Objective To observe the occurrence of myocardial apoptosis and discussing the mechanism of the effects of glucocorticoid on myocardial apoptosis in septic rats in order to provide the rationale for clinical strategy.Methods A total of 60 Wistar rats weighing 230-280 g were randomly (random number) divided into control group and experimental group (n =30 in each group).Cecal ligation and puncture (CLP) was performed in rats to induce sepsis,and Cefoperazone Sodium/Sulbactam Sodium (200 mg/kg) was injected into caudal vein 4 hours after CLP,twice a day.In addition,glucocorticoid was given to rats of experimental group.After rats sacrificed,their left ventricular myocardia were rapidly taken out and myocardial apoptosis rate was measured and the level of Bcl-2 was assayed at 6 h,24 h,and 72 h after CLP.Measured data were analyzed with independent-samples t-test and One-Way ANOVA.Results The rates of myocardial apoptosis in experimental group were obviously lower than those in control groups respectively (F=9.11,t=5.681,P＜0.01) (6ht=11.416,P＜0.01; 24ht=6.217,P＜0.01; 72 h t =3.76,P ＜0.01).The rates of myocardial apoptosis in 24 h in control and 72 h control groups were distinctively higher than those in 6 h control group,respectively (F =13.254,sig =0.000,P ＜0.01 ; sig =0.004,P ＜ 0.01).The rates ofmyocardial apoptosis in group 24 h control were higher than those in 72 h control group (sig =0.039,P ＜ 0.05).The rates of myocardial apoptosis make no difference among experimental group (F =2.488,6/24 h sig =0.132,P ＞ 0.05 ; 24/72 h sig =0.549,P ＞ 0.05 ; 6/72 h sig =0.053,P ＞ 0.05).Conclusions The rate of myocardial apoptosis is peaked at 24 h in sepsis rat,and the rate of myocardial apoptosis can be obviously decreased by administration of glucocorticoid.

Objective:To evaluate direct bilirubin /total bilirubin(D/T), B-mode ultrasound(BUS), multislice spiral computed tomography (MSCT), magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound (EUS) in the diagnosis of choledocholithiasis abdominal pain (CAP).Methods:We retrospectively analyzed the materials of patients who were diagnosed with choledocholithiasis abdominal pain by above imagines in the emergency department of Beijing Friendship Hospital during March 2016 to December 2018. The stones were taken out by endoscopic retrograde cholangiopancreatography or surgical operation as the golden standard.Results:Among 256 patients, 195 cases, 138 cases, 107 cases and 26 cases were diagnosed by EUS, MRCP, CT and BUS, respectively. The sensitivity were 0.86, 0.62, 0.45, 0.13, respectively. The specificity were 0.86, 0.81, 0.75, 0.87. The positive predictive value were 0.97, 0.96, 0.91, 0.83.The negative predictive value were 0.55, 0.19, 0.21, 0.16. The accuracy rate were 0.88, 0.64, 0.48, 0.30, respectively. The sensitivity of D/T and D/T combined with EUS in the diagnosis of CAP were 0.57 and 0.67, and the accuracy were 0.16 and 0.56, respectively.Conclusions:EUS has a high diagnostic value for CAP. MRCP is superior to CT in the value of diagnosis of CAP. BUS in imaging diagnosis of CAP value is relatively low, but D/T combined with BUS can improve the sensitivity and accuracy of diagnosis for CAP.

Aged, 80 and over ; Carcinoma, Renal Cell ; drug therapy ; Female ; Humans ; Interferon-alpha ; adverse effects ; therapeutic use ; Interleukin-2 ; adverse effects ; therapeutic use ; Lung Diseases, Interstitial ; chemically induced ; diagnosis ; Recombinant Proteins ; adverse effects ; therapeutic use

Objective To explore the relationship between those myocardial markers serum cardiac troponin T (cTNT),serum cardiac troponin I (cTNI),N-terminal pro-brain natriuretic peptide (NT-proBNP),echocardiography and myocardial injury in the oldest-old septic patients,as well as to evaluate prognosis in the oldest-old septic patients.Methods 140 oldest-old septic patients hospitalized in Beijing Friendship Hospital from January 1 st,2015 to Jun 31st,2017 were collected and analyzed retrospectively.They were divided into survival group (90 cases) death group (50 cases)according to their survival time.Serum cTNT,cTNI and NT-proBNP level at 1,3 and 7d post-diagnosis were collected and echocardiography left ventricular diastolic diameter (EDD),left ventricular systolic diameter (ESD),right ventricular diameter (RV),left ventricular ejection fraction (EF) was performed.Results 140 oldest-old septic patients were enrolled in the analysis.There were 90 cases in survival group and 50 cases in death group.Mean values of cTNT,cTNI,NT-proBNP,EDD,ESD in survival group were obviously higher than those in death group (P ＜ 0.05),left ventricular ejection fraction (LVEF) in survival group was lower than that in death group (P ＜ 0.01).But there were no difference in E/A and RV between survival group and death group (P ＞ 0.05).There were positive correlation between cTNT,cTNI,NT-proBNP and EDD,ESD (P ＜ 0.05),negative correlation between cTNT,cTNI,NT-proBNP and LVEF (P ＜ 0.05),and no correlation between cTNT,cTNI,NT-proBNP and E/A,RV (P ＞0.05).There were obviously correlation between cTNT,cTNI,NT-proBNP,EDD,ESD and mortality rate (OR ＞ 1,P ＜ 0.05).It was shown the prognosis value of cTNT,cTNI,NT-proBNP,EDD,ESD to mortality rate in oldest-old septic patient.The prognosis value was cTNT ＞ NT-proBNP ＞ cTNI ＞ EDD ＞ ESD.Conclusions There were obviously correlation between cT NT,cTNI,NT-proBNP,EDD,ESD and myocardium restrain,heart dysfunction as well as mortality rate.cTNT was the best prognosis indicator in sensitivity,and NT-proBNP was the best prognosis indicator in specificity.The combination of cTNT and NT-proBNP can better forecast the prognosis of the oldest-old septic patient.

Organ transplantation is the most effective method to treat end-stage organ failure. As the increase of transmission risk of donor-derived diseases, the quality, safety and selection criteria of transplanted organs become more and more important. Chapter 7 of the European Union's Guide to the Quality and Safety of Organs for Transplantation (6th Edition) proposed basic requirements in terms of donor and organ quality assessment, selection criteria and procedures, which were worthy of study and practice in clinical practice.

Periodontitis imparting the increased risk of atherosclerotic cardiovascular diseases is partially due to the immune subversion of the oral pathogen, particularly the Porphyromonas gingivalis (P. gingivalis), by inducing apoptosis. However, it remains obscure whether accumulated apoptotic cells in P. gingivalis-accelerated plaque formation are associated with impaired macrophage clearance. Here, we show that smooth muscle cells (SMCs) have a greater susceptibility to P. gingivalis-induced apoptosis than endothelial cells through TLR2 pathway activation. Meanwhile, large amounts of miR-143/145 in P.gingivalis-infected SMCs are extracellularly released and captured by macrophages. Then, these miR-143/145 are translocated into the nucleus to promote Siglec-G transcription, which represses macrophage efferocytosis. By constructing three genetic mouse models, we further confirm the in vivo roles of TLR2 and miR-143/145 in P. gingivalis-accelerated atherosclerosis. Therapeutically, we develop P.gingivalis-pretreated macrophage membranes to coat metronidazole and anti-Siglec-G antibodies for treating atherosclerosis and periodontitis simultaneously. Our findings extend the knowledge of the mechanism and therapeutic strategy in oral pathogen-associated systemic diseases.
Animals ; Mice ; Endothelial Cells ; Toll-Like Receptor 2 ; Macrophages ; Apoptosis ; Atherosclerosis ; Myocytes, Smooth Muscle ; MicroRNAs

Drug-induced hyperglycemia/diabetes is a global issue. Some drugs induce hyperglycemia by activating the pregnane X receptor (PXR), but the mechanism is unclear. Here, we report that PXR activation induces hyperglycemia by impairing hepatic glucose metabolism due to inhibition of the hepatocyte nuclear factor 4-alpha (HNF4α)‒glucose transporter 2 (GLUT2) pathway. The PXR agonists atorvastatin and rifampicin significantly downregulated GLUT2 and HNF4α expression, and impaired glucose uptake and utilization in HepG2 cells. Overexpression of PXR downregulated GLUT2 and HNF4α expression, while silencing PXR upregulated HNF4α and GLUT2 expression. Silencing HNF4α decreased GLUT2 expression, while overexpressing HNF4α increased GLUT2 expression and glucose uptake. Silencing PXR or overexpressing HNF4α reversed the atorvastatin-induced decrease in GLUT2 expression and glucose uptake. In human primary hepatocytes, atorvastatin downregulated GLUT2 and HNF4α mRNA expression, which could be attenuated by silencing PXR. Silencing HNF4α downregulated GLUT2 mRNA expression. These findings were reproduced with mouse primary hepatocytes. Hnf4α plasmid increased Slc2a2 promoter activity. Hnf4α silencing or pregnenolone-16α-carbonitrile (PCN) suppressed the Slc2a2 promoter activity by decreasing HNF4α recruitment to the Slc2a2 promoter. Liver-specific Hnf4α deletion and PCN impaired glucose tolerance and hepatic glucose uptake, and decreased the expression of hepatic HNF4α and GLUT2. In conclusion, PXR activation impaired hepatic glucose metabolism partly by inhibiting the HNF4α‒GLUT2 pathway. These results highlight the molecular mechanisms by which PXR activators induce hyperglycemia/diabetes.

Peptides that are composed of dextrorotary (d)-amino acids have gained increasing attention as a potential therapeutic class. However, our understanding of the in vivo fate of d-peptides is limited. This highlights the need for whole-body, quantitative tracking of d-peptides to better understand how they interact with the living body. Here, we used mouse models to track the movement of a programmed death-ligand 1 (PD-L1)-targeting d-dodecapeptide antagonist (DPA) using positron emission tomography (PET). More specifically, we profiled the metabolic routes of [⁶⁴Cu]DPA and investigated the tumor engagement of [⁶⁴Cu/⁶⁸Ga]DPA in mouse models. Our results revealed that intact [⁶⁴Cu/⁶⁸Ga]DPA was primarily eliminated by the kidneys and had a notable accumulation in tumors. Moreover, a single dose of [⁶⁴Cu]DPA effectively delayed tumor growth and improved the survival of mice. Collectively, these results not only deepen our knowledge of the in vivo fate of d-peptides, but also underscore the utility of d-peptides as radiopharmaceuticals.

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and is poorly controlled. Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression, and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment. Therefore, this study developed a novel and selective inhibitor of CSF1R and VEGFR, SYHA1813, possessing potent antitumor activity against GBM. SYHA1813 inhibited VEGFR and CSF1R kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo. SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models, including temozolomide (TMZ) insensitive tumors. Notably, SYHA1813 could penetrate the blood-brain barrier (BBB) and prolong the survival time of mice bearing intracranial GBM xenografts. Moreover, SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody. As a clinical proof of concept, SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial. The data of this study support the rationale for an ongoing phase I clinical study (ChiCTR2100045380).