Tyrosine kinase inhibitors(TKIs)are used to treat patients with chronic myelogenous leukemia(CML),leading to a nearly normal life expectancy.Sprycel(dasatinib)-induced chylothorax has rarely been reported in patients ...Tyrosine kinase inhibitors(TKIs)are used to treat patients with chronic myelogenous leukemia(CML),leading to a nearly normal life expectancy.Sprycel(dasatinib)-induced chylothorax has rarely been reported in patients undergoing CML treatment.We report a 10-year case history of chronic chylothorax that persisted despite discontinuation of dasatinib in a patient with otherwise excellent results after switching to another TKI.Herein,we discuss a conservative treatment approach that uses symptom-based thoracentesis instead of surgical ligation of the thoracic duct.This approach may reduce patient morbidity and prevent the need for complex surgical procedures.TKIs have revolutionized CML treatment;however,these powerful medications are not without patient morbidity.展开更多
This study evaluated the impact of chronicity (onset of injury to admission in-terval) on three domains of functional outcomes for a large group of traumatic brain injured (TBI) survivors. Subjects included 528 TBI ad...This study evaluated the impact of chronicity (onset of injury to admission in-terval) on three domains of functional outcomes for a large group of traumatic brain injured (TBI) survivors. Subjects included 528 TBI adults who were treated in post-hospital residential rehabilitation centers. Subjects were assigned to one of three chronicity groups: 1) Early Interval (EI), 2.00 - 8.00 months n = 245, 2) Mid Interval (MI), 8.01 - 24.00 months n = 129, and (3) Late Interval (LI), 24.01 months and greater n = 154. Functional status was assessed with the MPAI-4. RM MANCOVA was applied to evaluate differences among groups from admission to discharge. Rasch analysis demonstrated satisfactory construct validity and internal consistency (Person reliability = 0.90 - 0.94, Item reliability = 0.99) for the admission and discharge MPAI-4s. Controlling for LOS and age, the RM MANCOVA revealed that each chronicity group showed significant improvement in MPAI-4 abilities, adjustment, and participation indices from admission to discharge (p < 0.001). Improvement observed from admission to discharge was the greatest among the EI group (p < 0.001). This study demonstrated the utility of multivariate statistical approaches for understanding the complexities of TBI treatment outcomes. As measured across three domains of functioning, rehabilitation was effective in reducing disability for participants in each chronicity group. Of the three groups, EI participants presented as the most disabled at admission but also made the greatest gains when assessed at discharge.展开更多
Downregulation of the inwardly rectifying potassium channel Kir4.1 is a key step for inducing retinal Müller cell activation and interaction with other glial cells,which is involved in retinal ganglion cell apopt...Downregulation of the inwardly rectifying potassium channel Kir4.1 is a key step for inducing retinal Müller cell activation and interaction with other glial cells,which is involved in retinal ganglion cell apoptosis in glaucoma.Modulation of Kir4.1 expression in Müller cells may therefore be a potential strategy for attenuating retinal ganglion cell damage in glaucoma.In this study,we identified seven predicted phosphorylation sites in Kir4.1 and constructed lentiviral expression systems expressing Kir4.1 mutated at each site to prevent phosphorylation.Following this,we treated Müller glial cells in vitro and in vivo with the m Glu R I agonist DHPG to induce Kir4.1 or Kir4.1 Tyr^(9)Asp overexpression.We found that both Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression inhibited activation of Müller glial cells.Subsequently,we established a rat model of chronic ocular hypertension by injecting microbeads into the anterior chamber and overexpressed Kir4.1 or Kir4.1 Tyr^(9)Asp in the eye,and observed similar results in Müller cells in vivo as those seen in vitro.Both Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression inhibited Müller cell activation,regulated the balance of Bax/Bcl-2,and reduced the m RNA and protein levels of pro-inflammatory factors,including interleukin-1βand tumor necrosis factor-α.Furthermore,we investigated the regulatory effects of Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression on the release of pro-inflammatory factors in a co-culture system of Müller glial cells and microglia.In this co-culture system,we observed elevated adenosine triphosphate concentrations in activated Müller cells,increased levels of translocator protein(a marker of microglial activation),and elevated interleukin-1βm RNA and protein levels in microglia induced by activated Müller cells.These changes could be reversed by Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression in Müller cells.Kir4.1 overexpression,but not Kir4.1 Tyr^(9)Asp overexpression,reduced the number of proliferative and migratory microglia induced by activated Müller cells.Collectively,these results suggest that the tyrosine residue at position nine in Kir4.1 may serve as a functional modulation site in the retina in an experimental model of glaucoma.Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression attenuated Müller cell activation,reduced ATP/P2X receptor–mediated interactions between glial cells,inhibited microglial activation,and decreased the synthesis and release of pro-inflammatory factors,consequently ameliorating retinal ganglion cell apoptosis in glaucoma.展开更多
BACKGROUND Knee osteoarthritis(KOA),a common disabling pathology characterized by knee joint pain,swelling,and functional impairment,primarily affects middle-aged and older adults.In addition to physical limitations,c...BACKGROUND Knee osteoarthritis(KOA),a common disabling pathology characterized by knee joint pain,swelling,and functional impairment,primarily affects middle-aged and older adults.In addition to physical limitations,chronic pain often leads to psychological problems,including anxiety and depression,which further impact patients’quality of life.AIM To examine the efficacy and safety of celecoxib plus duloxetine in managing chronic pain,anxiety,and depression in patients with KOA.METHODS A retrospective analysis was conducted on 123 patients with KOA treated at our center between February 2020 and February 2023.Of these,66 received celecoxib plus duloxetine,and 57 received celecoxib alone.Outcomes were assessed using the Visual Analog Scale(VAS),the Western Ontario and McMaster Universities Osteoarthritis Index(WOMAC),and the Self-Rating Anxiety Scales(SAS)/Self-Rating Depression Scales(SDS).Safety was evaluated by monitoring changes in liver function enzymes(alanine aminotransferase,aspartate aminotransferase),creatinine,and blood urea nitrogen.RESULTS Patients receiving celecoxib plus duloxetine showed significantly greater reductions in VAS and WOMAC and greater improvements in SAS and SDS scores compared with those receiving celecoxib alone.Hepatorenal function did not differ significantly between the treatment groups.Logistic regression analysis identified patient age,educational background,and treatment regimen as independent predictors of inadequate improvement in negative emotional symptoms.CONCLUSION In patients with KOA,celecoxib plus duloxetine effectively mitigates chronic pain and improves anxiety and depressive symptoms without increasing adverse hepatic or renal effects.These findings support its use as a safe and effective treatment option.展开更多
BACKGROUND Anxiety,depression,and other negative emotions are common among patients with chronic renal failure(CRF).Analyzing the factors related to negative emotions is necessary to provide targeted nursing care.AIM ...BACKGROUND Anxiety,depression,and other negative emotions are common among patients with chronic renal failure(CRF).Analyzing the factors related to negative emotions is necessary to provide targeted nursing care.AIM To explore the correlations among life satisfaction,pleasure levels,and negative emotions in patients with CRF.METHODS One hundred patients with CRF who received therapy at the First Affiliated Hospital of Jinzhou Medical University between December 2022 and February 2025 were included.The Depression,Anxiety,and Stress Scale(DASS-21),Satisfaction with Life Scale(SWLS),and Temporal Experience of Pleasure Scale(TEPS)were used to evaluate negative emotions,life satisfaction,and pleasure level,respectively.Pearson’s correlation coefficient analyzed the correlation between life satisfaction,pleasure level,and negative emotions.Linear regression analysis identified the factors affecting negative emotions.RESULTS The average DASS-21 score among patients with CRF was 51.90±2.30,with subscale scores of 17.90±1.50 for depression,18.53±1.18 for anxiety,and 15.47±2.36 for stress,all significantly higher than the domestic norm(P<0.05).The average SWLS score was 22.17±4.90.Correlation analysis revealed a negative correlation between the SWLS and total DASS-21 scores(P<0.05),but not with the individual depression,anxiety,or stress dimensions.The average TEPS score was 67.80±8.34.TEPS scores were negatively correlated with the DASS-21 score and the stress dimension(P<0.05),but not with depression or anxiety.Linear regression analysis showed that TEPS scores significantly influenced DASS-21 scores(P<0.05).CONCLUSION Patients with CRF experience high levels of negative emotions,which are negatively correlated with life satisfaction and pleasure.Furthermore,pleasure level had an impact on negative emotions.展开更多
Chronic pain and disability following acute orthopedic trauma are not only physical concerns but also deeply intertwined with psychological well-being.The recent retrospective cohort study by Yang et al,published,prov...Chronic pain and disability following acute orthopedic trauma are not only physical concerns but also deeply intertwined with psychological well-being.The recent retrospective cohort study by Yang et al,published,provides compelling evidence of significant associations between depression,anxiety,and postoperative recovery.These findings align with an expanding body of literature that confirms the need for orthopedic rehabilitation to adopt a biopsychosocial perspective.This letter contextualizes Yang et al’s study within current evidence,highlighting the roles of sleep disturbance,catastrophizing,stress,neurobiological mechanisms,and coping strategies in shaping recovery.It further emphasizes the importance of integrating nursing-led and multidisciplinary interventions to address both physical and psychological domains,ultimately promoting holistic recovery.展开更多
Neuroinflammation is an inflammatory response in the central nervous system associated with various neurological conditions.The inflammatory process is typically treated with non-steroidal and steroidal anti-inflammat...Neuroinflammation is an inflammatory response in the central nervous system associated with various neurological conditions.The inflammatory process is typically treated with non-steroidal and steroidal anti-inflammatory drugs,which have a range of serious adverse effects.As an alternative,naturally derived molecules such as quercetin and its derivatives show promising anti-inflammatory properties and beneficial effects on various physiological functions.Our objective was to synthesize the evidence on the anti-inflammatory effect of quercetin and its derivatives in in vivo models,in the face of neuroinflammatory insults induced by lipopolysaccharide,through a systematic review and meta-analysis.A search of the preclinical literature was conducted across four databases(Pub Med,Web of Science,Scielo,and Google Scholar).Studies were selected based on inclusion and exclusion criteria,assessed for methodological quality using CAMARADES,and risk of bias using the SYRCLE tool,and data were extracted from the studies.The quantitative assessment of quercetin effects on the expression of pro-inflammatory cytokines and microgliosis was performed through a meta-analysis.A total of 384 potentially relevant articles were identified,of which 11 studies were included in the analysis.The methodological quality was assessed,resulting in an average score of 5.8/10,and the overall risk of bias analysis revealed a lack of methodological clarity in most studies.Furthermore,through the meta-analysis,it was observed that treatment with quercetin statistically reduces pro-inflammatory cytokines,such as tumor necrosis factor alpha,interleukin 6,interleukin 1β(n=89;SMD=–2.00;95%CI:–3.29 to–0.71),and microgliosis(n=33;SMD=–2.56;95%CI:–4.07 to–1.10).In terms of underlying mechanisms,quercetin and its derivatives exhibit antioxidant and anti-apoptotic properties,possibly through the nuclear factor erythroid 2-related factor 2(Nrf2)/HO-1 pathways,increasing the expression of antioxidant enzymes and reducing reactive species,and modulating the caspase pathway,increasing levels of anti-apoptotic proteins and decreasing proapoptotic proteins.Quercetin and its derivatives exhibit highly pleiotropic actions that simultaneously contribute to preventing neuroinflammation.However,despite promising results in animal models,future directions should focus on well-designed clinical studies to assess the safety,bioavailability,and efficacy of quercetin and its derivatives in humans.Additionally,standardization of methods and dosages in studies is crucial to ensure consistency of findings and optimize their application in clinical settings.展开更多
Myalgic encephalomyelitis/chronic fatigue syndrome-an insidious disease:The recent COVID-19 pandemic has brought substantial attention to the overlapping symptoms between long COVID and myalgic encephalomyelitis/chron...Myalgic encephalomyelitis/chronic fatigue syndrome-an insidious disease:The recent COVID-19 pandemic has brought substantial attention to the overlapping symptoms between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS),a chronic and poorly understood neurological disorder(Shankar et al.,2024).展开更多
Chronic cerebral hypoperfusion can lead to neuronal necrosis,trigger inflammatory responses,promote white matter damage,and ultimately result in cognitive impairment.Consequently,chronic cerebral hypoperfusion is an i...Chronic cerebral hypoperfusion can lead to neuronal necrosis,trigger inflammatory responses,promote white matter damage,and ultimately result in cognitive impairment.Consequently,chronic cerebral hypoperfusion is an important factor influencing the onset and progression of vascular dementia.The myelin sheath is a critical component of white matter,and damage and repair of the white matter are closely linked to myelin sheath integrity.This article reviews the role of microglia in vascular dementia,focusing on their effects on myelin sheaths and the potential therapeutic implications.The findings suggest that ischemia and hypoxia cause disruption of the blood-brain barrier and activate microglia,which may worsen blood-brain barrier damage through the release of matrix-degrading enzymes.Microglia-mediated metabolic reprogramming is recognized as an important driver of inflammation.Damage to the blood-brain barrier and subsequent inflammation can lead to myelin injury and accelerate the progression of vascular dementia.Early activation of microglia is a protective response that contributes to the maintenance of blood-brain barrier integrity through sensing,debris-clearing,and defensive mechanisms.However,prolonged activation can trigger a shift in microglia toward the pro-inflammatory M1 phenotype,resulting in myelin damage and cognitive impairment.Triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid cells 1 have been identified as potential biomarkers for vascular dementia,as both are closely linked to cognitive decline.Although effective clinical treatments for myelin damage in the central nervous system are currently lacking,researchers are actively working to develop targeted therapies.Several drugs,including nimodipine,dopaminergic agents,simvastatin,biotin,and quetiapine,have been evaluated for clinical use in treating microglial and myelin damage.Future research will face challenges in developing targeted therapeutic strategies for vascular dementia,requiring further investigation into the timing,duration,and specific mechanisms of microglial activation,as well as the exploration of new drug combinations and additional therapeutic targets.展开更多
BACKGROUND Chronic atrophic gastritis(CAG)is a clinically refractory gastric disease often characterized by high recurrence rates and adverse drug reactions.Anwei decoction(AWD),a traditional Chinese medicine formula,...BACKGROUND Chronic atrophic gastritis(CAG)is a clinically refractory gastric disease often characterized by high recurrence rates and adverse drug reactions.Anwei decoction(AWD),a traditional Chinese medicine formula,has been shown to significantly improve clinical symptoms in patients with CAG,as demonstrated by a multicenter cohort study(overall effective rate:82.5%,P<0.01).However,the unclear molecular mechanisms and therapeutic targets of AWD limit its international acceptance.AIM To investigate the therapeutic mechanisms of AWD against CAG from an integrated perspective.METHODS In this study,N-methyl-N’-nitro-N-nitrosoguanidine was used to establish a CAG rat model.Serum-derived constituents transferred from AWD were first identified using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry.The concentrations of inflammatory cytokines in serum samples were determined by enzyme-linked immunosorbent assay.Moreover,gastric mucosal tissues were analyzed by quantitative realtime polymerase chain reaction to measure messenger RNA(mRNA)levels of the NLRP3 inflammasome.Western blotting was used to detect the protein expression of NLRP3,caspase-1,and interleukin(IL)-1β.To elucidate the regulatory mechanisms underlying AWD treatment,structural alterations of the gut microbiota(GM)and associated metabolites were analyzed using integrated high-throughput sequencing(16S rRNA)and liquid chromatography-mass spectrometry based untargeted metabolomics.This comprehensive approach systematically clarified AWD’s multi-target therapeutic mechanisms against CAG.RESULTS AWD notably reduced serum levels of pro-inflammatory cytokines,such as IL-1β,IL-18,tumor necrosis factor-α,and lipopolysaccharide,demonstrating significant statistical differences(all P<0.01).Additionally,AWD substantially inhibited NLRP3 mRNA expression in gastric mucosal tissue(P<0.01)and concurrently decreased the protein abundance of NLRP3,IL-1β,and caspase-1(all P<0.01),thereby suppressing inflammasome signaling activation.GM analysis indicated that AWD intervention significantly increased the relative abundance of beneficial bacteria.Associated microbial metabolites likely inhibited the NLRP3 inflammasome pathway by modulating immune cell function.Non-targeted metabolomics further indicated that AWD exerted anti-inflammatory effects by regulating critical metabolic pathways,including the Kaposi’s sarcoma-associated herpesvirus infection pathway,autophagy processes,and glycosylphosphatidylinositol-anchor biosynthesis.CONCLUSION AWD alleviates the pathological progression of CAG through multi-target synergistic mechanisms.On one hand,AWD directly suppresses gastric mucosal inflammation by inhibiting NLRP3 inflammasome activation.On the other hand,AWD remodels intestinal microbiota-metabolite homeostasis,enhances intestinal barrier function,and regulates mucosal immune responses.展开更多
Synaptic plasticity is essential for maintaining neuronal function in the central nervous system and serves as a critical indicator of the effects of neurodegenerative disease.Glaucoma directly impairs retinal ganglio...Synaptic plasticity is essential for maintaining neuronal function in the central nervous system and serves as a critical indicator of the effects of neurodegenerative disease.Glaucoma directly impairs retinal ganglion cells and their axons,leading to axonal transport dysfuntion,subsequently causing secondary damage to anterior or posterior ends of the visual system.Accordingly,recent evidence indicates that glaucoma is a degenerative disease of the central nervous system that causes damage throughout the visual pathway.However,the effects of glaucoma on synaptic plasticity in the primary visual cortex remain unclear.In this study,we established a mouse model of unilateral chronic ocular hypertension by injecting magnetic microbeads into the anterior chamber of one eye.We found that,after 4 weeks of chronic ocular hypertension,the neuronal somas were smaller in the superior colliculus and lateral geniculate body regions of the brain contralateral to the affected eye.This was accompanied by glial cell activation and increased expression of inflammatory factors.After 8 weeks of ocular hypertension,we observed a reduction in the number of excitatory and inhibitory synapses,dendritic spines,and activation of glial cells in the primary visual cortex contralateral to the affected eye.These findings suggest that glaucoma not only directly damages the retina but also induces alterations in synapses and dendritic spines in the primary visual cortex,providing new insights into the pathogenesis of glaucoma.展开更多
Traumatic spinal cord injury result in considerable and lasting functional impairments,triggering complex inflammatory and pathological events.Spinal cord scars,often metaphorically referred to as“fire barriers,”aim...Traumatic spinal cord injury result in considerable and lasting functional impairments,triggering complex inflammatory and pathological events.Spinal cord scars,often metaphorically referred to as“fire barriers,”aim to control the spread of neuroinflammation during the acute phase but later hinder axon regeneration in later stages.Recent studies have enhanced our understanding of immunomodulation,revealing that injury-associated inflammation involves various cell types and molecules with positive and negative effects.This review employs bibliometric analysis to examine the literature on inflammatory mediators in spinal cord injury,highlighting recent research and providing a comprehensive overview of the current state of research and the latest advances in studies on neuroinflammation related to spinal cord injury.We summarize the immune and inflammatory responses at different stages of spinal cord injury,offering crucial insights for future research.Additionally,we review repair strategies based on inflammatory mediators for the injured spinal cord.Finally,this review discusses the current status and future directions of translational research focused on immune-targeting strategies,including pharmaceuticals,biomedical engineering,and gene therapy.The development of a combined,precise,and multitemporal strategy for the repair of injured spinal cords represents a promising direction for future research.展开更多
Background:The development of gastric cancer(GC)encompasses precancerous conditions like chronic atrophic gastritis(CAG)and premalignant lesions of gastric cancer(PLGC).In these situations,abnormal Notch signaling res...Background:The development of gastric cancer(GC)encompasses precancerous conditions like chronic atrophic gastritis(CAG)and premalignant lesions of gastric cancer(PLGC).In these situations,abnormal Notch signaling results in mucosal impairment and the initiation of cancer.Banxia Xiexin Decoction(BXD),a well-known formula in traditional Chinese medicine(TCM),shows promise in treating gastric disorders,but its mechanisms in gastric restoration remain unclear.Methods:Using MNNG-induced CAG and PLGC rat models,BXD was administered for 12 weeks.Gastric mucosal pathology was assessed via hematoxylin-eosin staining.Proliferation(Ki-67)and angiogenesis(VEGFA)markers were evaluated by immunohistochemistry.Network pharmacology identified BXD’s targets and pathways.Notch pathway components(Notch1,Jagged1,Dll4,Hes1)were analyzed via qPCR,Western blot,and immunohistochemistry.Results:BXD significantly ameliorated mucosal atrophy,glandular structural disorder,and dysplasia in CAG and PLGC rats.Network pharmacology revealed 323 overlapping targets between BXD and PLGC,with Notch signaling as a central pathway.BXD downregulated Notch1,Jagged1,Dll4,and Hes1 expression at transcriptional and protein levels,suppressed Ki-67(proliferation)and VEGFA(angiogenesis)overexpression,and restored gastric mucosal integrity.Conclusion:BXD inhibits Notch signaling,reduces aberrant proliferation and angiogenesis,and interrupts Correa’s gastric carcinogenesis cascade.This study provides mechanistic evidence supporting BXD as a TCM-based intervention for gastric precancerous lesions.展开更多
The shared links between Alzheimer’s disease and type 2 diabetes mellitus:Alzheimer’s disease(AD)and type 2 diabetes mellitus(T2DM)are two prevalent conditions that come with substantial daily struggles.Emerging evi...The shared links between Alzheimer’s disease and type 2 diabetes mellitus:Alzheimer’s disease(AD)and type 2 diabetes mellitus(T2DM)are two prevalent conditions that come with substantial daily struggles.Emerging evidence highlights that these diseases share similar pathophysiological features,including insulin resistance and chronic inflammation,which contribute to their rapid progression(Chen et al.,2022).Insulin resistance,a hallmark of T2DM,has been suggested to exacerbate neurodegeneration in AD.Similarly,chronic low-grade inflammation in T2DM parallels with neuroinflammation,which is observed in AD,suggesting overlapping pathophysiological mechanisms in T2DM and AD.展开更多
Epilepsy affects over 50 million people worldwide.Drug-resistant epilepsy(DRE)accounts for up to a third of these cases,and neuro-inflammation is thought to play a role in such cases.Despite being a long-debated issue...Epilepsy affects over 50 million people worldwide.Drug-resistant epilepsy(DRE)accounts for up to a third of these cases,and neuro-inflammation is thought to play a role in such cases.Despite being a long-debated issue in the field of DRE,the mechanisms underlying neuroinflammation have yet to be fully elucidated.The pro-inflammatory microenvironment within the brain tissue of people with DRE has been probed using single-cell multimodal transcriptomics.Evidence suggests that inflammatory cells and pro-inflammatory cytokines in the nervous system can lead to extensive biochemical changes,such as connexin hemichannel excitability and disruption of neurotransmitter homeostasis.The presence of inflammation may give rise to neuronal network abnormalities that suppress endogenous antiepileptic systems.We focus on the role of neuroinflammation and brain network anomalies in DRE from multiple perspectives to identify critical points for clinical application.We hope to provide an insightful overview to advance the quest for better DRE treatments.展开更多
Brain-derived neurotrophic factor is a key factor in stress adaptation and avoidance of a social stress behavioral response.Recent studies have shown that brain-derived neurotrophic factor expression in stressed mice ...Brain-derived neurotrophic factor is a key factor in stress adaptation and avoidance of a social stress behavioral response.Recent studies have shown that brain-derived neurotrophic factor expression in stressed mice is brain region–specific,particularly involving the corticolimbic system,including the ventral tegmental area,nucleus accumbens,prefrontal cortex,amygdala,and hippocampus.Determining how brain-derived neurotrophic factor participates in stress processing in different brain regions will deepen our understanding of social stress psychopathology.In this review,we discuss the expression and regulation of brain-derived neurotrophic factor in stress-sensitive brain regions closely related to the pathophysiology of depression.We focused on associated molecular pathways and neural circuits,with special attention to the brain-derived neurotrophic factor–tropomyosin receptor kinase B signaling pathway and the ventral tegmental area–nucleus accumbens dopamine circuit.We determined that stress-induced alterations in brain-derived neurotrophic factor levels are likely related to the nature,severity,and duration of stress,especially in the above-mentioned brain regions of the corticolimbic system.Therefore,BDNF might be a biological indicator regulating stress-related processes in various brain regions.展开更多
Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela ...Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation of tau protein, an endogenous microtubule-associated protein that protects the integrity of neuronal cytoskeletons. Tau hyperphosphorylation results in protein misfolding and subsequent accumulation of tau tangles forming neurotoxic aggregates. These misfolded proteins are characteristic of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease and can lead to downstream neuroinflammatory processes, including assembly and activation of the inflammasome complex. Inflammasomes refer to a family of multimeric protein units that, upon activation, release a cascade of signaling molecules resulting in caspase-induced cell death and inflammation mediated by the release of interleukin-1β cytokine. One specific inflammasome, the NOD-like receptor protein 3, has been proposed to be a key regulator of tau phosphorylation where it has been shown that prolonged NOD-like receptor protein 3 activation acts as a causal factor in pathological tau accumulation and spreading. This review begins by describing the epidemiology and pathophysiology of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease. Next, we highlight neuroinflammation as an overriding theme and discuss the role of the NOD-like receptor protein 3 inflammasome in the formation of tau deposits and how such tauopathic entities spread throughout the brain. We then propose a novel framework linking traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease as inflammasomedependent pathologies that exist along a temporal continuum. Finally, we discuss potential therapeutic targets that may intercept this pathway and ultimately minimize long-term neurological decline.展开更多
BACKGROUND Colorectal polyps are commonly observed in patients with chronic liver disease(CLD)and pose a significant clinical concern because of their potential for malignancy.AIM To explore the clinical characteristi...BACKGROUND Colorectal polyps are commonly observed in patients with chronic liver disease(CLD)and pose a significant clinical concern because of their potential for malignancy.AIM To explore the clinical characteristics of colorectal polyps in patients with CLD,a nomogram was established to predict the presence of adenomatous polyps(AP).METHODS Patients with CLD who underwent colonoscopy at Tianjin Second People’s Hospital from January 2020 to May 2023 were evaluated.Clinical data including laboratory results,colonoscopy findings,and pathology reports were collected.Key variables for the nomogram were identified through least absolute shrinkage and selection operator regression,followed by multivariate logistic regression.The performance of the model was evaluated using the area under the receiver area under curve,as well as calibration curves and decision curve analysis.RESULTS The study enrolled 870 participants who underwent colonoscopy,and the detection rate of AP in patients with CLD was 28.6%.Compared to individuals without polyps,six risk factors were identified as predictors for AP occurrence:Age,male sex,body mass index,alcohol consumption,overlapping metabolic dysfunction-associated steatotic liver disease,and serum ferritin levels.The novel nomogram(AP model)demonstrated an area under curve of 0.801(95%confidence interval:0.756-0.845)and 0.785(95%confidence interval:0.712-0.858)in the training and validation groups.Calibration curves indicated good agreement among predicted and actual probabilities(training:χ^(2)=11.860,P=0.157;validation:χ^(2)=7.055,P=0.530).The decision curve analysis underscored the clinical utility of the nomogram for predicting the risk of AP.CONCLUSION The AP model showed reasonable accuracy and provided a clinical foundation for predicting the occurrence of AP in patients with CLD,which has a certain predictive value.展开更多
Spinal cord injury is an intractable traumatic injury. The most common hurdles faced during spinal cord injury are failure of axonal regrowth and reconnection to target sites. These also tend to be the most challengin...Spinal cord injury is an intractable traumatic injury. The most common hurdles faced during spinal cord injury are failure of axonal regrowth and reconnection to target sites. These also tend to be the most challenging issues in spinal cord injury. As spinal cord injury progresses to the chronic phase, lost motor and sensory functions are not recovered. Several reasons may be attributed to the failure of recovery from chronic spinal cord injury. These include factors that inhibit axonal growth such as activated astrocytes, chondroitin sulfate proteoglycan, myelin-associated proteins, inflammatory microglia, and fibroblasts that accumulate at lesion sites. Skeletal muscle atrophy due to denervation is another chronic and detrimental spinal cord injury–specific condition. Although several intervention strategies based on multiple outlooks have been attempted for treating spinal cord injury, few approaches have been successful. To treat chronic spinal cord injury, neural cells or tissue substitutes may need to be supplied in the cavity area to enable possible axonal growth. Additionally, stimulating axonal growth activity by extrinsic factors is extremely important and essential for maintaining the remaining host neurons and transplanted neurons. This review focuses on pharmacotherapeutic approaches using small compounds and proteins to enable axonal growth in chronic spinal cord injury. This review presents some of these candidates that have shown promising outcomes in basic research(in vivo animal studies) and clinical trials: AA-NgR(310)ecto-Fc(AXER-204), fasudil, phosphatase and tensin homolog protein antagonist peptide 4, chondroitinase ABC, intracellular sigma peptide,(-)-epigallocatechin gallate, matrine, acteoside, pyrvate kinase M2, diosgenin, granulocyte-colony stimulating factor, and fampridine-sustained release. Although the current situation suggests that drug-based therapies to recover function in chronic spinal cord injury are limited, potential candidates have been identified through basic research, and these candidates may be subjects of clinical studies in the future. Moreover, cocktail therapy comprising drugs with varied underlying mechanisms may be effective in treating the refractory status of chronic spinal cord injury.展开更多
文摘Tyrosine kinase inhibitors(TKIs)are used to treat patients with chronic myelogenous leukemia(CML),leading to a nearly normal life expectancy.Sprycel(dasatinib)-induced chylothorax has rarely been reported in patients undergoing CML treatment.We report a 10-year case history of chronic chylothorax that persisted despite discontinuation of dasatinib in a patient with otherwise excellent results after switching to another TKI.Herein,we discuss a conservative treatment approach that uses symptom-based thoracentesis instead of surgical ligation of the thoracic duct.This approach may reduce patient morbidity and prevent the need for complex surgical procedures.TKIs have revolutionized CML treatment;however,these powerful medications are not without patient morbidity.
文摘This study evaluated the impact of chronicity (onset of injury to admission in-terval) on three domains of functional outcomes for a large group of traumatic brain injured (TBI) survivors. Subjects included 528 TBI adults who were treated in post-hospital residential rehabilitation centers. Subjects were assigned to one of three chronicity groups: 1) Early Interval (EI), 2.00 - 8.00 months n = 245, 2) Mid Interval (MI), 8.01 - 24.00 months n = 129, and (3) Late Interval (LI), 24.01 months and greater n = 154. Functional status was assessed with the MPAI-4. RM MANCOVA was applied to evaluate differences among groups from admission to discharge. Rasch analysis demonstrated satisfactory construct validity and internal consistency (Person reliability = 0.90 - 0.94, Item reliability = 0.99) for the admission and discharge MPAI-4s. Controlling for LOS and age, the RM MANCOVA revealed that each chronicity group showed significant improvement in MPAI-4 abilities, adjustment, and participation indices from admission to discharge (p < 0.001). Improvement observed from admission to discharge was the greatest among the EI group (p < 0.001). This study demonstrated the utility of multivariate statistical approaches for understanding the complexities of TBI treatment outcomes. As measured across three domains of functioning, rehabilitation was effective in reducing disability for participants in each chronicity group. Of the three groups, EI participants presented as the most disabled at admission but also made the greatest gains when assessed at discharge.
基金supported by the National Natural Science Foundation of China,Nos.32271043(to ZW)and 82171047(to YM)the both Science and Technology Major Project of Shanghai,No.2018SHZDZX01 and ZJLabShanghai Center for Brain Science and Brain-Inspired Technology(to ZW)。
文摘Downregulation of the inwardly rectifying potassium channel Kir4.1 is a key step for inducing retinal Müller cell activation and interaction with other glial cells,which is involved in retinal ganglion cell apoptosis in glaucoma.Modulation of Kir4.1 expression in Müller cells may therefore be a potential strategy for attenuating retinal ganglion cell damage in glaucoma.In this study,we identified seven predicted phosphorylation sites in Kir4.1 and constructed lentiviral expression systems expressing Kir4.1 mutated at each site to prevent phosphorylation.Following this,we treated Müller glial cells in vitro and in vivo with the m Glu R I agonist DHPG to induce Kir4.1 or Kir4.1 Tyr^(9)Asp overexpression.We found that both Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression inhibited activation of Müller glial cells.Subsequently,we established a rat model of chronic ocular hypertension by injecting microbeads into the anterior chamber and overexpressed Kir4.1 or Kir4.1 Tyr^(9)Asp in the eye,and observed similar results in Müller cells in vivo as those seen in vitro.Both Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression inhibited Müller cell activation,regulated the balance of Bax/Bcl-2,and reduced the m RNA and protein levels of pro-inflammatory factors,including interleukin-1βand tumor necrosis factor-α.Furthermore,we investigated the regulatory effects of Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression on the release of pro-inflammatory factors in a co-culture system of Müller glial cells and microglia.In this co-culture system,we observed elevated adenosine triphosphate concentrations in activated Müller cells,increased levels of translocator protein(a marker of microglial activation),and elevated interleukin-1βm RNA and protein levels in microglia induced by activated Müller cells.These changes could be reversed by Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression in Müller cells.Kir4.1 overexpression,but not Kir4.1 Tyr^(9)Asp overexpression,reduced the number of proliferative and migratory microglia induced by activated Müller cells.Collectively,these results suggest that the tyrosine residue at position nine in Kir4.1 may serve as a functional modulation site in the retina in an experimental model of glaucoma.Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression attenuated Müller cell activation,reduced ATP/P2X receptor–mediated interactions between glial cells,inhibited microglial activation,and decreased the synthesis and release of pro-inflammatory factors,consequently ameliorating retinal ganglion cell apoptosis in glaucoma.
文摘BACKGROUND Knee osteoarthritis(KOA),a common disabling pathology characterized by knee joint pain,swelling,and functional impairment,primarily affects middle-aged and older adults.In addition to physical limitations,chronic pain often leads to psychological problems,including anxiety and depression,which further impact patients’quality of life.AIM To examine the efficacy and safety of celecoxib plus duloxetine in managing chronic pain,anxiety,and depression in patients with KOA.METHODS A retrospective analysis was conducted on 123 patients with KOA treated at our center between February 2020 and February 2023.Of these,66 received celecoxib plus duloxetine,and 57 received celecoxib alone.Outcomes were assessed using the Visual Analog Scale(VAS),the Western Ontario and McMaster Universities Osteoarthritis Index(WOMAC),and the Self-Rating Anxiety Scales(SAS)/Self-Rating Depression Scales(SDS).Safety was evaluated by monitoring changes in liver function enzymes(alanine aminotransferase,aspartate aminotransferase),creatinine,and blood urea nitrogen.RESULTS Patients receiving celecoxib plus duloxetine showed significantly greater reductions in VAS and WOMAC and greater improvements in SAS and SDS scores compared with those receiving celecoxib alone.Hepatorenal function did not differ significantly between the treatment groups.Logistic regression analysis identified patient age,educational background,and treatment regimen as independent predictors of inadequate improvement in negative emotional symptoms.CONCLUSION In patients with KOA,celecoxib plus duloxetine effectively mitigates chronic pain and improves anxiety and depressive symptoms without increasing adverse hepatic or renal effects.These findings support its use as a safe and effective treatment option.
文摘BACKGROUND Anxiety,depression,and other negative emotions are common among patients with chronic renal failure(CRF).Analyzing the factors related to negative emotions is necessary to provide targeted nursing care.AIM To explore the correlations among life satisfaction,pleasure levels,and negative emotions in patients with CRF.METHODS One hundred patients with CRF who received therapy at the First Affiliated Hospital of Jinzhou Medical University between December 2022 and February 2025 were included.The Depression,Anxiety,and Stress Scale(DASS-21),Satisfaction with Life Scale(SWLS),and Temporal Experience of Pleasure Scale(TEPS)were used to evaluate negative emotions,life satisfaction,and pleasure level,respectively.Pearson’s correlation coefficient analyzed the correlation between life satisfaction,pleasure level,and negative emotions.Linear regression analysis identified the factors affecting negative emotions.RESULTS The average DASS-21 score among patients with CRF was 51.90±2.30,with subscale scores of 17.90±1.50 for depression,18.53±1.18 for anxiety,and 15.47±2.36 for stress,all significantly higher than the domestic norm(P<0.05).The average SWLS score was 22.17±4.90.Correlation analysis revealed a negative correlation between the SWLS and total DASS-21 scores(P<0.05),but not with the individual depression,anxiety,or stress dimensions.The average TEPS score was 67.80±8.34.TEPS scores were negatively correlated with the DASS-21 score and the stress dimension(P<0.05),but not with depression or anxiety.Linear regression analysis showed that TEPS scores significantly influenced DASS-21 scores(P<0.05).CONCLUSION Patients with CRF experience high levels of negative emotions,which are negatively correlated with life satisfaction and pleasure.Furthermore,pleasure level had an impact on negative emotions.
文摘Chronic pain and disability following acute orthopedic trauma are not only physical concerns but also deeply intertwined with psychological well-being.The recent retrospective cohort study by Yang et al,published,provides compelling evidence of significant associations between depression,anxiety,and postoperative recovery.These findings align with an expanding body of literature that confirms the need for orthopedic rehabilitation to adopt a biopsychosocial perspective.This letter contextualizes Yang et al’s study within current evidence,highlighting the roles of sleep disturbance,catastrophizing,stress,neurobiological mechanisms,and coping strategies in shaping recovery.It further emphasizes the importance of integrating nursing-led and multidisciplinary interventions to address both physical and psychological domains,ultimately promoting holistic recovery.
基金supported by the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior-Brasil(CAPES)[Finance Code 001](to MGS)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico(CNPq)fellowship[research grants 309840/2022-8]。
文摘Neuroinflammation is an inflammatory response in the central nervous system associated with various neurological conditions.The inflammatory process is typically treated with non-steroidal and steroidal anti-inflammatory drugs,which have a range of serious adverse effects.As an alternative,naturally derived molecules such as quercetin and its derivatives show promising anti-inflammatory properties and beneficial effects on various physiological functions.Our objective was to synthesize the evidence on the anti-inflammatory effect of quercetin and its derivatives in in vivo models,in the face of neuroinflammatory insults induced by lipopolysaccharide,through a systematic review and meta-analysis.A search of the preclinical literature was conducted across four databases(Pub Med,Web of Science,Scielo,and Google Scholar).Studies were selected based on inclusion and exclusion criteria,assessed for methodological quality using CAMARADES,and risk of bias using the SYRCLE tool,and data were extracted from the studies.The quantitative assessment of quercetin effects on the expression of pro-inflammatory cytokines and microgliosis was performed through a meta-analysis.A total of 384 potentially relevant articles were identified,of which 11 studies were included in the analysis.The methodological quality was assessed,resulting in an average score of 5.8/10,and the overall risk of bias analysis revealed a lack of methodological clarity in most studies.Furthermore,through the meta-analysis,it was observed that treatment with quercetin statistically reduces pro-inflammatory cytokines,such as tumor necrosis factor alpha,interleukin 6,interleukin 1β(n=89;SMD=–2.00;95%CI:–3.29 to–0.71),and microgliosis(n=33;SMD=–2.56;95%CI:–4.07 to–1.10).In terms of underlying mechanisms,quercetin and its derivatives exhibit antioxidant and anti-apoptotic properties,possibly through the nuclear factor erythroid 2-related factor 2(Nrf2)/HO-1 pathways,increasing the expression of antioxidant enzymes and reducing reactive species,and modulating the caspase pathway,increasing levels of anti-apoptotic proteins and decreasing proapoptotic proteins.Quercetin and its derivatives exhibit highly pleiotropic actions that simultaneously contribute to preventing neuroinflammation.However,despite promising results in animal models,future directions should focus on well-designed clinical studies to assess the safety,bioavailability,and efficacy of quercetin and its derivatives in humans.Additionally,standardization of methods and dosages in studies is crucial to ensure consistency of findings and optimize their application in clinical settings.
基金supported by the Judith Jane Mason and Harold Stannett Williams Memorial Foundation National Medical Program(#Mason2210)to JX。
文摘Myalgic encephalomyelitis/chronic fatigue syndrome-an insidious disease:The recent COVID-19 pandemic has brought substantial attention to the overlapping symptoms between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS),a chronic and poorly understood neurological disorder(Shankar et al.,2024).
基金supported by the Natural Science Foundation of Beijing,No.7232279(to XW)the National Natural Science Foundation of China,No.U21A20400(to QW)Key Project of Beijing University of Chinese Medicine,Nos.2022-JYB-JBZR-004(to XW),2024-JYB-JBZD-043(to CL).
文摘Chronic cerebral hypoperfusion can lead to neuronal necrosis,trigger inflammatory responses,promote white matter damage,and ultimately result in cognitive impairment.Consequently,chronic cerebral hypoperfusion is an important factor influencing the onset and progression of vascular dementia.The myelin sheath is a critical component of white matter,and damage and repair of the white matter are closely linked to myelin sheath integrity.This article reviews the role of microglia in vascular dementia,focusing on their effects on myelin sheaths and the potential therapeutic implications.The findings suggest that ischemia and hypoxia cause disruption of the blood-brain barrier and activate microglia,which may worsen blood-brain barrier damage through the release of matrix-degrading enzymes.Microglia-mediated metabolic reprogramming is recognized as an important driver of inflammation.Damage to the blood-brain barrier and subsequent inflammation can lead to myelin injury and accelerate the progression of vascular dementia.Early activation of microglia is a protective response that contributes to the maintenance of blood-brain barrier integrity through sensing,debris-clearing,and defensive mechanisms.However,prolonged activation can trigger a shift in microglia toward the pro-inflammatory M1 phenotype,resulting in myelin damage and cognitive impairment.Triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid cells 1 have been identified as potential biomarkers for vascular dementia,as both are closely linked to cognitive decline.Although effective clinical treatments for myelin damage in the central nervous system are currently lacking,researchers are actively working to develop targeted therapies.Several drugs,including nimodipine,dopaminergic agents,simvastatin,biotin,and quetiapine,have been evaluated for clinical use in treating microglial and myelin damage.Future research will face challenges in developing targeted therapeutic strategies for vascular dementia,requiring further investigation into the timing,duration,and specific mechanisms of microglial activation,as well as the exploration of new drug combinations and additional therapeutic targets.
基金supported by a grant from NIH(R01AI132695)to RM。
文摘Chronic wasting disease—a prion disease affecting cervids:Many neurological conditions,including Alzheimer's and Parkinson's diseases,amyotrophic lateral sclerosis,frontotemporal dementias,among others,are caused by the accumulation of misfolded proteins in the brain.These diseases affect not only humans,but also animals.
基金Supported by the National Natural Science Foundation of China,No.81860843Guangxi Administration of Traditional Chinese Medicine Project,No.GZSY23-36 and No.GXZYA20240150。
文摘BACKGROUND Chronic atrophic gastritis(CAG)is a clinically refractory gastric disease often characterized by high recurrence rates and adverse drug reactions.Anwei decoction(AWD),a traditional Chinese medicine formula,has been shown to significantly improve clinical symptoms in patients with CAG,as demonstrated by a multicenter cohort study(overall effective rate:82.5%,P<0.01).However,the unclear molecular mechanisms and therapeutic targets of AWD limit its international acceptance.AIM To investigate the therapeutic mechanisms of AWD against CAG from an integrated perspective.METHODS In this study,N-methyl-N’-nitro-N-nitrosoguanidine was used to establish a CAG rat model.Serum-derived constituents transferred from AWD were first identified using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry.The concentrations of inflammatory cytokines in serum samples were determined by enzyme-linked immunosorbent assay.Moreover,gastric mucosal tissues were analyzed by quantitative realtime polymerase chain reaction to measure messenger RNA(mRNA)levels of the NLRP3 inflammasome.Western blotting was used to detect the protein expression of NLRP3,caspase-1,and interleukin(IL)-1β.To elucidate the regulatory mechanisms underlying AWD treatment,structural alterations of the gut microbiota(GM)and associated metabolites were analyzed using integrated high-throughput sequencing(16S rRNA)and liquid chromatography-mass spectrometry based untargeted metabolomics.This comprehensive approach systematically clarified AWD’s multi-target therapeutic mechanisms against CAG.RESULTS AWD notably reduced serum levels of pro-inflammatory cytokines,such as IL-1β,IL-18,tumor necrosis factor-α,and lipopolysaccharide,demonstrating significant statistical differences(all P<0.01).Additionally,AWD substantially inhibited NLRP3 mRNA expression in gastric mucosal tissue(P<0.01)and concurrently decreased the protein abundance of NLRP3,IL-1β,and caspase-1(all P<0.01),thereby suppressing inflammasome signaling activation.GM analysis indicated that AWD intervention significantly increased the relative abundance of beneficial bacteria.Associated microbial metabolites likely inhibited the NLRP3 inflammasome pathway by modulating immune cell function.Non-targeted metabolomics further indicated that AWD exerted anti-inflammatory effects by regulating critical metabolic pathways,including the Kaposi’s sarcoma-associated herpesvirus infection pathway,autophagy processes,and glycosylphosphatidylinositol-anchor biosynthesis.CONCLUSION AWD alleviates the pathological progression of CAG through multi-target synergistic mechanisms.On one hand,AWD directly suppresses gastric mucosal inflammation by inhibiting NLRP3 inflammasome activation.On the other hand,AWD remodels intestinal microbiota-metabolite homeostasis,enhances intestinal barrier function,and regulates mucosal immune responses.
基金supported by the National Natural Science Foundation of China,No.82271115(to MY).
文摘Synaptic plasticity is essential for maintaining neuronal function in the central nervous system and serves as a critical indicator of the effects of neurodegenerative disease.Glaucoma directly impairs retinal ganglion cells and their axons,leading to axonal transport dysfuntion,subsequently causing secondary damage to anterior or posterior ends of the visual system.Accordingly,recent evidence indicates that glaucoma is a degenerative disease of the central nervous system that causes damage throughout the visual pathway.However,the effects of glaucoma on synaptic plasticity in the primary visual cortex remain unclear.In this study,we established a mouse model of unilateral chronic ocular hypertension by injecting magnetic microbeads into the anterior chamber of one eye.We found that,after 4 weeks of chronic ocular hypertension,the neuronal somas were smaller in the superior colliculus and lateral geniculate body regions of the brain contralateral to the affected eye.This was accompanied by glial cell activation and increased expression of inflammatory factors.After 8 weeks of ocular hypertension,we observed a reduction in the number of excitatory and inhibitory synapses,dendritic spines,and activation of glial cells in the primary visual cortex contralateral to the affected eye.These findings suggest that glaucoma not only directly damages the retina but also induces alterations in synapses and dendritic spines in the primary visual cortex,providing new insights into the pathogenesis of glaucoma.
基金supported by the National Natural Science Foundation of China,Nos.82272470 (to GN),82072439 (to GN),81930070 (to SF)the Tianjin Health Key Discipline Special Project,No.TJWJ2022XK011 (to GN)+2 种基金the Outstanding Youth Foundation of Tianjin Medical University General Hospital,No.22ZYYJQ01 (to GN)Tianjin Key Medical Disciplines,No.TJYXZDXK-027A (to SF)National Key Research and Development Program-Stem Cells and Transformation Research,No.2019YFA0112100 (to SF)
文摘Traumatic spinal cord injury result in considerable and lasting functional impairments,triggering complex inflammatory and pathological events.Spinal cord scars,often metaphorically referred to as“fire barriers,”aim to control the spread of neuroinflammation during the acute phase but later hinder axon regeneration in later stages.Recent studies have enhanced our understanding of immunomodulation,revealing that injury-associated inflammation involves various cell types and molecules with positive and negative effects.This review employs bibliometric analysis to examine the literature on inflammatory mediators in spinal cord injury,highlighting recent research and providing a comprehensive overview of the current state of research and the latest advances in studies on neuroinflammation related to spinal cord injury.We summarize the immune and inflammatory responses at different stages of spinal cord injury,offering crucial insights for future research.Additionally,we review repair strategies based on inflammatory mediators for the injured spinal cord.Finally,this review discusses the current status and future directions of translational research focused on immune-targeting strategies,including pharmaceuticals,biomedical engineering,and gene therapy.The development of a combined,precise,and multitemporal strategy for the repair of injured spinal cords represents a promising direction for future research.
基金supported by the National Natural Science Foundation of China(Grant No.82274442)the Key Research Project in Traditional Chinese Medicine of Tianjin Municipal Health Commission(Grant No.202007)the Integrated Traditional Chinese and Western Medicine Research Project of Tianjin Municipal Health Commission(Grant No.2023134).
文摘Background:The development of gastric cancer(GC)encompasses precancerous conditions like chronic atrophic gastritis(CAG)and premalignant lesions of gastric cancer(PLGC).In these situations,abnormal Notch signaling results in mucosal impairment and the initiation of cancer.Banxia Xiexin Decoction(BXD),a well-known formula in traditional Chinese medicine(TCM),shows promise in treating gastric disorders,but its mechanisms in gastric restoration remain unclear.Methods:Using MNNG-induced CAG and PLGC rat models,BXD was administered for 12 weeks.Gastric mucosal pathology was assessed via hematoxylin-eosin staining.Proliferation(Ki-67)and angiogenesis(VEGFA)markers were evaluated by immunohistochemistry.Network pharmacology identified BXD’s targets and pathways.Notch pathway components(Notch1,Jagged1,Dll4,Hes1)were analyzed via qPCR,Western blot,and immunohistochemistry.Results:BXD significantly ameliorated mucosal atrophy,glandular structural disorder,and dysplasia in CAG and PLGC rats.Network pharmacology revealed 323 overlapping targets between BXD and PLGC,with Notch signaling as a central pathway.BXD downregulated Notch1,Jagged1,Dll4,and Hes1 expression at transcriptional and protein levels,suppressed Ki-67(proliferation)and VEGFA(angiogenesis)overexpression,and restored gastric mucosal integrity.Conclusion:BXD inhibits Notch signaling,reduces aberrant proliferation and angiogenesis,and interrupts Correa’s gastric carcinogenesis cascade.This study provides mechanistic evidence supporting BXD as a TCM-based intervention for gastric precancerous lesions.
基金supported by grants from NIH T32(DK007260,to WC)the Steno North American Fellowship awarded by the Novo Nordisk Foundation(NNF23OC0087108,to WC).
文摘The shared links between Alzheimer’s disease and type 2 diabetes mellitus:Alzheimer’s disease(AD)and type 2 diabetes mellitus(T2DM)are two prevalent conditions that come with substantial daily struggles.Emerging evidence highlights that these diseases share similar pathophysiological features,including insulin resistance and chronic inflammation,which contribute to their rapid progression(Chen et al.,2022).Insulin resistance,a hallmark of T2DM,has been suggested to exacerbate neurodegeneration in AD.Similarly,chronic low-grade inflammation in T2DM parallels with neuroinflammation,which is observed in AD,suggesting overlapping pathophysiological mechanisms in T2DM and AD.
基金supported by the National Natural Science Foundation of China(82030037)the Translational and Application Project of Brain-inspired and Network Neuroscience on Brain Disorders(11000023T000002036286).
文摘Epilepsy affects over 50 million people worldwide.Drug-resistant epilepsy(DRE)accounts for up to a third of these cases,and neuro-inflammation is thought to play a role in such cases.Despite being a long-debated issue in the field of DRE,the mechanisms underlying neuroinflammation have yet to be fully elucidated.The pro-inflammatory microenvironment within the brain tissue of people with DRE has been probed using single-cell multimodal transcriptomics.Evidence suggests that inflammatory cells and pro-inflammatory cytokines in the nervous system can lead to extensive biochemical changes,such as connexin hemichannel excitability and disruption of neurotransmitter homeostasis.The presence of inflammation may give rise to neuronal network abnormalities that suppress endogenous antiepileptic systems.We focus on the role of neuroinflammation and brain network anomalies in DRE from multiple perspectives to identify critical points for clinical application.We hope to provide an insightful overview to advance the quest for better DRE treatments.
基金supported financially by the National Natural Science Foundation of China,No.82071272(to YZ).
文摘Brain-derived neurotrophic factor is a key factor in stress adaptation and avoidance of a social stress behavioral response.Recent studies have shown that brain-derived neurotrophic factor expression in stressed mice is brain region–specific,particularly involving the corticolimbic system,including the ventral tegmental area,nucleus accumbens,prefrontal cortex,amygdala,and hippocampus.Determining how brain-derived neurotrophic factor participates in stress processing in different brain regions will deepen our understanding of social stress psychopathology.In this review,we discuss the expression and regulation of brain-derived neurotrophic factor in stress-sensitive brain regions closely related to the pathophysiology of depression.We focused on associated molecular pathways and neural circuits,with special attention to the brain-derived neurotrophic factor–tropomyosin receptor kinase B signaling pathway and the ventral tegmental area–nucleus accumbens dopamine circuit.We determined that stress-induced alterations in brain-derived neurotrophic factor levels are likely related to the nature,severity,and duration of stress,especially in the above-mentioned brain regions of the corticolimbic system.Therefore,BDNF might be a biological indicator regulating stress-related processes in various brain regions.
文摘Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation of tau protein, an endogenous microtubule-associated protein that protects the integrity of neuronal cytoskeletons. Tau hyperphosphorylation results in protein misfolding and subsequent accumulation of tau tangles forming neurotoxic aggregates. These misfolded proteins are characteristic of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease and can lead to downstream neuroinflammatory processes, including assembly and activation of the inflammasome complex. Inflammasomes refer to a family of multimeric protein units that, upon activation, release a cascade of signaling molecules resulting in caspase-induced cell death and inflammation mediated by the release of interleukin-1β cytokine. One specific inflammasome, the NOD-like receptor protein 3, has been proposed to be a key regulator of tau phosphorylation where it has been shown that prolonged NOD-like receptor protein 3 activation acts as a causal factor in pathological tau accumulation and spreading. This review begins by describing the epidemiology and pathophysiology of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease. Next, we highlight neuroinflammation as an overriding theme and discuss the role of the NOD-like receptor protein 3 inflammasome in the formation of tau deposits and how such tauopathic entities spread throughout the brain. We then propose a novel framework linking traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease as inflammasomedependent pathologies that exist along a temporal continuum. Finally, we discuss potential therapeutic targets that may intercept this pathway and ultimately minimize long-term neurological decline.
基金Supported by the National Natural Science Foundation of China,No.62375202Natural Science Foundation of Tianjin,No.23JCYBJC00950+1 种基金Tianjin Health Science and Technology Project Key Discipline Special,No.TJWJ2022XK034Research Project in Key Areas of Traditional Chinese Medicine in 2024,No.2024022.
文摘BACKGROUND Colorectal polyps are commonly observed in patients with chronic liver disease(CLD)and pose a significant clinical concern because of their potential for malignancy.AIM To explore the clinical characteristics of colorectal polyps in patients with CLD,a nomogram was established to predict the presence of adenomatous polyps(AP).METHODS Patients with CLD who underwent colonoscopy at Tianjin Second People’s Hospital from January 2020 to May 2023 were evaluated.Clinical data including laboratory results,colonoscopy findings,and pathology reports were collected.Key variables for the nomogram were identified through least absolute shrinkage and selection operator regression,followed by multivariate logistic regression.The performance of the model was evaluated using the area under the receiver area under curve,as well as calibration curves and decision curve analysis.RESULTS The study enrolled 870 participants who underwent colonoscopy,and the detection rate of AP in patients with CLD was 28.6%.Compared to individuals without polyps,six risk factors were identified as predictors for AP occurrence:Age,male sex,body mass index,alcohol consumption,overlapping metabolic dysfunction-associated steatotic liver disease,and serum ferritin levels.The novel nomogram(AP model)demonstrated an area under curve of 0.801(95%confidence interval:0.756-0.845)and 0.785(95%confidence interval:0.712-0.858)in the training and validation groups.Calibration curves indicated good agreement among predicted and actual probabilities(training:χ^(2)=11.860,P=0.157;validation:χ^(2)=7.055,P=0.530).The decision curve analysis underscored the clinical utility of the nomogram for predicting the risk of AP.CONCLUSION The AP model showed reasonable accuracy and provided a clinical foundation for predicting the occurrence of AP in patients with CLD,which has a certain predictive value.
文摘Spinal cord injury is an intractable traumatic injury. The most common hurdles faced during spinal cord injury are failure of axonal regrowth and reconnection to target sites. These also tend to be the most challenging issues in spinal cord injury. As spinal cord injury progresses to the chronic phase, lost motor and sensory functions are not recovered. Several reasons may be attributed to the failure of recovery from chronic spinal cord injury. These include factors that inhibit axonal growth such as activated astrocytes, chondroitin sulfate proteoglycan, myelin-associated proteins, inflammatory microglia, and fibroblasts that accumulate at lesion sites. Skeletal muscle atrophy due to denervation is another chronic and detrimental spinal cord injury–specific condition. Although several intervention strategies based on multiple outlooks have been attempted for treating spinal cord injury, few approaches have been successful. To treat chronic spinal cord injury, neural cells or tissue substitutes may need to be supplied in the cavity area to enable possible axonal growth. Additionally, stimulating axonal growth activity by extrinsic factors is extremely important and essential for maintaining the remaining host neurons and transplanted neurons. This review focuses on pharmacotherapeutic approaches using small compounds and proteins to enable axonal growth in chronic spinal cord injury. This review presents some of these candidates that have shown promising outcomes in basic research(in vivo animal studies) and clinical trials: AA-NgR(310)ecto-Fc(AXER-204), fasudil, phosphatase and tensin homolog protein antagonist peptide 4, chondroitinase ABC, intracellular sigma peptide,(-)-epigallocatechin gallate, matrine, acteoside, pyrvate kinase M2, diosgenin, granulocyte-colony stimulating factor, and fampridine-sustained release. Although the current situation suggests that drug-based therapies to recover function in chronic spinal cord injury are limited, potential candidates have been identified through basic research, and these candidates may be subjects of clinical studies in the future. Moreover, cocktail therapy comprising drugs with varied underlying mechanisms may be effective in treating the refractory status of chronic spinal cord injury.
