Objective To explore time-related changes in renal function,renal injury biomarkers,and renal pathology in rats entering a low-pressure and low-oxygen(LPLO)environment simulating moving from the plains to a plateau.Methods Thirty male Sprague-Dawley rats were divided randomly into five groups(n=6 rats per group).Rats in the Control group were placed outside the chamber under normal pressure and oxygen conditions.Rats in the experimental groups were placed in an LPLO chamber to simulate a plateau environment at 5000 m above sea level,and were maintained in the chamber for 3,7,14,and 28 days,respectively.Serum levels of creatinine(CRE),cystatin C(CysC),neutrophil gelatinase-associated lipocalin(NGAL),kidney injury molecule-1(KIM-1),and interleukin-18(IL-18)were measured as biomarkers of renal injury.Pathological changes in the kidney were observed by hematoxylin and eosin and periodic acid-Schiff staining,with quantitative assessment of the following parameters:average glomerular diameter,peritubular capillary(PTC)density per tubule,tubular injury score,and outer medulla(OM)congestion score.Results NGAL,KIM-1,CysC,and CRE were significantly increased in the experimental compared with the Control group(all P＜0.05).The average glomerulus diameter was significantly reduced in the LPLO 3 d group and significantly increased in the LPLO 14 d group(both P＜0.05).The peritubular capillary(PTC)/tubule ratio was significantly decreased.The renal tubular injury and OM congestion scores were significantly increased(both P＜0.05).Regression analysis showed that PTC/tubule was linearly negatively correlated with the LPLO duration,while CRE,CysC,and pathological indicators(mean glomerular diameter,OM congestion score,renal tubular injury score)were curvilinearly correlated with the duration of LPLO(all P＜0.05).Variables with a curvilinear correlation were analyzed using restricted cubic splines(RCS).Each curve exhibited an inverted-L shape,with inflection points on day 7,indicating that the rate of increase of all indicators was highest within the first 7 days of LPLO,and the rate of increase then slowed from 7 days to 28 days.Conclusions A simulated move from a plains to a plateau environment was associated with significant structural and functional renal damage,but the kidneys then showed a self-adaptive adjustment process towards the plateau environment.

Objective To explore time-related changes in renal function,renal injury biomarkers,and renal pathology in rats entering a low-pressure and low-oxygen(LPLO)environment simulating moving from the plains to a plateau.Methods Thirty male Sprague-Dawley rats were divided randomly into five groups(n=6 rats per group).Rats in the Control group were placed outside the chamber under normal pressure and oxygen conditions.Rats in the experimental groups were placed in an LPLO chamber to simulate a plateau environment at 5000 m above sea level,and were maintained in the chamber for 3,7,14,and 28 days,respectively.Serum levels of creatinine(CRE),cystatin C(CysC),neutrophil gelatinase-associated lipocalin(NGAL),kidney injury molecule-1(KIM-1),and interleukin-18(IL-18)were measured as biomarkers of renal injury.Pathological changes in the kidney were observed by hematoxylin and eosin and periodic acid-Schiff staining,with quantitative assessment of the following parameters:average glomerular diameter,peritubular capillary(PTC)density per tubule,tubular injury score,and outer medulla(OM)congestion score.Results NGAL,KIM-1,CysC,and CRE were significantly increased in the experimental compared with the Control group(all P＜0.05).The average glomerulus diameter was significantly reduced in the LPLO 3 d group and significantly increased in the LPLO 14 d group(both P＜0.05).The peritubular capillary(PTC)/tubule ratio was significantly decreased.The renal tubular injury and OM congestion scores were significantly increased(both P＜0.05).Regression analysis showed that PTC/tubule was linearly negatively correlated with the LPLO duration,while CRE,CysC,and pathological indicators(mean glomerular diameter,OM congestion score,renal tubular injury score)were curvilinearly correlated with the duration of LPLO(all P＜0.05).Variables with a curvilinear correlation were analyzed using restricted cubic splines(RCS).Each curve exhibited an inverted-L shape,with inflection points on day 7,indicating that the rate of increase of all indicators was highest within the first 7 days of LPLO,and the rate of increase then slowed from 7 days to 28 days.Conclusions A simulated move from a plains to a plateau environment was associated with significant structural and functional renal damage,but the kidneys then showed a self-adaptive adjustment process towards the plateau environment.

AIM:To investigate the expression profile and biological significance of long noncoding RNA(lncRNA)zinc finger antisense 1(ZFAS1)in the brains of mice with diabetic encephalopathy(DE).METHODS:Ten db/m mice served as the normal control group,while twenty 22-week-old db/db mice were used to establish the DE model and randomly divided into two subgroups:ten as the db/db model control and the remaining ten receiving ZFAS1 gene knockdown(db/db+sh-ZFAS1)via lentiviral transfection.Weekly measurements of body weight and blood glucose levels were performed.Brain tissues were collected for Nissl staining to evaluate neuronal damage,TUNEL assay to detect apop-tosis,and immunofluorescence staining to examine neural biomarker expression.Serum levels of tumor necrosis factor-α(TNF-α)and oxidative stress markers,including reactive oxygen species(ROS),malondialdehyde(MDA),superoxide dismutase(SOD),catalase(CAT)and glutathione peroxidase(GSH-Px),were determined.Western blot was conducted to quantify the protein expression levels of B-cell lymphoma-2(Bcl-2),Bcl-2-associated X protein(Bax),p38 mitogen-activated protein kinase and phosphorylated p38(p-p38)in brain tissues.The expression levels of ZFAS1 and caspase-3 mRNA were determined by RT-qPCR.RESULTS:Knockdown of ZFAS1 in db/db mice significantly improved cognitive function,alleviated hippocampal neuronal damage,and reduced body weight and blood glucose levels(P<0.01).More-over,oxidative stress was mitigated,as evidenced by decreased MDA and ROS levels(P<0.01)and increased activity of antioxidant enzymes,GSH-Px,SOD and CAT(P<0.01 or P<0.05).Meanwhile,ZFAS1 silencing down-regulated Bax and p-p38/p38 protein expression(P<0.01 or P<0.05)while up-regulating Bcl-2(P<0.01).Consistently,RT-qPCR confirmed significant down-regulation of ZFAS1 and caspase-3 mRNA levels(P<0.01).CONCLUSION:lncRNA ZFAS1 is highly expressed in the hippocampus of DE mice.Down-regulation of ZFAS1 expression enhances cognitive func-tion,suppresses oxidative stress,and inhibits neuronal apoptosis,thereby attenuating neural damage in DE.

Objectives:To investigate the clinical value of cardiac magnetic resonance imaging(CMR)feature-tracking strain analysis in risk stratification of diabetic heart failure with preserved ejection fraction(HFpEF).Methods:In this retrospective study,a total of 215 patients with diabetic HFpEF who underwent CMR at Chinese Academy of Medical Sciences Fuwai Hospital from January 2012 to December 2018 were included.Myocardial strain parameters were calculated using CMR feature-tracking technology.Patients were followed up by medical records or telephone calls.Composite endpoint event,all-cause death or heart failure hospitalization during follow-up were recorded.Patients were divided into event group and event-free group.Univariable and multivariable Cox proportional hazard regression analyses were performed to determine the risk factors for the outcomes in diabetic HFpEF.The effects of hypertension and obesity on the prognosis of diabetic HFpEF patients and whether they affect the prognostic value of CMR feature-tracking strain analysis were also analyzed.Results:During a follow-up of(7.1±1.8)years,93(43.3%)patients had endpoint events(event group),including 28 all-cause deaths and 65 heart failure hospitalization.Compared with the event-free group(n=122),patients in the event group had significantly lower left ventricular ejection fraction,higher prevalence and extent of late gadolinium enhancement,and significantly reduced global longitudinal strain(GLS),global circumferential strain,global radial strain,and global systolic longitudinal strain rate(all P<0.05).The absolute GLS value was significantly lower in event group than in event-free group,regardless of the presence of hypertension and obesity.Multivariate Cox regression analysis showed that estimated glomerular filtration rate(HR=0.983,95%CI:0.972-0.993,P=0.001),left atrial volume index(HR=1.015,95%CI:1.005-1.026,P=0.004),and GLS(HR=1.142,95%CI:1.060-1.231,P<0.001)were independent risk factors for adverse cardiovascular events in diabetic HFpEF patients.However,adjusted N-terminal pro-brain natriuretic peptide was not an independent prognostic factor.The cut-offvalue of GLS to predict outcome was-14.09%from ROC curve analysis.The Kaplan-Meier curve showed that in patients with and without hypertension and obesity,patients with the GLS>-14.09%had lower event-free survival compared to patients with GLS≤-14.09%(all P<0.05),and the ability of GLS to predict adverse outcomes was not affected by hypertension and obesity.Conclusions:GLS obtained by CMR feature-tracking strain analysis is an independent predictor of adverse outcomes in diabetic HFpEF,and its ability to predict adverse outcomes is independent of hypertension and obesity.

AIM:To investigate the expression profile and biological significance of long noncoding RNA(lncRNA)zinc finger antisense 1(ZFAS1)in the brains of mice with diabetic encephalopathy(DE).METHODS:Ten db/m mice served as the normal control group,while twenty 22-week-old db/db mice were used to establish the DE model and randomly divided into two subgroups:ten as the db/db model control and the remaining ten receiving ZFAS1 gene knockdown(db/db+sh-ZFAS1)via lentiviral transfection.Weekly measurements of body weight and blood glucose levels were performed.Brain tissues were collected for Nissl staining to evaluate neuronal damage,TUNEL assay to detect apop-tosis,and immunofluorescence staining to examine neural biomarker expression.Serum levels of tumor necrosis factor-α(TNF-α)and oxidative stress markers,including reactive oxygen species(ROS),malondialdehyde(MDA),superoxide dismutase(SOD),catalase(CAT)and glutathione peroxidase(GSH-Px),were determined.Western blot was conducted to quantify the protein expression levels of B-cell lymphoma-2(Bcl-2),Bcl-2-associated X protein(Bax),p38 mitogen-activated protein kinase and phosphorylated p38(p-p38)in brain tissues.The expression levels of ZFAS1 and caspase-3 mRNA were determined by RT-qPCR.RESULTS:Knockdown of ZFAS1 in db/db mice significantly improved cognitive function,alleviated hippocampal neuronal damage,and reduced body weight and blood glucose levels(P<0.01).More-over,oxidative stress was mitigated,as evidenced by decreased MDA and ROS levels(P<0.01)and increased activity of antioxidant enzymes,GSH-Px,SOD and CAT(P<0.01 or P<0.05).Meanwhile,ZFAS1 silencing down-regulated Bax and p-p38/p38 protein expression(P<0.01 or P<0.05)while up-regulating Bcl-2(P<0.01).Consistently,RT-qPCR confirmed significant down-regulation of ZFAS1 and caspase-3 mRNA levels(P<0.01).CONCLUSION:lncRNA ZFAS1 is highly expressed in the hippocampus of DE mice.Down-regulation of ZFAS1 expression enhances cognitive func-tion,suppresses oxidative stress,and inhibits neuronal apoptosis,thereby attenuating neural damage in DE.

Objectives:To investigate the clinical value of cardiac magnetic resonance imaging(CMR)feature-tracking strain analysis in risk stratification of diabetic heart failure with preserved ejection fraction(HFpEF).Methods:In this retrospective study,a total of 215 patients with diabetic HFpEF who underwent CMR at Chinese Academy of Medical Sciences Fuwai Hospital from January 2012 to December 2018 were included.Myocardial strain parameters were calculated using CMR feature-tracking technology.Patients were followed up by medical records or telephone calls.Composite endpoint event,all-cause death or heart failure hospitalization during follow-up were recorded.Patients were divided into event group and event-free group.Univariable and multivariable Cox proportional hazard regression analyses were performed to determine the risk factors for the outcomes in diabetic HFpEF.The effects of hypertension and obesity on the prognosis of diabetic HFpEF patients and whether they affect the prognostic value of CMR feature-tracking strain analysis were also analyzed.Results:During a follow-up of(7.1±1.8)years,93(43.3%)patients had endpoint events(event group),including 28 all-cause deaths and 65 heart failure hospitalization.Compared with the event-free group(n=122),patients in the event group had significantly lower left ventricular ejection fraction,higher prevalence and extent of late gadolinium enhancement,and significantly reduced global longitudinal strain(GLS),global circumferential strain,global radial strain,and global systolic longitudinal strain rate(all P<0.05).The absolute GLS value was significantly lower in event group than in event-free group,regardless of the presence of hypertension and obesity.Multivariate Cox regression analysis showed that estimated glomerular filtration rate(HR=0.983,95%CI:0.972-0.993,P=0.001),left atrial volume index(HR=1.015,95%CI:1.005-1.026,P=0.004),and GLS(HR=1.142,95%CI:1.060-1.231,P<0.001)were independent risk factors for adverse cardiovascular events in diabetic HFpEF patients.However,adjusted N-terminal pro-brain natriuretic peptide was not an independent prognostic factor.The cut-offvalue of GLS to predict outcome was-14.09%from ROC curve analysis.The Kaplan-Meier curve showed that in patients with and without hypertension and obesity,patients with the GLS>-14.09%had lower event-free survival compared to patients with GLS≤-14.09%(all P<0.05),and the ability of GLS to predict adverse outcomes was not affected by hypertension and obesity.Conclusions:GLS obtained by CMR feature-tracking strain analysis is an independent predictor of adverse outcomes in diabetic HFpEF,and its ability to predict adverse outcomes is independent of hypertension and obesity.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation and joint damage, accompanied by the accumulation of plasma cells, which contributes to its pathogenesis. Understanding the genetic alterations occurring during plasma cell differentiation in RA can deepen our comprehension of its pathogenesis and guide the development of targeted therapeutic interventions. Here, our study elucidates the intricate molecular mechanisms underlying plasma cell differentiation by demonstrating that PRDX1 interacts with DOK3 and modulates its degradation by the autophagy-lysosome pathway. This interaction results in the inhibition of plasma cell differentiation, thereby alleviating the progression of collagen-induced arthritis. Additionally, our investigation identifies Salvianolic acid B (SAB) as a potent small molecular glue-like compound that enhances the interaction between PRDX1 and DOK3, consequently impeding the progression of collagen-induced arthritis by inhibiting plasma cell differentiation. Collectively, these findings underscore the therapeutic potential of developing chemical stabilizers for the PRDX1-DOK3 complex in suppressing plasma cell differentiation for RA treatment and establish a theoretical basis for targeting PRDX1-protein interactions as specific therapeutic targets in various diseases.

Objective To develop an erythrocyte-based delivery system for butyrylcholinesterase(BChE)that is capable of prophylaxis against organophosphorus nerve agents.Methods Recombinant BChE was produced and analyzed for oligomerization via polyacrylamide gel electrophoresis(PAGE)and Western blotting.A modified hypotonic preswelling method was employed to prepare BChE-loaded erythrocytes.The drug loading capacity and encapsulation efficiency were quantified using enzyme-linked immunosorbent assay(ELISA).Catalytic activity was assessed in vitro with an activity detection kit.The system was characterized via scanning electron microscopy(SEM),flow cytometry and a hematology analyzer.Results Recombinant BChE predominantly existed as dimers(85％dimer,15％monomer).The optimized volume ratio of erythrocytes to hypotonic solution was determined as 1:7.Compared with native and empty erythrocytes,BChE-loaded erythrocytes exhibited significantly higher catalytic activity(P＜0.001).The mean corpuscular volume of BChE-loaded erythrocytes increased(P＜0.001),while the mean content of corpuscular hemoglobin and hemoglobin in erythrocytes per 100 mL decreased(P＜0.001).SEM revealed no morphological differences(biconcave disc shape).Hypotonic preswelling moderately increased erythrocyte apoptosis(P＜0.001),but no statistical difference was observed between BChE-loaded and hypotonic-treated erythrocytes(P＞0.05).CD47 expression remained unchanged compared to native erythrocytes(P＞0.05).Conclusion The modified hypotonic preswelling method can generate BChE-loaded erythrocytes that retain the characteristics of native erythrocytes while conferring catalytic activity,offering a novel strategy for clinical intervention against organophosphorus poisoning.

Objective To explore the clinical efficacy of the regimen based on sacubitril/valsartan and empagliflozin in the treatment of elderly hypertension patients with type 2 diabetes(T2DM)and determine the impact on left ventricular remodeling.Methods A prospective randomized trial was conducted on 100 elderly patients with essential hypertension combined with T2DM admitted in our hospital from January 2022 to January 2023.All of them had left ventricular hypertrophy(LVH).They were randomly divided into an observation group(n=50,empagliflozin combined with sacubitril/valsartan)and a control group(n=50,empagliflozin combined with valsartan).Baseline data,and SBP,DBP,left ventricular ejection fraction,left ventricular mass(LVM),interventricular septal thickness(IVST),left ventricular posterior wall thickness(LVPWT),and LVM index(LVMI)before and at 3 and 6 months after treatment were recorded and compared between the two groups.The incidence of adverse events was also compared between them.Results Repeated measures ANOVA showed that the values of SBP,DBP,IVST,LVPWT,LVM and LVMI were gradually reduced in the two groups with the extension of treatment time,and reached the lowest levels at 6 months of treatment(Ftime=4.829,10.037,121.202,65.784,214.796,162.801,P＜0.05,P＜0.01).With the elapse of treatment time,the observation group obtained more significant declines in terms of SBP,DBP,IVST,LVPWT,LVM and LVMI(Ftreatment×time=5.252,5.685,4.574,6.239,8.292,11.660,P＜0.05,P＜0.01).The inter-group effect was statistically significant.After 6 months of treatment,the values of above indicators were notably lower in the observation group than the control group(Ftreatment=79.151,97.673,4.250,8.080,9.598,20.091,P＜0.05,P＜0.01).SBP(129.80±7.67 mm Hg vs 138.48±12.35 mm Hg.P＜0.01),DBP(79.76±5.96 mm Hg vs 87.46±9.57 mm Hg,P＜0.01),IVST,LVPWT,LVM and LVMI were obviously lower in the observation group than the control group.Both valsartan+empagliflozin and sacubitril/valsartan+empagliflozin showed good safety.Conclusion Sacubitril/valsartan can effectively improve blood pressure,cardiac function,and left ventricular remodeling in elderly hypertensive patients with T2DM and LVH,with good safety.