Objective To explore the mechanism of IgA nephropathy(IgAN)caused by multi-glycosides of Tripterygium wilfordii(GTW)through the regulation of Silent information regulatory factor 1(SIRT 1)/nuclear transcription factor E2-related factor 2(Nrf 2)/antioxidant enzyme heme oxygenase 1(HO-1)signaling pathway.Methods Forty-five male SD rats were selected and randomly divided into two groups:the blank group(n=9)and the model group(n=36).In addition to the blank group,the BSA+CCl4+LPS group was used.At the end of 12 weeks,two rats were randomly selected for verification,and the model was successfully established.The 34 model rats were randomly divided into 3 groups:the model group(n=10),prednisone group(n=12),and GTW group(n=12).Urine,blood and kidney tissues were harvested 4 weeks after drug administration.Urinary erythrocyte number,24-h urinary protein quantification(24 h-UTP),alanine transaminase(ALT),serum albumin(ALB),urea nitrogen(BUN),and blood creatinine(SCr)were performed for each group;the protein expression of SIRT1,Nrf2,HO-1 and PINK1 was detected by Western blotting analysis;real-time polymerase chain reaction(RT-PCR)detection of SIRT1,Nrf2,HO-1 and PINK1 mRNA expression in rat kidney tissue;and detection of IgA deposition in the renal mesangial area by immunofluorescence.Kidney histopathological changes were observed in all the rats by hematoxylin-eosin(HE)staining.Results The results compared with those in the blank group,the urinary red blood cell count and 24 h-UTP,ALT,BUN,and SCr levels were significantly greater(P<0.01);The ALB level was significantly lower(P<0.01);renal tissue SIRT1,Nrf2,HO-1,PINK1 protein and mRNA expression were significantly lower(P<0.01);IgA deposition in the mesentery was obvious;renal pathological damage was severe;and the difference was statistically significant. Compared with those in the model group,urinary red blood cell counts and 24 h-UTP,ALT,BUN,and SCr levels in the prednisone and GTW groups were significantly lower (P<0.01);ALB levels were significantly greater (P<0.01);SIRT1,Nrf2,HO-1,PINK1 protein and mRNA expression were significantly greater (P<0.01);IgA deposition in the mesangial area was reduced,and renal pathology was improved,with statistically significant difference. Conclusions GTW may alleviate oxidative stress injury,protect renal function,and improve renal injury by activating the SIRT 1/Nrf 2/HO-1 signaling pathway.

Objective To explore the mechanism of IgA nephropathy(IgAN)caused by multi-glycosides of Tripterygium wilfordii(GTW)through the regulation of Silent information regulatory factor 1(SIRT 1)/nuclear transcription factor E2-related factor 2(Nrf 2)/antioxidant enzyme heme oxygenase 1(HO-1)signaling pathway.Methods Forty-five male SD rats were selected and randomly divided into two groups:the blank group(n=9)and the model group(n=36).In addition to the blank group,the BSA+CCl4+LPS group was used.At the end of 12 weeks,two rats were randomly selected for verification,and the model was successfully established.The 34 model rats were randomly divided into 3 groups:the model group(n=10),prednisone group(n=12),and GTW group(n=12).Urine,blood and kidney tissues were harvested 4 weeks after drug administration.Urinary erythrocyte number,24-h urinary protein quantification(24 h-UTP),alanine transaminase(ALT),serum albumin(ALB),urea nitrogen(BUN),and blood creatinine(SCr)were performed for each group;the protein expression of SIRT1,Nrf2,HO-1 and PINK1 was detected by Western blotting analysis;real-time polymerase chain reaction(RT-PCR)detection of SIRT1,Nrf2,HO-1 and PINK1 mRNA expression in rat kidney tissue;and detection of IgA deposition in the renal mesangial area by immunofluorescence.Kidney histopathological changes were observed in all the rats by hematoxylin-eosin(HE)staining.Results The results compared with those in the blank group,the urinary red blood cell count and 24 h-UTP,ALT,BUN,and SCr levels were significantly greater(P<0.01);The ALB level was significantly lower(P<0.01);renal tissue SIRT1,Nrf2,HO-1,PINK1 protein and mRNA expression were significantly lower(P<0.01);IgA deposition in the mesentery was obvious;renal pathological damage was severe;and the difference was statistically significant. Compared with those in the model group,urinary red blood cell counts and 24 h-UTP,ALT,BUN,and SCr levels in the prednisone and GTW groups were significantly lower (P<0.01);ALB levels were significantly greater (P<0.01);SIRT1,Nrf2,HO-1,PINK1 protein and mRNA expression were significantly greater (P<0.01);IgA deposition in the mesangial area was reduced,and renal pathology was improved,with statistically significant difference. Conclusions GTW may alleviate oxidative stress injury,protect renal function,and improve renal injury by activating the SIRT 1/Nrf 2/HO-1 signaling pathway.

OBJECTIVE To compare the efficacy and safety of Cefazolin sodium for injection， Cefuroxime sodium for injection， and Ceftazidime for injection from nationally organized centralized drug procurement （hereinafter referred to as “centralized procurement”） and non-centralized procurement in patients with bacterial infection. METHODS The case data of hospitalized patients who had used 3 kinds of Cephalosporins for injection from centralized procurement or non-centralized procurement in the treatment of bacterial infections were retrospectively collected from 19 medical institutions in Kunming from January 2020 to September 2022. After balancing the baseline differences between the groups with the propensity score matching method， the effectiveness and safety differences of 3 kinds of Cephalosporins for injection from centralized procurement or non- centralized procurement were compared respectively. RESULTS After balancing the baseline differences among the groups， 394 cases in each group of Cefazolin sodium for injection from centralized procurement or non-centralized procurement， 472 cases in each group of Cefuroxime sodium for injection from centralized procurement or non-centralized procurement， 504 cases in group of Ceftazidime for injection from centralized procurement and 590 cases in group of non-centralized procurement were included in the analysis. In terms of effectiveness， there were no significant differences in clinical response rate， 72 h response rate， bacterial clearance rate， and the recovery rate of body temperature， white blood cell count， neutrophil count， neutrophil percentage， C-reactive protein， procalcitonin recovery between the centralized procurement group and non-centralized procurement group of Cefazolin sodium for injection and Cefuroxime sodium for injection （P＞0.05）. The proportion of patients in centralized procurement group of Ceftazidime for injection with C-reactive protein restored to normal reference range was significantly higher than that in non-centralized procurement group （46.9% vs. 27.9%， P＜0.05）， but there were no statistically significant differences in other effectiveness indicators among groups （P＞0.05）. In terms of safety， there was no statistical difference in the incidence of adverse drug reactions between centralized procurement group and non-centralized procurement group of 3 kinds of Cephalosporins for injection （P＞0.05）； the incidence of platelet count reduction in centralized procurement group of Cefazolin sodium for injection was significantly higher than non-centralized procurement group （20.7% vs. 7.1%， P＜0.05）， the incidence of eosinophilia elevation in centralized procurement group of Ceftazidime for injection was significantly higher than non-centralized procurement group （5.3% vs. 1.9%， P＜0.05）. In addition， there was no statistically significant difference in the abnormal rates of other laboratory indicators among the three types of injection Cephalosporins （P＞ 0.05）. CONCLUSIONS The efficacy of 3 kinds of Cephalosporin for injection from centralized procurement is not inferior to non- centralized procurement varieties， and the safety is equivalent to that of non-centralized procurement varieties.

Odontoblasts are primarily responsible for synthesizing and secreting extracellular matrix proteins,which are crucial for dentinogenesis.Our previous single-cell profile and RNAscope for odontoblast lineage revealed that cyclic adenosine monophosphate responsive element-binding protein 3 like 1(Creb3l1)was specifically enriched in the terminal differentiated odontoblasts.In this study,deletion of Creb3l1 in the Wnt1+lineage led to insufficient root elongation and dentin deposition.Assay for transposase-accessible chromatin with high-throughput sequencing(ATAC-seq)and RNA sequencing were performed to revealed that in CREB3L1-deficient mouse dental papilla cells(mDPCs),the genes near the closed chromatin regions were mainly associated with mesenchymal development and the downregulated genes were primarily related to biological processes including cell differentiation,protein biosynthesis and transport,all of which were evidenced by a diminished ability of odontoblastic differentiation,a significant reduction in intracellular proteins,and an even greater decline in extracellular supernatant proteins.Dentin matrix protein 1(Dmp1),dentin sialophosphoprotein(Dspp),and transmembrane protein 30B(Tmem30b)were identified as direct transcriptional regulatory targets.TMEM30B was intensively expressed in the differentiated odontoblasts,and exhibited a significant decline in both CREB3L1-deficient odontoblasts in vivo and in vitro.Deletion of Tmem30b impaired the ability of odontoblastic differentiation,protein synthesis,and protein secretion in mDPCs.Moreover,overexpressing TMEM30B in CREB3L1-deficient mDPCs partially rescued the extracellular proteins secretion.Collectively,our findings suggest that CREB3L1 participates in dentinogenesis and facilitates odontoblastic differentiation by directly enhancing the transcription of Dmp1,Dspp,and other differentiation-related genes and indirectly promoting protein secretion partially via TMEM30B.

Odontoblasts are primarily responsible for synthesizing and secreting extracellular matrix proteins,which are crucial for dentinogenesis.Our previous single-cell profile and RNAscope for odontoblast lineage revealed that cyclic adenosine monophosphate responsive element-binding protein 3 like 1(Creb3l1)was specifically enriched in the terminal differentiated odontoblasts.In this study,deletion of Creb3l1 in the Wnt1+lineage led to insufficient root elongation and dentin deposition.Assay for transposase-accessible chromatin with high-throughput sequencing(ATAC-seq)and RNA sequencing were performed to revealed that in CREB3L1-deficient mouse dental papilla cells(mDPCs),the genes near the closed chromatin regions were mainly associated with mesenchymal development and the downregulated genes were primarily related to biological processes including cell differentiation,protein biosynthesis and transport,all of which were evidenced by a diminished ability of odontoblastic differentiation,a significant reduction in intracellular proteins,and an even greater decline in extracellular supernatant proteins.Dentin matrix protein 1(Dmp1),dentin sialophosphoprotein(Dspp),and transmembrane protein 30B(Tmem30b)were identified as direct transcriptional regulatory targets.TMEM30B was intensively expressed in the differentiated odontoblasts,and exhibited a significant decline in both CREB3L1-deficient odontoblasts in vivo and in vitro.Deletion of Tmem30b impaired the ability of odontoblastic differentiation,protein synthesis,and protein secretion in mDPCs.Moreover,overexpressing TMEM30B in CREB3L1-deficient mDPCs partially rescued the extracellular proteins secretion.Collectively,our findings suggest that CREB3L1 participates in dentinogenesis and facilitates odontoblastic differentiation by directly enhancing the transcription of Dmp1,Dspp,and other differentiation-related genes and indirectly promoting protein secretion partially via TMEM30B.

OBJECTIVE To evaluate the accuracy of three individualized drug delivery tools,i.e.JPKD,SmartDose and NextDose,in predicting tacrolimus dose and blood concentration after kidney transplantation,and analyze the influential factors of prediction accuracy.METHODS The clinical data of adult hospitalized patients treated with tacrolimus after kidney transplantation from January 2021 to June 2023 were retrospectively collected.Three individualized dosing tools,i.e.JPKD,SmartDose and NextDose,were used to predict the dose and plasma concentration of tacrolimus.The absolute prediction error(APE)and prediction error(PE)between the measured value and the predicted value,and prediction success rate were calculated(APE＜30％indicating a good forecast).Pearson assay or Spearman assay was used to analyze the correlation between the predicted dosage and actual dosage,as well as the predicted and measured blood concentration values using three software;univariate analysis was used to investigate the influential factors for prediction accuracy of JPKD,SmartDose and NextDose.RESULTS A total of 110 hospitalized patients were included in this study,and 193 tacrolimus doses and plasma concentrations were monitored.The predicted doses of JPKD,SmartDose and NextDose were(2.0±0.7),(2.7±1.9),(1.8±0.8)mg,their measured value was(1.9±0.6)mg,and the correlation coefficients between the predicted values and the measured value were 0.841,0.450,0.247(P＜0.001);the median APEs were 6.00％,52.07％and 30.40％,and the median PEs were 5.00％,18.50％and-3.50％;the prediction success rates were 98.45％,30.05％and 49.22％.The predicted values of tacrolimus concentrations using JPKD,SmartDose,NextDose were(6.74±3.36),(6.93±5.02),9.00(5.80±12.60)ng/mL,the measured value was 8.64(7.11,9.77)ng/mL,and the correlation coefficients between the predicted values and the measured value were 0.997(P＜0.001),-0.066(P=0.360),0.920(P＜0.001).The median APEs were 5.54％,45.91％and 35.56％,and PEs were-4.94％(median),-17.050％(median)and 36.93％(average value);the prediction success rates were 97.93％,32.64％and 37.31％.Univariate analysis showed that the dosage,blood concentration,body weight,transplantation time and others were related to the prediction accuracy(P＜0.05).CONCLUSIONS The good prediction rates of tacrolimus dose and blood concentration in kidney transplant patients using three personalized drug delivery tools,from high to low,are JPKD,NextDose,and SmartDose,suggesting that JPKD can be prioritized in clinical use.

OBJECTIVE To explore the correlation between SLCO1B3 gene polymorphisms and early postoperative tacrolimus concentrations in renal transplant recipients. METHODS A total of 68 patients who underwent kidney transplantation in the First Hospital of Kunming were selected, tacrolimus plasma concentrations were monitored by chemoluminescence, CYP3A5*3, SLCO1B3 T334G and G699A gene polymorphisms were detected by polymerase chain reaction, and genotyping was performed to analyze the correlation between each genotype and tacrolimus plasma concentrations. RESULTS Different genotypes of CYP3A5*3 had significant effects on postoperative tacrolimus plasma concentration and standardized plasma concentration(P＜0.05), and different genotypes of SLCO1B3 T334G and G699A gene loci had no significant effect on postoperative tacrolimus plasma concentration and standardized plasma concentration. CONCLUSION Compared with CYP3A5*3/*3 genotype, CYP3A5*1 allele carriers need to reach the same tacrolimus concentration to increase tacrolimus dose. SLCO1B3 T334G and G699A gene polymorphisms has no effect on tacrolimus plasma concentration in the early stage after renal transplantation.

Rejection has constantly been an unresolved challenge in the field of organ transplantation. The research on the mechanism of rejection plays a significant role in improving the efficacy of organ transplantation and enhancing the survival rate of graft. The innate and specific immune responses of the human body jointly participate in the graft rejection, leading to graft injury. In recent years, multiple researchers have conducted in-depth studies on the mechanism underlying the role of microRNA (miR) in regulating rejection. Among them, miR-155 has been widely considered as a key factor involved in immune regulation. The expression level and functional status of miR-155 may be intimately associated with the occurrence of rejection, which may become a new target for overcoming rejection. In this article, relevant studies on the role of miR-155 in regulating key immune cells in innate and specific immune responses were reviewed, aiming to provide novel ideas for the development of new immunosuppressants and rejection therapy.

Tacrolimus (Tac) is a commonly used immunosuppressant after organ transplantation, which has high immunosuppressive efficacy. However, the pharmacokinetics of Tac significantly differ among individuals, and gene polymorphism is the main influencing factor. In recent years, the gene polymorphism of drug transporter has become a novel research hotspot. Nevertheless, the effect of the gene polymorphism of transporter on Tac pharmacokinetics remains controversial. Consequently, the correlation between the gene polymorphism of transporter and Tac blood concentration plays a significant role in guiding Tac-based individualized immunosuppressive therapy. In this article, the research progresses on the gene polymorphism of adenosine triphosphate-binding cassette (ABC) transporter and solute carrier (SLC) transporter in organ transplantation was reviewed. The correlation between the gene polymorphism of transporter and Tac blood concentration was summarized, aiming to provide reference for Tac-based individualized therapy.