BACKGROUND: Chronic kidney disease (CKD) is associated with common pathophysiological processes, such as inflammation and fibrosis, in both the heart and the kidney. However, the underlying molecular mechanisms that drive these processes are not yet fully understood. Therefore, this study focused on the molecular mechanism of heart and kidney injury in CKD. METHODS: We generated an microRNA (miR)-26a knockout (KO) mouse model to investigate the role of miR-26a in angiotensin (Ang)-II-induced cardiac and renal injury. We performed Ang-II modeling in wild type (WT) mice and miR-26a KO mice, with six mice in each group. In addition, Ang-II-treated AC16 cells and HK2 cells were used as in vitro models of cardiac and renal injury in the context of CKD. Histological staining, immunohistochemistry, quantitative real-time polymerase chain reaction (PCR), and Western blotting were applied to study the regulation of miR-26a on Ang-II-induced cardiac and renal injury. Immunofluorescence reporter assays were used to detect downstream genes of miR-26a, and immunoprecipitation was employed to identify the interacting protein of LIM and senescent cell antigen-like domain 1 (LIMS1). We also used an adeno-associated virus (AAV) to supplement LIMS1 and explored the specific regulatory mechanism of miR-26a on Ang-II-induced cardiac and renal injury. Dunnett's multiple comparison and t -test were used to analyze the data. RESULTS: Compared with the control mice, miR-26a expression was significantly downregulated in both the kidney and the heart after Ang-II infusion. Our study identified LIMS1 as a novel target gene of miR-26a in both heart and kidney tissues. Downregulation of miR-26a activated the LIMS1/integrin-linked kinase (ILK) signaling pathway in the heart and kidney, which represents a common molecular mechanism underlying inflammation and fibrosis in heart and kidney tissues during CKD. Furthermore, knockout of miR-26a worsened inflammation and fibrosis in the heart and kidney by inhibiting the LIMS1/ILK signaling pathway; on the contrary, supplementation with exogenous miR-26a reversed all these changes. CONCLUSIONS Our findings suggest that miR-26a could be a promising therapeutic target for the treatment of cardiorenal injury in CKD. This is attributed to its ability to regulate the LIMS1/ILK signaling pathway, which represents a common molecular mechanism in both heart and kidney tissues.
Animals ; MicroRNAs/metabolism* ; Angiotensin II/toxicity* ; Mice ; Renal Insufficiency, Chronic/chemically induced* ; Mice, Knockout ; Disease Models, Animal ; Male ; Signal Transduction/genetics* ; LIM Domain Proteins/genetics* ; Mice, Inbred C57BL ; Cell Line ; Humans

The occurrence of benign prostate hyperplasia(BPH)was related to disrupted sex steroid hormones,and metformin(Met)had a clinical response to sex steroid hormone-related gynaecological disease.How-ever,whether Met exerts an antiproliferative effect on BPH via sex steroid hormones remains unclear.Here,our clinical study showed that along with prostatic epithelial cell(PEC)proliferation,sex steroid hormones were dysregulated in the serum and prostate of BPH patients.As the major contributor to dysregulated sex steroid hormones,elevated dihydrotestosterone(DHT)had a significant positive rela-tionship with the clinical characteristics of BPH patients.Activation of adenosine 5'-monophosphate(AMP)-activated protein kinase(AMPK)by Met restored dysregulated sex steroid hormone homeostasis and exerted antiproliferative effects against DHT-induced proliferation by inhibiting the formation of androgen receptor(AR)-mediated Yes-associated protein(YAP1)-TEA domain transcription factor(TEAD4)heterodimers.Met's anti-proliferative effects were blocked by AMPK inhibitor or YAP1 over-expression in DHT-cultured BPH-1 cells.Our findings indicated that Met would be a promising clinical therapeutic approach for BPH by inhibiting dysregulated steroid hormone-induced PEC proliferation.

Objective To investigate the mechanism of matrix metalloproteinase(MMP)-9 involved in epithelial mesenchymal transformation(EMT)in chronic sinusitis(CRS).Methods The expression of MMP-9 from polypoid middle turbinate tissue was detected by immunohistochemical staining qPCR and Western blot assay in 42 patients with CRS and 8 patients underwent septoplasty.Primary human nasal epithelial cells HNEpc were cultured in vitro and divided into the control group,the TGF-β1 group(5 μg/L TGF-β1 intervention)and the TGF-β1+si-MMP-9 group(transfected with si-MMP-9 and 5 μg/L TGF-β1 intervention).The expression of MMP-9 was detected by cell immunofluorescence staining.Expression levels of TGF-β1,MMP-9 and EMT-related proteins E-cadherin,vimentin and α-SMA were detected by Western blot assay.Results(1)The positive expression rate of MMP-9 was significantly higher in the nasal mucosa of CRS with nasal polyps(CRSwNP)group(54.5%,12/22)than that of the CRS without polyps(25.0%,5/20)group and the control group(12.8%,1/8).The relative expression levels of MMP-9 mRNA and protein in nasal mucosa were higher in the CRSwNP group than those in the CRSsNP group and the control group(P＜0.05).(2)Compared with the control group,the expressions levels of TGF-β1,MMP-9,vimentin and α-SMA were increased in the TGF-β1 group,while the expression of E-cadherin was decreased(P＜0.05).Compared with the TGF-β1 group,expression levels of TGF-β1,MMP-9,vimentin and α-SMA were decreased in the TGF-β1+si-MMP-9 group,and the expression of E-cadherin was increased(P＜0.05).Conclusion The expression of MMP-9 is increased in CRS patients,which may be involved in the development of CRS through the regulation of EMT.

ObjectiveTo investigate the effects of Bushen Huoxue prescription on the cardiac function， inflammation， and quality of life of the patients with chronic heart failure resistant to diuretics. MethodA total of 78 patients who met the inclusion criteria were randomized into observation and control groups （39 cases）. Both groups received standardized treatment for diuretic resistance in accordance with the guidelines. In addition， the observation group received Bushen Huoxue prescription. The cardiac function indicators， total response rate regarding symptom alleviation， exercise endurance， urine volume， body mass， quality of life， and levels of inflammatory cytokines were compared between the two groups before and after treatment. ResultBefore treatment， the two groups of patients showed no significant differences in terms of 24 h urine volume， body mass， 6 minute walk test （6MWT）， Minnesota Living with Heart Failure Questionnaire （MLHFQ） score， N-terminal pro-B-type natriuretic peptide （NT-proBNP） level， left ventricular ejection fraction （LVEF）， stroke volume （SV）， and serum levels of interleukin-6 （IL-6）， interleukin-4 （IL-4）， and tumor necrosis factor-alpha （TNF-α）. After treatment， the observation group outperformed the control group in terms of the response rates regarding traditional Chinese medicine symptom scores and New York Heart Association （NYHA） grading of cardiac function （P<0.05）. After treatment， the body mass， MLHFQ score， and IL-6， TNF-α， and NT-proBNP levels decreased in both groups （P<0.05， P<0.01）， and the observation group showed more significant decreases than the control group （P<0.05， P<0.01）. Both groups showed increases in 24-h urine volume， 6MWT， LVEF， SV， and IL-4 after treatment （P<0.05， P<0.01）， and the observation group showed more significant increases than the control group （P<0.05， P<0.01）. ConclusionThe combination of Bushen Huoxue prescription with standardized treatment is effective in ameliorating the clinical symptoms of the patients with chronic heart failure resistant to diuretics. Moreover， it alleviates diuretic resistance and improves the cardiac function without causing obvious adverse reactions.

ObjectiveTo explore the clinical efficacy of Huangjin Shuangshen Jiawei （HJSSJW） granules in treating postoperative anxiety and depression after percutaneous coronary intervention （PCI） for coronary heart disease and the effects of this medicine on inflammatory cytokines. MethodNinety-four patients diagnosed with anxiety and depression after PCI were randomized into observation and control groups （47 cases） by the double-blind method. On the basis of conventional Western medical treatment， the observation group was treated with HJSSJW granules for 12 weeks， and the control group with the simulant of HJSSJW granules for 12 weeks. The two groups were compared in terms of Hamilton Anxiety and Depression Scales （HAMA-14， HAMD-24）， Pittsburgh Sleep Quality Inventory （PSQI）， Seattle Angina Score （SAQ）， TCM symptom scores， traditional Chinese medicine （TCM） symptom score and response rate， serum levels of hypersensitive-C reactive protein （hs-CPR）， tumor necrosis factor （TNF）-α， and interleukin （IL-6）， and incidence of major adverse cardiovascular events （MACEs） and adverse reactions. ResultAfter treatment， both groups showed declined scores of HAMA-14， HAMD-24， and PSQI （P<0.05， P<0.01） and the observation group had lower scores of HAMA-14， HAMD-24， and PSQI than the control group （P<0.01）. The scores of SAQ in both groups increased after treatment （P<0.01）， and the observation group had higher score of each dimension than the control group （P<0.05）. The TCM symptom scores decreased in both groups after treatment （P<0.01）， and they were lower in the observation group than in the control group （P<0.05）. The total response rate regarding TCM symptoms in the observation group was higher than that in the control group （χ²=9.225， P<0.01）. After treatment， the levels of hs-CPR， IL-6， and TNF-α became lowered in both groups （P<0.01）， and the observation group had lower levels of hs-CPR， IL-6， and TNF-α than the control group （P<0.05）. The incidence of MACEs in the observation group was lower than that in the control group during the 90 d of the follow-up period （χ²=4.242， P<0.05）. No adverse reactions associated with the use of HJSSJW granules were observed during the trial period. ConclusionHJSSJW granules can alleviate the bad mood， improve sleep， mitigate somatic symptoms， improve the quality of life， reduce inflammatory damage， and improve prognosis， being safe for clinical use in patients with postoperative anxiety and depression after PCI for coronary heart disease.

Objective To explore the intervention effect and molecular mechanism of Xinkang Granules on inflammatory factors in rats with chronic heart failure based on cGAS/STING signaling pathway.Methods SD rats were randomly divided into normal group and modeling group.The chronic heart failure model was established by intraperitoneal injection of Doxorubicin Hydrochloride.After successfully modeling,the rats were further divided into model group,Valsartan group and Xinkang Granules group.The model group was treated with distilled water every day,the Valsartan group was treated with Valsartan solution every day,and the Xinkang Granules group was treated with Xinkang Granules every day,all given for 4 consecutive weeks.Echocardiography was used to detect cardiac function,the pathological changes of myocardium were detected by hematoxylin-eosin staining(HE),the ultrastructural changes of myocardium in each group were observed by transmission electron microscope,and the contents of interleukin-1β(IL-1β)and interleukin-6(IL-6)in serum were detected by enzyme-linked immunosorbent assay(ELISA).The mRNA expression levels of mitochondrial transcription factor A(TFAM),cyclic guanosine monophosphate-adenylate synthase(cGAS),interferon-stimulated gene(STING)and IL-6 in myocardial tissue of rats in each group were detected by real-time fluorescence quantitative method(qPCR).The protein expressions of cGAS and STING in rat myocardial tissue were detected by immunohistochemical method.Results Compared with the blank group,the rats in the model group had significant inflammatory cell infiltration and inflammatory edema in myocardial tissue,their cardiac function was significantly reduced(P＜0.05,P＜0.01),and serum inflammatory factors were significantly increased(P＜0.01).The mRNA expression of TFAM in myocardial tissue was significantly reduced(P＜0.01),the mRNA expressions of IL-6,cGAS,and STING were significantly increased(P＜0.01),and the protein expressions of cGAS and STING in the myocardial tissue were significantly increased(P＜0.01).Compared with the model group,the cardiac function of the rats in the Xinkang Granules group was significantly improved(P＜0.05,P＜0.01),the inflammatory infiltration of myocardial cells was reduced,the expression of serum inflammatory factors was significantly reduced(P＜0.01),the mRNA expression of TFAM in myocardial tissue was significantly increased(P＜0.05),and the mRNA expressions of IL-6,cGAS,and STING were significantly decreased(P＜0.01),the protein expressions of cGAS and STING in myocardial tissue were significantly decreased(P＜0.01).Conclusion Xinkang Granules can reduce the expression of inflammatory factors and improve cardiac function in rats with chronic heart failure.Its mechanism may be related to inhibiting the cGAS/STING signaling pathway.

There are some limitations in the localization of epileptogenic zone commonly used by human eyes to identify abnormal discharges of intracranial electroencephalography in epilepsy. However, at present, the accuracy of the localization of epileptogenic zone by extracting intracranial electroencephalography features needs to be further improved. As a new method using dynamic network model, neural fragility has potential application value in the localization of epileptogenic zone. In this paper, the neural fragility analysis method was used to analyze the stereoelectroencephalography signals of 35 seizures in 20 patients, and then the epileptogenic zone electrodes were classified using the random forest model, and the classification results were compared with the time-frequency characteristics of six different frequency bands extracted by short-time Fourier transform. The results showed that the area under curve (AUC) of epileptic focus electrodes based on time-frequency analysis was 0.870 (delta) to 0.956 (high gamma), and its classification accuracy increased with the increase of frequency band, while the AUC by using neural fragility could reach 0.957. After fusing the neural fragility and the time-frequency characteristics of the γ and high γ band, the AUC could be further increased to 0.969, which was improved on the original basis. This paper verifies the effectiveness of neural fragility in identifying epileptogenic zone, and provides a theoretical reference for its further clinical application.
Humans ; Electroencephalography/methods* ; Epilepsy/diagnosis* ; Seizures ; Stereotaxic Techniques

Background Occupational stress and depressive symptoms of disease prevention and control personnel are serious. Objective To investigate the relationship between occupational stress, psychological capital, and depressive symptoms of disease prevention and control personnel, and analyze the potential mediating effect of psychological capital on the relationship between occupational stress and depressive symptoms. Methods From July to September 2020, a cluster random sampling method was used to select 2201 employees from 21 centers for disease control and prevention as study subjects covering all levels of administrative divisions in Jiangsu Province. A total of 2036 valid questionnaires were collected with a recovery rate of 92.5%. The Core Occupational Stress Scale, Patient Health Questionnaire, and Psychological Capital Questionnaire were used to investigate their occupational stress, depressive symptoms, and psychological capital. Stratified regression analysis was used to explore the effects of occupational stress and psychological capital on depressive symptoms. A mediating effect model was used to analyze and verify the potential mediating effect of psychological capital on the relationship between occupational stress and depressive symptoms. Results The total scores in M (P₂₅, P₇₅) of occupational stress, depressive symptoms, and psychological capital in the target population were 42.0 (37.0, 48.0), 8.0 (4.0, 9.0), and 4.6 (4.0, 5.0) respectively. The positive rate of occupational stress was 31.0% (631/2036), and the positive rate of depressive symptoms was 22.0% (448/2036). The dimensional scores of organization and reward, and demand and effort of occupational stress were positively correlated with the total score of depressive symptoms [Spearman correlation coefficients (r_s) were 0.371 and 0.269, P<0.05]. The dimensional scores of social support and autonomy of occupational stress and the score of psychological capital were negatively correlated with the total score of depressive symptoms (r_s=−0.373, −0.112, −0.494, P<0.05). The organization and reward, and demand and effort had positive effects on depressive symptoms (b=0.188, 0.177, P<0.05), while social support and autonomy had negative effects on depressive symptoms (b=−0.290, −0.078, P<0.05), and associated with a 22.5% increase of explanatory variance. Psychological capital had a negative effect on depressive symptoms (b=−0.368, P<0.05), and associated with an 11.0% increase of explanatory variance. Psychological capital had mediating effects on the associations of social support, organization and reward, and autonomy with depressive symptoms, and the mediating effect values were −0.210 (95%CI: −0.253-−0.171), 0.096 (95%CI: 0.071-0.122), and −0.164 (95%CI: −0.229-−0.103), respectively. The corresponding mediating effect percentages were 40.23%, 26.97%, and 45.56%, respectively. Conclusion Occupational stress of disease prevention and control personnel can directly affect depressive symptoms, but also indirectly through psychological capital. Psychological capital plays a partial mediating role in the associations of social support, organization and reward, and autonomy of occupational stress with depressive symptoms. The occurrence of depressive symptoms can be reduced by decreasing occupational stress and increasing psychological capital.

Objective To study the effect of magnetic rewarming on the morphology and biomechanical properties of vitrified umbilical artery. Methods The vitrified umbilical artery was rewarmed by magnetothermal method and traditional water bath. The temperature distribution and stress in the solution system were analyzed, and the rewarming effect was evaluated by tissue staining and mechanical test. Results Compared with water bath rewarming, the temperature gradient and thermal stress generated by magnetic rewarming were smaller, which could effectively reduce the thermal stress damage during the rewarming stage and achieve rapid and uniform rewarming. Magnetic rewarming could effectively avoid umbilical artery fractures and micro-cracks. After rewarming, the extracellular matrix, collagen fibers, elastic fibers and muscle fibers of the umbilical artery were evenly distributed, which preserved the macro and micro structures of the umbilical artery. The umbilical artery showed different degrees of hardening after water bath and magnetic rewarming, but the elastic modulus and limit stress of the latter were not significantly different from those of fresh umbilical artery, and the latter had unidirectional stretching characteristics similar to that of fresh umbilical artery, showing good elasticity and toughness. Conclusions Compared with water bath rewarming, magnetothermal method can effectively reduce the damage of rewarming stage, ensure the macroscopic, microscopic structure integrity of umbilical artery and better biomechanical properties. The research findings provide important references for cryopreservation of large tissues or organs such as umbilical artery.

Objective:To evaluate the efficacy and safety of rituximab in the treatment of adult primary focal segmental glomerulosclerosis (FSGS).Methods:Adult FSGS patients treated with rituximab in the First Affiliated Hospital of Zhejiang University College of Medicine were retrospectively enrolled. One or two doses of rituximab (375 mg/m 2) were used aiming to achieve B cell depletion (defined as<5 B cells per microliter in peripheral blood) and the interval between the two doses was 2 weeks. The evaluated major outcomes were remission and relapse of nephropathy, and the secondary outcome measures were adverse events and renal outcomes. Results:A total of 14 patients (9 males) were enrolled, among whom 7 cases were steroid-dependent nephrotic syndrome (SDNS) or frequently relapsing nephrotic syndrome (FRNS), 6 cases were steroid-resistant nephrotic syndrome (SRNS) and one patient was new onset FSGS with contraindication to steroid. After treatment with rituximab, 7 patients with SDNS/FRNS achieved complete remission. At 6 months, the daily oral steroid dose reduced significantly compared with the baseline [(33.3±5.2) mg/d vs (6.7±6.6) mg/d, P<0.01]; while one patient still received tacrolimus 1.0 mg/d, the other 6 patients stopped using immunosuppressants; and the total number of relapse/total follow-up months decreased from 0.257 times/month to 0.058 times/month after the use of rituximab. For the other 6 SRNS patients and one patient with contraindication to steroid, three SRNS patients achieved partial remission and one patient with contraindication to steroid achieved complete remission at 34.50(20.25, 95.25) days after use of rituximab, and the other 3 SRNS patients failed to achieve remission, of whom one patient developed end stage renal disease at 23 months. Conclusions:Rituximab may reduce the risk of relapse and help steroid or immunosuppressant-tapering in adult steroid-dependent/frequently relapsing idiopathic FSGS. However, it is not effective in SRNS patients.