TIMP2 mediates endoplasmic reticulum stress contributing to sepsis-induced acute kidney injury.

Tissue inhibitor of metalloproteinase 2 (TIMP2) has been recognized as an important biomarker for predicting acute kidney injury (AKI) because of its involvement in the process of inflammation and apoptosis in septic AKI. Endoplasmic reticulum (ER) stress, a condition of disrupted ER homeostasis, is implicated in multiple pathophysiological processes, including kidney disease. Herein, we investigated the correlation between ER stress and septic AKI and further explored how TIMP2 regulated ER stress-mediated apoptosis. To assess the role of TIMP2 in sepsis-induced AKI, we used a cecal ligation and puncture (CLP) model in mice with tubule-specific deficiency of TIMP2 (Ksp-Cre/TIMP2flox/flox ) and their wild-type counterparts. Compared to the wild-type mice, TIMP2-deficient mice demonstrated lower serum creatinine levels and decreased ER stress-mediated apoptosis when subjected to CLP. Interestingly, in human kidney (HK-2) cells, overexpression of TIMP2 caused ER stress, whereas TIMP2 knockdown attenuated lipopolysaccharide-induced ER stress and apoptosis. TIMP2 interacted with the binding immunoglobulin protein, an ER chaperone, and facilitates its extracellular secretion, thereby triggering ER stress. This study identified that the deletion of TIMP2 in mouse tubules mitigated sepsis-induced AKI by inhibiting ER stress-mediated apoptosis, which might be a potential therapeutic strategy to alleviate renal injury.

Synergistic effect of elevated glucose levels with SARS-CoV-2 spike protein induced NOX-dependent ROS production in endothelial cells.

BACKGROUND: Diabetic patients infected with coronavirus disease 2019 (COVID-19) often have a higher probability of organ failure and mortality. The potential cellular mechanisms through which blood glucose exacerbates tissue damage due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still unclear. METHODS AND RESULTS: We cultured endothelial cells within differing glucose mediums with an increasing concentration gradient of SARS-CoV-2 Spike protein (S protein). S protein can cause the reduction of ACE2 and TMPRSS2, and activation of NOX2 and NOX4. A high glucose medium was shown to aggravate the decrease of ACE2 and activation of NOX2 and NOX4 in cultured cells, but had no effect on TMPRSS2. S protein mediated activation of the ACE2-NOX axis induced oxidative stress and apoptosis within endothelial cells, leading to cellular dysfunction via the reduction of NO and tight junction proteins which may collectively be exacerbated by elevated glucose. In addition, the glucose variability model demonstrated activation of the ACE2-NOX axis in a similar manner observed in the high glucose model in vitro. CONCLUSIONS: Our present study provides evidence for a mechanism through which hyperglycemia aggravates endothelial cell injury resulting from S protein mediated activation of the ACE2-NOX axis. Our research thus highlights the importance of strict monitoring and control of blood glucose levels within the context of COVID-19 treatment to potentially improve clinical outcomes.

The Clinical Effects of Abdominal Binder on Abdominal Surgery: A Meta-analysis.

Objective. We conducted a meta-analysis to quantitatively evaluate the effects of abdominal binder in abdominal surgeries. Methods. Through literature retrieval in globally recognized databases (MEDLINE, EMBASE, and Cochrane Central), trials investigating the application of abdominal binder in abdominal surgeries were systematically reviewed. The main outcomes, namely, 6-minute walk test (6MWT), visual analog scale (VAS) pain score, and symptom distress scale (SDS) score, were pooled to make an overall estimation. I2 index was calculated to identify heterogeneity, and sensitivity analysis was performed to validate the stability of main results and explore the source of heterogeneity. A funnel plot and Egger's test were applied to assess publication bias. Results. Ten randomized controlled trials consisting of 968 subjects were ultimately included for the pooled estimation. Abdominal binder significantly increased the distance of 6MWT with standard mean difference (SMD) of .555 (P < .001) and decreased the scores of VAS and SDS with SMD of -.979 (P < .001) and -.716 (P < .001), respectively. Despite of the significant heterogeneity indicated by I2 index statistic, the results of sensitivity analysis revealed the reliability of the main conclusions. While we identified no obvious publication bias regarding 6MWT (Egger's test P = .321), it seemed that significant publication biases existed with respect to the estimation of VAS (P < .001) and SDS (P = .006). Conclusion. The current meta-analysis verified that abdominal binder efficiently promoted recovery after abdominal surgeries in terms of facilitating mobilization, alleviating pain, and reducing postoperative distress. More rigorously designed clinical trials with large sample size are expected to further elaborate its clinical value.

The effects of celecoxib on the proliferation and ultrastructural changes of MDA-MB-231 breast cancer cells.

This study sought to investigate the effects of celecoxib on the proliferation and morphological changes of triple-negative breast cancer (TNBC) MDA-MB-231 cells. In this study, after MDA-MB-231 cells were treated with a certain concentration of celecoxib, a cell counting kit-8 (CCK-8) proliferation assay was used to detect cell viability. Western blotting was utilized to analyze the expression level of caspase-3, which is an apoptosis-related protein. In addition, the morphological changes in the cells and nuclei were determined with fluorescence and electron microscope. Apoptotic nuclei and obvious cytoplasmic vacuolization were observed with a microscope. Collectively, celecoxib can inhibit the proliferation of MDA-MB-231 cells by increasing caspase-3 expression and causing ultrastructural changes.

[Study on Chemical Constituents of Lonicera japonica Bud].

OBJECTIVE: To study the chemical constituents of Lonicera japonica bud. METHODS: The compounds were isolated and repeatedly purified by silica gel column chromatography, gel column chromatography and ODS chromatography. The structures were elucidated by physicochemical properties, MS and NMR. RESULTS: Eight compounds were isolated and their structures were identified as protocatechuic acid (1), 5-hydroxy-7,3',4'-trimethoxyflavone (2), hyperoside (3), 4-hydroxycinnamic acid (4), ethyl caffeate(5), apigenin (6), 5-hydroxy-6,7,8,4'-tetramethoxyflavone (7), and ethyl laurate (8). CONCLUSION: Compounds 5, 7 and 8 are obtained from this genus for the first time.

Downregulation of macrophage migration inhibitory factor attenuates NLRP3 inflammasome mediated pyroptosis in sepsis-induced AKI.

Sepsis-induced AKI (acute kidney injury) is considered an inflammation-related disease with high mortality. LPS-induced (Lipopolysaccharide) TLR4-NFκB pathway activation plays an important role in sepsis-induced AKI. Pyroptosis closely associated with inflammation response includes inflammasome formation, caspase1 activation and GSDMD N-terminal fragment cleavage that leads to cell membrane rupture and cell death, which may be related to the pathogenesis of sepsis-induced AKI. MIF (Macrophage migration inhibitory factor), associated with inflammation response, has been proved as a biomarker of sepsis, and perhaps regulate pyroptosis in sepsis-induced AKI. In this study, we focus on investigating the mechanism of MIF promoting pyroptosis in sepsis-induced AKI. MIF and pyroptosis-related proteins were up-regulated in kidney tissue of mice with CLP (cecum ligation puncture) surgery and in LPS-injured human kidney-2 (HK-2) cells. NLRP3 was down-regulated following the suppression of MIF topoisomerase activity by ISO-1 in kidney tissue of CLP mice. Knockdown of MIF alleviated NLRP3 inflammasome mediated pyroptosis in LPS-injured HK-2 cells. Meanwhile, we noted that phosphorylation of p65 was down-regulated by knockdown of MIF. Up-regulation of NLRP3 in response to LPS stimulation could be reversed by JSH-23, an inhibitor of NFκB pathway, but MIF was not affected. In conclusion, up-regulation of MIF in sepsis-induced AKI shows a renal damaged effect that aggravates NLRP3 inflammasome mediated cell pyroptosis through promoting phosphorylation of p65. This study demonstrated a novel mechanism of MIF regulating NLRP3 inflammasome mediated pyroptosis in sepsis-induced AKI.

Dexamethasone prevents TACE-induced adverse events: A meta-analysis.

BACKGROUND: While dexamethasone has been applied following transcatheter arterial chemoembolization (TACE) for years, its clinical effects have not been determined. In the current study, we aimed to evaluate the efficacy of dexamethasone in preventing adverse events induced by TACE. METHODS: Literature retrieval was conducted using globally recognized online databases, namely MEDLINE, EMBASE, and Cochrane Central, to identify randomized controlled trials (RCTs) of dexamethasone application in patients undergoing TACE. The relative odds ratios (ORs) of incidence rates of three adverse events, namely, fever, abdominal pain and nausea/vomiting, were calculated. The value of I was applied to evaluate the heterogeneity of the trials, and the overall publication bias was assessed with Egger test. RESULTS: Four RCTs containing 350 subjects were included for the pooled estimation. Dexamethasone significantly reduced the incidence rate of TACE-induced adverse events (OR = 1.237, 95% CI: 1.170-1.308, P < .001) with moderate heterogeneity (I = 46.0%). The result of Egger test revealed a publication bias for the included studies. CONCLUSION: The current meta-analysis confirmed the efficacy of dexamethasone in preventing TACE-induced adverse events. To confirm the practicality of dexamethasone use with TACE, further studies with large sample sizes are warranted to update the evidence-based analyses.

Evaluation of different surgical dressings in reducing postoperative surgical site infection of a closed wound: A network meta-analysis.

OBJECTIVE: To evaluate the effects of different surgical dressings in reducing surgical site infection (SSI) and identify the optimal dressings. METHODS: Randomized controlled trials investigating the application of surgical dressings were retrieved from electronic databases, including MEDLINE, EMBASE, and the Cochrane Library. The odds ratios (ORs) of the SSI rate were compared by direct meta-analysis, and the surface under the cumulative ranking (SUCRA) curve values were calculated based on the Bayesian theorem. A node-splitting model was applied to analyse the consistency of the comprehensive comparison results. RESULTS: Twenty-two studies containing 5487 participants were pooled for the comprehensive comparison. Among all the studies included, 9 types of surgical dressings were identified for comparison. The results of the direct meta-analysis revealed that novel dressings significantly reduced the overall SSI rate with an OR of 1.026 (95% CI: 1.013-1.040, p < 0.001), which was determined to have low heterogeneity (I2 = 32.1%). Specifically, 3 types of dressings presented significant effects in reducing SSI, namely, mupirocin-containing (OR = 1.076, 95% CI: 1.014-1.142, p = 0.015), dialkylcarbamoyl-chloride-containing (OR = 1.047, 95% CI: 1.012-1.083, p = 0.008) and vitamin E (VE)-silicone-containing (OR = 1.129, 95% CI: 1.016-1.255, p = 0.025) dressings. Network meta-analysis demonstrated that the VE-silicone dressing (SUCRA = 0.37) was the optimal dressing, followed by the mupirocin dressing, with a SUCRA of 0.31. CONCLUSION: The present network meta-analysis identified the superiority of VE-silicone and mupirocin dressings in preventing SSI. The evidence-based results provide suggestions and directions for future investigations on surgical dressings. More large-scale trials with rigorous designs are warranted to clarify the clinical value of novel dressings in surgical incision management.

[Clinical characteristics and risk factors of acute kidney injury in coronavirus disease 2019].

OBJECTIVE: To investigate the characteristics and the risk factors of coronavirus disease 2019 (COVID-19) associated acute kidney injury (AKI). METHODS: A retrospective cohort study was performed to examine the basic data, clinical characteristics and prognosis of patients with COVID-19 in Zhongnan Hospital of Wuhan University and Wuhan Fourth Hospital from January 1st to February 1st in 2020. According to the diagnostic criteria of Kidney Disease: Improving Global Outcomes (KDIGO), patients with AKI were included in AKI group and those without AKI were included in non-AKI group. The differences of each index between the two groups were compared. The prognostic value of AKI for COVID-19 was analyzed by Kaplan-Meier survival curve and Cox regression. RESULTS: A total of 394 COVID-19 patients were included, with a total mortality of 5.6%; 37 (9.4%) of them developed AKI. The mortality of patients with COVID-19 associated AKI was 18.9%. There were significant differences in age, gender, smoking history, hypertension history, malignancy history, cardiovascular disease history and cerebrovascular disease history between the two groups. In addition to the difference of serum creatinine (SCr) and blood urea nitrogen (BUN), white blood cell count (WBC), neutrophil count (NEU), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), D-dimer, procalcitonin (PCT) and C-reaction protein (CRP) in AKI group were significantly higher than those in non-AKI group [WBC (×109/L): 5.75 (4.13, 7.83) vs. 4.52 (3.35, 5.90), NEU (×109/L): 4.55 (2.81, 6.11) vs. 3.06 (2.03, 4.50), AST (U/L): 40.0 (24.5, 69.5) vs. 30.0 (23.0, 42.5), LDH (µmol×s-1×L-1): 5.21 (3.68, 7.57) vs. 4.24 (3.05, 5.53), D-dimer (µg/L): 456 (266, 2 172) vs. 290 (152, 610), PCT (µg/L): 0.33 (0.03, 1.52) vs. 0.01 (0.01, 0.11), CRP (mg/L): 53.80 (26.00, 100.90) vs. 23.60 (9.25, 51.10), all P < 0.05], while lymphocyte count (LYM) and platelet count (PLT) were decreased [LYM (×109/L): 0.68 (0.47, 1.05) vs. 0.91 (0.63, 1.25), PLT (×109/L): 142.0 (118.0, 190.0) vs. 171.0 (130.0, 2 190.0), both P < 0.05]. The mortality of AKI group was significantly higher than that of non-AKI group [18.9% (7/37) vs. 4.2% (15/357), P < 0.01]. Kaplan-Meier survival curve showed that the 30-day cumulative survival of AKI group was lower than that of non-AKI group (log-rank: P = 0.003). Cox analysis also showed that AKI increased the odds of patients with COVID-19 mortality by 3.2-fold [hazard ratio (HR) = 3.208, 95% confidence interval (95%CI) was 1.076-9.566, P = 0.037]. CONCLUSIONS: The risk of AKI is higher in patients with COVID-19. Early intervention to prevent AKI in patients with COVID-19 is of great significance to improve the prognosis of patients.

Antitumor effects of saikosaponin b2 on breast cancer cell proliferation and migration.

Saikosaponin b2 (SSb2) can be extracted from Bupleurum spp. roots (Radix Bupleuri), which belongs to the Umbelliferae family. The current study aimed to explore the effects of SSb2 on proliferation of breast cancer cells and to identify the mechanism by which SSb2 affects breast cancer cell migration. mRNA expression levels of STAT3 and vasodilator­stimulated phosphoprotein (VASP) were determined and increased expression was observed in 16 breast cancer tissues compared with the paracancerous tissues. MTT, wound healing, colony formation assays and western blot suggested that SSb2 inhibited MCF­7 proliferation and migration. It was further identified by western blot analysis that SSb2 treatment reduced levels of phosphorylated STAT3, VASP, matrix metallopeptidase (MMP) 2 and MMP9 in MCF­7 compared with the untreated cells. In addition, it was demonstrated that inhibition of STAT3 phosphorylation decreased VASP expression levels and induction of STAT3 phosphorylation increased VASP levels. Furthermore, it was observed that the treatment of Kunming mice with SSb2 at 30 mg/kg/day for 30 days induced no obvious changes in the liver or kidney tissues, as determined by haematoxylin and eosin staining. In conclusion, these results indicated that SSb2 may be a potential antitumor drug for the treatment of breast cancer, which acts by suppressing proliferation and migration by downregulating the STAT3 signalling pathway and inhibiting the expression of VASP, MMP2 and MMP9 expression.