Inhibition of gasdermin D palmitoylation by disulfiram is crucial for the treatment of myocardial infarction.

To investigate the role of S-palmitoylation in pyroptosis following acute myocardial infarction (AMI). Myocardial ischemic injury is mainly related to the death of terminally differentiated cardiomyocytes. Pyroptosis is a new form of programmed cell death and recently is identified a potential mechanism of cardiomyocyte loss. However, the role of S-palmitoylation in pyroptosis following MI remains elusive. AMI was mimicked by permanent left anterior descending artery ligation. The palmitoylated proteins labeled by Click-iT palmitic acid were precipitated using streptavidin magnetic bead conjugate. The short-term palmitic acid dietary intake by modified western diet with palm oil for 7 days is compared with modified western diet with olive oil. Palmitoylation is increased in myocardial infarction and anoxic cardiomyocytes. Pyroptosis, but not apoptosis and necrosis, is more relevant with palmitoylation in the process of myocardial ischemia injury. The gasdermin D (GSDMD) Cys192 palmitoylation promotes its cytomembrane localization by ZDHHC14. GSDMD Cys192 palmitoylation aggravates in vitro cardiomyocyte pyroptosis. The short-term palmitic acid dietary intake or ML348 deteriorates myocardial pyroptosis, infarct size and cardiac function in AMI mice by GSDMD palmitoylation. Disulfiram antagonizes Cys192 palmitoylation of GSDMD-N-terminal and reduces myocardial pyroptosis and injury in AMI mice. We identifies ZHDDC14 induced palmitoylation as a crucial node for modulating GSDMD-N-terminal cytomembrane localization and establishes Disulfiram targeting GSDMD Cys192 palmitoylation as a potential clinical intervention for myocardial pyroptosis.

Circulating adiponectin levels and risk of endometrial cancer: Systematic review and meta-analysis.

Previous epidemiological studies have presented conflicting results regarding associations between circulating adiponectin (APN) levels and the risk of endometrial cancer. Thus a meta-analysis was performed to investigate the association between these factors. Multiple electronic sources, including PubMed, SpringerLink and Google Scholar databases were searched to identify relevant studies for the present meta-analysis. All of the selected studies examined the correlation between circulating APN levels and endometrial cancer. The standardized mean difference (SMD) and 95% confidence intervals (CIs) were estimated and pooled using meta-analysis methods. Overall, 18 case-control studies met the inclusion criteria. A total of 5,692 participants and 2,337 cases of endometrial cancer were included in this meta-analysis. The SMD of the pooled analysis (95% CI) were -1.96 (-2.60, -1.31), P=0.000. When the cancer grades were compared, the APN values were not significantly different between the grades of endometrial cancer [G1 vs. G3, 1.02 (-0.68, 2.72), P>0.05; G1 vs. G2, 0.34 (-0.86, 1.54), P>0.05]. However, there was a significant association between high APN levels and postmenopausal endometrial cancer cases with an SMD (95% CI) of -2.27 (-4.36, -0.18) and P<0.05, however, no association was observed in premenopausal endometrial cancer cases with an SMD (95% CI) of -1.52 (-3.49, 0.45) and P>0.05. The low circulating APN level increases the risk of endometrial cancer, whereas the high APN level decreases this risk in postmenopausal women. Circulating APN as simple biomarkers may be a promising tool for the prevention, early diagnosis and disease monitoring of endometrial cancer.

Effect of photodynamic therapy combined with torasemide on the expression of matrix metalloproteinase 2 and sodium-potassium-chloride cotransporter 1 in rat peritumoral edema and glioma.

Peritumoral edema is a key stage in the infiltration and recurrence of glioma. Photodynamic therapy (PDT) increases the extent of peritumoral edema, which leads to a decrease in the effectiveness of PDT in treating glioma. The present study evaluated the effects of PDT combined with torasemide on the levels of matrix metalloproteinase (MMP) 2 and sodium-potassium-chloride cotransporter (NKCC) 1 in peritumoral edema regions of rat glioma. Adult male Wistar rats were inoculated with rat glioma C6 cells, and the presence of glioma was confirmed using magnetic resonance imaging 7 days subsequent to injection. The rats were randomly assigned to 4 groups (n=15): Control group, the rats received no treatment; PDT group, the rats received PDT at 80 J/cm2 for 10 min; torasemide group, the rats received 5 mg/kg torasemide intraperitoneally; and PDT + torasemide group, the rats received 5 mg/kg torasemide intraperitoneally for 3 days following PDT at 80 J/cm2 for 10 min. A total of 5 rats from each group were sacrificed 21 days following injection and the peritumoral edema tissues were harvested. MMP2 and NKCC1 expression levels were detected in the tissues using immunohistochemistry and western blot analysis. The mRNA expression levels of MMP2 and NKCC1 were observed using reverse transcription-quantitative polymerase chain reaction. Peritumoral edema was measured using a wet-to-dry weight (W/D) ratio, and survival times of the remaining 10 rats in each group were evaluated. Compared with the control group, tumor growth was significantly suppressed in the PDT group and the survival time was prolonged through a reduction in the expression of MMP2 (P<0.05), and an increased W/D ratio resulted in significantly increased expression of NKCC1 (P<0.05). Compared with the PDT group, the expression of NKCC1 and the W/D ratio in the PDT + torasemide group were significantly decreased (P<0.05), while no significant difference was observed in the expression levels of MMP2. In conclusion, PDT combined with torasemide prolonged the survival time of rats by inhibiting the growth of glioma through a reduction in the expression of MMP2, and by reducing peritumoral edema through a reduction in the expression levels of NKCC1.

Expression of B cell-specific Moloney murine leukemia virus integration site 1 in vulvar squamous cell carcinoma and its effect on the biological behavior of A-431 cells.

The aim of the present study was to investigate the expression of B cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) in vulvar squamous cell carcinoma (VSCC) and vulvar intraepithelial neoplasia (VIN). Furthermore, the present study investigated the effects of BMI-1 expression on the biological behavior of A-431 human epidermoid carcinoma cells. BMI-1 expression in human VSCC and VIN tissues was detected using immunohistochemistry. Subsequently, BMI-1 expression was silenced in A-431 cells using small interfering RNA (siRNA), and BMI-1 expression was detected using reverse transcription-quantitative polymerase chain reaction and western blotting. The effects of BMI-1 silencing on cell proliferation, apoptosis and invasive ability were determined using an MTT assay, Annexin V-fluorescein isothiocyanate/propidium iodide double-labeling experiment and Transwell assay, respectively. The expression rate of BMI-1 in normal vulvar, VIN and VSCC tissues was 0.0, 25.0 and 68.0% respectively, demonstrating an increasing trend in the severity of the disease. BMI-1 overexpression was found not to correlate with age, pathological stage, lymph node metastasis or degree of differentiation (P>0.05). BMI-1 siRNA transfection effectively inhibited BMI-1 messenger RNA and protein expression in A-431 cells. The mean rate of apoptosis promotion and proliferation inhibition in the most effectively silenced group were 20.19 and 46.82%, respectively, which was significantly higher than that of the cells in the blank and control siRNA groups (P<0.05). The number of invading cells was decreased in the most effectively silenced group compared with that of the blank and control siRNA groups. Abnormal expression of BMI-1 was also detected in VIN and VSCC tissues, and targeting of BMI-1 with siRNA was able to successfully silence BMI-1 expression in A-431 cells. Silencing of BMI-1 promoted apoptosis and inhibited the invasive abilities of A-431 cells in vitro.

A prospective randomized comparison of continuous hemihepatic with intermittent total hepatic inflow occlusion in hepatectomy for liver tumors.

BACKGROUND/AIMS: To evaluate whether continuous hemihepatic inflow occlusion (HHO) during hepatectomy can be safer than and be as effective as intermittent total hepatic inflow occlusion (THO) in reducing blood loss. METHODOLOGY: Eighty patients undergoing liver resections were included in a prospective randomized study comparing the intra- and postoperative course under THO (n=40) or HHO (n=40). THO was performed with periods of 20 minutes of occlusion and 5 minutes of releasing, while HHO was performed with continuous occlusion. The surface area of liver transection, amount of blood loss, measurements of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and postoperative evolution were recorded. RESULTS: The two groups were similar at entry in terms of preoperative liver function and in the proportion of patients experiencing major hepatectomy. The total ischemic time of the two groups was similar (p=0.37), but the operative time in the THO group was longer than in the HHO group (p=0.02). No significant difference was found between the HHO and THO group in blood loss during liver parenchyma transection (p=0.14), the elevations of ALT and AST on the first postoperative day (ALT: p=0.12; AST: p=0.66) and postoperative morbidity (p=0.35). CONCLUSIONS: On the basis of our findings, if it is feasible, continuous HHO is recommended for complex liver resection.

Mycobacterium avium infection in BALB/c and SCID mice.

BALB/c and severe combined immunodeficient (SCID) mice were inoculated intraperitoneally with Mycobacterium avium and the numbers of cfu were monitored for 70 days in spleen, liver, lung, kidney, brain and peritoneum. While BALB/c mice formed typical granulomas and controlled bacterial growth in organs, a delay in development of lesions and a modest containment of infection were observed in SCID mice. In the spleen of BALB/c mice, in which bacterial growth was contained, macrophages (Mo) and natural killer (NK) cell numbers increased > or = 4.2 times and T- and B-cell numbers increased > or = 1.8 times after 42 days of infection; conversely, a low recruitment of mononuclear cells was observed in the spleen of SCID mice, where M. avium proliferated efficiently. Unlike visceral organs, a pronounced decrease in the number of cfu was observed in the peritoneum of BALB/c mice, concomitantly with a > or = 31.7-fold increase in Mo and NK cells and a > or = 9.1-fold increase in T and B cells. In the peritoneum of SCID mice only a bacteriostatic effect was observed despite a > or = 56.7-fold increase in Mo and NK cells and a > or = 22.3-fold increase in T and B cells. These results suggest that while an intact immune response can efficiently control M. avium infection in the spleen and peritoneum of BALB/c mice, cells of the innate immune system such as Mo and NK cells play a role in the containment of bacterial growth in the peritoneum, but not spleen, of SCID mice.