To study the therapeutic effect and mechanisms of ethyl syringate(MD) on ulcerative colitis(UC), the MTT assay was used to detect the proliferation inhibition of RAW264.7 cells and HT-29 cells by different concentrations of MD(50, 100, 200, 400 μmol·L~(-1)). UC cell models were constructed by inducing RAW264.7 cells and HT-29 cells with lipopolysaccharide(LPS) and tumor necrosis factor-α(TNF-α). An animal model was established by inducing mice with 2.5% dextran sulfate sodium(DSS) to verify the therapeutic effect of MD on UC. A control group, a model group(LPS or TNF-α), and groups treated with different concentrations of MD(50, 100, 200, 400 μmol·L~(-1)) were set up in this study. Nitric oxide(NO) levels were measured using a NO detection kit. Intracellular reactive oxygen species(ROS) levels were assessed using a laser confocal microscope and ROS kit. Enzyme-linked immunosorbent assay(ELISA) was used to detect changes in the levels of interleukin-6(IL-6), TNF-α, interferon-γ(INF-γ), interleukin-10(IL-10), and myeloperoxidase(MPO) in cells and animal tissues. Western blot was used to detect the expression levels of phosphorylated Janus kinase 2(p-JAK2), Janus kinase 2(JAK2), phosphorylated signal transducer and activator of transcription 3(p-STAT3), signal transducer and activator of transcription 3(STAT3), zonula occludens-1(ZO-1), occludin, and claudin-1 in cells and animal tissues. The results showed that MD can improve the inflammatory response by inhibiting the production of NO and ROS and regulating the expression of inflammatory factors. It significantly reduced the disease activity index(DAI) in mice, improved the shortening of the colon, and repaired intestinal epithelial damage by inhibiting the activation of the JAK2/STAT3 pathway, thereby exerting anti-UC activity.
Animals ; Colitis, Ulcerative/chemically induced* ; Janus Kinase 2/genetics* ; STAT3 Transcription Factor/genetics* ; Mice ; Humans ; Signal Transduction/drug effects* ; Male ; RAW 264.7 Cells ; Reactive Oxygen Species/metabolism* ; Nitric Oxide/metabolism* ; HT29 Cells ; Salicylates/administration & dosage* ; Protective Agents/administration & dosage*

This study aims to explore the pharmacodynamic material basis of Jinbei Oral Liquid(JBOL) against idiopathic pulmonary fibrosis(IPF) based on serum pharmacochemistry and network pharmacology. The ultra-high performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry(UHPLC-Q-TOF-MS/MS) technology was employed to analyze and identify the components absorbed into rat blood after oral administration of JBOL. Combined with network pharmacology, the study explored the pharmacodynamic material basis and potential mechanism of JBOL against IPF through protein-protein interaction(PPI) network construction, "component-target-pathway" analysis, Gene Ontology(GO) functional enrichment, and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis. First, a total of 114 compounds were rapidly identified in JBOL extract according to the exact relative molecular mass, fragment ions, and other information of the compounds with the use of reference substances and a self-built compound database. Second, on this basis, 70 prototype components in blood were recognized by comparing blank serum with drug-containing serum samples, including 28 flavonoids, 25 organic acids, 4 saponins, 4 alkaloids, and 9 others. Finally, using these components absorbed into blood as candidates, the study obtained 212 potential targets of JBOL against IPF. The anti-IPF mechanism might involve the action of active ingredients such as glycyrrhetinic acid, cryptotanshinone, salvianolic acid B, and forsythoside A on core targets like AKT1, TNF, and ALB and thereby the regulation of multiple signaling pathways including PI3K/AKT, HIF-1, and TNF. In conclusion, JBOL exerts the anti-IPF effect through multiple components, targets, and pathways. The results would provide a reference for further study on pharmacodynamic material basis and pharmacological mechanism of JBOL.
Drugs, Chinese Herbal/pharmacokinetics* ; Animals ; Tandem Mass Spectrometry ; Network Pharmacology ; Rats ; Chromatography, High Pressure Liquid ; Rats, Sprague-Dawley ; Male ; Idiopathic Pulmonary Fibrosis/metabolism* ; Humans ; Administration, Oral ; Protein Interaction Maps/drug effects* ; Signal Transduction/drug effects*

BACKGROUND: Based on the China-VHD database, this study sought to develop and validate a Valvular Heart Disease- specific Age-adjusted Comorbidity Index (VHD-ACI) for predicting mortality risk in patients with VHD. METHODS & RESULTS: The China-VHD study was a nationwide, multi-centre multi-centre cohort study enrolling 13,917 patients with moderate or severe VHD across 46 medical centres in China between April-June 2018. After excluding cases with missing key variables, 11,459 patients were retained for final analysis. The primary endpoint was 2-year all-cause mortality, with 941 deaths (10.0%) observed during follow-up. The VHD-ACI was derived after identifying 13 independent mortality predictors: cardiomyopathy, myocardial infarction, chronic obstructive pulmonary disease, pulmonary artery hypertension, low body weight, anaemia, hypoalbuminaemia, renal insufficiency, moderate/severe hepatic dysfunction, heart failure, cancer, NYHA functional class and age. The index exhibited good discrimination (AUC, 0.79) and calibration (Brier score, 0.062) in the total cohort, outperforming both EuroSCORE II and ACCI (P < 0.001 for comparison). Internal validation through 100 bootstrap iterations yielded a C statistic of 0.694 (95% CI: 0.665-0.723) for 2-year mortality prediction. VHD-ACI scores, as a continuous variable (VHD-ACI score: adjusted HR (95% CI): 1.263 (1.245-1.282), P < 0.001) or categorized using thresholds determined by the Yoden index (VHD-ACI ≥ 9 vs. < 9, adjusted HR (95% CI): 6.216 (5.378-7.184), P < 0.001), were independently associated with mortality. The prognostic performance remained consistent across all VHD subtypes (aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation, tricuspid valve disease, mixed aortic/mitral valve disease and multiple VHD), and clinical subgroups stratified by therapeutic strategy, LVEF status (preserved vs. reduced), disease severity and etiology. CONCLUSION The VHD-ACI is a simple 13-comorbidity algorithm for the prediction of mortality in VHD patients and providing a simple and rapid tool for risk stratification.

Evading host immunity killing is a critical step for virus survival. Inhibiting viral immune escape is crucial for the treatment of viral diseases. Serine/threonine kinase 39 (STK39) was reported to play an essential role in ion homeostasis. However, its potential role and mechanism in viral infection remain unknown. In this study, we found that viral infection promoted STK39 expression. Consequently, overexpressed STK39 inhibited the phosphorylation of interferon regulatory factor 3 (IRF3) and the production of type I interferon, which led to viral replication and immune escape. Genetic ablation or pharmacological inhibition of STK39 significantly protected mice from viral infection. Mechanistically, mass spectrometry and immunoprecipitation assays identified that STK39 interacted with PPP2R1A (a scaffold subunit of protein phosphatase 2A (PP2A)) in a kinase activity-dependent manner. This interaction inhibited DDB1 and CUL4 associated factor 1 (DCAF1)-mediated PPP2R1A degradation, maintained the stabilization and phosphatase activity of PP2A, which, in turn, suppressed the phosphorylation of IRF3, decreased the production of type I interferon, and then strengthened viral replication. Thus, our study provides a novel theoretical basis for viral immune escape, and STK39 may be a potential therapeutic target for viral infectious diseases.

Objective To study the effects of dual-hemispheric transcranial direct current stimulation(Dual-tDCS)on upper limb motor function in chronic-phase stroke patients to provide theoretical references for neural mechanisms-based treatment of upper limb dysfunction.Methods Totally 24 chronic-phase stroke patients with upper limb motor dysfunction were selected from some hospital and divided into an experimental group(n=13)and a control group(n=11)the random number table.The control group was treated with tDCS pseudo-stimulation combined with conventional rehabilitation,while the experimental group was given with Dual-tDCS combined with conventional rehabilitation.The patient activities were assessed before and after treatment with Fugl-Meyer assessment upper limb scale(FMA-UL)and activities of daily living(ADL)scale.The changes of primary motor cortex(M1 area)and whole brain functional connectivity(FC)were compared before and after treatment.SPSS 24.0 statistical software was used for data analysis.Results After treatment,the two groups both had the FAM-UL and ADL scores increased significantly,and the experimental group had the scores statistically higher than those of the control group,and the differences were all statistically significant(P＜0.05).In the control group,the analysis on M1 area and whole brain FC after treatment indicated the FC decreased from M1 area at the unaffected side to midoccipital gyrus at the affected side and lingual gyrus and healthy angular gyrus at the unaffected side;there were no brain areas with changed FC found(P＜0.01).In the experimental group,the FC was lowered from M1 area at the unaffected side to cerebellum and cerebellar vermis at the unaffected side,while raised to precentral gyrus at the affected side(P＜0.01);the FC ascended from M1 area at the affected side to cerebellum and middle temporal gyrus at the affected side,while declined to precentral gyrus at the unaffected side(P＜0.01).Conclusion The neuromodulatory effect of Dual-tDCS on the brain improves FC in motor and non-motor-related brain areas in chronic-phase stroke patients,and may contribute to rehabilitation of upper limb motor dysfunction in chronic-phase stroke.[Chinese Medical Equipment Journal,2024,45(2):67-73]

ObjectiveTo explore the impact of autonomic nerve function on motor function in patients with post-stroke depression (PSD) from the perspective of regional homogeneity (ReHo). MethodsFrom January to December, 2020, a total of 60 inpatients and outpatients with cerebral infarction in the Affiliated Brain Hospital of Nanjing Medical University were divided into control group (n = 30) and PSD group (n = 30). Two groups were assessed using Fugl-Meyer Assessment (FMA), modified Barthel Index (MBI) and Hamilton Depression Scale (HAMD). Heart rate variability (HRV) was measured. Ten patients in each group were selected randomly to undergo resting state functional magnetic resonance imaging (rs-fMRI) to calculate ReHo. ResultsAll HRV indices were lower in PSD group than in the control group (|t| > 2.092, P < 0.05). In PSD group, FMA and MBI scores showed positive correlations with 24-hour standard deviation of normal-to-normal R-R intervals (SDNN), the root mean square of successive differences between normal heartbeats over 24 hours (RMSSD), the percentage of differences between adjacent normal R-R intervals over 24 hours that were greater than 50 ms (PNN50), total power (TP), very low frequency power (VLF) and low frequency power (LF) (r > 0.394, P < 0.05), and showed negative correlations with HAMD scores (|r| > 0.919, P < 0.001). HAMD scores in PSD group were negatively correlated with SDNN, RMSSD, PNN50, TP and VLF (|r| > 0.769, P < 0.001). Compared with the control group, the ReHo increased in PSD group in the right rectus gyrus (142 voxels, t = 6.575), the left medial and paracingulate gyri (204 voxels, t = 4.925) (GRF correction, P_-Voxel < 0.005，P_-Cluster < 0.05); and reduced in the right cerebellum (191 voxels, t = -6.487), the left middle temporal gyrus (140 voxels, t = -5.516), and the left precentral gyrus (119 voxels, t = -4.764) (GRF correction, P_-Voxel < 0.005，P_-Cluster < 0.05) in PSD group. ConclusionAutonomic nerve function is related to motor dysfunction in patients with PSD. The modulation of emotional, cognitive and motor brain regions by the autonomic nervous system may play a role in influencing the motor function in patients with PSD.

Objective To explore clinical effect of the fifth metatarsal head excision and non-excision in rheumatoid arthritis(RA)forefoot deformity reconstruction.Methods Retrospective analysis was performed on 50 patients(76 feet)with moderate to severe forefoot deformity caused by RA treated from May 2015 to January 2019.According to degeneration of the fifth metatarsophalangeal joint,the fifth metatarsal head was retained or excised by wind-like forefoot reconstruction,and divid-ed into the fifth metatarsal head preservation group(preservation group)and the fifth metatarsal head resection group(resec-tion group).Twenty-four female patients in preservation group,aged from 47 to 81 years old with an average of(60.37±8.60)years old;the course of disease ranged from 13 to 22 years with an average of(19.00±3.06)years;body mass index(BMI)ranged from 21 to 28 kg·m-2 with an average of(23.53±2.47)kg·m-2;six patients(6 feet)with moderate hallux valgus defor-mity and 18 patients(30 feet)with severe hallux valgus deformity;treated with the first metatarsophalangeal joint fusion com-bined with the second th the fourth metatarsophalangeal joint arthroplasty and the fifth metatarsophalangeal joint cleanup.Twenty-six female patients in resection group were female,aged from 30 to 80 years old with an average of(58.53±13.70)years old;the course of disease ranged from 8 to 25 years with an average of(17.94±3.92)years;BMI raged from 20 to 28 kg·m-2 with an average of(24.60±2.03)kg·m-2;4 patients(4 feet)with moderate bunion valgus deformity and 22 patients(36 feet)with severe bunion valgus deformity;treated by the first metatarsophalangeal joint fusion combined with the second th the fifth metatarsophalangeal joint resection of the metatarsophalangeal head.Operation time and postoperative complications between two groups were observed,hallux valgus angle(HVA),intermetatarsal angles between the first and the second metatarsals(I-MAFS),intermetatarsal angles between the first and fifth metatarsals(IMAFF),Japanese Society for Surgery of Foot(JSSF)score before surgery and at the latest follow-up were compared.Results Fifty patients were followed-up from 14 to 46(25.30± 8.83)months in resection group and 12 to 48 with an average of(24.30±1 1.12)months in preservation group,while no signifi-cant difference between two groups(P＞0.05).There were no significant difference in operation time and postoperative compli-cations between two groups(P＞0.05).JSSF scores,HVA,IMAFS and IMAFF in fesection group were improved from(45.09± 3.35)points,(38.90±13.67)°,(12.88±1.72)°,(32.50±2.99)° before operation to(81.60±3.27)points,(15.40±0.90),(9.06±2.27)°,(22.20±1.98)° at the latest follow-up(P＜0.05);preservation group were improved from(47.09±3.96)points,(43.30±12.65)°,(13.99±3.13)°,(33.20±6.14)° to(83.10±3.66)points,(15.20±1.54)°,(8.99±1.02)°,(24.70±1.88)°,respectively.There were no significant difference in JSSF score,HVA,IMAFS and IMAFF between two groups before opera-tion and the latest follow-up(P＞0.05).At the latest follow-up,there were statistically significant differences in pain and defor-mity in JSSF scores between two groups(P＜0.05).Conclusion Both rheumatoid anterior foot reconstruction and anterior foot reconstruction fifth metatarsophalangeal joint debridement showed significant improvement in clinical efficacy and imaging re-sults.Compared with rheumatoid prefoot reconstruction,the fifth metatarsophalangeal joint reconstruction for the treatment of moderate and severe deformity of rheumatoid prefoot showed better improvement in pain,but worse improvement in deformity.For the moderate to severe deformity of the forefoot caused by rheumatoid disease,patients with mild to moderate degenerative deformity of the articular surface of the fifth metatarsal phalanges may be considered for use.

Objectives: To construct a nomogram for prediction of intrahepatic cholangiocarcinoma (ICC) lymph node metastasis based on inflammation-related markers,and to conduct its clinical verification. Methods: Clinical and pathological data of 858 ICC patients who underwent radical resection were retrospectively collected at 10 domestic tertiary hospitals in China from January 2010 to December 2018. Among the 508 patients who underwent lymph node dissection,207 cases had complete variable clinical data for constructing the nomogram,including 84 males,123 females,109 patients≥60 years old,98 patients<60 years old and 69 patients were pathologically diagnosed with positive lymph nodes after surgery. Receiver operating characteristic curve was drawn to calculate the accuracy of preoperative imaging examinations to determine lymph node status,and the difference in overall survival time was compared by Log-rank test. Partial regression squares and statistically significant preoperative variables were screened by backward stepwise regression analysis. R software was applied to construct a nomogram,clinical decision curve and clinical influence curve,and Bootstrap method was used for internal verification. Moreover,retrospectively collecting clinical information of 107 ICC patients with intraoperative lymph node dissection admitted to 9 tertiary hospitals in China from January 2019 to June 2021 was for external verification to verify the accuracy of the nomogram. 80 patients with complete clinical data but without lymph node dissection were divided into lymph node metastasis high-risk group and low-risk group according to the score of the nomogram among the 858 patients. Log-rank test was used to compare the overall survival of patients with or without lymph node metastasis diagnosed by pathology. Results: The area under the curve of preoperative imaging examinations for lymph node status assessment of 440 patients was 0.615,with a false negative rate of 62.8% (113/180) and a false positive rate of 14.2% (37/260). The median survival time of 207 patients used to construct a nomogram with positive or negative postoperative pathological lymph node metastases was 18.5 months and 27.1 months,respectively (P<0.05). Five variables related to lymph node metastasis were screened out by backward stepwise regression analysis,which were combined calculi,neutrophil/lymphocyte ratio,albumin,liver capsule invasion and systemic immune inflammation index,according to which a nomogram was constructed with concordance index(C-index) of 0.737 (95%CI: 0.667 to 0.806). The C-index of external verification was 0.674 (95%CI:0.569 to 0.779). The calibration prediction curve was in good agreement with the reference curve. The results of the clinical decision curve showed that when the risk threshold of high lymph node metastasis in the nomogram was set to about 0.32,the maximum net benefit could be obtained by 0.11,and the cost/benefit ratio was 1∶2. The results of clinical influence curve showed that when the risk threshold of high lymph node metastasis in the nomogram was set to about 0.6,the probability of correctly predicting lymph node metastasis could reach more than 90%. There was no significant difference in overall survival time between patients with high/low risk of lymph node metastasis assessed by the nomogram and those with pathologically confirmed lymph node metastasis or without lymph node metastasis (Log-rank test:P=0.082 and 0.510,respectively). Conclusion: The prediction accuracy of preoperative nomogram for ICC lymph node metastasis based on inflammation-related markers is satisfactory,which can be used as a supplementary method for preoperative diagnosis of lymph node metastasis and is helpful for clinicians to make personalized decision of lymph node dissection for patients with ICC.

Child ; Humans ; Factor VII Deficiency

Objective To investigate the spontaneous neural activity in the brain of patients with Alzheimer' s disease (AD) used 3 indicators of resting state-functional magnetic resonance (rs-fMRI) amplitude of low frequency fluctuation (ALFF), fractional amplitude of low frequency fluctuation (fALFF) and percentage amplitude fluctuation (PerAF). Methods Totally 36 clinically diagnosed AD patients and 40 healthy volunteers were scanned by fMRI in resting state respectively. ALFF, fALFF and PerAF were used to calculate and compare the changes of brain regions between the two groups. Results Compared with the normal control group, mALFF value in AD group increased significantly in bilateral caudate nucleus, medial frontal gyrus, superior frontal gyrus, gyrus rectus, anterior cingulate gyrus, olfactive cortex, left middle frontal gyrus and inferior frontal gyrus (P<0. 05). mALFF values decreased significantly in the right middle temporal gyrus, inferior temporal gyrus, inferior occipital gyrus, middle occipital gyrus, bilateral calcarine, cuneus, lingual gyrus, superior occipital gyrus, vermis, precuneus and other regions (P<0. 05). In AD group, mfALFF value of right inferior temporal gyrus, anterior cerebellar lobe, fusiform gyrus, left superior frontal gyrus, medial frontal gyrus, middle frontal gyrus, inferior frontal gyrus, gyrus rectus and anterior cingulate gyrus increased significantly (P<0. 05); mfALFF values decreased significantly in bilateral lingual gyrus, left calcarine, cuneus, superior occipital gyrus, middle occipital gyrus and vermis (P<0. 05). In AD group, mPerAF value increased significantly in bilateral gyrus rectus, anterior cingulate gyrus, medial frontal gyrus, left superior frontal gyrus, caudate nucleus, middle frontal gyrus, inferior frontal gyrus, olfactive cortex and insula (P<0. 05); mPerAF values decreased significantly in bilateral calcarine, cuneus, superior occipital gyrus, lingual gyrus, precuneus, left fusiform gyrus, inferior occipital gyrus, right superior parietal lobule, angular gyrus, middle temporal gyrus, inferior temporal gyrus and middle occipital gyrus (P < 0. 05). Conclusion The default mode network (DMN) and visual network of AD patients are characterized by abnormal brain activity, with the most significant neural activity in the prefrontal cortex and visual cortex.