated with the lung injury score(Pearson’s r>0.85,P<0.001).Conclusion Innate adaptive immune crosstalk,particularly dysregulated immune cell infiltration,drives sepsis-induced ALI pathogenesis.The 7 hub genes mechanistically connect immune dyshomeostasis to tissue injury,suggesting novel targets for precision immunomodulation and biomarker development in critical care.
基金the Innovation 2030-Major Project of Brain Science and Brain-lnspired Intelligence Technology(2021ZD0200600)Shanghai Science and Technology Committee(22YF1439100,YDZX20213100001003)National Natural Science Foundation of China(82201678).
文摘To the editor:Non-suicidal self-injury(NSSI)is an array of directly prepense or repetitive self-harm behaviours without suicidal intent.Individuals engage in self-injurious behaviours to reduce negative mental and cognitive states or evoke positive emotions.
文摘Polytrauma with significant bone and volumetric muscle loss presents substantial clinical challenges.Although immune responses significantly influence fracture healing post-polytrauma,the cellular and molecular underpinnings of polytrauma-induced immune dysregulation require further investigation.While previous studies examined either injury site tissue or systemic tissue(peripheral blood),our study uniquely investigated both systemic and local immune cells at the same time to better understand polytrauma-induced immune dysregulation and associated impaired bone healing.Using single-cell RNA sequencing(scRNA-seq)in a rat polytrauma model,we analyzed blood,bone marrow,and the local defect soft tissue to identify potential cellular and molecular targets involved in immune dysregulation.We identified a trauma-associated immunosuppressive myeloid(TIM)cell population that drives systemic immune dysregulation,immunosuppression,and potentially impaired bone healing.We found CD1d as a global marker for TIM cells in polytrauma.
基金supported by the Technological Foundation Project of Traditional Chinese Medicine Science of Zhejiang Province (Nos. 2003C130 and 2004C142)the Foundation Project for Medical Science and Technology of the Health Bureau of Zhejiang Province (No. 2003B134), China
文摘During the development and progression of severe acute pancreatitis(SAP) ,conspicuous immune dysregulation develops,which is mainly manifested as excessive immune response in the early stage and immunosuppression in the late stage. This process involves complex changes in a variety of immune molecules and cells,such as cytokines,complements,lymphocytes,and leukocytes. With the gradual deepening of studies on the development and progression of SAP,the role of immune dysregulation in the pathogenesis of SAP has attracted more and more attention. In this article,we review the advances in research on the immune dysregulation in SAP and the immunotherapy of this disease through exploring the formation of excessive immune response and immune suppression as well as their mutual transformation.
基金Supported by Research Grants of National Basic Research Program of China (973 Program, 2010CB529305)Innovation and Technology Support Programme, Hong Kong (ITS/214/12)
文摘Epstein-Barr virus(EBV)-associated gastric carcinoma(EBVaGC)comprises nearly 10%of gastric carcinoma cases worldwide.Recently,it was recognised to have unique clinicopathologic characteristics,including male predominance,lower rates of lymph node involvement,and better prognosis.EBVaGC is further characterised by abnormal hypermethylation of tumour suppressor gene promoter regions,causing down-regulation of their expression.In the present review,we critically discuss the role of EBV in gastric carcinogenesis,summarising the role of viral proteins and microRNAs with respect to aberrant methylation in EBVaGC.Given the role of epigenetic dysregulation in tumourigenesis,epigenetic modifiers may represent a novel therapeutic strategy.
基金the National Nature Science Foundation of China(81771521)Key Research and Development Plan of Liaoning Science and Technology Department(2018225051)+1 种基金Guangdong Provincial Key R&D Program(2018B030337001)the National Key Research and Development Program of China(2016YFC1306600).
文摘Parkinson’s disease(PD)is the second most common neurodegenerative disease,which manifests with both motor and non-motor symptoms.Circadian rhythm dysregulation,as one of the most challenging non-motor features of PD,usually appears long before obvious motor symptoms.Moreover,the dysregulated circadian rhythm has recently been reported to play pivotal roles in PD pathogenesis,and it has emerged as a hot topic in PD research.In this review,we briefly introduce the circadian rhythm and circadian rhythm-related genes,and then summarize recent research progress on the altered circadian rhythm in PD,ranging from clinical features to the possible causes of PD-related circadian disorders.We believe that future comprehensive studies on the topic may not only help us to explore the mechanisms of PD,but also shed light on the better management of PD.
基金supported by the DST-INSPIRE(Department of Science and Technology,Government of India Innovation in Science Pursuit for Inspired Research)fellowship(Award No:DST/INSPIRE Fellowship/2010/dated 16.03.2010)
文摘The present study was designed to evaluate the hepatoprotective and antioxidant potentials of silibinin(SBN)against N-nitrosodimethylamine(DMN)-induced toxic insults in the rat liver.The liver damage was induced in Wistar albino rats by repeated administration of DMN(10 mg·kg-1 b.w.,i.p.)on 3 consecutive days per week for 3 weeks.SBN(100 mg·kg-1 b.w.,p.o.)was given daily to the DMN treated rats for two weeks.The marker enzymes of liver toxicity and second-line enzymic and non-enzymic antioxidants were evaluated in serum and liver tissues before and after SBN treatment.Histopathology of the liver was evaluated by H & E staining.The DMN treatment produced a progressive increase in all the serum marker enzymes(AST,ALT,ALP,LDH,and γ-GT),peaking on Day 21.This treatment produced highly significant decreases in all the second-line antioxidant parameters(GSH,GST,GR,GPx,and vitamins C and E).The SBN treatment significantly reversed the DMN-induced damages,towards normalcy.Histopathological studies confirmed the development of liver toxicity in DMN-treated rats,which was reversed by SBN treatment in corroboration with the aforementioned biochemical results,indicating the hepatoprotective and antioxidant properties of SBN.In conclusion,the DMN-induced degenerative changes in the liver were alleviated by SBN treatment and this protective ability may be attributed to its antioxidant,free radical scavenging,and membrane stabilizing properties.
文摘This case report describes a woman aged approximately 50 years who has suffered from balance dysregulation and dizziness for more than 10 years. Although the subject underwent several examinations to confirm the etiology of her symptoms, the root cause remained unknown. The symptoms were thought to be caused by electromagnetic wave hypersensitivity because the subject experienced uneasiness and dizziness when a cell phone was held close to her body. A cell phone was used to diagnose the collection of harmful electromagnetic waves, and an amalgam filling was determined to be the cause. The amalgam filling was removed under strict protection, and the subject’s symptoms completely disappeared soon after the filling was removed.
基金National Natural Science Foundation of China,No.31571443(to QY)Jilin Provincial Science and Technology Department,No.20140414031GH and No.20150101121JC(to QY)+1 种基金Health and Family Planning Commission of Jilin Province,No.2014Z068(to QY)Graduate Innovation Fund of Jilin University,No.2014031(to RWZ)
文摘Gastric cancer(GC) is one of the most common cancers in the world and a significant threat to the health of patients, especially those from China and Japan. The prognosis for patients with late stage GC receiving the standard of care treatment, including surgery, chemotherapy and radiotherapy, remains poor. Developing novel treatment strategies, identifying new molecules for targeted therapy, and devising screening techniques to detect this cancer in its early stages are needed for GC patients. The discovery of non-coding RNAs(nc RNAs), primarily micro RNAs(mi RNAs) and long non-coding RNAs(lnc RNAs), helped to elucidate the mechanisms of tumorigenesis, diagnosis and treatment of GC. Recently, significant research has been conducted on non-coding RNAs and how the regulatory dysfunction of these RNAs impacts the tumorigenesis of GC. In this study, we review papers published in the last five years concerning the dysregulation of noncoding RNAs, especially mi RNAs and lnc RNAs, in GC. We summarize instances of aberrant expression of the ncR NAs in GC and their effect on survival-related events, including cell cycle regulation, AKT signaling, apoptosis and drug resistance. Additionally, we evaluate how nc RNA dysregulation affects the metastatic process, including the epithelial-mesenchymal transition, stem cells, transcription factor activity, and oncogene and tumor suppressor expression. Lastly, we determine how ncR NAs affect angiogenesis in the microenvironment of GC. We further discuss the use of ncR NAs as potential biomarkers for use in clinical screening, early diagnosis and prognosis of GC. At present, no ideal ncR NAs have been identified as targets for the treatment of GC.
文摘Ca^2＋ dysregulation is an early event observed in Alzheimer＇s disease（AD） patients preceding the presence of its clinical symptoms.Dysregulation of neuronalCa^2＋ will cause synaptic loss and neuronal death,eventually leading to memory impairments and cognitive decline.Treatments targetingCa^2＋ signaling pathways are potential therapeutic strategies against AD.The complicated interactions make it challenging and expensive to study the underlying mechanisms as to how Ca^2＋ signaling contributes to the pathogenesis of AD.Computational modeling offers new opportunities to study the signaling pathway and test proposed mechanisms.In this mini-review,we present some computational approaches that have been used to study Ca^2＋ dysregulation of AD by simulating Ca^2＋signaling at various levels.We also pointed out the future directions that computational modeling can be done in studying the Ca^2＋ dysregulation in AD.
文摘BACKGROUND Immune dysregulation,polyendocrinopthy,enteropathy,X-linked(IPEX)syndrome is a rare X-linked recessive disease caused by mutations in the forkhead box protein 3(FOXP3)gene,which is a master transcriptional regulator for the development and function of CD4+CD25+regulatory T(Treg)cells.The dysfunction of these cells leads to multiple system autoimmune diseases.We present a case of IPEX due to a mutation not reported in the literature before.CASE SUMMARY We report a male patient with IPEX syndrome who presented with refractory diarrhea and malabsorption leading to failure to thrive,as well as with hypothyroidism and nephrotic syndrome.Laboratory investigation showed increased total IgE and Treg cells,decreased free triiodothyronine(FT3)and free thyroxine(FT4),and proteinuria.Multiple dietary and supportive treatments were introduced but did not improve the diarrhea during his hospital stay.Ultimately,whole exome sequencing revealed that the patient was hemizygous for the exon 5,c.542G>A(p.Ser181Asn)mutation of the FOXP3 gene,which has not been previously reported.The patient remains on prednisone and euthyrox while awaiting hematopoietic stem cell transplantation at the time of the compilation of this case report.CONCLUSION We report a novel FOXP3 gene mutation involved in IPEX.A high level of suspicion should be maintained in an early-onset refractory diarrhea patient.
文摘Cell phone and personal computer users have increased considerably in recent years, particularly in more developed countries. These devices have facilitated communication on a global scale. However, there have been a number of reports of abnormalities occurring in the body due to the electromagnetic waves emitted by such electronic devices. The long lists of both general and severe symptoms, including headaches, fatigue, tinnitus, dizziness, memory loss, irregular heartbeat, and whole-body skin symptoms, have been reported that are apparently associated with the condition of electromagnetic hypersensitivity. In dentistry, titanium dental implants may be commonly associated with antenna-like activity, but the underlying mechanism remains unknown. In the current case studies, balance difficulties were found to occur when the patients had titanium dental implants. These implants seemed to be acting as antennae and collecting harmful electromagnetic waves. Further studies are required to confirm this hypothesis.
文摘BACKGROUND High risk of alcohol and drug use disorders in people with attentiondeficit/hyperactivity disorder(ADHD)calls for exploratory research of relationships with clinical features of ADHD.AIM To estimate prevalence of alcohol/drug use disorders and associations with ADHD symptom severity and emotional dysregulation,in adults with ADHD.METHODS This observational cross-sectional clinical study consisted of patients admitted to a private psychiatric outpatient clinic in Oslo,Norway(2014-2018).Five-hundred and fifty-eight eligible patients diagnosed with ADHD(Diagnostic and Statistical Manual of Mental Disorders,Fifth Edition(DSM-5)criteria)agreed to participate.Alcohol and drug use disorders were diagnosed using the Mini International Neuropsychiatric Interview(MINI).Dependence and abuse were merged into“use”disorder as in MINI version 7.0/DSM-5.Questions were related both to lifetime and the past 12-mo.ADHD severity was assessed by the Adult ADHD Self Report Scale(ASRS).Subdivisions of the ASRS questionnaire as inattentive items and hyperactive/impulsivity items were recorded separately.Emotional dysregulation was assessed by the eight-item version of Barkley’s Current Behavior Scale-Self Report.RESULTS The 12-mo prevalence was 5.3%for alcohol use disorder and 13.7%for drug use disorder.The lifetime prevalence was 12.0%for alcohol use disorder and 27.7%for drug use disorder.Men had higher rates of both alcohol use disorder and drug use disorder compared to women.The prevalence of drug use disorder was more than twice that of alcohol use disorder for both sexes.The drugs most participants reported having used were(in descending order):Amphetamine(19.1%),cannabis(17.1%),cocaine or ecstasy(7.4%),benzodiazepines(7.4%),and heroin or other opioids(2.9%).Lifetime drug use disorder was significantly associated with both hyperactivity-impulsivity symptoms and emotional dysregulation symptom severity.Lifetime alcohol use disorder,on the other hand,was not significantly associated with ADHD symptoms or emotional dysregulation when adjusted for gender and age.CONCLUSION Patients with ADHD have a high lifetime prevalence of drug use disorder,which is associated with higher levels of hyperactivity-impulsivity symptoms and emotional dysregulation.
文摘Background: Central or hypothalamic hypogonadism as an initial manifestation of Shapiro Syndrome has not been described in the literature. Herein, we report first case in which initial presentation of central hypogonadism led to a confirmed diagnosis of Shapiro Syndrome during a casual evaluation of hypothalamic pituitary anatomy with MRI of brain. Case presentation: 53 year old Caucasian man was documented to manifest Central or hypogonadotropic hypogonadism following evaluation of excessive sweating episodes, lack of libido and erectile dysfunction for a duration of several years. Brain MRI performed for assessment of the etiology documented no pituitary abnormality. Instead agenesis of Corpus Callosum was noted. The subject had been hospitalized on many occasions at this and several other medical centers with hypothermia or hyperthermia without a documentation of a definite cause. Therefore, the diagnosis of Shapiro Syndrome was made. Conclusion: This report is the first documentation of subject manifesting central, more likely to be hypothalamic rather than hypogonadotropic hypogonadism in conjunction with Shapiro Syndrome.
基金Supported by Projects of Foreign Science and Technology Cooperation of Anhui Province of Anhui Province,No.1604b0602027New Century Excellent Talents in University,Ministry of Education of China,No.NCET-13-0644Wanjiang Scholars Program of Anhui Province of China
文摘AIM To explore novel therapeutic target of cisplatin resistance in human gastric cancer.METHODS The sensitivity of SGC7901 cells and cisplatin-resistant SGC7901 cells(SGC7901/DDP) for cisplatin were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay. High-quality total RNA which isolated from SGC7901/DDP cells and SGC7901 cells were used for mR NA microarray analysis. Results were analyzed bioinformatically to predict their roles in the development of cisplatin resistance and the expression of 13 dysregulated mR NAs we selected were validated by quantitative real-time polymerase chain reaction(qR T-PCR). RESULTS SGC7901/DDP cells highly resistant to cisplatin demonstrated by MTT assay. A total of 1308 m RNAs(578 upregulated and 730 downregulated) were differentially expressed(fold change ≥ 2 and P-value < 0.05) in the SGC7901/DDP cells compared with SGC7901 cells. The expression of mR NAs detected by q RT-PCR were consistent with the microarray results. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway and protein-protein interaction analysis demonstrated that the differentially expressed mR NAs were enriched in PI3K-Akt, Notch, MAPK, ErbB, Jak-STAT, NF-kappa B signaling pathways which may be involved in cisplatin resistance. Several genes such as PDE3 B, VEGFC, IGFBP3, TLR4, HIPK2 and EGF may associated with drug resistance of gastric cancer cells to cisplatin.CONCLUSION Exploration of those altered mR NAs may provide more promising strategy in diagnosis and therapy for gastric cancer with cisplatin resistance.
基金supported by Henan Provincial Key Laboratory of Medicine and Henan Provincial Clinical Medical Research Center for Respiratory Diseases.
文摘Lung cancer is the leading cause of cancer-related mortality globally,including small-cell lung cancer and non-small-cell lung cancer.As the most prevalent histological subtype of non-small-cell lung cancer,lung adenocarcinoma(LUAD)accounts for approximately 40%of all lung cancer cases.1 Due to the heterogeneity of LUAD,accurate categorization is required to create a treatment plan for LUAD patients,while the existing paradigm does not adequately capture the enormously heterogeneous characteristics of LUAD.The rise of epigenetics has brought new perspectives for tumor heterogeneity exploration.Epigenetic modifications,such as aberrant DNA methylation and microRNA(miRNA),are essential in controlling gene expression,heterogeneity,and clinical implication.2 Meanwhile,epigenetic disruptions contribute to lung cancer tumorigenesis,the generation of a malignant phenotype and aggression,and chemoresistance,which could serve as credible biomarkers for lung cancer molecular categorization,early diagnosis,prognosis classification,and treatment efficacy prediction.3 Through integrative clustering of the gene expression profiles regulated by epigenetics,we determined and validated four lung adenocarcinoma epigenetic subtypes(LAESs)with distinct prognoses and biological peculiarities from four independent multi-center lung adenocarcinoma cohorts.
