OBJECTIVE: To evaluate the dynamic changes of glucocorticoid (GC) dose and the feasibility of GC discontinuation in rheumatoid arthritis (RA) patients under the background of Chinese medicine (CM). METHODS: This multicenter retrospective cohort study included 1,196 RA patients enrolled in the China Rheumatoid Arthritis Registry of Patients with Chinese Medicine (CERTAIN) from September 1, 2019 to December 4, 2023, who initiated GC therapy. Participants were divided into the Western medicine (WM) and integrative medicine (IM, combination of CM and WM) groups based on medication regimen. Follow-up was performed at least every 3 months to assess dynamic changes in GC dose. Changes in GC dose were analyzed by generalized estimator equation, the probability of GC discontinuation was assessed using Kaplan-Meier curve, and predictors of GC discontinuation were analyzed by Cox regression. Patients with <12 months of follow-up were excluded for the sensitivity analysis. RESULTS: Among 1,196 patients (85.4% female; median age 56.4 years), 880 (73.6%) received IM. Over a median 12-month follow-up, 34.3% (410 cases) discontinued GC, with significantly higher rates in the IM group (40.8% vs. 16.1% in WM; P<0.05). GC dose declined progressively, with IM patients demonstrating faster reductions (median 3.75 mg vs. 5.00 mg in WM at 12 months; P<0.05). Multivariate Cox analysis identified age <60 years [P<0.001, hazard ratios (HR)=2.142, 95% confidence interval (CI): 1.523-3.012], IM therapy (P=0.001, HR=2.175, 95% CI: 1.369-3.456), baseline GC dose ⩽7.5 mg (P=0.003, HR=1.637, 95% CI: 1.177-2.275), and absence of non-steroidal anti-inflammatory drugs use (P=0.001, HR=2.546, 95% CI: 1.432-4.527) as significant predictors of GC discontinuation. Sensitivity analysis (545 cases) confirmed these findings. CONCLUSIONS RA patients receiving CM face difficulties in following guideline-recommended GC discontinuation protocols. IM can promote GC discontinuation and is a promising strategy to reduce GC dependency in RA management. (Trial registration: ClinicalTrials.gov, No. NCT05219214).
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Arthritis, Rheumatoid/drug therapy* ; Glucocorticoids/therapeutic use* ; Medicine, Chinese Traditional ; Retrospective Studies

Objective:To investigate the relationship among seminal oxidation-reduction potential(nORP),sperm DNA frag-mentation(DFI)and semen parameters in patients with varicocele.Methods:Clinical data of 522 patients treated in the reproduc-tive andrology clinic of the Northern Theater General Hospital from November 2023 to December 2023 were retrospectively analyzed,in-cluding 435 men of childbearing age and 87 men of infertile age.The patients were divided into the varicocele group(n=116)and non-varicocele group(n=406)according to clinical diagnosis.The differences of seminal plasma nORP,DFI,sperm high DNA stain ability(HDS)and semen parameters were analyzed between the two groups.The relationship among general clinical data,seminal plasma nORP,semen parameters,DFI and HDS in patients with varicocele were further analyzed.According to the severity of varico-cele,the patients were divided into three groups,including mild,moderate and severe.And the differences of seminal plasma nORP and semen parameters,DFI and HDS among all groups were analyzed.The differences of seminal plasma nORP,semen parameters,DFI and HDS were compared between the varicocele and non-varicocele groups.Results:The total sperm count,sperm concentra-tion,progressive motility sperm percentage(PR％)and normal sperm morphology rate(NSMR)in patients with varicocele were sig-nificantly lower than those in control group(P＜0.05).And seminal plasma nORP,DFI and HDS in patients with varicocele were sig-nificantly higher than those in control group(P＜0.05).Seminal plasma nORP in patients with varicocele was significantly negatively correlated with total sperm,sperm concentration and NSMR(P＜0.05),and significantly positively correlated with DFI and HDS(P＜0.05).There were significant differences in nORP,total sperm count,sperm concentration,PR％,DFI and HDS among mild,moderate and severe varicocele groups(P＜0.05).Seminal plasma nORP,sperm concentration,PR％and DFI in severe group were significantly lower than those in mild and moderate groups(P＜0.05).Sperm count and HDS in severe group were significantly lower than those in mild group(P＜0.05).In infertile patients,seminal plasma nORP,DFI and HDS in varicocele group were significantly higher than those in control group(P＜0.05).And PR％in varicocele group was significantly lower than that in control group(P＜0.05).Conclusions:Seminal plasma nORP in patients with varicocele may be an important marker of oxidative stress affecting DFI and semen parameters.

Objective To investigate the neurovascular coupling(NVC)status in the acute phase of patients with minor ischemic stroke(MIS)or transient ischemic attack(TIA)due to intracranial large artery moderate-to-severe stenosis or occlusion using multimodal MRI techniques and to explore its correlation with quality of life(QoL).Methods This prospective,consecutive study enrolled patients with MIS or TIA due to intracranial large artery moderate-to-severe stenosis or occlusion form the Department of Neurology,the First Affiliated Hospital of Xi'an Jiaotong University,between June 2022 and October 2023.Recruit healthy subjects with matched age,sex,and handedness form the community during the same period.Patients were divided into left-sided involvement and right-sided involvement groups based on the affected side of the responsible vessel,while the healthy subjects were set as the healthy control group.Post-hoc power analysis was performed using G*Power 3.1 software.General characteristics(age,gender,body mass index,education level)were collected and compared across all three groups.Clinical data and QoL assessment were collected and compared between the two patient groups.Collected clinical data including type of cerebrovascular events(TIA,MIS),the National Institutes of Health stroke scale(NIHSS)score at admission,the responsible vessel(internal carotid artery,middle cerebral artery)and its side location,the degree of responsibility artery stenosis(moderate-severe stenosis[50%-99%stenosis rate],occlusion[100%stenosis rate]),the intracranial collateral circulation status(American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology[ASITN/SIR]collateral circulation grading),cerebrovascular risk factors(hypertension,diabetes,hyperlipidemia,smoking history),and the laboratory test indicators at admission(glycated hemoglobin,triglycerides,total cholesterol,high-density lipoprotein cholesterol,low-density lipoprotein cholesterol,blood uric acid,blood homocysteine).QoL was assessed using the stroke impact scale(SIS),covering eight functional domains and a patient-reported overall recovery item.Multimodal MR data were acquired for all subjects.Whole-brain cerebral blood flow(CBF)images were generated using statistics parameter mapping 12(SPM 12)software,while regional homogeneity(ReHo)images were generated using DPABI software.The voxel-wise ratio of CBF to ReHo(CBF/ReHo)was calculated as the regional NVC parameter.Differences in regional NVC characteristics were compared between patient groups and the healthy control group.Correlations between NVC parameters and SIS scores within patient groups were explored.Results(1)A total of 38 patients with MIS or TIA due to intracranial large artery moderate-to-severe stenosis or occlusion were included(26 males,12 females,aged 36-69 years,with mean age of[52±11]years),with 23 in the left-sided involvement group and 15 in the right-sided involvement group.Nineteen healthy subjects were included(10 males,9 females,aged 37-67 years,with mean age of[53±10]years).Post-hoc power analysis showed statistical power of 0.808 for comparing the left-sided involvement group with the healthy control group and 0.762 for comparing the right-sided involvement group with control group.(2)No statistically significant differences were found on gender,age,education level,or body mass index across the three groups(all P＞0.05).No statistically significant differences were observed on the type of cerebrovascular event,cerebrovascular risk factors,distribution of the responsible vessel,degree of stenosis in the responsible vessel,admission NIHSS score,or laboratory test results between the two patient groups(all P＞0.05).There were no statistically significant differences in the total SIS score and the scores of subscales between the two patient groups(all P＞0.05).(3)Compared with the healthy control group,the left-sided involvement group exhibited reduced CBF/ReHo values in the left superior and middle temporal gyri,supramarginal gyrus,middle and inferior frontal gyri,precentral gyrus,angular gyrus,postcentral gyrus,insula,and posterior cerebellar lobe(FDR-corrected,all P＜0.05).In the right-sided involvement group,reduced CBF/ReHo values were observed in the right supramarginal gyrus,right postcentral gyrus,inferior temporal gyrus,and insula(FDR-corrected,all P＜0.05).(4)Correlation analysis revealed that the SIS total score in the left-sided involvement group negatively correlated with CBF/ReHo values in the right inferior frontal gyrus(T=-5.91)and the right middle temporal gyrus(T=-6.65,FDR-corrected,both P＜0.05).The SIS subscale score for activities of daily living in the left-sided involvement group showed negative correlations with CBF/ReHo values in the right angular gyrus(T=-7.36),right medial superior frontal gyrus(T=-6.97),right orbitofrontal cortex(T=-8.99),and left thalamus(T=-7.51,FDR-corrected,all P＜0.05).No significant correlation was observed between the SIS total score and CBF/ReHo values in patients with right-sided involvement group.The SIS subscale for communication score in the right-sided involvement group correlated with CBF/ReHo in the left lingual gyrus(T=-12.15),left olfactory cortex(T=-7.68),and right anterior cingulate and paracingulate cortex(T=-9.46,FDR-corrected,all P＜0.05).Conclusions Patients with MIS or TIA due to intracranial large artery moderate-to-severe stenosis or occlusion show abnormal NVC in the acute phase,especially those with left hemisphere involvement,who exhibit more extensive impairments.QoL in left-sided involvement patients is strongly linked to NVC in the right orbitofrontal cortex and right middle temporal gyrus.These findings require further validation in larger-scale studies.

Objective:To investigate the role of the angiopoietin (Ang)/tyrosine kinase receptor 2 (Tie2) pathway in mediating histone-induced coagulation activation in mice with acute lung injury, and the protective mechanism of unfractionated heparin (UFH).Methods:Twenty-four mice were randomly divided into three groups ( n=8 per group): Control group, Histone group, and Histone + UFH group using the random number table method. The Histone group and Histone + UFH group were administered 50 mg/kg histone via the tail vein. One hour later, UFH was given at a dosage of 400 U/kg by the same way. The Control group was administered an equivalent volume of sterile saline solution. Four hours after modeling, tissue samples were collected. HE staining was performed to observe the pathology of lung tissue. Lung lobe wet and dry weights were measured to assess the degree of pulmonary edema. Immunohistochemistry was used to observe the expression of fibrinogen (FIB) in lung tissue. ELISA was used to detect the levels of thrombin-antithrombin complex (TAT), plasminogen activator inhibitor type-1 (PAI-1), and D-dimer (D-D) in plasma. The qRT-PCR was used to measure the mRNA expression levels of tissue factor (TF), FIB, PAI-1, angiopoietin (Ang)-1, Ang-2, and Tie2 in lung tissue. Western blot was used to measure the protein expression levels of TF, FIB, Ang-1, Ang-2, and pTie2 in lung tissue. Results:The HE staining results revealed that, compared to the Control group, the Histone group exhibited thickened alveolar walls, significant neutrophil infiltration, and alveolar congestion with edema, indicating histone-induced ALI ( P<0.001). In contrast, the Histone + UFH group exhibited milder lung injury ( P<0.001), suggesting that UFH mitigated the lung damage induced by histones. The lung wet/dry weight ratio and lung water content percentage were significantly higher in the Histone group than in the Control group ( P<0.001), while UFH reduced the severity of pulmonary edema ( P<0.01). Immunohistochemistry revealed intravascular thrombus formation and fibrin deposition in the Histone group, which were reduced by UFH. ELISA results showed significantly elevated levels of TAT, PAI-1, and D-D in the Histone group ( P<0.001), and UFH decreased the levels of these parameters stimulated by histone ( P<0.05). The qRT-PCR showed increased mRNA expression of TF, FIB, PAI-1, and Ang-2, and decreased expression of Ang-1 and Tie2 in lung tissues in the Histone group, while UFH mitigated the effects of histones on mRNA expression of these parameters. Western blot analysis indicated increased protein expression of TF, FIB, and Ang-2 ( P<0.01), and decreased expression of Ang-1 and Tie2 in lung tissues in the Histone group ( P<0.01), and UFH reduced the impact of histones on the protein expression of these parameters ( P<0.05). Conclusions:Histones can cause lung injury, pulmonary edema, and coagulation activation in mice lung tissue. UFH can effectively alleviate histone induced lung injury, and coagulation activation in by histones via the Ang/Tie2 signaling pathway.

Objective:To investigate whether paclitaxel (PTX) can induce immunogenic cell death (ICD) in vascular smooth muscle cells (VSMCs), and explore the new molecular mechanism of PTX-coated balloon angioplasty in intracranial atherosclerotic stenosis.Methods:(1) Cell culture and identification: VSMCs were induced into synthetic vascular smooth muscle cells (sVSMCs); the mRNA and protein expressions of smooth muscle protein 22-α (SM22-α) and α-smooth muscle actin (α-SMA) in VSMCsS and sVSMCs were detected by real-time fluorescent quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and Western blotting, respectively. Human acute monocytic leukemia cell line THP-1 was induced into dendritic cells (DCs); the CD86 and CD83 expressions in THP-1 and DCs were detected by flow cytometry. (2) Cell viability detection: cell counting kit-8 (CCK-8) assay was used to detect the cell viability of sVSMCs after 0, 0.01, 0.05, 0.5, 5, 10, 50, and 100 μmol/L PTX or under 0, 50, 100, 200, 400, and 600 mmHg (1 mmHg=0.133 kPa) pressures. (3) ICD marker detection: sVSMCs were collected and divided into blank-control group, dimethyl sulfoxide (DMSO) group and PTX group (cultured with 3.2 μmol/L PTX) at normal state and pressure procedure (188 mmHg), respectively; calreticulin (CRT) expression was detected by immunofluorescent staining; adenosine triphosphate (ATP) expression was detected by luciferase assay, and high mobility group protein B1 (HMGB1) expression was detected by enzyme-linked immunosorbent assay (ELISA). (4) ICD-related immune activation assay detection: sVSMCs and DCs were collected and divided into DCs group, PTX+DCs group (cultured with 3.2 μmol/L PTX), DCs+sVSMCs group, and PTX+DCs+sVSMCs group (cultured with 3.2 μmol/L PTX); CD86 and CD83 expressions were detected by flow cytometry; interleukin (IL)-2, IL-10 and interferon-γ (IFN-γ) levels were detected by ELISA. The sVSMCs, DCs and CD8 +T cells were collected and divided into sVSMCs group, sVSMCs+DCs group, sVSMCs+CD8 +T cell group, sVSMCs+DCs+CD8 +T cell group, PTX+sVSMCs group (cultured with 3.2 μmol/L PTX), and PTX+sVSMCs+DCs+CD8 +T cell group (cultured with 3.2 μmol/L PTX); proliferation of these cells was detected by cell clone formation assay. Results:(1) The SM22-α and α-SMA mRNA and protein expressions in the sVSMCs group were significantly lower than those in the VSMCs group ( P<0.05); rate of double-positive CD83 and CD86 in the DCs group was significantly higher than that in the THP-1 group ( P<0.05). (2) The sVSMCs viability decreased in a concentration-dependent manner after PTX treatment at concentrations of 0, 0.01, 0.05, 0.5, 5, 10, 50, and 100 μmol/L, respectively, with significant differences ( P<0.05); half maximal inhibitory concentration (IC 50) of PTX on sVSMCs was 3.2 μmol/L; no significant difference in sVSMCs viability after 3.2 μmol/L PTX treatment was noted under 0, 50, 100, 200, 400, and 600 mmHg pressures ( P>0.05). (3) Under normal state and pressure procedure, CRT fluorescent intensity of sVSMCs in the PTX group (42.00±3.50, 24.19±2.41) was significantly higher than that in the blank-control group (8.60±1.8, 8.42±1.7) and DMSO group (10.23±1.47, 9.71±1.01), ATP luminescence intensity (17 399.33±2 035.58, 17 445.67±2 449.34) was significantly higher than that in the blank-control group (9 021.33±726.84, 10 271.33±2 194.22) and DMSO group (11 977.33±960.91, 11 683.33±419.50), and HMGB1 concentration ([3 258.31±502.08] pg/mL, [3 265.27±246.06] pg/mL) was significantly higher than that in the blank-control group ([1 156.48±184.96] pg/mL, [1 205.20±196.36] pg/mL) and DMSO group ([1 309.59±75.03] pg/mL, [1 265.51±14.52] pg/mL, P<0.05). (4) The PTX+DCs+sVSMCs group had significantly higher CD83, CD86, IFN-γ and IL-2 expressions and lower IL-10 expression than the DCs group, PTX+DCs group, and DCs+sVSMCs group ( P<0.05); the PTX+sVSMCs group and PTX+sVSMCs+DCs+CD8 +T cell group had significantly lower clone formation rate compared with the sVSMCs group, sVSMCs+DCs group, sVSMCs+CD8 +T cell group, and sVSMCs+DCs+CD8 +T cell group ( P<0.05). Conclusion:PTX can promote ICD in VSMCs by promoting DCs activation and enhancing CD8 +T cell toxicity.

Objective:To investigate the mechanism of mitochondrial DNA (mtDNA)-reactive oxygen species (ROS)-dynamin-related protein 1 (Drp1) axis in regulating phenotypic transformation of vascular smooth muscle cells (VSMCs).Methods:(1) VSMCs were divided into a control group, a synthetic VSMCs group, and a Drp1 siRNA+synthetic VSMCs group; cells in the Drp1 siRNA+synthetic VSMCs group were transfected with 50 nmol/L Drp1 siRNA for 48 h; cells in the latter two groups were treated with 20 ng/mL platelet-derived growth factor (PDGF)-BB, while cells in the control group were treated with an equal volume of solvent. After another 24 h of culture, Drp1 expression in VSMCs, and mitochondrial Drp1 and mitofusin 2 (Mfn2) expressions were detected by Western blotting, and changes in mitochondrial morphology were detected by mitochondrial fluorescent staining. (2) VSMCs were divided into a control group, a synthetic VSMCs group, and a mitochondrial fission inhibitor 1 (Mdivi-1)+synthetic VSMCs group; cells in the Mdivi-1+synthetic VSMCs group were pretreated with 50 μmol/L Mdivi-1 for 2 h; and cells in the latter two groups were treated with 20 ng/mL PDGF-BB, while cells in the control group were treated with an equal volume of solvent. After 24 hours of continued culture, expressions of α-smooth muscle actin (α-SMA), smooth muscle protein 22-α (SM22-α), proliferating cell nuclear antigen (PCNA), and Cyclin D1 were detected by Western blotting; invasion and migration abilities of VSMCs were detected by Transwell assay and scratch wound healing assay, respectively. (3) VSMCs were divided into a control group, a synthetic VSMCs group, and a N-acetylcysteine (NAC)+synthetic VSMCs group; cells in the NAC+synthetic VSMCs group were pretreated with 5 mmol/L NAC for 1 h; cells in the latter two groups were treated with 20 ng/mL PDGF-BB, while cells in the control group were treated with an equal volume of solvent. After 24 h of continued culture, expressions of Drp1, phosphorylated (p)-Drp1, α-SMA, SM22-α, PCNA, and Cyclin D1 were detected by Western blotting; changes in mitochondrial morphology were detected by mitochondrial fluorescent staining; intracellular ROS level was detected by 2', 7' -dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescent probe; cell invasion and migration abilities were detected by Transwell assay and scratch wound healing assay, respectively. (4) VSMCs were divided into a control group, a synthetic VSMCs group, and a 5-Aza-2'-deoxycytidine (5-Aza-dC)+synthetic VSMCs group; cells in the 5-Aza-dC+synthetic VSMCs group were pretreated with 2 μmol/L 5-Aza-dC for 1 h; and then, cells in the latter two groups were treated with 20 ng/mL PDGF-BB, while cells in the control group were treated with an equal volume of solvent. After 24 h of continued culture, agarose gel electrophoresis was used to analyze the methylation degree in the mitochondrial D-loop region; intracellular ROS level was detected using DCFH-DA fluorescent probe; expressions of mitochondrial DNMT1, α-SMA, SM22-α, PCNA, and Cyclin D1 were detected by Western blotting; invasion and migration abilities were detected by Transwell assay and scratch wound healing assay, respectively.Results:(1) Compared with the control group and synthetic VSMCs group, the Drp1 siRNA+synthetic VSMCs group had significantly decreased Drp1 protein expression ( P<0.05). Compared with the control group, the synthetic VSMCs group had significantly increased Drp1 protein expression and decreased Mfn2 protein expression in the mitochondria ( P<0.05); compared with the synthetic VSMCs group, the Drp1 siRNA+synthetic VSMCs group had statistically decreased Drp1 protein expression and increased Mfn2 protein expression in the mitochondria ( P<0.05). Results of mitochondrial fluorescent staining showed that mitochondria in the control group were with filamentous structure, while mitochondrial fission in the synthetic VSMCs group was enhanced, and morphology of mitochondria in the Drp1 siRNA+synthetic VSMCs group tended to be continuous and complete. (2) Compared with the control group, the synthetic VSMCs group had statistically decreased α-SMA and SM22-α protein expressions and increased PCNA and Cyclin D1 protein expressions ( P<0.05). Compared with the synthetic VSMCs group, the Mdivi-1+synthetic VSMCs group had significantly increased α-SMA and SM22-α protein expressions and decreased PCNA and Cyclin D1 protein expressions ( P<0.05). Results of Transwell and scratch wound healing assays showed that compared with the control group, the synthetic VSMCs group had larger number of migrating cells and faster cell scratch healing; compared with the synthetic VSMCs group, the Mdivi-1+synthetic VSMCs group had smaller number of migrating cells and slower cell scratch healing. (3) Compared with the control group (1.10±0.02), the synthetic VSMCs group (1.53±0.02) had significantly increased p-Drp1 protein expression ( P<0.05). Compared with the synthetic VSMCs group, the NAC+synthetic VSMCs group (0.90±0.02) had statistically decreased p-Drp1 protein expression ( P<0.05). Results of mitochondrial fluorescent staining showed that mitochondria in cells of the control group were in a filamentous structure, while mitochondrial fission in cells of the synthetic VSMCs group was enhanced, and morphology of mitochondria in the NAC+synthetic VSMCs group tended to be continuous and complete. Results of DCFH-DA fluorescent probe showed that ROS level in the synthetic VSMCs group was higher than that in the control group, and ROS level in the NAC+synthetic VSMCs group was lower than that in the synthetic VSMCs group. Compared with the control group, the synthetic VSMCs group had significantly decreased α-SMA and SM22-α protein expressions and increased PCNA and Cyclin D1 protein expressions ( P<0.05). Compared with the synthetic VSMCs group, the NAC+synthetic VSMCs group had significantly increased α-SMA and SM22-α protein expressions and decreased PCNA and Cyclin D1 protein expressions ( P<0.05). Results of Transwell and scratch wound healing assays showed that compared with the control group, the synthetic VSMCs group had larger number of migrating cells and faster cell scratch healing; compared with the synthetic VSMCs group, the NAC+synthetic VSMCs group had smaller number of migrating cells and slower cell scratch healing. (4) Results of agarose gel electrophoresis showed that compared with the control group, the synthetic VSMCs group had significantly increased methylation rate in the mitochondrial D-loop region ( P<0.05); compared with the synthetic VSMCs group, the 5-Aza-dC+synthetic VSMCs group had statistically decreased methylation rate in the mitochondrial D-loop region ( P<0.05). Compared with the control group, the synthetic VSMCs group had statistically increased mitochondrial DNMT1 protein expression (1.03±0.03 vs. 0.55±0.03, P<0.05); and compared with the synthetic VSMCs group, the the 5-Aza-dC+synthetic VSMCs group (0.62±0.03) had significantly decreased mitochondrial DNMT1 protein expression ( P<0.05). Results of DCFH-DA fluorescent probe showed that ROS level in the synthetic VSMCs group was higher than that in the control group; ROS level in the 5-Aza-dC+synthetic VSMCs group was lower than that in the synthetic VSMCs group. Compared with the control group, the synthetic VSMCs group had significantly decreased α-SMA and SM22-α protein expressions and increased PCNA and Cyclin D1 protein expressions ( P<0.05). Compared with the synthetic VSMCs group, the 5-Aza-dC+synthetic VSMCs group had significantly increased α-SMA and SM22-α protein expressions and decreased PCNA and Cyclin D1 protein expressions ( P<0.05). Results of Transwell and scratch wound healing assays showed that compared with the control group, the synthetic VSMCs group had larger number of migrating cells and faster scratch healing. Compared with the synthetic VSMCs group, the 5-Aza-dC+synthetic VSMCs group had smaller number of migrating cells and slower scratch healing. Conclusion:The mtDNA-ROS-Drp1 axis may regulate the phenotypic transformation of VSMCs by modulating mitochondrial epigenetic modifications.

Objective To observe the effects of 3 different nutritional support modes of nasogastric tube nutrition,nasoenteric tube nutrition and nasoenteric tube combined with nasogastric tube nutrition on the biliary-related indices of critically ill patients.Methods The observational research method was conducted,the patients admitted to the department of intensive care unit(ICU)of Qingdao Hospital,University of Health and Rehabilitation Sciences(Qingdao Municipal Hospital)from June 2023 to May 2024 serving as the subjects of the study.The subjects were divided into three groups,namely the nasogastric tube group(indwelling nasogastric tube for enteral nutrition),the nasoenteric tube group(indwelling nasoenteric tube for enteral nutrition),and the mixed nutrition group(indwelling nasoenteric tube combined with naso-gastric tube for enteral nutrition)according to the different modes of enteral nutrition given.The clinical data of the patients was collected,including gender,age,previous underlying diseases,nutritional risk screening 2002(NRS2002)score,acute physiology and chronic health evaluationⅡ(APACHEⅡ),gallbladder volume,data on laboratory-related indices,and prognosis during hospitalisation.Compare the differences between the observed indicators and their change values before and after the initiation of enteral nutrition within each group;analyse the correlation between gallbladder volume and other observed indicators using Spearman's correlation analysis;screen the influencing factors of gallbladder volume using univariate regression analysis;screen the influencing factors of ICU patients'survival during hospitalisation using multifactorial Logistic regression analysis,and plot the receiver operator characteristic curve(ROC curve)of the subjects to analyse the predictive value of each influencing factor on patients'prognosis.Results A total of 141 patients who met the inclusion criteria were included in the study,comprising 54 cases in the nasogastric tube group,38 cases in the nasoenteric tube group,and 49 cases in the mixed nutrition group.Of the patients who survived during ICU hospitalization,105 survived,while 36 died,mortality was 25.53%.① No statistically significant differences were observed in the comparison of gender,age,previous underlying disease,NRS2002 score,and APACHEⅡscore among the enrolled groups.② A comparative analysis was conducted on the biliary-related indexes of the nasogastric tube and nasoenteric tube groups before and after the initiation of enteral nutrition.The results revealed no statistically significant differences between the two groups.On the 7th day of enteral nutrition initiation,the gallbladder volume of the nasoenteric tube group was found to be significantly larger than the gallbladder volume on the 1st day(cm3:28.00±6.36 vs.25.20±4.75,P<0.05).In the mixed nutrition group,the gallbladder volume on the initiation of enteral nutrition on day 7 was significantly smaller than that on the 1st day of initiating enteral nutrition(cm3:25.03±4.69 vs.28.68±5.96,P<0.05).③A comparative analysis was conducted among the three groups,revealing significant variations in the values of alanine aminotransferase(ALT),aspartate aminotransferase(AST),total bilirubin(TBil),indirect bilirubin(IBil),alkaline phosphatase(ALP),γ-glutamyltranspeptidase(γ-GT),and gallbladder volume across the groups.From 1-7 days following the initiation of enteral nutrition,the bile-related indexes in the nasoenteric tube group exhibited an increasing trend,while the bile-related indexes in the mixed nutrition group demonstrated a decreasing trend.④ Spearman correlation analysis showed that gallbladder volume was significantly and positively correlated with AST,ALT,ALP,and γ-GT(r values of 0.398,0.299,0.242,and 0.262,respectively,all P<0.01).⑤ Multivariate Logistic regression analysis demonstrated that the initiation of enteral nutrition for 7 days was associated with a significant advantage,as indicated by an odds ratio(OR)of 1.031,with a 95%confidence interval(95%CI)of 1.004-1.058,and a P value was 0.024.Furthermore,the initiation of enteral nutrition for 7 d AST(OR=1.031,95%CI was 1.004-1.058,P=0.024),TBil(OR=1.187,95%CI was 1.039-1.355,P=0.011),and IBil(OR=0.707,95%CI was 0.542-0.921,P=0.010),and γ-GT(OR=0.985,95%CI was 0.972-0.999,P=0.034)were all factors affecting the survival of ICU patients during hospitalisation.Conclusions In the context of patients receiving intensive care,the prolonged utilisation of nasoenteric feeding tubes for a duration exceeding seven days has been observed to potentially induce an augmentation in gallbladder volume and an elevation in biliary-related indices,including ALT,AST,ALP,and γ-GT.The concomitant administration of nasogastric feeding,grounded in the foundation of simple nasoenteric tube nutrition,has been demonstrated to result in a reduction of these biliary-related indices to a certain extent.

AIM To investigate the effects of Huazhuo Jiedu Shugan Formula(HJSGF)on improving learning and memory impairment in a rat model of vascular dementia(VD)via SIRT1/PGC-1α/PPARγ pathway.METHODS The SD rats were randomly divided into the sham control group,the model group,the donepezil group(0.5 mg/kg),and the low-,medium-and high-dose HJSGF groups(2.7,5.4,10.8 g/kg),with 10 rats in each group.The VD rat models established by bilateral common carotid artery permanent ligation(2-VO)had their neurological behavior assessment using the Longa5-point scale,and their modeling success confirmed by the Morris water maze test and their 3-week corresponding dosing of drugs by gavage afterward.After the drug administration,the rats had their spatial memory ability tested through behavioral experiments;their serum levels of IL-18 and IL-1β measured by ELISA;their histopathological changes and neuronal morphology in the hippocampal CA1 region observed by HE staining and Nissl staining;and their hippocampal protein expressions of SIRT1,PGC-1α and PPARγ detected by immunohistochemistry and Western blot.RESULTS Compared with the sham control group,the model group showed prolonged escape latency(P＜0.01);decreased platform crossing times and target quadrant residence time(P＜0.01);disorganized arrangement of hippocampal CA1 neurons,nuclear condensation,reduced Nissl bodies,increased secretion and protein expressions of IL-1β and IL-18(P＜0.01);and reduced hippocampal protein expressions of SIRT1,PGC-1α and PPARγ(P＜0.01).Compared with the model group,the groups intervened with donepezil or HJSGF showed shortened escape latency(P＜0.05,P＜0.01);increased platform crossing times and target quadrant residence time(P＜0.05,P＜0.01);alleviated damage of the hippocampal CA1 region,reduced secretion and protein expressions of IL-1β and IL-18(P＜0.05,P＜0.01);and elevated hippocampal protein expressions of SIRT1,PGC-1α and PPARγ(P＜0.05,P＜0.01).CONCLUSION HJSGF may alleviate the inflammatory responses in VD rats and therefore improve their learning and memory impairment by activating the SIRT1/PGC-1α/PPARγ signaling pathway.

Objective This study aimed to investigate the correlation of cerebral perfusion and cognitive function status in patients with minor stroke(MS)or transient ischemic attack(TIA)complicated by severe intracranial arterial stenosis or occlusion(hereafter referred to as ICAS-MSTIA).Methods Retrospectively enrol consecutive ICAS-MSTIA patients admitted to the Department of Neurology,the First Affiliated Hospital of Xi'an Jiaotong University,from June 2023 to May 2024.In the meantime,healthy controls were openly recruited.The ICAS-MSTIA patients were divided into two groups based on the side of intracranial large artery stenosis or occlusion:the left intracranial large artery involvement group and the right intracranial large artery involvement group.All patients with intracranial large artery stenosis or occlusion underwent MR scanning within 2 weeks after the first episode of TIA or MS,while there was no specific time requirement for MR examination in the healthy control group.On the day of MR scanning,the Montreal cognitive assessment(MoCA)scale was used to evaluate the participants'global cognitive function and performance in various cognitive domains,including visuospatial/executive function,naming,attention,language,abstraction,delayed recall,and orientation.General information of all participants was collected,including age,sex,educational level,body mass index,and history of smoking and alcohol consumption.Clinical data were collected from both left and right intracranial large artery involvement groups,including cerebrovascular risk factors(such as,diabetes mellitus,hypertension,and hyperlipidemia),National Institutes of Health stroke scale(NIHSS)score at admission,responsible stenotic or occluded arteries(internal carotid artery,middle cerebral artery),degree of stenosis in the responsible vessel(severe stenosis[stenosis rate 70%-99%],occlusion[stenosis rate100%])and non-responsible vessel(no stenosis[0],mild stenosis[stenosis rate＞0-49%]),collateral circulation compensation(American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology[ASTIN/SIR]collateral circulation classification),and responsible events(TIA,MS).General data and MoCA scale scores were compared across the three groups,while clinical data were compared between the left and right intracranial large artery involvement groups.Statistical parametric mapping 12(SPM 12)was used to perform voxel-wise independent samples t-tests on cerebral blood flow(CBF)differences among the left ICAS-MSTIA group,right ICAS-MSTIA group,and healthy control group,with cluster-level family-wise error(FWE)correction applied for adjustment.Multiple linear regression analysis was conducted to evaluate the relationship between global CBF values and total MoCA scores in ICAS-MSTIA patients with left or right intracranial large artery involvement.Results A total of 33 ICAS-MSTIA patients and 33 healthy controls were enrolled in the study.Among the ICAS-MSTIA patients,21 had left intracranial large artery involvement and 12 had right involvement.(1)Among the three groups,statistically significant differences were observed in the proportions of individuals with reported smoking history(P=0.024)and alcohol consumption history(P=0.011).The left intracranial large artery involvement group had a higher NIHSS score(0[0,2]vs.0[0,0],P=0.044)and a higher proportion of patients with internal carotid artery involvement(13/21 cases vs.2/12 cases,P=0.027)compared with the right side group.No statistically significant differences were observed in other general or clinical data across the three groups or between the two non-control groups(all P＞0.05).(2)Statistically significant differences were found across the three groups in the MoCA scale total score and scores of visuospatial/executive function,attention,language,abstraction,delayed recall,and orientation cognitive domains(all P＜0.05),while no significant difference was noted in the naming score(P=0.063).The left intracranial large artery involvement group had lower total MoCA score and lower scores in visuospatial/executive function,attention,language,abstraction,delayed recall,and orientation in comparison to the healthy control group(all P＜0.016 7).The right intracranial large artery involvement group had significantly lower scores in language,abstraction,and orientation domains than the healthy control group(all P＜0.016 7).Additionally,the left side group had a lower attention domain score than the right side group(P＜0.016 7).No other statistically significant differences were found in pairwise comparisons(all P＞0.016 7).(3)Patients in both the left and right intracranial large artery involvement groups exhibited a significant decrease in CBF in extensive regions on the affected side,including the temporal lobe,dorsolateral prefrontal cortex,and occipital lobe.Furthermore,after correction,in the left involvement group CBF was higher in the contralateral lingual gyrus,cuneus,and calcarine sulcus compared with the healthy control group(P＜0.05).While in the right involvement group,no regions had increased CBF compared to the healthy control group.(4)Multiple linear regression showed positive correlation between CBF in ipsilateral precentral gyrus and superior temporal gyrus,and the total MoCA score in patients with left intracranial large artery involvement(FWE-corrected,P＜0.05).In contrast,there was no correlation between CBF and total MoCA score in patients with right intracranial large artery involvement.Conclusions ICAS-MSTIA patients exhibited various degrees of impairment in cerebral perfusion and cognitive function.A significant positive correlation is observed between these two impairments in patients with left intracranial large artery involvement.

Objective This study aimed to investigate the correlation of cerebral perfusion and cognitive function status in patients with minor stroke(MS)or transient ischemic attack(TIA)complicated by severe intracranial arterial stenosis or occlusion(hereafter referred to as ICAS-MSTIA).Methods Retrospectively enrol consecutive ICAS-MSTIA patients admitted to the Department of Neurology,the First Affiliated Hospital of Xi'an Jiaotong University,from June 2023 to May 2024.In the meantime,healthy controls were openly recruited.The ICAS-MSTIA patients were divided into two groups based on the side of intracranial large artery stenosis or occlusion:the left intracranial large artery involvement group and the right intracranial large artery involvement group.All patients with intracranial large artery stenosis or occlusion underwent MR scanning within 2 weeks after the first episode of TIA or MS,while there was no specific time requirement for MR examination in the healthy control group.On the day of MR scanning,the Montreal cognitive assessment(MoCA)scale was used to evaluate the participants'global cognitive function and performance in various cognitive domains,including visuospatial/executive function,naming,attention,language,abstraction,delayed recall,and orientation.General information of all participants was collected,including age,sex,educational level,body mass index,and history of smoking and alcohol consumption.Clinical data were collected from both left and right intracranial large artery involvement groups,including cerebrovascular risk factors(such as,diabetes mellitus,hypertension,and hyperlipidemia),National Institutes of Health stroke scale(NIHSS)score at admission,responsible stenotic or occluded arteries(internal carotid artery,middle cerebral artery),degree of stenosis in the responsible vessel(severe stenosis[stenosis rate 70%-99%],occlusion[stenosis rate100%])and non-responsible vessel(no stenosis[0],mild stenosis[stenosis rate＞0-49%]),collateral circulation compensation(American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology[ASTIN/SIR]collateral circulation classification),and responsible events(TIA,MS).General data and MoCA scale scores were compared across the three groups,while clinical data were compared between the left and right intracranial large artery involvement groups.Statistical parametric mapping 12(SPM 12)was used to perform voxel-wise independent samples t-tests on cerebral blood flow(CBF)differences among the left ICAS-MSTIA group,right ICAS-MSTIA group,and healthy control group,with cluster-level family-wise error(FWE)correction applied for adjustment.Multiple linear regression analysis was conducted to evaluate the relationship between global CBF values and total MoCA scores in ICAS-MSTIA patients with left or right intracranial large artery involvement.Results A total of 33 ICAS-MSTIA patients and 33 healthy controls were enrolled in the study.Among the ICAS-MSTIA patients,21 had left intracranial large artery involvement and 12 had right involvement.(1)Among the three groups,statistically significant differences were observed in the proportions of individuals with reported smoking history(P=0.024)and alcohol consumption history(P=0.011).The left intracranial large artery involvement group had a higher NIHSS score(0[0,2]vs.0[0,0],P=0.044)and a higher proportion of patients with internal carotid artery involvement(13/21 cases vs.2/12 cases,P=0.027)compared with the right side group.No statistically significant differences were observed in other general or clinical data across the three groups or between the two non-control groups(all P＞0.05).(2)Statistically significant differences were found across the three groups in the MoCA scale total score and scores of visuospatial/executive function,attention,language,abstraction,delayed recall,and orientation cognitive domains(all P＜0.05),while no significant difference was noted in the naming score(P=0.063).The left intracranial large artery involvement group had lower total MoCA score and lower scores in visuospatial/executive function,attention,language,abstraction,delayed recall,and orientation in comparison to the healthy control group(all P＜0.016 7).The right intracranial large artery involvement group had significantly lower scores in language,abstraction,and orientation domains than the healthy control group(all P＜0.016 7).Additionally,the left side group had a lower attention domain score than the right side group(P＜0.016 7).No other statistically significant differences were found in pairwise comparisons(all P＞0.016 7).(3)Patients in both the left and right intracranial large artery involvement groups exhibited a significant decrease in CBF in extensive regions on the affected side,including the temporal lobe,dorsolateral prefrontal cortex,and occipital lobe.Furthermore,after correction,in the left involvement group CBF was higher in the contralateral lingual gyrus,cuneus,and calcarine sulcus compared with the healthy control group(P＜0.05).While in the right involvement group,no regions had increased CBF compared to the healthy control group.(4)Multiple linear regression showed positive correlation between CBF in ipsilateral precentral gyrus and superior temporal gyrus,and the total MoCA score in patients with left intracranial large artery involvement(FWE-corrected,P＜0.05).In contrast,there was no correlation between CBF and total MoCA score in patients with right intracranial large artery involvement.Conclusions ICAS-MSTIA patients exhibited various degrees of impairment in cerebral perfusion and cognitive function.A significant positive correlation is observed between these two impairments in patients with left intracranial large artery involvement.