OBJECTIVE: To explore the functional roles and underlying mechanisms of neferine in the context of angiotensin II (Ang II)-induced hypertension and vascular dysfunction. METHODS: Male mice were infused with Ang II to induce hypertension and randomly divided into treatment groups receiving neferine or a control vehicle based on baseline blood pressure using a random number table method. The hypertensive mouse model was constructed by infusing Ang II via a micro-osmotic pump (500 ng/kg per minute), and neferine (0.1, 1, or 10 mg/kg), valsartan (10 mg/kg), or double distilled water was administered intragastrically once daily for 6 weeks. A non-invasive blood pressure system, ultrasound, and hematoxylin and eosin staining were performed to assess blood pressure and vascular changes. RNA sequencing and network pharmacology were employed to identify differentially expressed transcripts (DETs) and pathways. Vascular ring tension assay was used to test vascular function. A7R5 cells were incubated with neferine for 24 h and then treated with Ang II to record the real-time Ca²⁺ concentration by confocal microscope. Immunohistochemistry (IHC) and Western blot were used to evaluate vasorelaxation, calcium, and the extracellular signal-regulated kinase (ERK)1/2 pathway. RESULTS: Neferine treatment effectively mitigated the elevation in blood pressure, pulse wave velocity, aortic thickening in the abdominal aorta of Ang II-infused mice (P<0.05). RNA sequencing and network pharmacology analysis identified 355 DETs that were significantly reversed by neferine treatment, along with 25 potential target genes, which were further enriched in multiple pathways and biological processes, such as ERK1 and ERK2 cascade regulation, calcium pathway, and vascular smooth muscle contraction. Further investigation revealed that neferine treatment enhanced vasorelaxation and reduced Ca²⁺-dependent contraction of abdominal aortic rings, independent of endothelium function (P<0.05). The underlying mechanisms were mediated, at least in part, via suppression of receptor-operated channels, store-operated channels, or voltage-operated calcium channels. Neferine pre-treatment demonstrated a reduction in intracellular Ca²⁺ release in Ang II stimulated A7R5 cells. IHC staining and Western blot confirmed that neferine treatment effectively attenuated the upregulation of p-ERK1/2 both in vivo and in vitro, which was similar with treatment of ERK1/2 inhibitor PD98059 (P<0.05). CONCLUSIONS Neferine remarkably alleviates Ang II-induced elevation of blood pressure, vascular dysfunction, and pathological changes in the abdominal aorta. This beneficial effect is mediated by the modulation of multiple pathways, including calcium and ERK1/2 pathways.
Animals ; Angiotensin II ; Male ; Benzylisoquinolines/therapeutic use* ; Network Pharmacology ; Blood Pressure/drug effects* ; Sequence Analysis, RNA ; Mice ; Hypertension/chemically induced* ; Mice, Inbred C57BL ; Calcium/metabolism*

Objective:To explore relevant factors to accurately diagnose BPPV in vertigo children. Methods:A retrospective study was conducted on the proportion of BPPV in children（<18 years） with vertigo who visited the Hearing and Vertigo Diagnosis and Treatment Center of Tianjin Medical University General Hospital from September 2017 to August 2023. The clinical characteristics of BPPV children, including general demographics, medical history, first visit department, comorbidities, canal involvement, response to treatment, and incidence of recurrence, were analyzed. Data analysis was conducted using SPSS 25.0 software. Results:BPPV was diagnosed in 22.8% of patients seen for vertigo during the study period. There are differences in the proportion of BPPV diagnosis among children with dizziness in different age groups（P<0.05）, and the diagnosis of BPPV in the 7-12-year-old group has a longer disease course than in the 13-17-year-old group（P<0.05）. 72.3%（47/65） of patients or their families were able to provide a typical history of positional vertigo. 49.2%（32/65） of BPPV patients had comorbidities, and there were differences in the proportion of comorbidities among different age groups of BPPV patients（P<0.05）. With the progress of study, the proportion of BPPV in children with vertigo has shown an upward trend, and the proportion of children with otolaryngology as the first diagnosis department has also increased（P<0.05）. The proportion of horizontal semicircular canals in children with BPPV has increased. All BPPV patients underwent canalith repositioning maneuvers, with good treatment outcomes and a recurrence rate of 12.3%（8/65）. The recurrence rate in the group of BPPV patients with comorbidities was 21.9%, which was higher than that in the group without comorbidities（P<0.05）. Conclusion:Childhood BPPV has clinical characteristics such as unclear medical history, high proportion of comorbidities, easy recurrence in BPPV children with comorbidities and high proportion of horizontal semicircular canal involvement. For children diagnosed with other vertigo diseases, do not ignore the BPPV diagnostic test. It is recommended to perform routine position tests on children with vertigo if conditions permit to reduce missed diagnosis of BPPV in children.
Humans ; Benign Paroxysmal Positional Vertigo/diagnosis* ; Child ; Retrospective Studies ; Adolescent ; Female ; Male ; Recurrence ; Vertigo/diagnosis* ; Comorbidity ; Child, Preschool

OBJECTIVES: To investigate the impact of high expression of transmembrane and coiled helix structural domain 1 (TMCO1) on prognosis of gastric cancer and the possible mechanisms. METHODS: TMCO1 expression in gastric cancer and its effect on gastric cancer progression and prognosis were analyzed using publicly available databases and clinical data of patients undergoing radical surgery in our hospital, and its possible biological functions were explored using KEGG and GO analyses. In gastric cancer HGC-27 cells, the effects of lentivirus-mediated TMCO1 overexpression and TMCO1 silencing on cell apoptosis, proliferation, invasion and migration were examined. RESULTS: TMCO1 expression was significantly elevated in gastric cancer tissues (P<0.05), and its high expression was positively correlated with cancer progression (P<0.001) and a lowered postoperative 5-year survival rate of the patients (P<0.05). Bioinformatic analyses suggested that TMCO1 may affect gastric cancer cell apoptosis via Wnt signaling. In HGC-27 cells, TMCO1 overexpression significantly promoted tumor cell proliferation, inhibited cell apoptosis, and enhanced cell migration and invasion, whereas TMCO1 silencing produced the opposite effects. Western blotting showed that β-catenin levels were significantly upregulated in TMCO1-overexpressing cells and downregulated in cells with TMCO1 silencing. CONCLUSIONS TMCO1 is overexpressed in gastric cancer tissues, and its high expression promotes gastric cancer progression and affects long-term prognosis of the patients possibly by activating the Wnt/ β-catenin signaling pathway to inhibit apoptosis of gastric cancer cells.
Humans ; Stomach Neoplasms/metabolism* ; Apoptosis ; Prognosis ; Cell Line, Tumor ; Cell Proliferation ; Cell Movement ; Wnt Signaling Pathway ; beta Catenin/metabolism* ; Gene Expression Regulation, Neoplastic

•A strategy for in situ metabolically synthesized active drug-based probes was proposed.•The potential purgative targets of SA were successfully hooked and identified.•The work provided a new insight for studying the direct targets of unstable active drugs.

Objective To explore the correlation between the expression level of secreted curl associated protein 5(SFRP5)and the condition and prognosis of patients with severe pneumonia.Methods A total of 168 patients with pneumonia admitted to the Department of Respiratory and Critical Care Medicine of this hospital from June 2022 to June 2024 were selected as the research subjects,and 78 healthy individuals who underwent physical examinations in this hospital during the same period were selected as the control group.According to the acute physiology and chronic health evaluation Ⅱ(APACHEⅡ)score,the patients were di-vided into the common pneumonia group(APACHE Ⅱ score＜15,n=82)and the severe pneumonia group(APACHE Ⅱ score≥ 15,n=86).Peripheral venous blood was collected from the three groups after fasting for 8 to 12 hours and peripheral blood mononuclear cells were extracted by centrifuging.Real-time fluores-cence quantitative PCR was used to detect the expression level of SFRP5 mRNA in peripheral blood mononu-clear cells,which was Used to determine the expression level of SFRP5.Pearson analysis was used to analyze the correlations between the expression level of SFRP5 and the levels of inflammatory factors,pulmonary function indices and the condition in patients with severe pneumonia.The receiver operating characteristic(ROC)curve was used to analyze the diagnostic efficiency of the expression level of SFRP5 for the prognosis of patients with severe pneumonia.Results There were also significant differences in the levels of WBC,C re-active protein(CRP),procalcitonin(PCT),interleukin(IL)-6,and IL-8 among the three groups(P＜0.05),with the highest levels observed in the severe pneumonia group and the lowest in the control group.There were significant differences in the levels of forced expiratory volume in the first second(FEV1),forced vital capacity(FVC),and FEV1/FVC among the three groups(P＜0.05),with the highest levels observed in the severe pneumonia group and the lowest in the control group.The expression level of SFRP5 in the severe pneumonia group was the lowest(0.46±0.13),followed by the common pneumonia group(0.78±0.15),and the control group was the highest level(1.23±0.22),with statistically significant differences(P＜0.05).The results of Pearson correlation analysis showed that the expression level of SFRP5 in patients with severe pneu-monia was negatively correlated with the levels of WBC,CRP,PCT,IL-6,IL-8,and the APACHE Ⅱ score(P＜0.05),and positively correlated with the levels of FEV1,FVC,and FEV1/FVC(P＜0.05).The area un-der the curve(AUC)of the expression level of SFRP5 for predicting poor prognosis in patients with severe pneumonia was 0.843(95％CI:0.748-0.912),with a sensitivity of 68.18％and a specificity of 89.06％.Conclusion The expression level of SFRP5 is related to the condition of patients with severe pneumonia,and SFRP5 can predict the prognosis of patients with severe pneumonia.

Objective To compare the effects of different doses of budesonide and formoterol fumarate powder for inhalation combined with montelukast sodium tablet in the treatment of cough variant asthma(CVA)and the improvement of airway function and inflammatory factors.Methods Elderly patients with cough variant asthma were randomly divided into group A and group B.Both groups of patients received budesonide and formoterol fumarate powder for inhalation combined with montelukast sodium tablet.Group A was given budesonide and formoterol fumarate powder for inhalation(Ⅱ),2 inhalation per time,twice a day;Group B was given budesonide and formoterol fumarate powder for inhalation,4 inhalation per time,twice a day;budesonide fumatrol inhalation powder mist for continuous treatment for 6 months,and montelukast sodium tablet 10 mg once a day for at least 3 months.The nighttime cough scores of the two groups were compared before treatment and after treatment.The percentage of forced expiratory volume in one second(FEV1)in the predicted value,the maximum mid expiratory flow(MMEF),the fractional exhaled nitric oxide(FeNO),interleukin-5(IL-5)and eosinophils were compared between the two groups.The incidence of adverse drug reactions and the recurrence rate within 1 year were compared between the two groups.Results A total of 45 cases were enrolled in both the group A and the group B.At 9 months after treatment,the nocturnal cough scores of the group A and the group B were(0.93±0.42)and(0.65±0.29)points,respectively;the percentage of FEV1 in the predicted value were(97.75±9.67)％and(100.93±11.06)％,respectively;the MMEF values were(2.81±1.04)and(3.08±1.09)L·s-1,respectively;the FeNO values were(18.94±9.75)and(15.94±7.96)ppb,respectively;the IL-5 levels were(10.88±7.06)and(8.11±5.56)pg·mL-1,respectively.The above indicators in group B showed statistically significant differences compared to group A(all P＜0.05).The total incidence of adverse drug reactions in group A and group B were 8.89％(5 cases/45 cases)and 13.33％(6 cases/45 cases),respectively.The recurrence rates was 15.56％(7 cases/45 cases)and 13.33％(6 cases/45 cases),respectively.There was no statistically significant difference in the above indicators between group B and group A(all P＞0.05).Conclusion For elderly patients with CVA,higher dose of budesonide and formoterol fumarate powder for inhalation combined with montelukast sodium tablet can better improve cough symptoms,reduce the level of airway hyperresponsiveness and inflammatory factors,reduce the recurrence rate,and the patients are well tolerated.

Objective:Varicocele(VC)induces male infertility by mediating changes in the testicular microenvironment,in which testicular hypoxia and high-pressure are important pathological conditions.This study aims to compare the mouse spermatogenesis(GC-2spd)cells and Sertoli(TM4)cells of mouse testis after hypoxic modeling and hypoxic and high-pressure combined modeling,and to explore the feasibility of establishing a hypoxic and high-pressure combined cell model.Methods:On the basis of cell hypoxia induced by CoCl2,the complex model of testicular cell hypoxia and high pressure was constructed by changing the osmotic pressure of GC-2 and TM4 cell medium with a high concentration of NaCl solution.After selecting the intervention concentration of CoCl2 by MTT test and detecting the expression level of HIF-1α for the determination of the optimal osmotic pressure conditions of the cell model,the cells were divided into normal group,hypoxia model group and composite model group.And the levels of OS,programmed cell death,inflammatory factors,and the expression levels of pyroptosis-related proteins were compared between the normal group and the groups with different modeling methods.Results:The optimal intervention concentration of CoCl2 in GC-2 and TM4 cells was 150 and 250μmol/L,respectively,and the expression of HIF-1α was the highest in both cells under osmotic pressure of 500 mOsmol/kg(P＜0.05).Compared with the normal group,the SOD levels of GC-2 and TM4 cells decreased(all P＜0.05),CAT level decreased(all P＜0.05),and MDA level increased(all P＜0.01),and the OS level of GC-2 and TM4 cells was more obvious than that of the hy-poxia model group(all P＜0.05).Compared with the normal group,apoptosis occurred in GC-2 and TM4 cells after composite model-ing(all P＜0.05).Compared with the normal group,the mRNA expressions of IL-1β,IL-18,TNF-α and COX-2 in GC-2 and TM4 cells significantly increased(P＜0.01)and higher than those in hypoxia model group(P＜0.05)and induced pyroptosis(P＜0.01).The expression level of GSDMD increased(P＜0.05).Conclusion:The cell model with hypoxia and high pressure com-bined modeling can not only induce oxidative stress and apoptosis of cells better than that with hypoxia alone,but also further cause in-flammatory response damage and pyroptosis,which simulates the changes of testis microenvironment mediated by hypoxia and high pressure combined conditions in VC.This cell model can be used for studying the pathogenesis of VC-associated male infertility,evalu-ating drug efficacy,and exploring pharmacological mechanisms.

Porcine arthritis,one of the common chronic diseases in large-scale pig farms,can signifi-cantly reduce the production performance of meat pigs.In this study,a strain of Haemophilus pa-rasuis(HPS)was isolated from the joint fluid of a lame pig.The HPS was analyzed in terms of se-rotypes,virulence genes,and resistance genes.Additionally,it was treated with sensitive antibiotics to provide a theoretical basis for the comprehensive prevention and treatment of arthritis in meat pigs in future production settings.A strain of HPS type 14 was isolated from the joint fluid of dis-eased pigs.The HPS isolate demonstrated sensitivity to β-lactams and tetracyclines,while florfeni-col and polymyxin effectively inhibited its growth at low concentrations.However,the bacteria ex-hibited resistance to sulfonamides and ciprofloxacin.The treatment of affected pigs with clinical ar-thritis using doxycycline and enrofloxacin injections proved effective.Compared to the infected group,in which the sick pigs experienced difficulty flexing their carpal and tarsal joints and exhibi-ted significant lameness,the pigs in the treatment group showed marked improvement.Their joints were only slightly swollen,and the clinical symptoms of arthropathy were alleviated.

BACKGROUND:Current strategies for the treatment of the corticospinal tract after spinal cord injury mainly focus on exercise rehabilitation,drug therapy,transcranial magnetoelectric stimulation,endogenous regulation such as transcription factors and specific signaling pathways.Among them,transcription factors and their specific signaling pathways are the key factors regulating the axonal regeneration of corticospinal tract after spinal cord injury.A large number of preclinical studies have confirmed that the synergy between transcription factors and their signaling pathways has a significant regulatory effect on the axonal regeneration of neurons in the corticospinal tract after spinal cord injury.Therefore,it has broad application prospects to explore new combination therapy strategies targeting transcription factors and specific signaling pathways for spinal cord injury.OBJECTIVE:To systematically summarize the regulatory effects of transcription factors and their signaling pathways on the axonal regeneration of neurons in the corticospinal tract after spinal cord injury and the underlying molecular mechanisms,and explore the application of combined therapy strategies targeting transcription factors and signaling pathways in the neuroplasticity of the corticospinal tract after spinal cord injury,in order to provide a new combination strategy for the treatment of spinal cord injury.METHODS:The search terms included"spinal cord injury,axon regeneration,transcription factors,signaling pathway,corticospinal tract,central nervous system,synergistic system,neuroprotective system"in Chinese and English.A literature retrieval was conducted in WanFang,Web of Science,and PubMed for relevant literature published from database inception to September 2024.Finally,101 articles were included for analysis and summary.RESULTS AND CONCLUSION:(1)The article outlines the biological properties and intervention strategies for axonal regeneration of the corticospinal tract after spinal cord injury,analyses the reasons for focusing on the corticospinal tract after spinal cord injury,and elucidates the response and possibility of regeneration of the corticospinal tract after spinal cord injury.(2)In this study,the combined regulatory strategy of transcription factors centered on Krüppel-like factor 6,Krüppel-like factor 7,and neuronal restriction silencing factor can significantly promote the axonal regeneration of neurons in the corticospinal tract after spinal cord injury.(3)The phosphatidylinositol 3-kinase-protein kinase B-rapamycin target protein signaling pathway and Wnt5a pathway are the classical signaling pathways fortranscription factors to regulate the axonal regeneration of corticospinal tract neurons,and the combined treatment strategy can effectively promote the axonal regeneration and functional reconstruction of corticospinal tract neurons after spinal cord injury.(4)This article discusses the combined treatment strategies of transcription factors and specific signaling pathways in a comprehensive and detailed manner,such as Krüppel-like factor 6 combined with signal transducer and activator of transcription 3,Krüppel-like factor 7 combined with SOX11 transcription factor,combined inhibition of phosphatase and tensin homologs and neuronal restriction silencing factor,etc.,to exert a synergistic effect and promote the axonal regeneration of corticospinal tract neurons after spinal cord injury,which are significantly better than those of single treatment.It can effectively improve functional recovery and provide a reference scheme for the future treatment of axonal regeneration of corticospinal tract neurons after spinal cord injury.However,the specific mechanism of the combination therapy still needs to be further studied,and the current combination strategy is only widely used in animal models but not in clinical practice.(5)The combined therapy strategy based on transcription factors and specific signaling pathways has a significant therapeutic effect on the axonal regeneration of corticospinal tract neurons after spinal cord injury,and it is necessary to further explore the molecular mechanism of joint regulation in the future,in order to provide an effective combined therapy strategy for the rehabilitation and functional reconstruction of spinal cord injury.

Objective To explore the effect of transcutaneous auricular vagus nerve stimulation(taVNS)on postoperative recovery of gastrointestinal function in gynecological laparoscopic surgery patients.Methods Ninety-six patients who underwent elective laparoscopic total hysterectomy were selected.According to the random number table method,patients were divided into the taVNS group(group T)and the sham stimulation group(group F)with 48 patients in each group.The conventional general anesthesia method was used in both groups.The group T received taVNS once before surgery and once in the anaesthesia recovery room with 30 min per stimulation,while the group F was given sham stimulation for 30 min each.Postoperative recovery time of anal gas and defecation,the I-FEED scores on the 1st,2nd and 3rd postoperative days,the GSRS score on the 3rd postoperative day were recorded.The NRS scores on the 1st and 2nd postoperative days,postoperative remedial analgesia,occurrence of postoperative adverse effects and duration of postoperative hospitalization were recorded.Results Compared with the group F,the time to first postoperative anal exhaust and defecation was significantly shorter in the group T.The I-FEED scores on the 1st,2nd and 3rd postoperative days,and the GSRS score on 3rd postoperative day were significantly decreased in the group T.The proportion of patients with postoperative gastrointestinal intolerance and postoperative gastrointestinal dysfunction were reduced in the group T(P＜0.05).NRS scores at postoperative days 1,and 2 were decreased and the incidence of postoperative nausea was lower(P＜0.05).There were no significant differences in postoperative remedial analgesia,the occurrence of postoperative vomiting,dizziness,bradycardia and hypotension,and duration of postoperative hospitalization in the two groups of patients(P＞0.05).Conclusion taVNS can improve the recovery of postoperative gastrointestinal function,reduce postoperative nausea and alleviate postoperative pain in laparoscopic total hysterectomy patients.