Investigation of Transdermal Constituents and Molecular Mechanism of Euodiae Fructus in Treatment of Diarrhea by Transdermal Drug Delivery Based on Integrated Pharmacology and UPLC-Q-TOF-MS / 中国实验方剂学杂志

Objective:To identify the transdermal constituents of Euodiae Fructus and predict its molecular mechanism in treating diarrhea by transdermal drug delivery. Method:Ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry （UPLC-Q-TOF-MS） and integrated pharmacology methods were used. The rapid identification of transdermal constituents of Euodiae Fructus was realized by the means of comparison of reference substances， analysis of UNIFI system and mass spectrometry. On this basis， Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine （TCMIP） v2.0， SymMap， DisGeNET databases and literature were used to collected potential targets of transdermal constituents of Euodiae Fructus and targets for diarrhea-related diseases. The disease targets and drug targets were topologically analyzed to obtain the core targets， which were used for the Gene Ontology （GO） function and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis. Finally， Cytoscape 3.6.0 was used to build up a network of transdermal constituents-core targets-key pathways. Result:A total of 19 chemical constituents were speculatively identified from Euodiae Fructus extract， including quinolone alkaloids， limonins， indole alkaloids， organic acids and sterols. A total of 174 core targets of Euodiae Fructus for treating diarrhea were obtained by a topology analysis， signaling pathways of inflammatory response， cell proliferation， nutrient regulation and energy metabolism， signal transduction， bacterial infection were obtained through the analysis of KEGG enrichment. Conclusion:In this study， the transdermal constituents of Euodiae Fructus are identified for the first time， they can participate in the regulation of intestinal inflammation， maintain the integrity of intestinal mucosa， repaire and adjust the metabolism of the body by acting on Rac protein family， phosphatidylinositol 3-kinase， cytochrome P450 enzymes and aldo-keto reductase， respectively. In general， the molecular mechanism of Euodiae Fructus in the treatment of diarrhea is preliminarily elucidated.

Epidemiology of methicillin-resistant Staphylococcus aureus infection and empirical antibiotic therapy for MRSA infection: multicenter investigation / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) maybe changed by strict infection control measures, and the impact of empirical antibiotic therapy on the outcomes of MRSA infection was not clear. We aimed to investigate the present epidemiological status of MRSA infection and empirical antibiotic therapy for MRSA infection in university teaching hospitals in mainland China.</p><p><b>METHODS</b>The present study was a multicenter prospective observational study conducted in five university teaching hospitals. Patients who were consecutively admitted to the intensive care unit and signed a consent form from March 3, 2011 to May 31, 2011 were included. Patients with age <18 years or with a length of hospital stay <48 hours were excluded from this study. The following variables were collected or recorded: demographic data, general status, APACHE II score of the patient at the time of admission, infections, and the use of antibiotics during a stay. Primary outcomes and prognostic indicators included length of hospital stay and 28-day and 90-day mortality. The differences between the patients with appropriate empirical therapy and patients with inappropriate therapy were analyzed to detect the influences of antibiotic therapy on the prognosis of MRSA infection.</p><p><b>RESULTS</b>A total of 682 cases were enrolled. Thirty (66.2%) of 88 MRSA cases were treated with effective antibiotics for MRSA infection; only 20% received appropriate empirical antibiotic treatment. The empirical therapy group compared with the target therapy group had a shorter length of stay, but there were no significant differences in mortality rates. There were no significant differences in the length of hospital stay, length of stay, and 28-day and 90-day mortality between MRSA-infected patients who received or not received effective antibiotics. Two hundred and eighteen cases received sensitive antibiotics for MRSA.</p><p><b>CONCLUSIONS</b>The MRSA infection rates are at relatively low levels in university teaching hospitals in China. The empirical use of sensitive antibiotics for MRSA infection was at relatively high rate, and there is a tendency of overusing in patients without MRSA infection. On the other hand, the rate of appropriate empirical antibiotic therapy for patients with MRSA infection is relatively low.</p>

Meta-analysis of efficacy and safety of liver transplantation in treating cholangiocarcinoma / 中华外科杂志

<p><b>OBJECTIVE</b>To evaluate the therapeutic efficacy and safety of liver transplantation for patients with cholangiocarcinoma.</p><p><b>METHODS</b>According to the requirements of Cochrane systematic review, a thorough literature search was performed in Pubmed/Medline, Embase and Cochrane Central Register electronic databases ranged between 1995 and 2009 in terms of the key words "liver transplantation", and "cholangiocarcinoma" or "cholangiocellular carcinoma" or "bile duct cancer". And restricted the articles published in the English language. Two reviewers independently screened the studies for eligibility, evaluated the quality and extracted the data from the eligible studies with confirmation by cross-checking. Data were processed for a meta-analysis by Stata 10 software with 1-, 3-, 5-year survival rates and incidence of complications.</p><p><b>RESULTS</b>A total of 14 clinical trials containing 605 patients were finally enrolled in this study. The overall 1-, 3-, 5-year pooled survival rates were 73% (95%CI: 0.65 - 0.80), 42% (95%CI: 0.33 - 0.51) and 39% (95%CI: 0.28 - 0.51), respectively. Of note, preoperative adjuvant therapies (OLT-PAT group) rendered the transplanted individuals comparably favorable outcomes with 1-, 3-, 5-year pooled survival rates of 83% (95%CI: 0.57 - 0.98), 57% (95%CI: 0.18 - 0.92) and 65% (95%CI: 0.40 - 0.87), respectively. In addition, the overall pooled incidence of complications was 62% (95%CI: 0.44 - 0.78), among which that of OLT-PAT group (58%, 95%CI: 0.20 - 0.92) was relatively acceptable compared to those of liver transplantation alone (61%, 95%CI: 0.33 - 0.85) and liver transplantation with extended bile duct resection (78%, 95%CI: 0.55 - 0.94).</p><p><b>CONCLUSIONS</b>In comparison to curative resection of cholangiocarcinoma with the 5-year survival rate reported from 20% to 40%, the role of liver transplantation alone is so limited, but neoadjuvant radiochemotherapy combined with liver transplantation can bring better short- and long-term prognosis.</p>

Selective breeding of mice strains with different sensitivity to isoflurane / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The mechanisms of action of volatile anesthetics are still unknown. Recently, the use of genetics as a means to investigate anesthetic action has increased in scale. However, only limited forward genetic approach studies were performed in mammals, especially with volatile anesthetics as the selection agent. In the present study, a selective breeding process was designed to produce strains of mice with different sensitivity to isoflurane.</p><p><b>METHODS</b>One hundred and sixty male and female virgin outbred ICR/CD-1 mice at 65 - 70 days of age were selected as original generation, and the median effective dose (ED(50)) of inhaled isoflurane were measured by probit analysis with the loss of righting reflex as the endpoint of anesthesia. The most sensitive males and females were selected and mated one another randomly, as with the most resistant males and females. Thus two branches of mice (sensitive and resistant to isoflurane) were created and allowed to produce the next generation. At 65 - 70 days of age, screening experiment was performed in offspring, by selecting the most sensitive mice in sensitive branch and the most resistant mice in resistant branch. Selected males and females within each branch were mated one another randomly to produce the following generation. The same procedure was performed in the offspring. The process of screening and breeding was repeated for 8 generations, and then strains were conserved by mating the offspring one another randomly within each branch for 3 generations. Each pair of mice was allowed to produce the second litters as a backup, and isoflurane ED(50) was measured in mice from the second litters.</p><p><b>RESULTS</b>Isoflurane righting reflex ED(50)s (95% confidence limit (CL)) in original mice were 0.65% (0.58% - 0.72%) in females and 0.63% (0.56% - 0.69%) in males. After the 4th generation, isoflurane ED(50)s in resistant branch were significantly higher than those in sensitive branch (P < 0.05), for both in females and males. In the 11th generation, isoflurane ED(50) in the two branches differed by 32% in females and 36% in males.</p><p><b>CONCLUSIONS</b>After 8 generations of selective breeding and 3 generations of strain conservation, two strains of mice with high and low sensitivity to isoflurane were developed. The separation of inhaled anesthetic requirement in parents could be transferred to the offspring in mice.</p>

The prevention and treatment of post-resectional live failure for hepatocellular carcinoma / 中华外科杂志

<p><b>OBJECTIVE</b>To investigate the cause of liver failure after hepatectomy for hepatocellular carcinoma and explore its prevention and treatment.</p><p><b>METHODS</b>The clinical data of 1000 patients with hepatocellular carcinoma undergone hepatectomy from July 2000 to June 2008 were retrospectively analyzed. There were 922 male and 78 female, aging from 21 to 89 years old.</p><p><b>RESULTS</b>Among the 1000 patients, there were 18 patients with liver failure after hepatectomy (1.8%). Among the 18 patients with liver failure, 13 patients were more than 65 years old, 14 patients were with more than 20% of indocyanine green retention rate at 15 minutes, 14 patients were with more than 1000 ml blood loss during operation, 6 patients were with F4/F3 liver fibrosis (Metavir Scores), and 9 patients were with less than 40.0% liver volume of residue liver.</p><p><b>CONCLUSIONS</b>Patients with hepatocellular carcinoma with less than volume of residue liver, much more blood loss or transfusion, more than 20% of ICGR15, F4/F3 liver cirrhosis are prone to be with liver failure after hepatectomy. Artificial liver or liver transplantation may be the important alternative for liver failure after hepatectomy.</p>

Blood-brain barrier penetration of cefepime after neurosurgery / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>It has been confirmed that the concentration of cefepime in cerebrospinal fluid (CSF) could reach the 10% of its concentration in plasma, exceeding the inhibitory concentration to 90% of organisms (MIC(90)) for common bacteria. However, the blood-brain barrier (BBB) penetration ability of cefepime is still unclear. The aim of this study was to measure the CSF concentration of cefepime in patients after neurosurgical operations, and to determine the penetration of the drug through an incomplete BBB.</p><p><b>METHODS</b>Eight patients who received ventricular drainage (VD group) and 5 who underwent lumbar puncture drainage (LPD group) were enrolled into this study. Cefepime (2 g) was injected intravenously in 30 minutes after the neurosurgeries. The concentrations of cefepime in the CSF and plasma were measured by high-pressure liquid chromatography (HPLC) at different time points.</p><p><b>RESULTS</b>The CSF concentrations of cefepime at different time points in the VD group were significantly higher than those in the LPD group (P < 0.05). In the VD group, the concentration of cefepime in CSF reached the peak ((22.54 +/- 14.06) microg/ml) at 1 to 2 hours after the injection, while in the LPD group at 4 hours ((5.61 +/- 3.73) microg/ml). In both groups, the peak was higher than the MIC(90) of most common bacteria in intensive care unit. The ratio of CSF to plasma cefepime concentrations ranged from 0.30 to 2.14 in the VD group and 0.03 to 1.14 in the LPD group.</p><p><b>CONCLUSION</b>After neurosurgeries, CSF concentration of cefepime can reach a therapeutic level. Thus, the drug could be used to prevent and treat postoperative intracranial infection.</p>

Experimental study on transcription regulation of mouse hepcidin gene by NF-kB / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate the involvement of NF-kappaB (NF-kB) regulation of hepcidin gene transcription in acute phase response and its molecular mechanism.</p><p><b>METHODS</b>First, a mouse model of acute phase response was established by intraperitoneal injection of LPS. The relationship between hepcidin expression and dose or time of LPS injection was assessed. Then, electrophoretic mobility shift assay (EMSA) was performed to explore the possibility of the involvement of NF-kB in regulation of hepcidin gene transcription. Next, pAVU6+27-NF-kB, NF-kB p65-specific siRNA expression vector was constructed and transfected into mouse primary hepatocytes using DOTAP liposomal transfection reagents. Hepcidin expression changes after silencing of NF-kB p65 and hepcidin expression after LPS induction were tested.</p><p><b>RESULTS</b>Hepcidin expression showed a time and dose-dependent manner with regard to LPS injection. At 10 h after 50 microg LPS injection, hepcidin expression reached its peak. The result of EMSA exhibited an evident lag band at -53 - -64 bp, indicating regulation of hepcidin gene expression by NF-kB. After mouse primary hepatocytes were transiently transfected with NF-kB p65-specific siRNAs, Western blot showed that inhibition rate of NF-kB expression was 50%-67%. Hepcidin expression of transfected hepatocytes dropped down obviously in comparison with that of untransfected hepatocytes, and could not be induced by LPS.</p><p><b>CONCLUSION</b>Transcription factor NF-kB is likely to be an important molecule in transcription regulation of hepcidin gene. As a key component, p65 subunit binds to hepcidin gene at -53 - -64 bp, and upregulates hepcidin expression.</p>