There are a large number of drug transporters widely distributed in various tissues and organs in the human body.They are involved in the membrane transport of numerous endogenous substances,toxins,and drugs.The transmembrane transport mediated by transporters not only plays an important role in maintaining the homeostasis of the internal environment,but also closely related to drug absorption,distribution,metabolism,and excretion processes.In clinical practice,drug-drug and drug-endogenous molecule interactions based on drug transporters may affect therapeutic efficacy or lead to toxic side effects.Therefore,it is particularly important to closely monitor and evaluate the risks of transporters mediated drug-drug interactions in the drug development and marketing process.This review summarized the classification,functions,tissue distribution and substrate specificity of typical drug transporters in new drug development.Subsequently,the research progress regarding drug-drug interactions involving 24 drug transporters for 55 newly approved drugs by the US Food and Drug Administration in 2023 is comprehensively reviewed.The aim is to provide reference for further drug-drug interaction research together with its scientific significance during new drug development stage.

There are a large number of drug transporters widely distributed in various tissues and organs in the human body.They are involved in the membrane transport of numerous endogenous substances,toxins,and drugs.The transmembrane transport mediated by transporters not only plays an important role in maintaining the homeostasis of the internal environment,but also closely related to drug absorption,distribution,metabolism,and excretion processes.In clinical practice,drug-drug and drug-endogenous molecule interactions based on drug transporters may affect therapeutic efficacy or lead to toxic side effects.Therefore,it is particularly important to closely monitor and evaluate the risks of transporters mediated drug-drug interactions in the drug development and marketing process.This review summarized the classification,functions,tissue distribution and substrate specificity of typical drug transporters in new drug development.Subsequently,the research progress regarding drug-drug interactions involving 24 drug transporters for 55 newly approved drugs by the US Food and Drug Administration in 2023 is comprehensively reviewed.The aim is to provide reference for further drug-drug interaction research together with its scientific significance during new drug development stage.

Objective:To evaluate the efficacy and safety of mosapride citrate dispersible tablet (MP) combined with Shugan Jieyu capsule (SGJY) in the treatment of functional dyspepsia (FD).Methods:From April 2018 to January 2019, FD patients from 10 hospitals including Renji Hospital, Shanghai Jiaotong University School of Medicine, Luohe Hospital of Traditional Chinese Medicine, the Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Handan Hospital of Traditional Chinese Medicine and Nanshi Hospital of Nanyang were selected for a randomized, double-blind, placebo-controlled trial. The patient health questionnaire-9 (PHQ-9) and generalized anxiety disorder-7 (GAD-7) were used to assess depression and anxiety in FD patients, respectively. According to the random number table method, 200 FD patients who met the inclusion criteria were randomly divided into SGJY+ MP group and placebo+ MP group, with 100 patients in each group, and all the patients were given oral MP. The patients of the SGJY+ MP group and the placebo+ MP group were given oral SGJY or placebo on the basis of MP, respectively. The patients of both groups were treated continuously for 6 weeks. Total FD symptom scores, PHQ-9 and GAD-7 scores, as well as efficiency and safety were evaluated after treatment. Independent samples t-test and chi-square test were used for statistical analysis. Results:A total of 193 patients were included into the full analysis set with 94 cases in the SGJY+ MP group and 99 cases in the placebo+ MP group. A total of 183 patients completed the 6-week trial, including 89 cases in the SGJY+ MP group and 94 cases in the placebo+ MP group. A total of 198 patients were included in the safety analysis set, including 99 cases in the SGJY+ MP group and 99 cases in the placebo+ MP group.After treatment, the total FD symptom scores of the SGJY+ MP group and the placebo+ MP group were both lower than those of baseline before treatment (3.71±3.06 vs. 11.79±5.18 and 4.17±3.69 vs. 11.19±5.05), and the differences were both statistically significant ( t=-24.87 and -23.27, both P<0.001). The efficacy of the SGJY+ MP group was higher than that of the placebo+ MP group (86.5%, 77/89 vs. 74.5%, 70/94), and the difference was statistically significant ( χ2=4.69, P=0.030). The efficacy of patients with moderate-to-severe anxiety and depression in the SGJY+ MP group was both higher than that of patients in the placebo+ MP group (10/10 vs. 3/7, 85.0%, 17/20 vs. 8/14), and the differences were statistically significant ( χ2=5.66 and 5.33, P=0.017 and 0.010). The efficacy of patients with postprandial distress syndrome (PDS) subtype in the SGJY+ MP group was higher than that of patients in the placebo+ MP group (93.0%, 53/57 vs. 76.5%, 39/51), and the difference was statistically significant (χ 2=5.82, P=0.016). The PHQ-9 scores of patients with depression in both SGJY+ MP and placebo+ MP groups were lower than those at baseline before treatment (3.63±2.76 vs. 7.87±2.24 and 3.35±2.51 vs. 7.63±2.25), and the differences were statistically significant ( t=-14.88 and -15.87, both P<0.001). There was no significant difference in proportion of depressed patients with a ≥50% reduction in PHQ-9 scores from baseline value between the SGJY+ MP group and the placebo+ MP group (60.2%, 50/83 vs. 62.8%, 54/86; χ2=0.05, P=0.825). The GAD-7 scores of anxious patients both the SGJY+ MP group and the placebo+ MP group were lower than the baseline value before treatment (3.27±2.57 vs. 7.09±2.08 and 3.86±2.49 vs. 6.84±1.66), and the differences were statistically significant ( t=-13.30 and -11.47, both P<0.001). The proportion of anxious patients with a ≥50% reduction in GAD-7 scores from baseline in the SGJY+ MP group was higher than that of the placebo+ MP group (54.4%, 43/79 vs. 36.5%, 27/74), and the difference was statistically significant ( χ2=4.53, P=0.033). There were no serious adverse events in both the SGJY+ MP group and the placebo+ MP group during the treatment. There were no significant differences in the incidence of adverse events and adverse reactions during the treatment between the SGJY+ MP group and the placebo+ MP group (7.1%, 7/99 vs. 5.1%, 5/99, and 3.0%, 3/99 vs. 3.0%, 3/99, respectively; both P>0.05). Conclusion:SGTY can safely and effectively improve the efficacy of the prokinetic drugs in the treatment of FD symptoms, especially in FD patients with PDS subtype or with moderate-to-severe anxiety and with depression.

【Objective】 To explore the expression of USP9X in platelets and its effect on platelet function. 【Methods】 The expression of USP9X in human and mouse was evaluated by PCR and Western blot. Platelets from young and old mice were separated and prepared, and the expression of USP9X was detected. USP9X inhibitos were used to assess the regulation of USP9X in platelet function, including aggregation, ATP release and spreading. Platelet lysates were collected in different time points to evaluate the change of phosphorylation of Akt in USP9X inhibitors treated platelets. 【Results】 Both human and mouse platelets expressed USP9X. Compared to the young mice, the old mice showed significantly enhanced expression of USP9X(P<0.05). To assess the effect of USP9X on platelet function, USP9X inhibitor was used to pre-incubate platelets for 30 min and platelet function were examined later. Results showed that USP9X inhibitor significantly decreased platelet activation including aggregation, ATP release and spreading(P<0.05). Compared to the control group, the inhibitor treated group showed a significant decrease in the spreading area after 45 minutes. The Western blot results showed a significant decrease in Akt phosphorylation levels of platelets in the USP9X inhibitor treated group. 【Conclusion】 Both human and mouse platelet express USP9X, and inhibition of USP9X decreased platelet function including aggregation, ATP release and spreading. USP9X can also influence the phosphorylation of Akt. The inhibitor of USP9X may become a potential therapeutic target for thrombosis intervention.

Objective:To evaluate the efficacy and safety of mosapride citrate dispersible tablet (MP) combined with Shugan Jieyu capsule (SGJY) in the treatment of functional dyspepsia (FD).Methods:From April 2018 to January 2019, FD patients from 10 hospitals including Renji Hospital, Shanghai Jiaotong University School of Medicine, Luohe Hospital of Traditional Chinese Medicine, the Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Handan Hospital of Traditional Chinese Medicine and Nanshi Hospital of Nanyang were selected for a randomized, double-blind, placebo-controlled trial. The patient health questionnaire-9 (PHQ-9) and generalized anxiety disorder-7 (GAD-7) were used to assess depression and anxiety in FD patients, respectively. According to the random number table method, 200 FD patients who met the inclusion criteria were randomly divided into SGJY+ MP group and placebo+ MP group, with 100 patients in each group, and all the patients were given oral MP. The patients of the SGJY+ MP group and the placebo+ MP group were given oral SGJY or placebo on the basis of MP, respectively. The patients of both groups were treated continuously for 6 weeks. Total FD symptom scores, PHQ-9 and GAD-7 scores, as well as efficiency and safety were evaluated after treatment. Independent samples t-test and chi-square test were used for statistical analysis. Results:A total of 193 patients were included into the full analysis set with 94 cases in the SGJY+ MP group and 99 cases in the placebo+ MP group. A total of 183 patients completed the 6-week trial, including 89 cases in the SGJY+ MP group and 94 cases in the placebo+ MP group. A total of 198 patients were included in the safety analysis set, including 99 cases in the SGJY+ MP group and 99 cases in the placebo+ MP group.After treatment, the total FD symptom scores of the SGJY+ MP group and the placebo+ MP group were both lower than those of baseline before treatment (3.71±3.06 vs. 11.79±5.18 and 4.17±3.69 vs. 11.19±5.05), and the differences were both statistically significant ( t=-24.87 and -23.27, both P<0.001). The efficacy of the SGJY+ MP group was higher than that of the placebo+ MP group (86.5%, 77/89 vs. 74.5%, 70/94), and the difference was statistically significant ( χ2=4.69, P=0.030). The efficacy of patients with moderate-to-severe anxiety and depression in the SGJY+ MP group was both higher than that of patients in the placebo+ MP group (10/10 vs. 3/7, 85.0%, 17/20 vs. 8/14), and the differences were statistically significant ( χ2=5.66 and 5.33, P=0.017 and 0.010). The efficacy of patients with postprandial distress syndrome (PDS) subtype in the SGJY+ MP group was higher than that of patients in the placebo+ MP group (93.0%, 53/57 vs. 76.5%, 39/51), and the difference was statistically significant (χ 2=5.82, P=0.016). The PHQ-9 scores of patients with depression in both SGJY+ MP and placebo+ MP groups were lower than those at baseline before treatment (3.63±2.76 vs. 7.87±2.24 and 3.35±2.51 vs. 7.63±2.25), and the differences were statistically significant ( t=-14.88 and -15.87, both P<0.001). There was no significant difference in proportion of depressed patients with a ≥50% reduction in PHQ-9 scores from baseline value between the SGJY+ MP group and the placebo+ MP group (60.2%, 50/83 vs. 62.8%, 54/86; χ2=0.05, P=0.825). The GAD-7 scores of anxious patients both the SGJY+ MP group and the placebo+ MP group were lower than the baseline value before treatment (3.27±2.57 vs. 7.09±2.08 and 3.86±2.49 vs. 6.84±1.66), and the differences were statistically significant ( t=-13.30 and -11.47, both P<0.001). The proportion of anxious patients with a ≥50% reduction in GAD-7 scores from baseline in the SGJY+ MP group was higher than that of the placebo+ MP group (54.4%, 43/79 vs. 36.5%, 27/74), and the difference was statistically significant ( χ2=4.53, P=0.033). There were no serious adverse events in both the SGJY+ MP group and the placebo+ MP group during the treatment. There were no significant differences in the incidence of adverse events and adverse reactions during the treatment between the SGJY+ MP group and the placebo+ MP group (7.1%, 7/99 vs. 5.1%, 5/99, and 3.0%, 3/99 vs. 3.0%, 3/99, respectively; both P>0.05). Conclusion:SGTY can safely and effectively improve the efficacy of the prokinetic drugs in the treatment of FD symptoms, especially in FD patients with PDS subtype or with moderate-to-severe anxiety and with depression.

Objective:To systematically evaluate the correlation of high sensitivity C-reactive protein (hs-CRP) with contrast-induced nephropathy (CIN) in patients following coronary angiography (CAG) or percutaneous coronary intervention (PCI).Methods:PubMed, web of science, CBM, CNKI and Wanfang Data were searched for studies on hs-CRP levels in patients undergoing CAG or PCI patients from the incipience of the database to March 7, 2021. Meta-analysis was performed by RevMan 5.3 and Stata 12.0 software.Results:Fourteen related studies were included involving 11 885 patients undergoing CAG or PCI (1 034 cases with CIN and 10 851 cases without CIN). The results of meta-analysis showed that the level of hs-CRP in CIN group was significantly higher than that in non-CIN group (WMD=3.77,95 %CI:2.80—4.74, P<0.001, I2=93%), patients with higher levels of hs-CRP before CAG or PCI were more likely to develop CIN. Sensitivity analysis shows that the results of this study had good stability. The results of subgroup analysis show that the differences in sample size, study population, geographical location and the definition of CIN were statistically significant. Conclusion:Available evidence shows that high hs-CRP level is a risk factor for CIN in patients undergoing CAG or PCI, large sample trials are still needed to support this conclusion.

OBJECTIVE：To study the improvement effect and possible mechanism of Leontopodium leontopodioides combined with Astragalus membranaceus on the renal function of mesangial proliferative glomerulonephritis （MsPGN） model rats. METHODS：Totally 85 rats were randomly divided into sham operation group （n＝10）and modeling group （n＝75）. Sham operation group underwent sham operation ，and MsPGN model was induced by immunological method [Freund ’s adjuvant+BSA + lipopolysaccharide（LPS）] in modeling group. After successfully modeling ，70 rats were randomly divided into model group ，L. leontopodioides+A. membranaceus high-dose，medium-dose and low-dose groups （4.05，2.03，1.02 g/kg，by total crude drug ），L. leontopodioides alone group （2.70 g/kg，by crude drug ），Tripterygium glycosides tablet group （positive control 1，0.02 g/kg）， Lotensin tablet group （positive control 2，0.02 g/kg），with 10 rats in each group. Sham operation group and model group were given constant volume of normal saline intragastrically ； administration groups were given relevant drug solution intrasgastrcially at a volume of 15 mL/kg，once a day ，for consecutive 5 weeks. At last administration ，24 h urinary lnzyxyqy2003@163.com protein，urine creatinine and serum creatinine were determined in rats. The right kidney was weighed ，and HE staining was used to observe the pathomorpholog y changes of renal tissue. Immunohistochemistry was used to detect the protein expression of NF-κB p65 in renal tissue. Western blotting assay was used to determine the protein expressions of NF-κB p65，IκBα，ERK，p-ERK and p 38 MAPK in renal tissue. RESULTS ：Compared with sham operation group ，right kidney weight ，24 h urine protein and serum creatinine levels ，protein expressions of NF-κB p65， p-ERK and p 38 MAPK in renal tissue were increased significantly in model group （P＜0.05 or P＜0.01）；the level of urine creatinine and protein expression of IκBα in renal tissue were decreased significantly（P＜0.05 or P＜0.01）；there were obvious glomerular hypertrophy ，diffuse increase of mesangial cells ，necrosis of renal tubules and other pathomorphological changes in renal tissue. Compared with model group ，right kidney weight and serum creatinine level were decreased significantly in L. leontopodioides alone group （P＜0.05），while urine creatinine level was increased significantly （P＜0.05），but there was no statistical significance in the level of 24 h urine protein （P＞0.05）；the right kidney weight ，24 h urine protein ，serum creatinine level and protein expression levels of NF-κB p65，p-ERK and p38 MAPK in renal tissue were decreased significantly in L. leontopodioides+A. membranaceus high-dose group （P＜0.05），while the urine creatinine level and protein expression level of IκBα in renal tissue were increased significantly （P＜0.05 or P＜0.01）；there was no statistical significance in above indexes in L. leontopodioides+A. membranaceus medium-dose，low-dose groups （P＞0.05）；pathological changes of renal tissue were improved to different extents in administration groups ，especially in L. leontopodioides +A. membranaceus high-dose group. CONCLUSIONS ： High dose of L. leontopodioides +A. membranaceus can improve renal function of MsPGN model rats by inhibiting MAPK/NF-κB signal pathway.

Objective To investigate the expression levels and clinical significances of ubiquitin-like with PHD and ring finger domains 1 (UHRF1) and P53 in colon carcinoma.Methods The expressions of UHRF1 and P53 in 70 colon cancer tissues and 30 normal colon ones were detected by means of immunohistochemistry to analyze the correlation of these two proteins in the occurrence and development of colon carcinoma,and the relationship between their expressions and clinico-pathological factors as well as prognosis was discussed.Results The expression levels of UHRF1 and P53 in cancer tissues were significantly higher than those of cancer-adjacent tissues (87.1％ vs.56.7％,x2 =11.366,P =0.001;64.3％ vs.6.7％,x2 =27.988,P =0.000) and showed a positive correlation between the two proteins (r =0.248,P =0.038).Both UHRF1 and P53 were associated with TNM stages (x2 =4.426,P =0.049;x2 =6.000,P =0.016) and the depth of invasion (x2 =12.553,P =0.002;x2 =4.904,P =0.036).However,they were irrelevant with the age (x2 =0.473,P=0.494;x2 =0.090,P=0.799) and gender (x2 =2.297,P=0.166;x2 =0.512,P=0.617) of patients,as well as the size (x2 =0.638,P =0.481;x2 =2.392,P =0.215) and histological grading of tumors (x2 =2.088,P =0.352;0.303,P =0.859).Kaplan-Meier analysis showed that the median survival time of patients with UHRF1,P53 positive expression was 21.83 months that was lower than patients with UHRF1 positive expression of 24.49 months (Z =-0.624,P =0.533).Both former of which was distinctly lower than that of negative ones of 37.33 months (Z =-2.856,P =0.004;Z =-2.694,P =0.007).Conclusion Both UHRF1 and P53 are highly expressed in colon cancer tissues,which imply that UHRF1 and P53 may be strongly related with colon cancer development and can be a predictor for colon cancer prognosis.

Objective To study the expressions of apoptotic protease activating factor-1(Apaf-1)and astrocyte elevated gene-1(AEG-1)in colonic carcinoma,and to explore their correlations with the clinical path-ological features. Methods The expressions of Apaf-1 and AEG-1 were detected in 63 colonic carcinoma sam-ples and 30 normal colonic mucosa adjacent to tumor nest by immunohistochemical method,and their correla-tions with clinical features of colonic carcinoma were analyzed. Results The positive expressions of Apaf-1 and AEG-1 in colonic carcinoma were 23. 81%(15 / 63)and 68. 25%(43 / 63),respectively. The positive expre-ssions of Apaf-1 and AEG-1 in normal colonic mucosa were 76. 67%(23 / 30)and 26. 67%(8 / 30),respec-tively. The positive expression rate of AEG-1 was significantly higher in colonic carcinoma than that in normal tissue(χ2 = 14. 192,P = 0. 000). However,the expression of Apaf-1 was signi-ficantly lower in colonic carci-noma than that in normal tissue(χ2 = 23. 497,P = 0. 000). The expression of Apaf-1 was negatively correlated to the expression of AEG-1(r = - 0. 339,P = 0. 007). The expressions of AEG-1 and Apaf-1 were associated with differentiation degree(χ2 = 4. 643,P = 0. 031;χ2 = 12. 034,P = 0. 001)and clinical stage(χ2 = 6. 628, P = 0. 010;χ2 = 8. 246,P = 0. 004),but they were not correlated with age(χ2 = 1. 462,P = 0. 227;χ2 =2. 401,P = 0. 121)and tumor size(χ2 = 0. 333,P = 0. 564;χ2 = 0. 590,P = 0. 442). Conclusion The expression of AEG-1 is up-regulated in colonic carcinoma,but the expression of Apaf-1 is down-regulated,with a significant negative correlation. Apaf-1 and AEG-1 may be closely related to the occurrence and development of colon carcinoma. Therefore,combination detection of Apaf-1 and AEG-1 may be more valuable for the prog-nosis evaluation of colonic carcinoma.

OBJECTIVETo find the potential serum specific miRNAs with diagnostic value in early pancreatic cancer and study the alteration of miRNAs levels in the process of origin and development of pancreatic cancer and discuss the diagnostic value of miRNAs in early pancreatic cancer.

METHODSDMBA-induced rat model was established. The miRNAs expression profile of early stage was screened out by microarray. And confirmation study was performed.

RESULTSThe 35 and 12 abnormally expressed miRNAs were acquired in pancreatic tissue and blood respectively. There were no significant differences between normal pancreas and pancreatic cancer in expressions of hsa-let-7c, hsa-miR-122-5p, hsa-miR-142-5p, hsa-miR-199a-3p and hsa-miR-451a (P > 0.05).

CONCLUSIONSmiRNAs are the potential biomarkers of early pancreatic cancer. The establishment of the miRNAs expression profile has build the foundation of exploring the molecular mechanism of origin of pancreatic cancer.

Animals ; Biomarkers, Tumor ; blood ; metabolism ; Disease Models, Animal ; Male ; MicroRNAs ; blood ; metabolism ; Pancreas ; metabolism ; Pancreatic Neoplasms ; diagnosis ; genetics ; Prognosis ; Rats ; Rats, Sprague-Dawley ; Transcriptome