This study investigates the pharmacokinetics and metabolic characteristics of three marine-derived piericidins as potential drug leads for kidney disease: piericidin A (PA) and its two glycosides (GPAs), glucopiericidin A (GPA) and 13-hydroxyglucopiericidin A (13-OH-GPA). The research aims to facilitate lead selection and optimization for developing a viable preclinical candidate. Rapid absorption of PA and GPAs in mice was observed, characterized by short half-lives and low bioavailability. Glycosides and hydroxyl groups significantly enhanced the absorption rate (13-OH-GPA > GPA > PA). PA and GPAs exhibited metabolic instability in liver microsomes due to Cytochrome P450 enzymes (CYPs) and uridine diphosphoglucuronosyl transferases (UGTs). Glucuronidation emerged as the primary metabolic pathway, with UGT1A7, UGT1A8, UGT1A9, and UGT1A10 demonstrating high elimination rates (30%-70%) for PA and GPAs. This rapid glucuronidation may contribute to the low bioavailability of GPAs. Despite its low bioavailability (2.69%), 13-OH-GPA showed higher kidney distribution (19.8%) compared to PA (10.0%) and GPA (7.3%), suggesting enhanced biological efficacy in kidney diseases. Modifying the C-13 hydroxyl group appears to be a promising approach to improve bioavailability. In conclusion, this study provides valuable metabolic insights for the development and optimization of marine-derived piericidins as potential drug leads for kidney disease.
Animals ; Male ; Mice ; Aquatic Organisms/chemistry* ; Biological Availability ; Cytochrome P-450 Enzyme System/metabolism* ; Glucuronosyltransferase/metabolism* ; Microsomes, Liver/metabolism* ; Molecular Structure ; Biological Products/pharmacokinetics* ; Pyridines/pharmacokinetics*

Objective To study the effect of massive blood transfusion program(MTP) in early massive blood transfusion and preventing coagulopathy.Methods Fifty cases of massive blood transfusion were clinically collected and performed the statistical analysis and processing before and after intervention according to the blood transfusion scheme of MTP.The statistical comparison was performed by using the data before and after intervention.Results PLT was decreased with the increase of transfusing of RBC.After transfusing 15 U of RBC,the PT test,INR and APTT were increased significant(P＜0.05).After transfusing 20 U of RBC,the Fib was decreased significant(P＜0.05).The MTP had statistical difference between before and after intervention(P＜0.01).Conclusion The MTP application has an important significance to prevent the occurrence of coagulopathy and evaluate the coagulation status.

Objective To detection analysis of blood infectious disease markers in patients before blood transfusion or before surgery .Methods HBsAg ,anti-HBs ,HBeAg ,anti-HBe ,anti-HBc ,anti-HCV ,anti-HIV ,TP-Ab were detected for 3 542 cases of se-rum using chemiluminescence immunoassay(CLIA) and ELISA .Results For HBsAg ,there were 704 cases of positive among 3 542 cases ,the proportion was 19 .8% ;For anti-HCV ,there were 52 cases of positive among 3 032 cases ,the proportion was 1 .72% ;For anti-HIV ,there were 3 cases of positive among 3 049 cases ,the proportion was 0 .09% ;For TP-Ab ,there were 200 cases of positive among 3 153 cases ,the proportion was 6 .34% .The infection rate was different in different gender of HBV ,anti HCV ,anti HIV and TP-Ab .But for HBV ,anti-HCV and TP-Ab ,the detection rate of male was higher than female(P<0 .05);The infection rate was different in different age of HBV ,anti HCV ,anti HIV and TP-Ab different age .The detection rate of HBV and Anti-HCV in 21-40 years old was the highest ,They were 31 .9% and 2 .33% ;The detection rate of TP-Ab increases with age increased ,more than 60 years old was the highest ,up to 7 .55% .Detection of the above two methods ,for HBsAg ,there were 51 cases did not match ,the proportion was 1 .44% ;for anti-HCV ,there were 1 case did not match ,the proportion was 0 .03% ;for Tp-Ab ,there were 3 cases did not match ,the proportion was 0 .1% ;for anti-HIV ,CLIA agrees well with ELISA ,there were 3 cases of positive .The samples that did not match were detected by the third party verification of the reagent .The result displayed that CLIA was more accurate . Conclusion CLIA is a high-sensitivity detection method which could effectively avoid positive specimens missed ,detection of infec-tious disease markers in patients before transfusion or before surgery by CLIA had important significance .

Objective To study the changes in interleukin-32 (IL-32) in rats with Klebsiella bacillus pneumonia and approach its significance. Methods Seventy-two Sprague-Dawley(SD)rats were divide into control group,model group and experimental group by the method of random digits table,then the experimental group was subdivided into 4 hours and 1,3 and 5 days experimental subgroups(each n=6). The rat model of Klebsiella bacillus pneumonia was established by injection of 0.3 mL Klebsiella bacterial suspension into the trachea. Before the establishment of the model in the experimental group,IL-32 inhibitory agent,protease activated receptor-2(PAR2) was injected into the abdominal cavity. After model establishment,at different time points,blood was collected via tail vein to observe the changes in serum levels of IL-32,tumor necrosis factor-α(TNF-α),IL-6 and IL-8 in all the groups. The lungs were removed and stained with hematoxylin-eosin(HE)method to investigate the histopathological changes of the lung tissues under the light microscope. Results Compared to the control group, with the prolongation of time the levels of IL-32,TNF-α,IL-8 and IL-6 were increased gradually in the model group,and reached their peaks at 3 days〔IL-32(ng/L):84.40±28.24 vs. 18.57±3.86,t=5.544,P=0.002;TNF-α(ng/L):79.27±14.64 vs. 17.82±3.86, t=9.994, P=0.000;IL-8(ng/L):55.85±10.90 vs. 16.66±3.76,t=8.544, P=0.000;IL-6(ng/L):56.65±2.57 vs. 28.48±2.11,t=19.693,P=0.000〕;PAR2 could inhibit above indexes significantly,there was statistical difference at 3 days compared with the model group〔IL-32(ng/L):54.13±6.68 vs. 84.40±28.24,t=2.560,P=0.046;TNF-α(ng/L):49.12±3.56 vs. 79.27±14.64,t=4.901,P=0.003;IL-8 (ng/L):22.95±2.52 vs. 55.85±10.90,t=7.204,P=0.000;IL-6(ng/L):36.49±2.63 vs. 56.65±2.57,t=13.443, P=0.000〕. Under the light microscope,the inflammatory changes in the lung tissue in experimental group were milder than those in the model group. Conclusion As a pro-inflammatory cytokine,IL-32 can induce the production of TNF-α,IL-6 and IL-8,and the inhibition of IL-32 production may play a role in suppression of the development of Klebsiella bacillus pneumonia.

The methylation status of GNAS1 gene in pseudohypoparathyroidism type Ib patients was detected by methylation-specific PGR technique. There was an abnormal methylation of 1A region in all seven PHPIb patients. Loss of exon 1A methylation (imprinting defect) seems to be the cause of PHPIb.