Chronic heart failure(CHF)impairs cognitive function.Xijiaqi Formula(XJQ),a traditional Chinese medicine(TCM)used clinically to treat CHF,demonstrates potential for improving cognition in CHF patients.However,its prec...Chronic heart failure(CHF)impairs cognitive function.Xijiaqi Formula(XJQ),a traditional Chinese medicine(TCM)used clinically to treat CHF,demonstrates potential for improving cognition in CHF patients.However,its precise mechanism in treating post-CHF cognitive dysfunction remains unclear.This study systematically investigates XJQ’s effects on post-CHF cognitive dysfunction and the underlying mechanisms.The components of XJQ were identified through liquid chromatography-mass spectrometry.CHF was induced in rats via ligation of the left anterior descending coronary artery,followed by six weeks of XJQ treatment.Cardiac function was evaluated through echocardiography and hemodynamic parameters,while cognitive function was assessed using Morris water maze(MWM)and open field tests(OFT).XJQ treatment enhanced both cardiac and cognitive functions in CHF rats.Network pharmacology identified 12 core active components of XJQ and indicated its effect on cognitive dysfunction involved regulating synapses,inflammation,and phosphodiesterase 4(PDE4)-dependent cyclic adenosine monophosphate(cAMP)signaling.XJQ inhibited microglial and astrocyte activation,decreased proinflammatory cytokines,and mitigated neuronal damage.Notably,XJQ promoted synaptic repair and dendritic growth by downregulating PDE4 and upregulating cAMP,protein kinase A(PKA),cAMP-response element binding protein(CREB),brain-derived neurotrophic factor(BDNF),PSD95,and synapsin I levels.Molecular docking and Bio-layer interferometry assays confirmed direct binding of quercetin,kaempferol,isorhamnetin,and darutoside to PDE4.In conclusion,XJQ alleviates neuroinflammation and enhances synaptic plasticity to improve cognitive dysfunction in CHF rats via the PDE4/cAMP/PKA/CREB signaling pathway.These findings provide valuable insight into the heart-brain axis.展开更多
Postoperative cognitive dysfunction is a typical complication,which can be referred to as POCD.This complication is common in elderly patients.Among them,POCD is mainly manifested in the function of patients with atte...Postoperative cognitive dysfunction is a typical complication,which can be referred to as POCD.This complication is common in elderly patients.Among them,POCD is mainly manifested in the function of patients with attention deficit and memory reduction after surgery,among which serious patients are prone to personality change,which affects their social behavior ability.In the context of the current era,the cause of POCD is not clear,combined with the results of most studies,it is found that central nervous inflammation,is a key factor affecting POCD.From the perspective of central inflammation,this paper analyzes the relationship between central inflammation and POCD,and discusses the mechanism of action,aiming at effectively preventing and treating POCD and providing a reference for subsequent research in related fields.展开更多
Postoperative cognitive dysfunction is a seve re complication of the central nervous system that occurs after anesthesia and surgery,and has received attention for its high incidence and effect on the quality of life ...Postoperative cognitive dysfunction is a seve re complication of the central nervous system that occurs after anesthesia and surgery,and has received attention for its high incidence and effect on the quality of life of patients.To date,there are no viable treatment options for postoperative cognitive dysfunction.The identification of postoperative cognitive dysfunction hub genes could provide new research directions and therapeutic targets for future research.To identify the signaling mechanisms contributing to postoperative cognitive dysfunction,we first conducted Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of the Gene Expression Omnibus GSE95426 dataset,which consists of mRNAs and long non-coding RNAs differentially expressed in mouse hippocampus3 days after tibial fracture.The dataset was enriched in genes associated with the biological process"regulation of immune cells,"of which Chill was identified as a hub gene.Therefore,we investigated the contribution of chitinase-3-like protein 1 protein expression changes to postoperative cognitive dysfunction in the mouse model of tibial fractu re surgery.Mice were intraperitoneally injected with vehicle or recombinant chitinase-3-like protein 124 hours post-surgery,and the injection groups were compared with untreated control mice for learning and memory capacities using the Y-maze and fear conditioning tests.In addition,protein expression levels of proinflammatory factors(interleukin-1βand inducible nitric oxide synthase),M2-type macrophage markers(CD206 and arginase-1),and cognition-related proteins(brain-derived neurotropic factor and phosphorylated NMDA receptor subunit NR2B)were measured in hippocampus by western blotting.Treatment with recombinant chitinase-3-like protein 1 prevented surgery-induced cognitive impairment,downregulated interleukin-1βand nducible nitric oxide synthase expression,and upregulated CD206,arginase-1,pNR2B,and brain-derived neurotropic factor expression compared with vehicle treatment.Intraperitoneal administration of the specific ERK inhibitor PD98059 diminished the effects of recombinant chitinase-3-like protein 1.Collectively,our findings suggest that recombinant chitinase-3-like protein 1 ameliorates surgery-induced cognitive decline by attenuating neuroinflammation via M2 microglial polarization in the hippocampus.Therefore,recombinant chitinase-3-like protein1 may have therapeutic potential fo r postoperative cognitive dysfunction.展开更多
BACKGROUND Colorectal cancer(CRC)is one of the most prevalent and lethal malignant tumors worldwide.Currently,surgical intervention was the primary treatment modality for CRC.However,increasing studies have revealed t...BACKGROUND Colorectal cancer(CRC)is one of the most prevalent and lethal malignant tumors worldwide.Currently,surgical intervention was the primary treatment modality for CRC.However,increasing studies have revealed that CRC patients may experience postoperative cognitive dysfunction(POCD).AIM To establish a risk prediction model for POCD in CRC patients and investigate the preventive value of dexmedetomidine(DEX).METHODS A retrospective analysis was conducted on clinical data from 140 CRC patients who underwent surgery at the People’s Hospital of Qian Nan from February 2020 to May 2024.Patients were allocated into a modeling group(n=98)and a validation group(n=42)in a 7:3 ratio.General clinical data were collected.Additionally,in the modeling group,patients who received DEX preoperatively were incorporated into the observation group(n=54),while those who did not were placed in the control group(n=44).The incidence of POCD was recorded for both cohorts.Data analysis was performed using statistical product and service solutions 20.0,with t-tests orχ^(2) tests employed for group comparisons based on the data type.Least absolute shrinkage and selection operator regression was applied to identify influencing factors and reduce the impact of multicollinear predictors among variables.Multivariate analysis was carried out using Logistic regression.Based on the identified risk factors,a risk prediction model for POCD in CRC patients was developed,and the predictive value of these risk factors was evaluated.RESULTS Significant differences were observed between the cognitive dysfunction group and the non-cognitive dysfunction group in diabetes status,alcohol consumption,years of education,anesthesia duration,intraoperative blood loss,intraoperative hypoxemia,use of DEX during surgery,intraoperative use of vasoactive drugs,surgical time,systemic inflammatory response syndrome(SIRS)score(P<0.05).Multivariate Logistic regression analysis identified that diabetes[odds ratio(OR)=4.679,95%confidence interval(CI)=1.382-15.833],alcohol consumption(OR=5.058,95%CI:1.255-20.380),intraoperative hypoxemia(OR=4.697,95%CI:1.380-15.991),no use of DEX during surgery(OR=3.931,95%CI:1.383-11.175),surgery duration≥90 minutes(OR=4.894,95%CI:1.377-17.394),and a SIRS score≥3(OR=4.133,95%CI:1.323-12.907)were independent risk factors for POCD in CRC patients(P<0.05).A risk prediction model for POCD was constructed using diabetes,alcohol consumption,intraoperative hypoxemia,non-use of DEX during surgery,surgery duration,and SIRS score as factors.A receiver operator characteristic curve analysis of these factors revealed the model’s predictive sensitivity(88.56%),specificity(70.64%),and area under the curve(AUC)(AUC=0.852,95%CI:0.773-0.919).The model was validated using 42 CRC patients who met the inclusion criteria,demonstrating sensitivity(80.77%),specificity(81.25%),and accuracy(80.95%),and AUC(0.805)in diagnosing cognitive impairment,with a 95%CI:0.635-0.896.CONCLUSION Logistic regression analysis identified that diabetes,alcohol consumption,intraoperative hypoxemia,non-use of DEX during surgery,surgery duration,and SIRS score vigorously influenced the occurrence of POCD.The risk prediction model based on these factors demonstrated good predictive performance for POCD in CRC individuals.This study offers valuable insights for clinical practice and contributes to the prevention and management of POCD under CRC circumstances.展开更多
BACKGROUND To investigate whether seasonal differences in ambient temperature affect the incidence of early postoperative cognitive dysfunction(POCD)among elderly patients undergoing laparoscopic surgery in tropical r...BACKGROUND To investigate whether seasonal differences in ambient temperature affect the incidence of early postoperative cognitive dysfunction(POCD)among elderly patients undergoing laparoscopic surgery in tropical regions.Additionally,it explored the perioperative risk factors associated with early POCD following abdominal laparoscopic surgery.AIM To investigate the influence of seasonal differences in ambient temperature on POCD of elderly patients METHODS A total of 125 patients aged≥65 years from Hainan Province,China,who underwent laparoscopic surgery under general anesthesia with tracheal intubation,were enrolled. All patients completed the Mini-Mental State Examination one day before surgery and onpostoperative days 1, 3, and 7. A decline of ≥ 2 points from baseline was considered indicative of cognitivedysfunction. Serum levels of S100 calcium binding protein B and neuron-specific enolase were measured usingenzyme-linked immunosorbent assay at three time points: Preoperatively, immediately after extubation, and 24hours postoperatively. Perioperative clinical data were collected to identify potential risk factors for POCD.Propensity score matching (PSM) was performed (1:1, caliper = 0.03), resulting in 41 matched patient pairs betweenwinter and summer groups.RESULTSAfter PSM, baseline characteristics including age, gender, body mass index, education level, comorbidities, andsurgical variables were well balanced between groups. There were no significant differences in the incidence ofPOCD on postoperative days 1, 3, and 7 between patients undergoing laparoscopic surgery in winter vs summer.However, multivariable logistic regression revealed that surgical duration (day 1, P value = 0.049), advanced ageand elevated creatinine (day 3, P value = 0.044, P value = 0.008), and hypoalbuminemia (day 3, P value = 0.042;day7, P value = 0.015) were independently associated with early POCD.CONCLUSIONAmbient temperature differences between winter and summer in tropical regions did not significantly affect theincidence of early POCD in elderly patients undergoing laparoscopic surgery. Nonetheless, age, longer surgicalduration, elevated creatinine, and hypoalbuminemia emerged as key risk factors. These findings underscore theimportance of perioperative optimization to reduce the risk of POCD in elderly patients, regardless of seasonaltemperature variations.展开更多
BACKGROUND Diabetic cognitive dysfunction(DCD)is one of the chronic complications of diabetes,but its mechanism is currently unknown.Studies have shown that mitochondrial fission mediated by calcium overload is an imp...BACKGROUND Diabetic cognitive dysfunction(DCD)is one of the chronic complications of diabetes,but its mechanism is currently unknown.Studies have shown that mitochondrial fission mediated by calcium overload is an important mechanism of DCD.Blocking calcium overload and restoring calcium homeostasis are key steps in treatment.Transient receptor potential melastatin 7(TRPM7)is a novel player in causing calcium overload.Our previous studies have shown that genetic silencing of TRPM7 in type 1 diabetic rats leads to significant improvements in cognitive function,but the specific mechanism remains unclear.Troxerutin,extracted from the flowers of Sophora japonica,is one of the derivatives of rutin and has been shown to have neuroprotective effects.However,its association with TRPM7 remains unclear.AIM To use animal and cellular models,we investigated whether TRPM7 mediated mitochondrial fission by upregulation of calcineurin(CaN)/dynamin-related protein 1(Drp1)ser637 in DCD,and whether Troxerutin improved DCD by inhibiting TRPM7-mediated mitochondrial division.METHODS In this study,we used db/db mice and hippocampal neuronal cell lines(HT22)treated with high-concentration glucose as our study subjects.We evaluated cognitive function using Morris water maze,novel object recognition tasks,and Nesting tests.We observed mitochondrial morphology using transmission electron microscopy and measured mitochondrial energy metabolism indicators using a spectrophotometer.We also detected mRNA and protein expression of TRPM7,CaN,p-Drp1^(ser637),caspase-3,B-cell lymphoma 2 associated X protein,and B-cell lymphoma 2 using quantitative real-time polymerase chain reaction,western blotting,and immunofluorescence.RESULTS In the db/db diabetic mice with cognitive dysfunction,as well as in hippocampal neurons exposed to high-concentration glucose,TRPM7 and CaN expression were upregulated,phosphorylated Drp1^(ser637)expression was downregulated,and mitochondrial fission was increased.By modulating(inhibiting or overexpressing)TRPM7,it was further validated that TRPM7 activates the CaN/Drp1^(ser637)pathway,resulting in an increase in mitochondrial fission and neuronal cell apoptosis.Troxerutin downregulated TRPM7/CaN/Drp1^(ser637),reduced mitochondrial fission,and improved DCD.CONCLUSION TRPM7 promotes mitochondrial fission via the CaN/Drp1^(ser637)pathway.Troxerutin improves mitochondrial function and reduces neuronal damage by inhibiting this pathway,suggesting TRPM7 as a potential therapeutic target for DCD.展开更多
BACKGROUND Diabetes is associated with increased cognitive decline and dementia due to the loss of myelinated nerve fiber function,which is linked to oligodendrocyte dysfunction.The voltage-gated proton channel 1(Hv1)...BACKGROUND Diabetes is associated with increased cognitive decline and dementia due to the loss of myelinated nerve fiber function,which is linked to oligodendrocyte dysfunction.The voltage-gated proton channel 1(Hv1)is important for the cellular proton extrusion machinery.However,its role in regulating diabetesinduced cognitive dysfunction is unclear.AIM To investigate the role of Hv1 in cognitive impairment induced by diabetes and its potential mechanisms,focusing on neuroinflammation,oligodendrocyte apoptosis,and axonal demyelination.METHODS A diabetes model was established by administering a high-fat diet and streptozotocin injections in mice.Hv1 knockout(KO)and wild-type mice were used to evaluate cognitive function via behavioral tests and neuroinflammation using immunofluorescence.Oligodendrocyte apoptosis was assessed with the terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay, and axonal demyelination wasanalyzed using electron microscopy.RESULTSHv1 expression was significantly increased in the corpus callosum of diabetic mice. Hv1 KO alleviated cognitiveimpairment, reduced oligodendrocyte apoptosis, and decreased the expression of inflammatory factors, includinginterleukin-1 and tumor necrosis factor-α, in diabetic mice. Electron microscopy revealed a reduction in myelinthickness and an increased g-ratio in diabetic mice, which were reversed by Hv1 KO.CONCLUSIONHv1 plays a role in diabetes-induced cognitive dysfunction by modulating neuroinflammation and myelinintegrity. Hv1 KO demonstrates therapeutic potential in mitigating diabetes-related cognitive decline andassociated complications.展开更多
Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the...Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer’s disease.Conventional drugs,such as donepezil,can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline.Currently,active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer’s disease and other transgenic animal models,attracting considerable attention.However,the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab.This review first discusses the advancements in the pathogenesis of Alzheimer’s disease and active and passive immunotherapies targeting amyloid-beta and tau proteins.Furthermore,it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects.Although some antibodies have shown promise in patients with mild Alzheimer’s disease,substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer’s disease.展开更多
Phosphatidylethanolamine is a major phospholipid class abundant in the brain,particularly in the inner leaflet of the plasma and mitochondrial membranes.Although it is primarily synthesized from phosphatidylserine via...Phosphatidylethanolamine is a major phospholipid class abundant in the brain,particularly in the inner leaflet of the plasma and mitochondrial membranes.Although it is primarily synthesized from phosphatidylserine via decarboxylation in mitochondria or from ethanolamine via the cytidine diphosphate-ethanolamine pathway in the endoplasmic reticulum,phosphatidylethanolamine that resides in mitochondria is preferentially produced locally and is distinct and separate from the pool of phosphatidylethanolamine made in the endoplasmic reticulum.Mitochondria-derived phosphatidylethanolamine is not only essential for mitochondrial integrity but also is exported to other organelles to fulfill diverse cellular functions.Neurons are highly enriched with phosphatidylethanolamine,and the importance of phosphatidylethanolamine metabolism in neuronal health has recently been recognized following its reported links to Alzheimer’s disease,Parkinson’s disease,and hereditary spastic paraplegia,among other neurological disorders.Indeed,disturbances in mitochondrial function and phosphatidylethanolamine metabolism and the resulting neuronal dysfunction are the common features of individuals suffering from these diseases,highlighting the great importance of maintaining proper phosphatidylethanolamine homeostasis in neurons.In this review,we summarize the current knowledge of phosphatidylethanolamine metabolism and its role in neuronal function with a special emphasis on the phosphatidylethanolamine biosynthetic pathway in mitochondria.We then review findings on how phosphatidylethanolamine biosynthesis is affected in major neurodegenerative diseases.Finally,we highlight promising future research areas that will help advance the understanding of neuronal phosphatidylethanolamine mechanisms and identify phosphatidylethanolamine-targeted therapeutic strategies for combating such brain diseases.展开更多
Objective:To observe the efficacy of acupuncture combined with traditional Chinese herbs in the treatment of poststroke vascular dementia(VD)and the effects on serum interleukin(IL)-6 and superoxide dismutase(SOD).Met...Objective:To observe the efficacy of acupuncture combined with traditional Chinese herbs in the treatment of poststroke vascular dementia(VD)and the effects on serum interleukin(IL)-6 and superoxide dismutase(SOD).Methods:A total of 240 patients with poststroke VD were selected and randomly divided into two groups according to the random number table method,with 120 cases in each group.Both groups received Hua Tan Tong Luo(phlegmresolving and collateral-activating)formula,once daily;the observation group was additionally treated with Yi Shen Tiao Du(kidney-tonifying and Governor Vessel-regulating)acupuncture once daily for 6 consecutive days,followed by 1 d of rest.Both groups were treated for 15 d as one course,for a total of 2 courses.After treatment,the total effective rate was compared.Changes in scores of traditional Chinese medicine(TCM)symptoms,clinical dementia rating(CDR),National Institutes of Health stroke scale(NIHSS),and Chinese version of mini-mental state examination(MMSE),and serum levels of IL-6 and SOD were observed in both groups.Results:The total effective rate in the observation group was higher than that in the control group(P<0.05).After treatment,TCM symptom,CDR,and NIHSS scores,and serum IL-6 levels in both groups were lower than those before treatment(P<0.05),while MMSE scores and serum SOD levels were higher than those before treatment(P<0.05).After treatment,the observation group showed lower TCM symptom,CDR,and NIHSS scores,and serum IL-6 levels than the control group(P<0.05),and higher MMSE scores and serum SOD levels than the control group(P<0.05).Conclusion:Compared to Hua Tan Tong Luo formula alone,Yi Shen Tiao Du acupuncture combined with Hua Tan Tong Luo formula demonstrates better efficacy in reducing dementia severity,improving cognitive and neurological function,and inhibiting inflammation in patients with poststroke VD.展开更多
Long noncoding RNA and microRNA are regulatory noncoding RNAs that are implicated in Alzheimer's disease, but the role of long noncoding RNA-associated competitive endogenous RNA has not been fully elucidated. The...Long noncoding RNA and microRNA are regulatory noncoding RNAs that are implicated in Alzheimer's disease, but the role of long noncoding RNA-associated competitive endogenous RNA has not been fully elucidated. The long noncoding RNA growth arrest-specific 5(GAS5) is a member of the 5′-terminal oligopyrimidine gene family that may be involved in neurological disorders, but its role in Alzheimer's disease remains unclear. This study aimed to investigate the function of GAS5 and construct a GAS5-associated competitive endogenous RNA network comprising potential targets. RNA sequencing results showed that GAS5 was upregulated in five familial Alzheimer's disease(5×FAD) mice, APPswe/PSEN1dE9(APP/PS1) mice, Alzheimer's disease-related APPswe cells, and serum from patients with Alzheimer's disease. Functional experiments with targeted overexpression and silencing demonstrated that GAS5 played a role in cognitive dysfunction and multiple Alzheimer's disease-associated pathologies, including tau hyperphosphorylation, amyloid-beta accumulation, and neuronal apoptosis. Mechanistic studies indicated that GAS5 acted as an endogenous sponge by competing for microRNA-23b-3p(miR-23b-3p) binding to regulate its targets glycogen synthase kinase 3beta(GSK-3β) and phosphatase and tensin homologue deleted on chromosome 10(PTEN) expression in an Argonaute 2-induced RNA silencing complex(RISC)-dependent manner. GAS5 inhibited miR-23b-3p-mediated GSK-3β and PTEN cascades with a feedforward PTEN/protein kinase B(Akt)/GSK-3β linkage. Furthermore, recovery of GAS5/miR-23b-3p/GSK-3β/PTEN pathways relieved Alzheimer's disease-like symptoms in vivo, indicated by the amelioration of spatial cognition, neuronal degeneration, amyloid-beta load, and tau phosphorylation. Together, these findings suggest that GAS5 promotes Alzheimer's disease pathogenesis. This study establishes the functional convergence of the GAS5/miR-23b-3p/GSK-3β/PTEN pathway on multiple pathologies, suggesting a candidate therapeutic target in Alzheimer's disease.展开更多
Inflammation may play a role in postoperative cognitive dysfunction. 5＇ Adenosine monophos- phate-activated protein kinase, nuclear factor-kappa B, interleukin-1β, and tumor necrosis factor-a are involved in inflamm...Inflammation may play a role in postoperative cognitive dysfunction. 5＇ Adenosine monophos- phate-activated protein kinase, nuclear factor-kappa B, interleukin-1β, and tumor necrosis factor-a are involved in inflammation. Therefore, these inflammatory mediators may be involved in postoperative cognitive dysfunction. Western immunoblot analysis revealed 5＇ adenosine mo- nophosphate-activated protein kinase and nuclear factor-kappa B in the hippocampus of aged rats were increased 1-7 days after splenectomy. Moreover, interleukin-1β and tumor necrosis fac- tor-α were upregulated and gradually decreased. Therefore, these inflammatory mediators may participate in the splenectomy model of postoperative cognitive dysfunction in aged rats.展开更多
The causal mechanisms and treatment for the negative symptoms and cognitive dysfunction in schizophrenia are the main issues attracting the attention of psychiatrists over the last decade.The first part of this review...The causal mechanisms and treatment for the negative symptoms and cognitive dysfunction in schizophrenia are the main issues attracting the attention of psychiatrists over the last decade.The first part of this review summarizes the pathogenesis of schizophrenia,especially the negative symptoms and cognitive dysfunction from the perspectives of genetics and epigenetics.The second part describes the novel medications and several advanced physical therapies(e.g.,transcranial magnetic stimulation and transcranial direct current stimulation)for the negative symptoms and cognitive dysfunction that will optimize the therapeutic strategy for patients with schizophrenia in future.展开更多
This study established an aged rat model of cognitive dysfunction using anesthesia with 2% iso- flurane and 80% oxygen for 2 hours. Twenty-four hours later, Y-maze test results showed that isoflurane significantly imp...This study established an aged rat model of cognitive dysfunction using anesthesia with 2% iso- flurane and 80% oxygen for 2 hours. Twenty-four hours later, Y-maze test results showed that isoflurane significantly impaired cognitive function in aged rats. Gas chromatography-mass spectrometry results showed that isoflurane also significantly increased the levels of N,N-diethy- lacetamide, n-ethylacetamide, aspartic acid, malic acid and arabinonic acid in the hippocampus of isoflurane-treated rats. Moreover, aspartic acid, N,N-diethylacetamide, n-ethylacetamide and malic acid concentration was positively correlated with the degree of cognitive dysfunction in the isoflurane-treated rats. It is evident that hippocampal metabolite changes are involved in the formation of cognitive dysfunction after isoflurane anesthesia. To further verify these results, this study cultured hippocampal neurons in vitro, which were then treated with aspartic acid （100 μmol/L）. Results suggested that aspartic acid concentration in the hippocampus may be a biomarker for predicting the occurrence and disease progress of cognitive dysfunction.展开更多
Objective： To explore the relationship of postoperative cognitive dysfunction （POCD） in one-lung ventilation （OLV） patients and regional cerebral oxygen saturation （rSO2）. Methods： Twenty-nine male and twenty-...Objective： To explore the relationship of postoperative cognitive dysfunction （POCD） in one-lung ventilation （OLV） patients and regional cerebral oxygen saturation （rSO2）. Methods： Twenty-nine male and twenty-one female cases of OLV received thoracic surgery, with American Standards Association （ASA） physical status being at Grades Ⅰ-Ⅲ. Neuropsychological tests were performed on the day before operation and 7 d after operation, and there was an intraoperative continuous monitoring of rSO2. The values of rSO2 before anesthesia induction （t1）, at the beginning of OLV （t2）, and at the time of OLV 30 min （t3）, OLV 60 min （t4）, the end of OLV （t5）, and the end of surgery （t6） were recorded. The intraoperative average of rSO2 （ rSO2 ）, the intraoperative minimum value of rSO2 （rSO2, rn=n）, and the reduced maximum percentage of rSO2 （rSO2, %max） when compared with the baseline value were calculated. The volume of blood loss, urine output, and the amount of fluid infusion was recorded. Results： A total of 14 patients （28%） in the 50 cases suffered from POCD. The values of mini-mental state examination （MMSE）, the digit span and the digit symbol on the 7th day after the operation for POCD in OLV patients were found to be significantly lower than those before the operation （P〈0.05）. The values of MMSE and vocabulary fluency scores were significantly lower than those in the non-POCD group （P〈0.05）. The values of rSO2 in the POCD group of OLV patients at t2 and t3 and the values of rSO2 in the non-POCD group at t2 were found to be significantly higher than those at tl （P〈0.05）. The values of rSO2, %max in the POCD group were significantly higher than those in the non-POCD group （P〈0.05）. When the value of rSO2, %max is more than 10.1%, it may act as an early warning index for cognitive function changes, Conclusions： POCD after OLV may be associated with a decline in rSO2.展开更多
Occupational exposure to 1-bromopropane(1-BP) induces learning and memory deficits. However, no therapeutic strategies are currently available. Accumulating evidence has suggested that N-methyl-D-aspartate receptors(N...Occupational exposure to 1-bromopropane(1-BP) induces learning and memory deficits. However, no therapeutic strategies are currently available. Accumulating evidence has suggested that N-methyl-D-aspartate receptors(NMDARs) and neuroinflammation are involved in the cognitive impairments in neurodegenerative diseases. In this study we aimed to investigate whether the noncompetitive NMDAR antagonist MK801 protects against 1-BPinduced cognitive dysfunction. Male Wistar rats were administered with MK801(0.1 mg/kg) prior to 1-BP intoxication(800 mg/kg). Their cognitive performance was evaluated by the Morris water maze test. The brains of rats were dissected for biochemical, neuropathological,and immunological analyses. We found that the spatial learning and memory were significantly impaired in the1-BP group, and this was associated with neurodegeneration in both the hippocampus(especially CA1 and CA3)and cortex. Besides, the protein levels of phosphorylated NMDARs were increased after 1-BP exposure. MK801 ameliorated the 1-BP-induced cognitive impairments and degeneration of neurons in the hippocampus and cortex.Mechanistically, MK801 abrogated the 1-BP-induced disruption of excitatory and inhibitory amino-acid balance and NMDAR abnormalities. Subsequently, MK801 inhibited the microglial activation and release of pro-inflammatory cytokines in 1-BP-treated rats. Our findings, for the first time, revealed that MK801 protected against 1-BP-induced cognitive dysfunction by ameliorating NMDAR function and blocking microglial activation, which might provide a potential target for the treatment of 1-BP poisoning.展开更多
Postoperative cognitive dysfunction(POCD)is a common surgical complication.Diabetes mellitus(DM)increases risk of developing POCD after surgery.DM patients with POCD seriously threaten the quality of patients’life,ho...Postoperative cognitive dysfunction(POCD)is a common surgical complication.Diabetes mellitus(DM)increases risk of developing POCD after surgery.DM patients with POCD seriously threaten the quality of patients’life,however,the intrinsic mechanism is unclear,and the effective treatment is deficiency.Previous studies have demonstrated neuronal loss and reduced neurogenesis in the hippocampus in mouse models of POCD.In this study,we constructed a mouse model of DM by intraperitoneal injection of streptozotocin,and then induced postoperative cognitive dysfunction by transient bilateral common carotid artery occlusion.We found that mouse models of DM-POCD exhibited the most serious cognitive impairment,as well as the most hippocampal neural stem cells(H-NSCs)loss and neurogenesis decline.Subsequently,we hypothesized that small extracellular vesicles secreted by induced pluripotent stem cell-derived mesenchymal stem cells(iMSC-sEVs)might promote neurogenesis and restore cognitive function in patients with DM-POCD.iMSC-sEVs were administered via the tail vein beginning on day 2 after surgery,and then once every 3 days for 1 month thereafter.Our results showed that iMSC-sEVs treatment significantly recovered compromised proliferation and neuronal-differentiation capacity in H-NSCs,and reversed cognitive impairment in mouse models of DM-POCD.Furthermore,miRNA sequencing and qPCR showed miR-21-5p and miR-486-5p were the highest expression in iMSC-sEVs.We found iMSC-sEVs mainly transferred miR-21-5p and miR-486-5p to promote H-NSCs proliferation and neurogenesis.As miR-21-5p was demonstrated to directly targete Epha4 and CDKN2C,while miR-486-5p can inhibit FoxO1 in NSCs.We then demonstrated iMSC-sEVs can transfer miR-21-5p and miR-486-5p to inhibit EphA4,CDKN2C,and FoxO1 expression in H-NSCs.Collectively,these results indicate significant H-NSC loss and neurogenesis reduction lead to DM-POCD,the application of iMSC-sEVs may represent a novel cell-free therapeutic tool for diabetic patients with postoperative cognitive dysfunction.展开更多
Objective： To investigate the relationship between post-operative cognitive dysfunction（POCD） and regional cerebral oxygen saturation（rSO2） and β-amyloid protein（Aβ） in patients undergoing laparoscopic pancre...Objective： To investigate the relationship between post-operative cognitive dysfunction（POCD） and regional cerebral oxygen saturation（rSO2） and β-amyloid protein（Aβ） in patients undergoing laparoscopic pancreaticoduodenectomy. Methods： Fifty patients undergoing elective laparoscopic pancreaticoduodenectomy received five groups of neuropsychological tests 1 d pre-operatively and 7 d post-operatively, with continuous monitoring of rSO2 intra-operatively. Before anesthesia induction（t0）, at the beginning of laparoscopy（t1）, and at the time of pneumoperitoneum 120 min（t2）, pneumoperitoneum 240 min（t3）, pneumoperitoneum 480 min（t4）, the end of pneumoperitoneum（t5）, and 24 h after surgery, jugular venous blood was drawn respectively for the measurement of Aβ by enzyme-linked immunosorbent assay（ELISA）. Results： Twenty-one cases of the fifty patients suffered from POCD after operation. We found that the maximum percentage drop in rSO2（rSO2, %max） was significantly higher in the POCD group than in the non-POCD group. The rSO2, %max value of over 10.2% might be a potential predictor of neurocognitive injury for those patients. In the POCD group, the plasma Aβ levels after 24 h were significantly higher than those of pre-operative values（P〈0.01）. After 24 h, levels of plasma Aβ in the POCD group were significantly higher than those in the non-POCD group（P〈0.01）. Conclusions： The development of POCD in patients undergoing laparoscopic pancreaticoduodenectomy is associated with alterations of rSO2 and Aβ. Monitoring of rSO2 might be useful in the prediction of POCD, and Aβ might be used as a sensitive biochemical marker to predict the occurrence of POCD.展开更多
BACKGROUND Type 2 diabetes mellitus(T2DM) has been strongly associated with an increased risk of developing cognitive dysfunction and dementia.The mechanisms of diabetes-associated cognitive dysfunction(DACD) have not...BACKGROUND Type 2 diabetes mellitus(T2DM) has been strongly associated with an increased risk of developing cognitive dysfunction and dementia.The mechanisms of diabetes-associated cognitive dysfunction(DACD) have not been fully elucidated to date.Some studies proved lower cerebral blood flow(CBF) in the hippocampus was associated with poor executive function and memory in T2DM.Increasing evidence showed that diabetes leads to abnormal vascular endothelial growth factor(VEGF) expression and CBF changes in humans and animal models.In this study,we hypothesized that DACD was correlated with CBF alteration as measured by three-dimensional(3D) arterial spin labeling(3D-ASL) and VEGF expression in the hippocampus.AIM To assess the correlation between CBF(measured by 3D-ASL and VEGF expression) and DACD in a rat model of T2DM.METHODS Forty Sprague-Dawley male rats were divided into control and T2DM groups.The T2DM group was established by feeding rats a high-fat diet and glucose to induce impaired glucose tolerance and then injecting them with streptozotocin to induce T2DM.Cognitive function was assessed using the Morris water maze experiment.The CBF changes were measured by 3D-ASL magnetic resonance imaging.VEGF expression was determined using immunofluorescence.RESULTS The escape latency time significantly reduced 15 wk after streptozotocin injection in the T2DM group.The total distance traveled was longer in the T2DM group;also,the platform was crossed fewer times.The percentage of distance in the target zone significantly decreased.CBF decreased in the bilateral hippocampus in the T2DM group.No difference was found between the right CBF value and the left CBF value in the T2DM group.The VEGF expression level in the hippocampus was lower in the T2DM group and correlated with the CBF value.The escape latency negatively correlated with the CBF value.The number of rats crossing the platform positively correlated with the CBF value.CONCLUSION Low CBF in the hippocampus and decreased VEGF expression might be crucial in DACD.CBF measured by 3D-ASL might serve as a noninvasive imaging biomarker for cognitive impairment associated with T2DM.展开更多
The incidence of diabetes is gradually increasing in China,and diabetes and associated complications,such as cognitive dysfunction have gained much attention in recent time.However,the concepts,clinical treatment,and ...The incidence of diabetes is gradually increasing in China,and diabetes and associated complications,such as cognitive dysfunction have gained much attention in recent time.However,the concepts,clinical treatment,and prevention of cognitive dysfunction in patients with diabetes remain unclear.The Chinese Society of Endocrinology investigated the current national and overseas situation of cognitive dysfunction associated with diabetes.Based on research both in China and other countries worldwide,the Expert Consensus on Cognitive Dysfunction in Diabetes was established to guide physicians in the comprehensive standardized management of cognitive dysfunction in diabetes and to improve clinical outcomes in Chinese patients.This consensus presents an overview,definition and classification,epidemiology and pathogenesis,risk factors,screening,diagnosis,differential diagnosis,treatment,and prevention of cognitive dysfunction in patients with diabetes.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82430116 and 82574622)the Special Fund of Central Committee High Level Chinese Medicine Hospital(Nos.DZMG-LJRC-0014,DZMG-ZJXY-23013)+1 种基金Chinese Medicine Inheritance and Innovation“Thousand Million”Talents Project(Qihuang Project 2021)Qihuang Scholarsthe Medical and Health Industry Development Project of Tongzhou District(2023).
文摘Chronic heart failure(CHF)impairs cognitive function.Xijiaqi Formula(XJQ),a traditional Chinese medicine(TCM)used clinically to treat CHF,demonstrates potential for improving cognition in CHF patients.However,its precise mechanism in treating post-CHF cognitive dysfunction remains unclear.This study systematically investigates XJQ’s effects on post-CHF cognitive dysfunction and the underlying mechanisms.The components of XJQ were identified through liquid chromatography-mass spectrometry.CHF was induced in rats via ligation of the left anterior descending coronary artery,followed by six weeks of XJQ treatment.Cardiac function was evaluated through echocardiography and hemodynamic parameters,while cognitive function was assessed using Morris water maze(MWM)and open field tests(OFT).XJQ treatment enhanced both cardiac and cognitive functions in CHF rats.Network pharmacology identified 12 core active components of XJQ and indicated its effect on cognitive dysfunction involved regulating synapses,inflammation,and phosphodiesterase 4(PDE4)-dependent cyclic adenosine monophosphate(cAMP)signaling.XJQ inhibited microglial and astrocyte activation,decreased proinflammatory cytokines,and mitigated neuronal damage.Notably,XJQ promoted synaptic repair and dendritic growth by downregulating PDE4 and upregulating cAMP,protein kinase A(PKA),cAMP-response element binding protein(CREB),brain-derived neurotrophic factor(BDNF),PSD95,and synapsin I levels.Molecular docking and Bio-layer interferometry assays confirmed direct binding of quercetin,kaempferol,isorhamnetin,and darutoside to PDE4.In conclusion,XJQ alleviates neuroinflammation and enhances synaptic plasticity to improve cognitive dysfunction in CHF rats via the PDE4/cAMP/PKA/CREB signaling pathway.These findings provide valuable insight into the heart-brain axis.
基金Jiangsu University Student Innovation and Entrepreneurship Project,“Study on the Mechanism of TLR4-mediated Central Inflammation Induced by Glial Cell Activation to POCD”(Project No.:202313980027Y)。
文摘Postoperative cognitive dysfunction is a typical complication,which can be referred to as POCD.This complication is common in elderly patients.Among them,POCD is mainly manifested in the function of patients with attention deficit and memory reduction after surgery,among which serious patients are prone to personality change,which affects their social behavior ability.In the context of the current era,the cause of POCD is not clear,combined with the results of most studies,it is found that central nervous inflammation,is a key factor affecting POCD.From the perspective of central inflammation,this paper analyzes the relationship between central inflammation and POCD,and discusses the mechanism of action,aiming at effectively preventing and treating POCD and providing a reference for subsequent research in related fields.
基金supported by the National Natural Science Foundation of China,Nos.81730033,82171193(to XG)the Key Talent Project for Strengthening Health during the 13^(th)Five-Year Plan Period,No.ZDRCA2016069(to XG)+1 种基金the National Key R&D Program of China,No.2018YFC2001901(to XG)Jiangsu Provincial Medical Key Discipline,No.ZDXK202232(to XG)。
文摘Postoperative cognitive dysfunction is a seve re complication of the central nervous system that occurs after anesthesia and surgery,and has received attention for its high incidence and effect on the quality of life of patients.To date,there are no viable treatment options for postoperative cognitive dysfunction.The identification of postoperative cognitive dysfunction hub genes could provide new research directions and therapeutic targets for future research.To identify the signaling mechanisms contributing to postoperative cognitive dysfunction,we first conducted Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of the Gene Expression Omnibus GSE95426 dataset,which consists of mRNAs and long non-coding RNAs differentially expressed in mouse hippocampus3 days after tibial fracture.The dataset was enriched in genes associated with the biological process"regulation of immune cells,"of which Chill was identified as a hub gene.Therefore,we investigated the contribution of chitinase-3-like protein 1 protein expression changes to postoperative cognitive dysfunction in the mouse model of tibial fractu re surgery.Mice were intraperitoneally injected with vehicle or recombinant chitinase-3-like protein 124 hours post-surgery,and the injection groups were compared with untreated control mice for learning and memory capacities using the Y-maze and fear conditioning tests.In addition,protein expression levels of proinflammatory factors(interleukin-1βand inducible nitric oxide synthase),M2-type macrophage markers(CD206 and arginase-1),and cognition-related proteins(brain-derived neurotropic factor and phosphorylated NMDA receptor subunit NR2B)were measured in hippocampus by western blotting.Treatment with recombinant chitinase-3-like protein 1 prevented surgery-induced cognitive impairment,downregulated interleukin-1βand nducible nitric oxide synthase expression,and upregulated CD206,arginase-1,pNR2B,and brain-derived neurotropic factor expression compared with vehicle treatment.Intraperitoneal administration of the specific ERK inhibitor PD98059 diminished the effects of recombinant chitinase-3-like protein 1.Collectively,our findings suggest that recombinant chitinase-3-like protein 1 ameliorates surgery-induced cognitive decline by attenuating neuroinflammation via M2 microglial polarization in the hippocampus.Therefore,recombinant chitinase-3-like protein1 may have therapeutic potential fo r postoperative cognitive dysfunction.
基金Supported by the Research Fund of Qiannan Medical College for Nationalities,No.Qnyz202222.
文摘BACKGROUND Colorectal cancer(CRC)is one of the most prevalent and lethal malignant tumors worldwide.Currently,surgical intervention was the primary treatment modality for CRC.However,increasing studies have revealed that CRC patients may experience postoperative cognitive dysfunction(POCD).AIM To establish a risk prediction model for POCD in CRC patients and investigate the preventive value of dexmedetomidine(DEX).METHODS A retrospective analysis was conducted on clinical data from 140 CRC patients who underwent surgery at the People’s Hospital of Qian Nan from February 2020 to May 2024.Patients were allocated into a modeling group(n=98)and a validation group(n=42)in a 7:3 ratio.General clinical data were collected.Additionally,in the modeling group,patients who received DEX preoperatively were incorporated into the observation group(n=54),while those who did not were placed in the control group(n=44).The incidence of POCD was recorded for both cohorts.Data analysis was performed using statistical product and service solutions 20.0,with t-tests orχ^(2) tests employed for group comparisons based on the data type.Least absolute shrinkage and selection operator regression was applied to identify influencing factors and reduce the impact of multicollinear predictors among variables.Multivariate analysis was carried out using Logistic regression.Based on the identified risk factors,a risk prediction model for POCD in CRC patients was developed,and the predictive value of these risk factors was evaluated.RESULTS Significant differences were observed between the cognitive dysfunction group and the non-cognitive dysfunction group in diabetes status,alcohol consumption,years of education,anesthesia duration,intraoperative blood loss,intraoperative hypoxemia,use of DEX during surgery,intraoperative use of vasoactive drugs,surgical time,systemic inflammatory response syndrome(SIRS)score(P<0.05).Multivariate Logistic regression analysis identified that diabetes[odds ratio(OR)=4.679,95%confidence interval(CI)=1.382-15.833],alcohol consumption(OR=5.058,95%CI:1.255-20.380),intraoperative hypoxemia(OR=4.697,95%CI:1.380-15.991),no use of DEX during surgery(OR=3.931,95%CI:1.383-11.175),surgery duration≥90 minutes(OR=4.894,95%CI:1.377-17.394),and a SIRS score≥3(OR=4.133,95%CI:1.323-12.907)were independent risk factors for POCD in CRC patients(P<0.05).A risk prediction model for POCD was constructed using diabetes,alcohol consumption,intraoperative hypoxemia,non-use of DEX during surgery,surgery duration,and SIRS score as factors.A receiver operator characteristic curve analysis of these factors revealed the model’s predictive sensitivity(88.56%),specificity(70.64%),and area under the curve(AUC)(AUC=0.852,95%CI:0.773-0.919).The model was validated using 42 CRC patients who met the inclusion criteria,demonstrating sensitivity(80.77%),specificity(81.25%),and accuracy(80.95%),and AUC(0.805)in diagnosing cognitive impairment,with a 95%CI:0.635-0.896.CONCLUSION Logistic regression analysis identified that diabetes,alcohol consumption,intraoperative hypoxemia,non-use of DEX during surgery,surgery duration,and SIRS score vigorously influenced the occurrence of POCD.The risk prediction model based on these factors demonstrated good predictive performance for POCD in CRC individuals.This study offers valuable insights for clinical practice and contributes to the prevention and management of POCD under CRC circumstances.
文摘BACKGROUND To investigate whether seasonal differences in ambient temperature affect the incidence of early postoperative cognitive dysfunction(POCD)among elderly patients undergoing laparoscopic surgery in tropical regions.Additionally,it explored the perioperative risk factors associated with early POCD following abdominal laparoscopic surgery.AIM To investigate the influence of seasonal differences in ambient temperature on POCD of elderly patients METHODS A total of 125 patients aged≥65 years from Hainan Province,China,who underwent laparoscopic surgery under general anesthesia with tracheal intubation,were enrolled. All patients completed the Mini-Mental State Examination one day before surgery and onpostoperative days 1, 3, and 7. A decline of ≥ 2 points from baseline was considered indicative of cognitivedysfunction. Serum levels of S100 calcium binding protein B and neuron-specific enolase were measured usingenzyme-linked immunosorbent assay at three time points: Preoperatively, immediately after extubation, and 24hours postoperatively. Perioperative clinical data were collected to identify potential risk factors for POCD.Propensity score matching (PSM) was performed (1:1, caliper = 0.03), resulting in 41 matched patient pairs betweenwinter and summer groups.RESULTSAfter PSM, baseline characteristics including age, gender, body mass index, education level, comorbidities, andsurgical variables were well balanced between groups. There were no significant differences in the incidence ofPOCD on postoperative days 1, 3, and 7 between patients undergoing laparoscopic surgery in winter vs summer.However, multivariable logistic regression revealed that surgical duration (day 1, P value = 0.049), advanced ageand elevated creatinine (day 3, P value = 0.044, P value = 0.008), and hypoalbuminemia (day 3, P value = 0.042;day7, P value = 0.015) were independently associated with early POCD.CONCLUSIONAmbient temperature differences between winter and summer in tropical regions did not significantly affect theincidence of early POCD in elderly patients undergoing laparoscopic surgery. Nonetheless, age, longer surgicalduration, elevated creatinine, and hypoalbuminemia emerged as key risk factors. These findings underscore theimportance of perioperative optimization to reduce the risk of POCD in elderly patients, regardless of seasonaltemperature variations.
基金Supported by the Natural Science Foundation of Hebei Province,No.H2021206187 and No.H2021206452.
文摘BACKGROUND Diabetic cognitive dysfunction(DCD)is one of the chronic complications of diabetes,but its mechanism is currently unknown.Studies have shown that mitochondrial fission mediated by calcium overload is an important mechanism of DCD.Blocking calcium overload and restoring calcium homeostasis are key steps in treatment.Transient receptor potential melastatin 7(TRPM7)is a novel player in causing calcium overload.Our previous studies have shown that genetic silencing of TRPM7 in type 1 diabetic rats leads to significant improvements in cognitive function,but the specific mechanism remains unclear.Troxerutin,extracted from the flowers of Sophora japonica,is one of the derivatives of rutin and has been shown to have neuroprotective effects.However,its association with TRPM7 remains unclear.AIM To use animal and cellular models,we investigated whether TRPM7 mediated mitochondrial fission by upregulation of calcineurin(CaN)/dynamin-related protein 1(Drp1)ser637 in DCD,and whether Troxerutin improved DCD by inhibiting TRPM7-mediated mitochondrial division.METHODS In this study,we used db/db mice and hippocampal neuronal cell lines(HT22)treated with high-concentration glucose as our study subjects.We evaluated cognitive function using Morris water maze,novel object recognition tasks,and Nesting tests.We observed mitochondrial morphology using transmission electron microscopy and measured mitochondrial energy metabolism indicators using a spectrophotometer.We also detected mRNA and protein expression of TRPM7,CaN,p-Drp1^(ser637),caspase-3,B-cell lymphoma 2 associated X protein,and B-cell lymphoma 2 using quantitative real-time polymerase chain reaction,western blotting,and immunofluorescence.RESULTS In the db/db diabetic mice with cognitive dysfunction,as well as in hippocampal neurons exposed to high-concentration glucose,TRPM7 and CaN expression were upregulated,phosphorylated Drp1^(ser637)expression was downregulated,and mitochondrial fission was increased.By modulating(inhibiting or overexpressing)TRPM7,it was further validated that TRPM7 activates the CaN/Drp1^(ser637)pathway,resulting in an increase in mitochondrial fission and neuronal cell apoptosis.Troxerutin downregulated TRPM7/CaN/Drp1^(ser637),reduced mitochondrial fission,and improved DCD.CONCLUSION TRPM7 promotes mitochondrial fission via the CaN/Drp1^(ser637)pathway.Troxerutin improves mitochondrial function and reduces neuronal damage by inhibiting this pathway,suggesting TRPM7 as a potential therapeutic target for DCD.
基金Supported by the National Natural Science Foundation of China,No.82300894.
文摘BACKGROUND Diabetes is associated with increased cognitive decline and dementia due to the loss of myelinated nerve fiber function,which is linked to oligodendrocyte dysfunction.The voltage-gated proton channel 1(Hv1)is important for the cellular proton extrusion machinery.However,its role in regulating diabetesinduced cognitive dysfunction is unclear.AIM To investigate the role of Hv1 in cognitive impairment induced by diabetes and its potential mechanisms,focusing on neuroinflammation,oligodendrocyte apoptosis,and axonal demyelination.METHODS A diabetes model was established by administering a high-fat diet and streptozotocin injections in mice.Hv1 knockout(KO)and wild-type mice were used to evaluate cognitive function via behavioral tests and neuroinflammation using immunofluorescence.Oligodendrocyte apoptosis was assessed with the terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay, and axonal demyelination wasanalyzed using electron microscopy.RESULTSHv1 expression was significantly increased in the corpus callosum of diabetic mice. Hv1 KO alleviated cognitiveimpairment, reduced oligodendrocyte apoptosis, and decreased the expression of inflammatory factors, includinginterleukin-1 and tumor necrosis factor-α, in diabetic mice. Electron microscopy revealed a reduction in myelinthickness and an increased g-ratio in diabetic mice, which were reversed by Hv1 KO.CONCLUSIONHv1 plays a role in diabetes-induced cognitive dysfunction by modulating neuroinflammation and myelinintegrity. Hv1 KO demonstrates therapeutic potential in mitigating diabetes-related cognitive decline andassociated complications.
基金supported by the Nature Science Foundation of Liaoning Province,Nos.2022-MS-211,2021-MS-064,and 2024-MS-048(all to YC).
文摘Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer’s disease.Conventional drugs,such as donepezil,can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline.Currently,active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer’s disease and other transgenic animal models,attracting considerable attention.However,the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab.This review first discusses the advancements in the pathogenesis of Alzheimer’s disease and active and passive immunotherapies targeting amyloid-beta and tau proteins.Furthermore,it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects.Although some antibodies have shown promise in patients with mild Alzheimer’s disease,substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer’s disease.
基金supported by the National Institutes of Health(grant numbers R01NS089737,RF1NS130881,and R21AG089974,to QC).
文摘Phosphatidylethanolamine is a major phospholipid class abundant in the brain,particularly in the inner leaflet of the plasma and mitochondrial membranes.Although it is primarily synthesized from phosphatidylserine via decarboxylation in mitochondria or from ethanolamine via the cytidine diphosphate-ethanolamine pathway in the endoplasmic reticulum,phosphatidylethanolamine that resides in mitochondria is preferentially produced locally and is distinct and separate from the pool of phosphatidylethanolamine made in the endoplasmic reticulum.Mitochondria-derived phosphatidylethanolamine is not only essential for mitochondrial integrity but also is exported to other organelles to fulfill diverse cellular functions.Neurons are highly enriched with phosphatidylethanolamine,and the importance of phosphatidylethanolamine metabolism in neuronal health has recently been recognized following its reported links to Alzheimer’s disease,Parkinson’s disease,and hereditary spastic paraplegia,among other neurological disorders.Indeed,disturbances in mitochondrial function and phosphatidylethanolamine metabolism and the resulting neuronal dysfunction are the common features of individuals suffering from these diseases,highlighting the great importance of maintaining proper phosphatidylethanolamine homeostasis in neurons.In this review,we summarize the current knowledge of phosphatidylethanolamine metabolism and its role in neuronal function with a special emphasis on the phosphatidylethanolamine biosynthetic pathway in mitochondria.We then review findings on how phosphatidylethanolamine biosynthesis is affected in major neurodegenerative diseases.Finally,we highlight promising future research areas that will help advance the understanding of neuronal phosphatidylethanolamine mechanisms and identify phosphatidylethanolamine-targeted therapeutic strategies for combating such brain diseases.
基金supported by the Research Cultivation Project of Beijing Municipal Hospital(北京市属医院科研培育课题,No.PZ2022015).
文摘Objective:To observe the efficacy of acupuncture combined with traditional Chinese herbs in the treatment of poststroke vascular dementia(VD)and the effects on serum interleukin(IL)-6 and superoxide dismutase(SOD).Methods:A total of 240 patients with poststroke VD were selected and randomly divided into two groups according to the random number table method,with 120 cases in each group.Both groups received Hua Tan Tong Luo(phlegmresolving and collateral-activating)formula,once daily;the observation group was additionally treated with Yi Shen Tiao Du(kidney-tonifying and Governor Vessel-regulating)acupuncture once daily for 6 consecutive days,followed by 1 d of rest.Both groups were treated for 15 d as one course,for a total of 2 courses.After treatment,the total effective rate was compared.Changes in scores of traditional Chinese medicine(TCM)symptoms,clinical dementia rating(CDR),National Institutes of Health stroke scale(NIHSS),and Chinese version of mini-mental state examination(MMSE),and serum levels of IL-6 and SOD were observed in both groups.Results:The total effective rate in the observation group was higher than that in the control group(P<0.05).After treatment,TCM symptom,CDR,and NIHSS scores,and serum IL-6 levels in both groups were lower than those before treatment(P<0.05),while MMSE scores and serum SOD levels were higher than those before treatment(P<0.05).After treatment,the observation group showed lower TCM symptom,CDR,and NIHSS scores,and serum IL-6 levels than the control group(P<0.05),and higher MMSE scores and serum SOD levels than the control group(P<0.05).Conclusion:Compared to Hua Tan Tong Luo formula alone,Yi Shen Tiao Du acupuncture combined with Hua Tan Tong Luo formula demonstrates better efficacy in reducing dementia severity,improving cognitive and neurological function,and inhibiting inflammation in patients with poststroke VD.
基金supported by the National Natural Science Foundation of China,Nos. 82173806 and U1803281Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science,Nos. 2021-I2M-1-030 and 2022-I2M-2-002Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences,No. 2022-JKCS-08 (all to RL)。
文摘Long noncoding RNA and microRNA are regulatory noncoding RNAs that are implicated in Alzheimer's disease, but the role of long noncoding RNA-associated competitive endogenous RNA has not been fully elucidated. The long noncoding RNA growth arrest-specific 5(GAS5) is a member of the 5′-terminal oligopyrimidine gene family that may be involved in neurological disorders, but its role in Alzheimer's disease remains unclear. This study aimed to investigate the function of GAS5 and construct a GAS5-associated competitive endogenous RNA network comprising potential targets. RNA sequencing results showed that GAS5 was upregulated in five familial Alzheimer's disease(5×FAD) mice, APPswe/PSEN1dE9(APP/PS1) mice, Alzheimer's disease-related APPswe cells, and serum from patients with Alzheimer's disease. Functional experiments with targeted overexpression and silencing demonstrated that GAS5 played a role in cognitive dysfunction and multiple Alzheimer's disease-associated pathologies, including tau hyperphosphorylation, amyloid-beta accumulation, and neuronal apoptosis. Mechanistic studies indicated that GAS5 acted as an endogenous sponge by competing for microRNA-23b-3p(miR-23b-3p) binding to regulate its targets glycogen synthase kinase 3beta(GSK-3β) and phosphatase and tensin homologue deleted on chromosome 10(PTEN) expression in an Argonaute 2-induced RNA silencing complex(RISC)-dependent manner. GAS5 inhibited miR-23b-3p-mediated GSK-3β and PTEN cascades with a feedforward PTEN/protein kinase B(Akt)/GSK-3β linkage. Furthermore, recovery of GAS5/miR-23b-3p/GSK-3β/PTEN pathways relieved Alzheimer's disease-like symptoms in vivo, indicated by the amelioration of spatial cognition, neuronal degeneration, amyloid-beta load, and tau phosphorylation. Together, these findings suggest that GAS5 promotes Alzheimer's disease pathogenesis. This study establishes the functional convergence of the GAS5/miR-23b-3p/GSK-3β/PTEN pathway on multiple pathologies, suggesting a candidate therapeutic target in Alzheimer's disease.
文摘Inflammation may play a role in postoperative cognitive dysfunction. 5＇ Adenosine monophos- phate-activated protein kinase, nuclear factor-kappa B, interleukin-1β, and tumor necrosis factor-a are involved in inflammation. Therefore, these inflammatory mediators may be involved in postoperative cognitive dysfunction. Western immunoblot analysis revealed 5＇ adenosine mo- nophosphate-activated protein kinase and nuclear factor-kappa B in the hippocampus of aged rats were increased 1-7 days after splenectomy. Moreover, interleukin-1β and tumor necrosis fac- tor-α were upregulated and gradually decreased. Therefore, these inflammatory mediators may participate in the splenectomy model of postoperative cognitive dysfunction in aged rats.
基金This review was supported by the National Key R&D Program of China(2016YFC1306900)the National Natural Science Foundation of China(81622018)an Innovation Driven Project of Central South University(2020CX018).
文摘The causal mechanisms and treatment for the negative symptoms and cognitive dysfunction in schizophrenia are the main issues attracting the attention of psychiatrists over the last decade.The first part of this review summarizes the pathogenesis of schizophrenia,especially the negative symptoms and cognitive dysfunction from the perspectives of genetics and epigenetics.The second part describes the novel medications and several advanced physical therapies(e.g.,transcranial magnetic stimulation and transcranial direct current stimulation)for the negative symptoms and cognitive dysfunction that will optimize the therapeutic strategy for patients with schizophrenia in future.
基金supported by the National Natural Science Foundation of China,No.30871306
文摘This study established an aged rat model of cognitive dysfunction using anesthesia with 2% iso- flurane and 80% oxygen for 2 hours. Twenty-four hours later, Y-maze test results showed that isoflurane significantly impaired cognitive function in aged rats. Gas chromatography-mass spectrometry results showed that isoflurane also significantly increased the levels of N,N-diethy- lacetamide, n-ethylacetamide, aspartic acid, malic acid and arabinonic acid in the hippocampus of isoflurane-treated rats. Moreover, aspartic acid, N,N-diethylacetamide, n-ethylacetamide and malic acid concentration was positively correlated with the degree of cognitive dysfunction in the isoflurane-treated rats. It is evident that hippocampal metabolite changes are involved in the formation of cognitive dysfunction after isoflurane anesthesia. To further verify these results, this study cultured hippocampal neurons in vitro, which were then treated with aspartic acid （100 μmol/L）. Results suggested that aspartic acid concentration in the hippocampus may be a biomarker for predicting the occurrence and disease progress of cognitive dysfunction.
基金supported by the Foundation of Shandong Science and Technology Project(No.2011YD18070),China
文摘Objective： To explore the relationship of postoperative cognitive dysfunction （POCD） in one-lung ventilation （OLV） patients and regional cerebral oxygen saturation （rSO2）. Methods： Twenty-nine male and twenty-one female cases of OLV received thoracic surgery, with American Standards Association （ASA） physical status being at Grades Ⅰ-Ⅲ. Neuropsychological tests were performed on the day before operation and 7 d after operation, and there was an intraoperative continuous monitoring of rSO2. The values of rSO2 before anesthesia induction （t1）, at the beginning of OLV （t2）, and at the time of OLV 30 min （t3）, OLV 60 min （t4）, the end of OLV （t5）, and the end of surgery （t6） were recorded. The intraoperative average of rSO2 （ rSO2 ）, the intraoperative minimum value of rSO2 （rSO2, rn=n）, and the reduced maximum percentage of rSO2 （rSO2, %max） when compared with the baseline value were calculated. The volume of blood loss, urine output, and the amount of fluid infusion was recorded. Results： A total of 14 patients （28%） in the 50 cases suffered from POCD. The values of mini-mental state examination （MMSE）, the digit span and the digit symbol on the 7th day after the operation for POCD in OLV patients were found to be significantly lower than those before the operation （P〈0.05）. The values of MMSE and vocabulary fluency scores were significantly lower than those in the non-POCD group （P〈0.05）. The values of rSO2 in the POCD group of OLV patients at t2 and t3 and the values of rSO2 in the non-POCD group at t2 were found to be significantly higher than those at tl （P〈0.05）. The values of rSO2, %max in the POCD group were significantly higher than those in the non-POCD group （P〈0.05）. When the value of rSO2, %max is more than 10.1%, it may act as an early warning index for cognitive function changes, Conclusions： POCD after OLV may be associated with a decline in rSO2.
基金supported by the National Natural Science Foundation of China(81872654,81703264)Fundamental Research Funds of Shandong University(2016JC020),ChinaNatural Science Foundation of Shandong Province(ZR2017MH002),China
文摘Occupational exposure to 1-bromopropane(1-BP) induces learning and memory deficits. However, no therapeutic strategies are currently available. Accumulating evidence has suggested that N-methyl-D-aspartate receptors(NMDARs) and neuroinflammation are involved in the cognitive impairments in neurodegenerative diseases. In this study we aimed to investigate whether the noncompetitive NMDAR antagonist MK801 protects against 1-BPinduced cognitive dysfunction. Male Wistar rats were administered with MK801(0.1 mg/kg) prior to 1-BP intoxication(800 mg/kg). Their cognitive performance was evaluated by the Morris water maze test. The brains of rats were dissected for biochemical, neuropathological,and immunological analyses. We found that the spatial learning and memory were significantly impaired in the1-BP group, and this was associated with neurodegeneration in both the hippocampus(especially CA1 and CA3)and cortex. Besides, the protein levels of phosphorylated NMDARs were increased after 1-BP exposure. MK801 ameliorated the 1-BP-induced cognitive impairments and degeneration of neurons in the hippocampus and cortex.Mechanistically, MK801 abrogated the 1-BP-induced disruption of excitatory and inhibitory amino-acid balance and NMDAR abnormalities. Subsequently, MK801 inhibited the microglial activation and release of pro-inflammatory cytokines in 1-BP-treated rats. Our findings, for the first time, revealed that MK801 protected against 1-BP-induced cognitive dysfunction by ameliorating NMDAR function and blocking microglial activation, which might provide a potential target for the treatment of 1-BP poisoning.
基金supported by the National Natural Science Foundation of China,No.82101463(to GWH)Natural Science Foundation of Jiangxi Provincial Science and Technology Department,No.20202BAB216013(to HLL)+1 种基金Jiangxi Provincial Health Commission General Science and Technology Project,No.202130370(to HLL)The Second Affiliated Hospital of Nanchang University’s Youth Innovation Team of Science and Technology Program,No.2019YNQN12009(to HLL)。
文摘Postoperative cognitive dysfunction(POCD)is a common surgical complication.Diabetes mellitus(DM)increases risk of developing POCD after surgery.DM patients with POCD seriously threaten the quality of patients’life,however,the intrinsic mechanism is unclear,and the effective treatment is deficiency.Previous studies have demonstrated neuronal loss and reduced neurogenesis in the hippocampus in mouse models of POCD.In this study,we constructed a mouse model of DM by intraperitoneal injection of streptozotocin,and then induced postoperative cognitive dysfunction by transient bilateral common carotid artery occlusion.We found that mouse models of DM-POCD exhibited the most serious cognitive impairment,as well as the most hippocampal neural stem cells(H-NSCs)loss and neurogenesis decline.Subsequently,we hypothesized that small extracellular vesicles secreted by induced pluripotent stem cell-derived mesenchymal stem cells(iMSC-sEVs)might promote neurogenesis and restore cognitive function in patients with DM-POCD.iMSC-sEVs were administered via the tail vein beginning on day 2 after surgery,and then once every 3 days for 1 month thereafter.Our results showed that iMSC-sEVs treatment significantly recovered compromised proliferation and neuronal-differentiation capacity in H-NSCs,and reversed cognitive impairment in mouse models of DM-POCD.Furthermore,miRNA sequencing and qPCR showed miR-21-5p and miR-486-5p were the highest expression in iMSC-sEVs.We found iMSC-sEVs mainly transferred miR-21-5p and miR-486-5p to promote H-NSCs proliferation and neurogenesis.As miR-21-5p was demonstrated to directly targete Epha4 and CDKN2C,while miR-486-5p can inhibit FoxO1 in NSCs.We then demonstrated iMSC-sEVs can transfer miR-21-5p and miR-486-5p to inhibit EphA4,CDKN2C,and FoxO1 expression in H-NSCs.Collectively,these results indicate significant H-NSC loss and neurogenesis reduction lead to DM-POCD,the application of iMSC-sEVs may represent a novel cell-free therapeutic tool for diabetic patients with postoperative cognitive dysfunction.
基金Project supported by the Shandong Science and Technology Development Project(No.2011YD18070),China
文摘Objective： To investigate the relationship between post-operative cognitive dysfunction（POCD） and regional cerebral oxygen saturation（rSO2） and β-amyloid protein（Aβ） in patients undergoing laparoscopic pancreaticoduodenectomy. Methods： Fifty patients undergoing elective laparoscopic pancreaticoduodenectomy received five groups of neuropsychological tests 1 d pre-operatively and 7 d post-operatively, with continuous monitoring of rSO2 intra-operatively. Before anesthesia induction（t0）, at the beginning of laparoscopy（t1）, and at the time of pneumoperitoneum 120 min（t2）, pneumoperitoneum 240 min（t3）, pneumoperitoneum 480 min（t4）, the end of pneumoperitoneum（t5）, and 24 h after surgery, jugular venous blood was drawn respectively for the measurement of Aβ by enzyme-linked immunosorbent assay（ELISA）. Results： Twenty-one cases of the fifty patients suffered from POCD after operation. We found that the maximum percentage drop in rSO2（rSO2, %max） was significantly higher in the POCD group than in the non-POCD group. The rSO2, %max value of over 10.2% might be a potential predictor of neurocognitive injury for those patients. In the POCD group, the plasma Aβ levels after 24 h were significantly higher than those of pre-operative values（P〈0.01）. After 24 h, levels of plasma Aβ in the POCD group were significantly higher than those in the non-POCD group（P〈0.01）. Conclusions： The development of POCD in patients undergoing laparoscopic pancreaticoduodenectomy is associated with alterations of rSO2 and Aβ. Monitoring of rSO2 might be useful in the prediction of POCD, and Aβ might be used as a sensitive biochemical marker to predict the occurrence of POCD.
基金Supported by The Endocrine Clinical Medical Center of Yunnan ProvinceNo.ZX20190202+2 种基金the Fund of the Diabetic Innovation Team in Yunnan Province,No.2019HC002the Special Joint Fund from Yunnan Provincial Department of Science and Technology and Kunming Medical University,Kunming,Yunnan,China,No.2018FE001(-267)the SKY Image Research Fund,China,No. Z-2014-07-2003-12。
文摘BACKGROUND Type 2 diabetes mellitus(T2DM) has been strongly associated with an increased risk of developing cognitive dysfunction and dementia.The mechanisms of diabetes-associated cognitive dysfunction(DACD) have not been fully elucidated to date.Some studies proved lower cerebral blood flow(CBF) in the hippocampus was associated with poor executive function and memory in T2DM.Increasing evidence showed that diabetes leads to abnormal vascular endothelial growth factor(VEGF) expression and CBF changes in humans and animal models.In this study,we hypothesized that DACD was correlated with CBF alteration as measured by three-dimensional(3D) arterial spin labeling(3D-ASL) and VEGF expression in the hippocampus.AIM To assess the correlation between CBF(measured by 3D-ASL and VEGF expression) and DACD in a rat model of T2DM.METHODS Forty Sprague-Dawley male rats were divided into control and T2DM groups.The T2DM group was established by feeding rats a high-fat diet and glucose to induce impaired glucose tolerance and then injecting them with streptozotocin to induce T2DM.Cognitive function was assessed using the Morris water maze experiment.The CBF changes were measured by 3D-ASL magnetic resonance imaging.VEGF expression was determined using immunofluorescence.RESULTS The escape latency time significantly reduced 15 wk after streptozotocin injection in the T2DM group.The total distance traveled was longer in the T2DM group;also,the platform was crossed fewer times.The percentage of distance in the target zone significantly decreased.CBF decreased in the bilateral hippocampus in the T2DM group.No difference was found between the right CBF value and the left CBF value in the T2DM group.The VEGF expression level in the hippocampus was lower in the T2DM group and correlated with the CBF value.The escape latency negatively correlated with the CBF value.The number of rats crossing the platform positively correlated with the CBF value.CONCLUSION Low CBF in the hippocampus and decreased VEGF expression might be crucial in DACD.CBF measured by 3D-ASL might serve as a noninvasive imaging biomarker for cognitive impairment associated with T2DM.
文摘The incidence of diabetes is gradually increasing in China,and diabetes and associated complications,such as cognitive dysfunction have gained much attention in recent time.However,the concepts,clinical treatment,and prevention of cognitive dysfunction in patients with diabetes remain unclear.The Chinese Society of Endocrinology investigated the current national and overseas situation of cognitive dysfunction associated with diabetes.Based on research both in China and other countries worldwide,the Expert Consensus on Cognitive Dysfunction in Diabetes was established to guide physicians in the comprehensive standardized management of cognitive dysfunction in diabetes and to improve clinical outcomes in Chinese patients.This consensus presents an overview,definition and classification,epidemiology and pathogenesis,risk factors,screening,diagnosis,differential diagnosis,treatment,and prevention of cognitive dysfunction in patients with diabetes.
