BACKGROUND:Studies have shown that there is a close relationship between dendritic spine plasticity and Alzheimer's disease,and that resistance or aerobic exercise has some efficacy in improving cognitive dysfunction,but the mechanism of action is unclear.OBJECTIVE:To investigate the effect of aerobic exercise or resistance exercise on dendritic spine plasticity in the hippocampal CA1 region of APP/PS1 transgenic mice.METHODS:Thirty 3-month-old male APP/PS1 mice were selected and randomly divided into three groups:a model group,a resistance exercise group,and an aerobic exercise group.The same litter of 3-month-old C57BL/6J mice were selected as a blank group.Mice in the resistance exercise group were subjected to ladder-climbing exercise and those in the aerobic exercise group were subjected to treadmill exercise for 12 weeks.At the end of the exercise intervention,the water maze experiment and the new arm of the Y maze were used to assess behavioral changes in mice.Hematoxylin-eosin staining,Nissl staining,Golgi staining,and electron microscopy were performed to observe neuronal morphology,Nissl bodies,dendritic spines,and ultrastructural changes in the synapses of the hippocampal region of the mouse brain.The protein expression levels of hippocampal amyloid-beta1-42,Ras,and Drebrin were measured using Western blot analysis.RESULTS AND CONCLUSION:Mice in the model group exhibited a prolonged escape latency over 5 consecutive days(P＜0.05,P＜0.01)and significantly fewer entries into the new arm of the Y maze(P＜0.01).Dendritic spine density in the CA1 region of the hippocampus,as well as Ras and Drebrin expression in the hippocampal tissues of mice in the model group,were lower than those in the normal group(P＜0.01),and amyloid-beta1-42 expression in the hippocampal tissues was higher in the model group compared with the normal group(P＜0.01).Mice in the resistance exercise group and the aerobic exercise group displayed a shortened escape latency over the same 5-day period(P＜0.05,P＜0.01)and showed a significantly greater number of entries into the new arm of the Y maze compared with the normal group(P＜0.01).Dendritic spine density in the CA1 region of the hippocampus,as well as Ras and Drebrin expression in the hippocampal tissues,were higher in both the resistance exercise group and the aerobic exercise group compared with the model group(P＜0.01).Amyloid-beta1-42 expression in the hippocampal tissue was lower in both exercise groups than in the model group(P＜0.01).To conclude,long-term regular aerobic or resistance exercise interventions can increase dendritic spine density and synaptic plasticity in the CA1 region of the hippocampus,enhancing spatial learning and memory abilities in a mouse model of Alzheimer's disease.These effects may be associated with increased expression of Ras and Drebrin proteins in the hippocampus.

Objective To identify serum metabolic markers served in the clinical diagnosis of ulcerative colitis(UC).Methods Ser-um samples from 29 UC patients,31 Crohn's disease(CD)patients,and 21 matched healthy controls(HC)admitted to Department of Gastroenterology,Nanjing Drum Tower Hospital during September 2022 and March 2024 were collected.The ultra-high-performance liquid chromatography coupled with quadrupole-orbitrap mass spectrometry(UHPLC-Q Exactive HF-X)technology was used to detect and analyze serum metabolites.A partial least squares discrimination analysis(PLS-DA)model was constructed,and the metabolites significantly up-regulated in UC were screened based on the variable importance in projection(VIP)score＞1,P value＜0.05,and fold change(FC)＞1.2.The pathway enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes(KEGG)database to reveal the biological pathways involved in the metabolites.The area under the receiver operating characteristic curve(AUCROC)was calculated to evaluate the diagnostic potential of the differential metabolites.Results A total of 1 522 metabo-lites were identified from the three sample groups.Among them,4 metabolites,namely leucodopachrome(VIP=1.964,P＜0.05,FC=1.916),tetrahydrodipicolinate(VIP=1.74,P＜0.05,FC=2.65),N-ethylmaleimide(VIP=1.519,P＜0.05,FC=1.597),and 5,6-dihydroxyindole(VIP=3.018,P＜0.05,FC=1.575),were significantly up-regulated in UC.Their AUCROC values for distinguishing UC from CD were 0.788(95%CI:0.655-0.921),0.773(95%CI:0.639-0.907),0.834(95%CI:0.720-0.949),and 0.899(95%CI:0.821-0.977),respectively,while those for distinguishing UC from HC were 0.966(95%CI:0.924-1.000),0.926(95%CI:0.857-0.995),0.969(95%CI:0.928-1.000),and 0.910(95%CI:0.830-0.990),respectively.KEGG pathway analysis showed that the up-regulated metabolites in UC were primarily enriched in biological pathways such as tyrosine metabolism,glycerophospholipid me-tabolism,and arachidonic acid metabolism.Conclusion The serum metabolic profile of UC patients is significantly changed,and the four differential metabolites mentioned above may serve as effective biomarkers for the differential diagnosis of UC,CD,and HC.

AIM:This study aimed to investigate the mechanisms by which treadmill exercise ameliorates de-pressive-like behaviors and hippocampal neuronal damage in chronic restraint stress(CRS)mice by regulating mitophagy via the Sirt1/PGC-1α signaling axis.METHODS:Forty C57BL/6J mice were randomly assigned to control,CRS,CRS+exercise(EXE)and EXE groups(n=10).The mice in CRS and CRS+EXE groups underwent 4 h of daily restraint for 28 consecutive days to establish a depression model.The mice in CRS+EXE and EXE groups received 8 weeks of treadmill training(6 sessions per week).Depressive-like behaviors were evaluated using the open field test,sucrose preference test,and tail suspension test.Hippocampal neuronal morphology and pathological changes were examined using hematoxy-lin-eosin and Nissl staining,while neuronal apoptosis was assessed through TUNEL staining.Mitochondrial ultrastructure was examined via transmission electron microscopy.Mitochondrial membrane potential and ATP content were measured using JC-1 assay and ATP assay kits,respectively.The expression levels of silent information regulator 1(Sirt1),peroxi-some proliferator-activated receptor γ coactivator-1α(PGC-1α),PTEN-induced kinase 1(PINK1)and parkin were as-sessed at both mRNA and protein levels by RT-qPCR and Western blot assays,as well as key markers of mitophagy[mi-crotubule-associated protein 1 light chain 3(LC3)and P62]and apoptosis(cleaved caspase-9 and cleaved caspase-3).RESULTS:Compared with control group,CRS mice exhibited significantly reduced central zone entries and time(P<0.01),decreased sucrose preference(P<0.01),increased immobility time(P<0.01),severe hippocampal neuronal damage,elevated apoptosis rate(P<0.01),mitochondrial deterioration;reduced membrane potential and ATP content(P<0.01),decreased mRNA expressions of Sirt1,PGC-1α,PINK1,and parkin(P<0.01),reduced protein levels of Sirt1,PGC-1α,PINK1,parkin and LC3(P<0.01),and increased expression of P62,cleaved caspase-9,and cleaved caspase-3(P<0.01).The mice in CRS+EXE group showed significant improvements in all these parameters compared to CRS group(P<0.05 or P<0.01).CONCLUSION:Treadmill exercise mitigates CRS-induced depressive-like behaviors,mi-tochondrial dysfunction,and neuronal apoptosis in mice by activating the hippocampal Sirt1/PGC-1α/mitophagy axis.

Objective To identify serum metabolic markers served in the clinical diagnosis of ulcerative colitis(UC).Methods Ser-um samples from 29 UC patients,31 Crohn's disease(CD)patients,and 21 matched healthy controls(HC)admitted to Department of Gastroenterology,Nanjing Drum Tower Hospital during September 2022 and March 2024 were collected.The ultra-high-performance liquid chromatography coupled with quadrupole-orbitrap mass spectrometry(UHPLC-Q Exactive HF-X)technology was used to detect and analyze serum metabolites.A partial least squares discrimination analysis(PLS-DA)model was constructed,and the metabolites significantly up-regulated in UC were screened based on the variable importance in projection(VIP)score＞1,P value＜0.05,and fold change(FC)＞1.2.The pathway enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes(KEGG)database to reveal the biological pathways involved in the metabolites.The area under the receiver operating characteristic curve(AUCROC)was calculated to evaluate the diagnostic potential of the differential metabolites.Results A total of 1 522 metabo-lites were identified from the three sample groups.Among them,4 metabolites,namely leucodopachrome(VIP=1.964,P＜0.05,FC=1.916),tetrahydrodipicolinate(VIP=1.74,P＜0.05,FC=2.65),N-ethylmaleimide(VIP=1.519,P＜0.05,FC=1.597),and 5,6-dihydroxyindole(VIP=3.018,P＜0.05,FC=1.575),were significantly up-regulated in UC.Their AUCROC values for distinguishing UC from CD were 0.788(95%CI:0.655-0.921),0.773(95%CI:0.639-0.907),0.834(95%CI:0.720-0.949),and 0.899(95%CI:0.821-0.977),respectively,while those for distinguishing UC from HC were 0.966(95%CI:0.924-1.000),0.926(95%CI:0.857-0.995),0.969(95%CI:0.928-1.000),and 0.910(95%CI:0.830-0.990),respectively.KEGG pathway analysis showed that the up-regulated metabolites in UC were primarily enriched in biological pathways such as tyrosine metabolism,glycerophospholipid me-tabolism,and arachidonic acid metabolism.Conclusion The serum metabolic profile of UC patients is significantly changed,and the four differential metabolites mentioned above may serve as effective biomarkers for the differential diagnosis of UC,CD,and HC.

AIM:This study aimed to investigate the mechanisms by which treadmill exercise ameliorates de-pressive-like behaviors and hippocampal neuronal damage in chronic restraint stress(CRS)mice by regulating mitophagy via the Sirt1/PGC-1α signaling axis.METHODS:Forty C57BL/6J mice were randomly assigned to control,CRS,CRS+exercise(EXE)and EXE groups(n=10).The mice in CRS and CRS+EXE groups underwent 4 h of daily restraint for 28 consecutive days to establish a depression model.The mice in CRS+EXE and EXE groups received 8 weeks of treadmill training(6 sessions per week).Depressive-like behaviors were evaluated using the open field test,sucrose preference test,and tail suspension test.Hippocampal neuronal morphology and pathological changes were examined using hematoxy-lin-eosin and Nissl staining,while neuronal apoptosis was assessed through TUNEL staining.Mitochondrial ultrastructure was examined via transmission electron microscopy.Mitochondrial membrane potential and ATP content were measured using JC-1 assay and ATP assay kits,respectively.The expression levels of silent information regulator 1(Sirt1),peroxi-some proliferator-activated receptor γ coactivator-1α(PGC-1α),PTEN-induced kinase 1(PINK1)and parkin were as-sessed at both mRNA and protein levels by RT-qPCR and Western blot assays,as well as key markers of mitophagy[mi-crotubule-associated protein 1 light chain 3(LC3)and P62]and apoptosis(cleaved caspase-9 and cleaved caspase-3).RESULTS:Compared with control group,CRS mice exhibited significantly reduced central zone entries and time(P<0.01),decreased sucrose preference(P<0.01),increased immobility time(P<0.01),severe hippocampal neuronal damage,elevated apoptosis rate(P<0.01),mitochondrial deterioration;reduced membrane potential and ATP content(P<0.01),decreased mRNA expressions of Sirt1,PGC-1α,PINK1,and parkin(P<0.01),reduced protein levels of Sirt1,PGC-1α,PINK1,parkin and LC3(P<0.01),and increased expression of P62,cleaved caspase-9,and cleaved caspase-3(P<0.01).The mice in CRS+EXE group showed significant improvements in all these parameters compared to CRS group(P<0.05 or P<0.01).CONCLUSION:Treadmill exercise mitigates CRS-induced depressive-like behaviors,mi-tochondrial dysfunction,and neuronal apoptosis in mice by activating the hippocampal Sirt1/PGC-1α/mitophagy axis.

BACKGROUND:Studies have shown that there is a close relationship between dendritic spine plasticity and Alzheimer's disease,and that resistance or aerobic exercise has some efficacy in improving cognitive dysfunction,but the mechanism of action is unclear.OBJECTIVE:To investigate the effect of aerobic exercise or resistance exercise on dendritic spine plasticity in the hippocampal CA1 region of APP/PS1 transgenic mice.METHODS:Thirty 3-month-old male APP/PS1 mice were selected and randomly divided into three groups:a model group,a resistance exercise group,and an aerobic exercise group.The same litter of 3-month-old C57BL/6J mice were selected as a blank group.Mice in the resistance exercise group were subjected to ladder-climbing exercise and those in the aerobic exercise group were subjected to treadmill exercise for 12 weeks.At the end of the exercise intervention,the water maze experiment and the new arm of the Y maze were used to assess behavioral changes in mice.Hematoxylin-eosin staining,Nissl staining,Golgi staining,and electron microscopy were performed to observe neuronal morphology,Nissl bodies,dendritic spines,and ultrastructural changes in the synapses of the hippocampal region of the mouse brain.The protein expression levels of hippocampal amyloid-beta1-42,Ras,and Drebrin were measured using Western blot analysis.RESULTS AND CONCLUSION:Mice in the model group exhibited a prolonged escape latency over 5 consecutive days(P＜0.05,P＜0.01)and significantly fewer entries into the new arm of the Y maze(P＜0.01).Dendritic spine density in the CA1 region of the hippocampus,as well as Ras and Drebrin expression in the hippocampal tissues of mice in the model group,were lower than those in the normal group(P＜0.01),and amyloid-beta1-42 expression in the hippocampal tissues was higher in the model group compared with the normal group(P＜0.01).Mice in the resistance exercise group and the aerobic exercise group displayed a shortened escape latency over the same 5-day period(P＜0.05,P＜0.01)and showed a significantly greater number of entries into the new arm of the Y maze compared with the normal group(P＜0.01).Dendritic spine density in the CA1 region of the hippocampus,as well as Ras and Drebrin expression in the hippocampal tissues,were higher in both the resistance exercise group and the aerobic exercise group compared with the model group(P＜0.01).Amyloid-beta1-42 expression in the hippocampal tissue was lower in both exercise groups than in the model group(P＜0.01).To conclude,long-term regular aerobic or resistance exercise interventions can increase dendritic spine density and synaptic plasticity in the CA1 region of the hippocampus,enhancing spatial learning and memory abilities in a mouse model of Alzheimer's disease.These effects may be associated with increased expression of Ras and Drebrin proteins in the hippocampus.

Objective This study explores the efficacy and underlying mechanisms of combining rhCYGB with 5-FU to target hypoxia-induced treatment resistance in liver cancer.The aim is to develop a novel combinato-rial therapy strategy for improving outcomes in patients with refractory liver cancer.Methods The half-maximal inhibitory concentration(IC50)of drugs on liver cancer cells under normoxia and hypoxia was determined,and dose-response curves were generated to assess sensitivity to 5-FU.The combined effects of rhCYGB and 5-FU were analyzed withCompuSyn and SynergyFinder 3.0.Tumor stem cell sphere formation assays and flow cytometry for CD133-positive cells were conducted to evaluate the impact on cancer stemness.Wound healing assays assessed the effects on migration.Results The IC50 values under hypoxia exhibited a significant fold change compared to normoxia(P<0.05),specifically a 15.27-fold,4.25-fold,and 2.34-fold increase for Hep3B,Huh7,and HepG2 cells respectively.Assessment of drug combination effects demonstrated a synergistic interaction between 5-FU and rhCYGB.Compared to the 5-FU monotherapy group,the combination of 5-FU and rhCYGB exerted an inhibitory effect on the formation of liver cancer stem cell spheres(P<0.05)and significantly downregulated the proportion of CD133-positive subpopulations in Hep3B cells(P<0.05).Wound healing assay results revealed a synergistic inhibitory effect on the migration of Hep3B cells after 48 hours of treatment with rhCYGB combined with 5-FU undernormoxia(P<0.05).Conclusions The combination of rhCYGB and 5-FU demonstrates syner-gistic effects in liver cancer.The underlying mechanism may involve the modulation of stemness and cell migration capacity.

Objectives:Analyze the clinical characteristics of patients with primary antiphospholipid syndrome (PAPS) progressing to systemic lupus erythematosus (SLE).Explore the risk factors for the progression from PAPS to SLE.Methods:The clinical data of 262 patients with PAPS enrolled in Peking Union Medical College Hospital from February 2005 to September 2021 were evaluated. Assessments included demographic data, clinical manifestations, laboratory tests (serum levels of complement, anti-nuclear antibodies, anti-double-stranded DNA antibodies), treatment, and outcomes. Kaplan-Meier analysis was used to calculate the prevalence of SLE in patients with PAPS. Univariate Cox regression analysis was employed to identify the risk factors for PAPS progressing to SLE.Results:Among 262 patients with PAPS, 249 had PAPS (PAPS group) and 13 progressed to SLE (5.0%) (PAPS-SLE group). Univariate Cox regression analysis indicated that cardiac valve disease ( HR=6.360), positive anti-double-stranded DNA antibodies ( HR=7.203), low level of complement C3 ( HR=25.715), and low level of complement C4 ( HR=10.466) were risk factors for the progression of PAPS to SLE, whereas arterial thrombotic events ( HR=0.109) were protective factors ( P<0.05 for all). Kaplan-Meier analysis showed that the prevalence of SLE in patients suffering from PAPS with a disease course>10 years was 9%-15%. Hydroxychloroquine treatment had no effect on the occurrence of SLE in patients with PAPS ( HR=0.753, 95% CI 0.231-2.450, P=0.638). Patients with≥2 risk factors had a significantly higher prevalence of SLE compared with those with no or one risk factor (13-year cumulative prevalence of SLE 48.7% vs. 0 vs. 6.2%, P<0.001 for both). Conclusions:PAPS may progress to SLE in some patients. Early onset, cardiac-valve disease, positive anti-dsDNA antibody, and low levels of complement are risk factors for the progression of PAPS to SLE (especially in patients with≥2 risk factors). Whether application of hydroxychloroquine can delay this transition has yet to be demonstrated.

OBJECTIVE To investigate the role and mechanism of microRNA-125b (miR-125b) in downregulating ion channel-related protein expression in a cardiac hypertrophy model.METHODS① In vivo:Lentiviral vectors for miR-125b overexpression and knockdown were constructed,and male C57BL/6 mice were divided into the following groups:sham group (thoracotomy without virus injection),LV-miR-125b group (mmu-miR-125b mimic),LV-miR-125b-inhibitor group (mmu-miR-125b-inhibitor),and negative control group (LV-NC).The mice were raised under normal conditions for 4 weeks.The ultrastructural changes in myocardium tissue sections of LV-miR-125b mice were observed using trans-mission electron microscopy.The cardiac hypertrophy model in mice was established using thoracic aortic constriction (TAC).Echocardiography was performed to measure ejection fraction (EF) and frac-tional shortening (FS),and the ratio of heart weight to body weight (HW/BW),ratio of heart weight to tibia length (HW/TL),as well as the expression level of the myocardial hypertrophy marker β-myosin heavy chain (β-MHC) were calculated to evaluate the success of the TAC-induced hypertrophy model.Subse-quently,C57BL/6 mice were divided into four groups:Sham group,TAC model group,LV-miR-125b-inhibitor+TAC group,and LV-NC+TAC group.Protein expression levels of cardiac sodium channel (Nav1.5) and calcium channel (Cav1.2) were detected using Western blotting.RT-qPCR was performed to assess the levels of miR-125b and mRNA expression of myocardial hypertrophy markers,including atrial natriuretic peptide (ANP),brain natriuretic peptide (BNP),and β-MHC.② In vitro:Primary cultured neonatal Kunming mouse cardiomyocytes were divided into four groups:cell control group (no treatment),miR-125b overexpression group,miR-125b-inhibitor group,and negative control group (NC).RT-qPCR was used to detect the levels of miR-125b,ANP,BNP,and β-MHC.Western blotting and immunofluorescence were performed to assess the expression levels of Nav1.5 and Cav1.2 in the cardiomyocytes.Luciferase reporter gene assay was used to evaluate the direct effect of miR-125b on the target proteins Nav1.5 and Cav1.2.RESULTS ① In vivo:Compared to the Sham group,the TAC model mice showed significantly increased the ratio of heart weight to body weight (HW/BW),the ratio of heart weight to tibia length (HW/TL),and expression levels of the myocardial hypertrophy marker β-MHC (P＜0.05),indicating the successful establishment of the TAC model.Furthermore,miR-125b expression was significantly elevated in the TAC model group (P＜0.01).In the LV-miR-125b group,compared to the LV-NC group,the expression levels of myocardial hypertrophy markers ANP,BNP,and β-MHC were significantly increased (P＜0.01),while the ejection fraction (EF) and fractional short-ening (FS) values of the mice were significantly reduced (P＜0.01).Additionally,Additionally,myocardium ultrastructure of LV-miR-125b group was damaged.Compared to the LV-NC+TAC group,the LV-miR-125b-inhibitor+TAC group showed a significant increase in ejection fraction (EF) and fractional shortening (FS) values (P＜0.05).Additionally,the levels of Nav1.5 and Cav1.2 in myocardium tissue were signifi-cantly elevated in the LV-miR-125b-inhibitor+TAC group compared to the LV-NC+TAC group (P＜0.05).② In vitro:Compared to the NC group,the miR-125b overexpression group showed a significant increase in miR-125b expression (P＜0.01),as well as elevated levels of ANP,BNP,and β-MHC (P＜0.01).However,miR-125b-inhibitor significantly reversed the increases in ANP,BNP,and β-MHC (P＜0.01).Western blotting and immunofluorescence results showed that,compared to the NC group,the miR-125b mimic group exhibited significantly decreased levels of Nav1.5 and Cav1.2 (P＜0.01),while miR-125b-inhibitor led to an increase in the levels of both Nav1.5 and Cav1.2.Luciferase assay results demon-strated that miR-125b directly binds to the ion channel proteins Nav1.5 and Cav1.2,encoded by the SCN5A and CACNA1C genes.CONCLUSION miR-125b promotes the development of cardiac hyper-trophy by inhibiting the voltage-gated ion channel proteins Nav1.5 and Cav1.2 Inhibition of miR-125b expression improves cardiac hypertrophy.

Background::C-reactive protein to albumin ratio (CRP/Alb ratio, CAR) has been suggested as a potential prognostic biomarker in lung cancer. This updated systematic review and meta-analysis aimed to assess the association between CAR and lung cancer prognosis in current literature.Methods::A systematic search of databases was conducted to identify relevant studies published up to April 2023. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to assess the association between CAR and overall survival (OS) and progression-free survival (PFS) and recurrence-free survival (RF) in lung cancer patients.Results::This meta-analysis includes 16 studies with a total of 5337 patients, indicating a significant association between higher CAR and poorer OS, PFS, and RFS in lung cancer patients, with a pooled HR of 1.78 (95% CI = 1.60–1.99), 1.57 (95% CI = 1.36–1.80), and 1.97 (95% CI = 1.40–2.77), respectively.Conclusions::This updated meta-analysis provides evidence for the potential prognostic role of CAR in lung cancer, suggesting its utility as an effective and noninvasive biomarker for identifying high-risk patients and informing treatment decisions in a cost-effective manner. However, further large-scale studies will be necessary to establish the optimal cut-off value for CAR in lung cancer and confirm the present findings.