Effects of flavonoids derived from Taxus yunnanensis on p-glycoprotein and cytochrome P450 3A4

AbstractThe intestinal uptake of paclitaxel is hampered by trans-membrane efflux transporters such as P-glycoprotein (P-gp), and paclitaxel is mainly metabolized by cytochrome P450 3A4 (CYP3A4) presented in the liver. Our previous results demonstrated that flavonoids extracted from Taxus yunnanensis could improve the oral absorption of paclitaxel. The current study was purposed to investigate the effects of the flavonoid extracts on P-gp and CYP3A4 in vitro. The expression and activity of P-gp were detected by western blotting and intracellular rhodamine 123 accumulation assay in Caco-2 cells treated with the flavonoids extract. The expression of CYP3A4 was investigated by western blotting in mouse primary hepatocytes and the activity of CYP3A4 was detected by LC-MS/MS method using rat liver microsomes. Our results showed that the flavonoid extracts from T. yunnanensis could inhibit P-gp activity and concurrently decrease the expression and activity of CYP3A4. In conclusion, activity of P-gp and CYP3A4 could be inhibited by flavonoids extracted from T. yunnanensis which might be potential candidates for development of oral formulation of paclitaxel

Association between sleep duration and quality with rapid kidney function decline and development of chronic kidney diseases in adults with normal kidney function: The China health and retirement longitudinal study

Research have shown that sleep is associated with renal function. However, the potential effects of sleep duration or quality on kidney function in middle-aged and older Chinese adults with normal kidney function has rarely been studied. Our study aimed to investigate the association of sleep and kidney function in middle-aged and older Chinese adults. Four thousand and eighty six participants with an eGFR ≥60 ml/min/1.73 m2 at baseline were enrolled between 2011 and 2015 from the China Health and Retirement Longitudinal Study. Survey questionnaire data were collected from conducted interviews in the 2011. The eGFR was estimated from serum creatinine and/or cystatin C using the Chronic Kidney Disease Epidemiology Collaboration equations (CKD-EPI). The primary outcome was defined as rapid kidney function decline. Secondary outcome was defined as rapid kidney function decline with clinical eGFR of <60 ml/min/1.73 m2 at the exit visit. The associations between sleep duration, sleep quality and renal function decline or chronic kidney disease (CKD) were assessed based with logistic regression model. Our results showed that 244 (6.0%) participants developed rapid decline in kidney function, while 102 (2.5%) developed CKD. In addition, participants who had 3–7 days of poor sleep quality per week had higher risks of CKD development (OR 1.86, 95% CI 1.24–2.80). However, compared with those who had 6–8 h of night-time sleep, no significantly higher risks of rapid decline in kidney function was found among those who had <6 h or >8 h of night time sleep after adjustments for demographic, clinical, or psychosocial covariates. Furthermore, daytime nap did not present significant risk in both rapid eGFR decline or CKD development. In conclusion, sleep quality was significantly associated with the development of CKD in middle-aged and older Chinese adults with normal kidney function

Fabrication of WC-Co Cutting Tool by Powder Injection Molding

In this work, a cutting tool for sand-mold milling was fabricated by powder injection molding (PIM) technology using 90WC-10Co alloy powder for machining sand molds in patternless sand-casting technology. The work included design of cutting tool tip, injection mold and binder system. Also, for the PIM process, mixing, injection molding, debinding and sintering process were investigated experimentally Finally the properties for final products were tested, such as micro structures, element composition, wear resistance and so on. The cutting tool fabricated by PIM had a final density of 14.21 g/cm(3) (95% of theoretical density) and a dimension accuracy over 98%. Also, in sand-mold machining test, it showed an abrasion loss of 0.16 mm after working for 3 hrs. The results showed that a whole cutting tool was fabricated using PIM technology successfully, and it showed out good mechanical performances.X1144sciescopuskc

Case report: Implantable cardioverter-defibrillator implantation with optimal medical treatment for lethal ventricular arrhythmia caused by recurrent coronary artery spasm due to tyrosine kinase inhibitors

Coronary artery spasm (CAS) may induce lethal ventricular arrhythmia due to severe and prolonged vessel constriction. Tyrosine kinase inhibitors are associated with the occurrence of CAS. Optimal medical treatment is the first-line therapeutic option for the management of CAS, whereas patients who experienced aborted sudden cardiac death (SCD) may benefit from implantable cardioverter-defibrillator (ICD) implantation. We report a case of a 63-year-old Chinese man receiving tyrosine kinase inhibitor treatment for liver cancer who presented with recurrent chest discomfort and syncope with an elevation of high-sensitivity troponin T. Emergent coronary angiography showed sub-total occlusion of the left anterior descending artery without other signs of CAS. Percutaneous transluminal coronary angioplasty with a drug-coated balloon was performed successfully with the guidance of intravascular ultrasound. After 5 months, the patient returned to the emergency room for chest discomfort and another episode of syncope. The electrocardiogram showed ST-segment elevation in the inferior and V5–V6 leads compared to the previous event. Coronary angiography was repeated immediately and showed significant luminal stenosis at the midportion of the right coronary artery (RCA), whereas, after administration of intracoronary nitroglycerine, a remarkable recovery of RCA patency was noticed. A diagnosis of CAS was made, and soon after that, the patient rapidly developed ventricular arrhythmia in the coronary care unit. After successful resuscitation, the patient recovered completely and received long-acting calcium channel blockers as well as nitrates therapy. ICD implantation was performed considering the high risk of recurrence of life-threatening ventricular arrhythmia. During the follow-up period, the patient has been free of angina, syncope, or ventricular arrhythmia, and ICD interrogation showed no ventricular tachycardia or ventricular fibrillation. We first reported the case of a patient with CAS induced by regorafenib treatment complicated with severe atherosclerotic coronary disease who survived from sudden cardiac arrest. ICD implantation is indicated in patients who experienced aborted SCD for the prevention of the next lethal ventricular arrhythmia

Conductive Polymer Waving in Liquid Nitrogen

The poor mechanical properties and processability of pristine heterocyclic conductive polymers represent the most notable scientific and technological challenges that have greatly limited the application of these polymers. We report a soft and mechanically processable free-standing pristine polypyrrole (PPy) membrane (PPy-N) that is as soft in liquid nitrogen (−196 °C) as it is at room temperature, despite a glass transition temperature (<i>T</i>_g) above 100 °C. This PPy membrane also displays a highly attractive combination of properties, including mechanical processability, lightweight (9 g m^–2), large surface area (14.5 m² g^–1), stable electrothermal behavior, amphiphilicity, excellent cytocompatibility, and easy synthesis, at virtually any size. This discovery demonstrates an approach to changing the mechanical property of heterocyclic conductive polymer with no chemical alterations or compounding and may enhance the development of inherently conducting polymers for applications in energy storage and biomedicine and as lightweight conducting and heating materials

Aldehyde Dehydrogenase 2 Ameliorates LPS-Induced Acute Kidney Injury through Detoxification of 4-HNE and Suppression of the MAPK Pathway

Lipopolysaccharide (LPS)-induced septic acute kidney injury (AKI) is determined as a devastating organ dysfunction elicited by an inappropriate response to infection with high morbidity and mortality rates. Previous evidence has illustrated an indispensable role of mitochondrial aldehyde dehydrogenase 2 (ALDH2) in the pathogenesis of sepsis-induced multiorgan abnormalities. Specifically, this study investigated the potential role of ALDH2 in sepsis-induced AKI. After LPS administration, we observed a significant decline in renal function, increased inflammatory cytokines, oxidative stress, 4-hydroxy-2-nonenal (4-HNE) accumulation, and apoptosis via MAPK activation in ALDH2−/− mice; in contrast, pretreatment with Alda-1 (an ALDH2 activator) alleviated the LPS-induced dysfunctions in mice. Moreover, in vitro analysis revealed that ALDH2 overexpression in mouse tubular epithelial cells (mTECs) improved the inflammatory response, oxidative stress, 4-HNE accumulation, and apoptosis via MAPK inhibition, whereas ALDH2 knockdown in mTECs aggravated these parameters via MAPK activation. Therefore, ALDH2 may protect against LPS-induced septic AKI by suppressing 4-HNE/MAPK pathway

Urinary TIMP-2 and IGFBP7 for the prediction of acute kidney injury following cardiac surgery

Abstract Background Acute kidney injury (AKI) following cardiac surgery is common and associated with poor patient outcomes. Early risk assessment for development of AKI remains a challenge. The combination of urinary tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) has been shown to be an excellent predictor of AKI following cardiac surgery, but reported studies are for predominately non-Asian populations. Methods Adult patients were prospectively enrolled at Zhongshan hospital in Shanghai, China. The primary analysis was prediction of AKI and stage 2–3 AKI by [TIMP-2]*[IGFBP7] measured 4 h after postoperative ICU admission assessed using receiver operating characteristic curve (ROC) analysis. Kinetics of [TIMP-2]*[IGFBP7] following ICU admission were also examined. Results We prospectively enrolled 57 cardiac surgery patients, of which 20 (35%) developed AKI and 6 (11%) developed stage 2–3 AKI. The area under the ROC curve (AUC) of [TIMP-2]*[IGFBP7] at 4 h after ICU admission was 0.80 (95% confidence interval (CI): 0.68–0.91) for development of AKI and 0.83 (95% CI: 0.69–0.96) for development of stage 2–3 AKI. Urinary [TIMP-2]*[IGFBP7] values at 4 h after ICU admission were significantly (P < 0.001) higher in patients who developed AKI than in patients who did not develop AKI (mean (standard error) of 1.08 (0.34) (ng/mL)2/1000 and 0.29 (0.05) (ng/mL)2/1000, respectively). The time-profile of [TIMP-2]*[IGFBP7] suggests the markers started to elevate by the time of ICU admission in patients who developed AKI and either decreased or remained flat in patients without AKI. Conclusion The combination of urinary TIMP-2 and IGFBP7 4 h after postoperative ICU admission identifies patients at risk for developing AKI, not just stage 2–3 AKI following cardiac surgery

Image_1_High expression ITGA2 affects the expression of MET, PD-L1, CD4 and CD8 with the immune microenvironment in pancreatic cancer patients.tif

PurposePancreatic cancer is characterized by a grim prognosis and is regarded as one of the most formidable malignancies. Among the genes exhibiting high expression in different tumor tissues, ITGA2 stands out as a promising candidate for cancer therapy. The promotion of cancer in pancreatic cancer is not effective. The objective of this study is to assess the presence of ITGA2, EMT and PD-L1 in pancreatic cancer.Experimental designWe examined the expression of ITGA2, MET, E-cadherin, PD-L1, CD4, and CD8 proteins in 62 pancreatic cancer tissue samples using multi-tissue immunofluorescence and immunohistochemistry techniques. Functional assays, such as the cell migration assay and transwell assay, were used to determine the biological role of ITGA2 in pancreatic cancer. The relationship of ITGA2,EMT and PD-L1 were examined using Western blot analysis and RT-qPCR assay.ResultsIn our study, we observed the expression of ITGA2, E-cadherin, and PD-L1 in both tumor and stroma tissues of pancreatic cancer. Additionally, a positive correlation between ITGA2, E-cadherin, and PD-L1 in the tumor region (r=0.559, PConclusionsWe identified a novel mechanism in which ITGA2 plays a crucial role in the regulation of pancreatic cancer growth and invasion. This mechanism involves the upregulation of MET and PD-L1 expression in pancreatic cancer cells. Additionally, we found that increased expression of ITGA2 is associated with a poor prognosis in pancreatic cancer patients. Furthermore, ITGA2 also affects immune regulation in these patients. Therefore, targeting ITGA2 is an effective method to enhance the efficacy of checkpoint immunotherapy and prohibiting tumor growth against pancreatic cancer.</p

Table_2_High expression ITGA2 affects the expression of MET, PD-L1, CD4 and CD8 with the immune microenvironment in pancreatic cancer patients.docx

PurposePancreatic cancer is characterized by a grim prognosis and is regarded as one of the most formidable malignancies. Among the genes exhibiting high expression in different tumor tissues, ITGA2 stands out as a promising candidate for cancer therapy. The promotion of cancer in pancreatic cancer is not effective. The objective of this study is to assess the presence of ITGA2, EMT and PD-L1 in pancreatic cancer.Experimental designWe examined the expression of ITGA2, MET, E-cadherin, PD-L1, CD4, and CD8 proteins in 62 pancreatic cancer tissue samples using multi-tissue immunofluorescence and immunohistochemistry techniques. Functional assays, such as the cell migration assay and transwell assay, were used to determine the biological role of ITGA2 in pancreatic cancer. The relationship of ITGA2,EMT and PD-L1 were examined using Western blot analysis and RT-qPCR assay.ResultsIn our study, we observed the expression of ITGA2, E-cadherin, and PD-L1 in both tumor and stroma tissues of pancreatic cancer. Additionally, a positive correlation between ITGA2, E-cadherin, and PD-L1 in the tumor region (r=0.559, PConclusionsWe identified a novel mechanism in which ITGA2 plays a crucial role in the regulation of pancreatic cancer growth and invasion. This mechanism involves the upregulation of MET and PD-L1 expression in pancreatic cancer cells. Additionally, we found that increased expression of ITGA2 is associated with a poor prognosis in pancreatic cancer patients. Furthermore, ITGA2 also affects immune regulation in these patients. Therefore, targeting ITGA2 is an effective method to enhance the efficacy of checkpoint immunotherapy and prohibiting tumor growth against pancreatic cancer.</p