A series of novel tetrahydrocarboline derivatives was designed and synthesized in order to discover more potent peroxisome proliferator-activated receptor (PPAR) alpha/gamma dual regulators. The structures of these compounds were confirmed by 1H NMR and HR-MS; their PPAR-regulating activities were evaluated in vitro. Compounds 6h, 6n, 6p and 6q exhibited more potent PPARalpha agonistic activities than the control drug WY14643, while compounds 60, 6g, 6i and 6q exhibited more potent PPARgamma agonistic activities than the control drug rosiglitazone. Compound 6q was discovered as a potent PPARalpha/gamma dual agonist and deserves further investigation.
Animals ; Carbolines ; chemical synthesis ; chemistry ; pharmacology ; Cells, Cultured ; Drug Design ; Hypoglycemic Agents ; chemical synthesis ; chemistry ; pharmacology ; Molecular Structure ; PPAR alpha ; agonists ; PPAR gamma ; agonists ; Peroxisome Proliferator-Activated Receptors ; agonists ; Pyrimidines ; metabolism ; Structure-Activity Relationship ; Thiazolidinediones ; metabolism ; Transfection

Thiazolidinediones (TZDs) are currently the only recognized insulin sensitizers available for the clinical treatment of type 2 diabetes. Although their advantages are recognized, the profiles of numerous adverse effects hinder the continued use of these drugs. Peroxisome proliferator-activated receptor γ (PPARγ) is known as a receptor for TZDs, and its underlying mechanisms of pharmacological actions and adverse effects have been deeply explored. To maximally preserve the PPARγ-mediated insulin sensitizing effects and reduce the occurrence of related adverse effects, the concept of "selective PPARγ modulators (SPPARMs)" has been proposed and developed, guiding the development of new drugs. In this review, we summarize the recent research progress in the definition of SPPARMs, the candidate classification and the molecular underpinnings, as well as present the discovery of the YR series compounds as an example, and discuss the potential application prospects of SPPARMs.

ObjectiveTo summarize the early clinical experience of the extracorporeal membrane oxygenation (ECMO) for protecting the liver donation after cardiac death (DCD).Methods Review and analysis the clinical data of 17 cases of liver transplantation with the donors from Chinese citizen after cardiac death from July 2009 to May 2011 in our liver transplantation center,and comprehend the primary diseases and the relevant index of the donors,the flow-sheet of donation and obtain of the organs from the donation after cardiac death,and the apply methods of extracorporeal membrane oxygenation during those processes.ResultsAll 17 cases had been diagnosed as brain death before,and waited for cardiac death,so all were clearly the donation of brain death plus cardiac death(DBCD).During the processes waiting for cardiac death,extracorporeal membrane oxygenation were introducted in every case,and the using time were 51-380 (mean 187)min.The donation after brain death plus cardiac death (DBCD) were all harvested liver donors and were transplanted to 17 receivers respectively.In our center,there was no operational death in liver transplantation in this series.The post-operation liver function recovered satisfactory,without transplant liver non-function or recovering delay.One case died of the pulmonary infection one month later after operation,and the other 16 cases all survived and were followed up to now.The longest survival time was 29 months.ConclusionThe donation after brain death plus cardiac death (DBCD) was the special donation type for citizen in China.The extracorporeal membrane oxygenation (ECMO) could well control the warm ischemia for protecting the liver donor just without ethics dispute.So,the using of the extracorporeal membrane oxygenation (ECMO) for the liver donation after cardiac death(DCD)of citizen in our China have very important contribution.

Objective:To investigate the application value of lauromacrogol in the treatment of varicose veins of lower limb.Methods:The medical records of 75 patients (75 affected limbs) with varicosis of great saphenous vein of lower limbs confirmed between September 2013 and September 2015 were analyzed retrospectively.According to the treatment regimen,the patients were divided into two groups.Among them,33 cases (33 limbs) treated by ultrasound guided injection of foam sclerosing agent lauromacrogol were included in the lauromacrogol group while 42 cases (42 limbs) treated by high ligation of great saphenous vein combined with stripping were included in the operation group.The operation time,intraoperative blood loss,off-bed time,treatment costs and incidence of postoperative complications were recorded.Patients were followed up for 6 to 12 months after operation,and the recurrence rate was recorded.Results:The operation time,off-bed and length of hospital stay of the lauromacrogol group were shorter than those of the operation group;the intraoperative blood loss and hospitalization expenses were less than those of the operation group (P＜0.05);The incidence rates of subcutaneous hematoma and skin numbness in the lauromacrogol group were significantly lower than those in the operation group (P＜0.05);The 12-month recurrence rate in the lauromacrogol group (12.12％) was lower than that in the operation group (33.33％)(P＜0.05).Conclusion:Injection of foam sclerosing agent lauromacrogol is an alternative minimally invasive therapy for treating varicosis of great saphenous vein of lower limbs.

Objective　To assess the willingness of students with latent tuberculosis infection (LTBI) in Jiangsu Province to undergo preventive treatment and identify factors influencing their decision, aiming to provide insights for tuberculosis prevention and control strategies in school. Methods The physical examination information of tuberculosis latent infection cases was collected from screenings of new school enrollment and contacts of tuberculosis patients in 6 cities of Jiangsu Province from December 2022 to December 2023. Data on past medical history and understanding of preventive treatment were gathered through an online questionnaire survey on the website of Juanxing, and the influencing factors related to the willingness to take preventive medication were analyzed by logistic regression analysis model. Results In December 2022 to December 2023, a total of 13 school tuberculosis outbreaks occurred in 6 cities, and 1 661 contacts were screened, among which 162 cases met the criteria for prophylactic medication, 96 cases were included in the study by filling in the questionnaire. A total of 22 600 new students from 56 schools participated in the TB screening upon enrollment, of which 358 tested positive for the tuberculin skin test alone, meeting the criteria for preventive medication, and 251 of them completed the willingness survey. Finally, 347 students who met the criteria for preventive treatment were included in the study, with 164 expressing to accept preventive treatment representing a treatment acceptance rate of 47.3%. The results of multivariate analysis showed that university (OR=17.950, 95%CI: 3.078-104.686, P=0.001) and contact with the source of school tuberculosis epidemic (OR=19.542, 95%CI: 6.289-60.726, P<0.001) were associated with increased willingness to receive preventive treatment, while unclear whether to pay for the drugs themselves (OR=0.349, 95%CI:0.133-0.916, P=0.032) was associated with decreased willingness to receive preventive treatment. Compared with Huai'an City, the willingness to receive preventive treatment was significantly lower among students from Nantong City (OR=0.005, 95%CI:0.000-0.063, P<0.001), Nanjing City (OR=0.022, 95%CI: 0.003-0.703, P<0.001) and Lianyungang City (OR=0.074, 95%CI:0.008-0.703, P=0.023). Conclusions The acceptance rate of preventive treatment among LTBI students in Jiangsu Province is not high and is affected by multiple factors. Health education and medication mobilization for preventive medication are essential.

Objective To establish nucleic acid testing techniques for detecting Nipah virus (NiV) and Hendra virus (HeV), and to test the NiV and HeV in peripheral blood collected from domestic pigs, cows and goats in Chongqing. Methods Peripheral blood samples of 580 domestic pigs, 250 cows, 180 goats were collected from Chongqing since June 2007 to June 2008. The lymphocytes were separated by density gradient centrifugation and total RNA was extracted using Trizol method for detection of NiV and HeV with one-step real-time RT-PCR. Sequence identification and analysis were performed for positive PCR prod-ucts. Virus isolation and culture were adopted for positive samples, and epidemiologic reports were submit-ted. Results Nucleic acid detections searching for NiV and HeV were successfully performed in animal blood samples collected from Chongqing. "Takeoff points" were not found in fluorescence amplification curves of all samples. Curves kept the same slope, and assays were judged as negative. Conclusion Until now, Neither NiV or HeV infection has been found in domestic animals blood samples collected from Chongqing, which suggest a lower possibility of outbreaks of Nipah disease and Hendra disease in Chongqing in the near future.

Objective To investigate the epidemiology of BDV infection in Yili horses and Yili donkeys and to analyze phylogenetic source of BDV in Yili area, Xinjiang. Methods We established fluo- rescence quantitative nested RT-PCR to detect BDV p24 segment in peripheral blood mononuclear cells (PBMCs) of 518 Yili horses and 206 Yili donkeys in Yili area, Xinjiang. Positive products were validated by detecting BDV p40 segment and plasmid to preclude the contamination, and were sequenced to analyze the homology of gene sequence, amino acid sequence and phylogenetic tree. Results The positive rates of BDV infection in PBMCs of 518 Yili horses and 206 Yili donkeys were 0.97% and 1.94%, respectively. The results of BDV p40 segment verification were positive in all of the samples of BDV p24 positive. All the samples tested were not contaminated by plasmid. There was a homology of the gene sequence of positive PCR samples with strain He/80. And the gene sequence revealed more than 93% identical to H1766 and strain V. Conclusion Our study suggested BDV natural infection in Yili horses and Yili donkeys. The en- demic BDV had a high degree of identity to strain He/80.

Objective To investigate the protective effect of polymyxin B (PMB) to the liver graft after liver transplantation and the underlying mechanism in rats.Methods Male SD rats were selected as the donors and recipients.Non-artery whole liver transplantation model was established in rats according to Kamada's two-cuff method.The rats were divided into two groups by the way of random number table method:control group (normal saline,0.5 ml) and PMB group (PMB,1 mg/ml,0.4 mg/kg+ normal saline 0.5 ml).The levels of portal vein plasma endtotoxin (EU/ml)were determined by endotoxin-analyzing machine of BET-24A. ALT,BUN,and TNF-α,IL-6 in serum were measured by using machine of Automatic Analyzer and ELISA,respectively.The CD14,TLR4,NFκB and AP-1 in the grafts were measured by RT-PCR and Western blotting,and pathological changes were observed. Results PMB decreased the levels of portal vein plasma endotoxin 1 h after reperfusion in PMB group as compared with control group (P＜0.05),and the levels of portal vein plasma endotoxin returned to the normal levels 6 h after reperfusion in both two groups (P＞0.05).After operation,the levels of ALT,TNFα and IL-6 in serum were significantly reduced (P＜0.05),the expression of CD14 and TLR4 mRNA in the grafts was significantly decreased (P＜0.05),the expression of Hsp60 protein and mRNA,and NF-κB and AP1 proteins in the grafts were reduced (P＜0.05),and the pathological damage to the grafts was significantly alleviated in PMB group as compared with control group.Conclusion PMB reduced the levels of portal vein plasma endotoxin after reperfusion in liver transplantation in rats.PMB improved liver function,reduced the injury of inflammatory response,decreased the levels of endotoxin signal pathway markers and alleviated the pathological damage to the grafts.

Objective To study the relationship between hepatic arterial buffer response (HABR),recovery of liver function,early biliary complications and small-for-size syndrome (SFSS).Methods Early hepatic hemodynamic parameters (including hepatic arterial flow (HAF),portal venous flow (PVF) were measured using duplex Doppler sonography in 34 patients who received living donor liver transplantation (preoperatively n＝26,intraoperatively n=26) and on postoperative days 1,2,3,and 7.Alanine aminotransferase (ALT),aspartate aminotransferase (AST) and total bilirubin (TBIL) level were measured preoperatively and on postoperative days 1,2,3,7,14,21,and 28.If TBIL level was elevated,we used B ultrasonography or CT and even ERCP to diagnose early biliary complications.The days taken for AST,AI T and TBIL to recover and the number of patients with early (＜60 days) biliary complications (bile leakage or bile stricture) and with small-for-size syndrome (SFSS) were recorded.Results Passive hepatic artery buffer response (HABR) was present in 11 patients early after living donor liver transplantation (group 1) and it disappeared in 23 patients (group 2).The recovery in days taken for normalization of AST (10.6± 8.8),AIT (11.6±9.0) and TBlL (average of 29) in group 1 were shorter than in group 2.However,the differences did not reach statistics difference (P＞0.05).The overall incidences of early biliary complications and small-for-size syndrome (SFSS) in group 1 were significantly lower than in group 2 (P=0.04).The survival rate in group 1 was 82 ％,compared with 74 ％ in group 2.Conclusions Passive hepatic arterial buffer response (HABR) disappeared in some patients early after living donor liver transplantation.There were high incidences of early biliary complications and small-for-size syndrome (SFSS) in these patients.Measurcment of hepatic buffer response in the early stage after living donor liver tranaplanta tion is valuable for predition of early biliary complications and small-for-size syndrome (SFSS),thus helping to prevent failure in transplantation.

Objective To investigate and compare the dynamic changes of plasma endotoxin and CD14/TLR4 levels in the portal vein following partial liver transplantation in rats. Methods 100 %(group Ⅰ), 50 % (group Ⅱ) and 30 % (group Ⅲ) orthotopic liver transplantation models in the SD rats→SD rats were established in vivo according to "Kamada two-cuff method". Based on the principle of dynamic turbidity law, the plasma endotoxin (EU/ml) levels were determined at the postoperative time points of 1, 3, 6, 12, 24 h in recipients. The mRNA expression levels of CD14 and TLR4 in liver grafts were detected by using real-time RT-PCR. Results Under the condition of no significant difference in surgical factors, the plasma endotoxin levels in the portal vein of groups Ⅱ and Ⅲ were higher than in group Ⅰ , and reached the peak at the first h postoperation. The endotoxin levels in group Ⅱ were lower than in group Ⅲ. The endotoxin levels in sham-operation group were the highest. The mRNA expression levels of CD14 and TLR4 in groups Ⅰ, Ⅱ and Ⅲ were significantly increased as compared with sham-operation group (P＜0. 01). Conclusion There exists portal vein plasma endotoxima in 100 %, 50 % and 30 % orthotopic liver transplantation in the rats. The smaller the graft volume, the higher and longer plasma endotoxin in portal vein, so is the relative quantification of the TLR4 and CD14 mRNA in liver grafts.