1.Clinical application of detachable string magnetically controlled capsule endoscopy for esophageal diseases in plateau area
Xueqin MA ; Jiahui CAI ; Airong YANG ; Yingcai MA
Chinese Journal of Digestive Endoscopy 2025;42(10):828-830
To explore the diagnostic value of detachable string magnetically controlled capsule gastroscope (ds-MCE) for esophageal diseases in plateau area, clinical data of 45 patients who underwent ds-MCE at Qinghai Special Hospital of Cardio-Cerebrovascular Diseases from January 2024 to June 2024 were retrospectively analyzed to explore the application characteristics and advantages of ds-MCE. The results showed that ds-MCE examination was successfully completed in all 45 patients. Diagnosis was confirmed in 30 cases (66.67%, 30/45) including 28 cases (93.33%) of esophagitis, 8 cases (26.67%) of esophageal ulcer, 8 cases (26.67%) of esophageal varices, 5 cases (16.67%) of hiatal herniawere, 3 cases (10.00%) of esophageal polyp, 1 case (3.33%) of achalasia, 1 case (3.33%) of esophageal papilloma, and 1 case (3.33%) of lower esophageal and cardiac carcinoma. Compared with traditional endoscopy and capsule endoscopy, ds-MCE has the advantages of no need for anesthesia and high safety, which provides a new and important diagnostic option for esophageal diseases in plateau area.
2.Association between the non-treatment threshold or upper limit of normal of alanine aminotransferase and liver pathological injury in patients with chronic hepatitis B virus infection and a persistently low level of alanine aminotransferase
Ming SHU ; Suwen JIANG ; Airong HU ; Qin CHEN ; Jialan WANG ; Menghan JIN ; Haojin ZHANG ; Shiqi YANG ; Shiyang FAN
Journal of Clinical Hepatology 2025;41(10):2044-2053
ObjectiveTo investigate the significance of different non-treatment thresholds or upper limits of normal (ULN) of alanine aminotransferase (ALT) in evaluating significant liver pathological injury in patients with chronic hepatitis B virus (HBV) infection, and to provide guidance for clinical diagnosis and treatment. MethodsThis study was conducted among 733 patients with chronic HBV infection who were hospitalized in Ningbo No. 2 Hospital from January 2015 to December 2023 and underwent liver biopsy and histopathological examination, and all patients had a persistent ALT level of ≤40 U/L and positive HBV DNA (>30 IU/mL). According to the treatment threshold or ULN of ALT, the patients were divided into group 1 with 575 patients (≤35 U/L for male patients, ≤25 U/L for female patients), group 2 with 430 patients (≤30 U/L for male patients, ≤19 U/L for female patients), group 3 with 443 patients (≤27 U/L for male patients, ≤24 U/L for female patients), group 4 with 446 patients (≤25 U/L), group 5 with 158 patients (>35 U/L for male patients, >25 U/L for female patients), and group 6 with 145 patients (>30 — ≤35 U/L for male patients, >19 — ≤25 U/L for female patients). Groups 2, 5, and 6 were compared to analyze the severity of liver pathological injury in patients with different ALT levels and the constituent ratio of patients with significant liver pathological injury, and groups 1, 2, 3, and 4 were compared to investigate the value of different ULN or non-treatment thresholds of ALT in determining liver inflammation grade (G), liver fibrosis stage (S), and the treatment indication based on liver pathology. The independent-samples t test was used for comparison of normally distributed continuous data between two groups; a one-way analysis of variance was used for comparison between multiple groups, and the least significant difference t-test or the Tambane’s test was used for further comparison between two groups; the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups, and the Kruskal-Wallis H test was used for comparison between multiple groups and further comparison between two groups; the chi-square test or the Fisher’s exact test was used for comparison of categorical data between groups; a Ridit analysis was used for comparison of ranked data. A multivariate Logistic regression analysis (forward stepwise) was performed with whether liver pathology met the treatment indication (≥G2 and/or ≥S2) as the dependent variable and related factors with a significant impact on the dependent variable (P <0.05) as the independent variable. The receiver operating characteristic (ROC) curve was plotted, and the area under the ROC curve (AUC), as well as sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio, was used to assess the diagnostic value of different non-treatment thresholds of ALT. ResultsAmong the 733 patients, 259 (35.33%) had ≥G2 liver inflammation, 211 (28.79%) had ≥S2 liver fibrosis, and 306 (41.75%) had treatment indication (≥G2 and/or ≥S2). There was a significant difference in liver inflammation grade (G0 — G4) between groups 2, 5, and 6 (χ2=22.869, P <0.001), and there were also significant differences in the constituent ratios of patients with ≥G2 or ≥G3 liver inflammation between the three groups (χ2=21.742 and 14.921, P<0.001 and P=0.001). There was a significant difference in liver fibrosis stage (S0 — S4) between groups 2, 5, and 6 (χ2=16.565, P<0.001), and there were also significant differences in the constituent ratios of patients with ≥S2, ≥S3 or S4 liver fibrosis between the three groups (χ2=13.264, 13.050, and 6.260, P=0.001, 0.001, and 0.044). There were significant differences between groups 2, 5, and 6 in the constituent ratios of patients with or without treatment indication based on liver pathology (χ2=20.728, P<0.001). There were significant differences between groups 2, 5, and 6 in the constituent ratio of male patients (χ2=24.836, P<0.05), age (F=5.710, P<0.05), ALT (F=473.193, P<0.05), aspartate aminotransferase (AST) (F=107.774, P<0.05), ALT/AST ratio (F=40.167, P<0.05), γ-glutamyl transpeptidase (GGT) (H=15.463, P<0.05), aspartate aminotransferase-to-platelet ratio index (APRI) (H=63.024, P<0.05), and LIF-5 (5 indicators for liver inflammation and fibrosis) (H=46.397, P<0.05). In groups 1 — 4, compared with the patients without treatment indication, the patients with treatment indication had a significantly lower constituent ratio of patients with positive HBeAg, significantly lower levels of platelet count (PLT) and HBV DNA, and significantly higher age, ALT, AST, GGT, APRI, FIB-4, and LIF-5 (all P<0.05). The Logistic regression analysis showed that age (odds ratio [OR]=1.044, 95% confidence interval [CI]: 1.025 — 1.063, P<0.001), GGT (OR=1.022, 95%CI: 1.007 — 1.038, P=0.003), and HBV DNA (OR=0.839, 95%CI: 0.765 — 0.919, P<0.001) were influencing factors for treatment indication based on liver pathology in group 1; HBeAg (OR=1.978, 95%CI: 1.269 — 3.082, P=0.003), age (OR=1.048, 95%CI: 1.025 — 1.071, P<0.001), GGT (OR=1.016, 95%CI: 1.001 — 1.031, P=0.041), and PLT (OR=0.995, 95%CI: 0.991 — 1.000, P=0.049) were influencing factors in group 2; age (OR=1.040, 95%CI: 1.014 — 1.066, P=0.002), ALT (OR=1.047, 95%CI: 1.005 — 1.092, P=0.029), HBV DNA (OR=0.817, 95%CI: 0.736 — 0.907, P<0.001), and LIF-5 (OR=7.382, 95%CI: 1.151 — 47.330, P=0.035) were influencing factors in group 3; age (OR=1.054, 95%CI: 1.031 — 1.077, P<0.001), ALT (OR=1.061, 95%CI: 1.016 — 1.107, P=0.008), and HBV DNA (OR=0.825, 95%CI: 0.743 — 0.917, P<0.001) were influencing factors in group 4. The diagnostic performance for identifying ≥G2 liver inflammation, ≥S2 liver fibrosis, and treatment indication in groups 1 — 4 had an AUC of >0.7; group 1 showed the lowest sensitivity (28.76%) and the highest specificity, positive predictive value, positive likelihood ratio, and negative likelihood ratio in judging treatment indication; group 2 had the highest sensitivity and negative predictive value and the lowest negative likelihood ratio; groups 3 and 4 had similar diagnostic indicators. ConclusionIn patients with chronic HBV infection and a persistently low ALT level, the severity of liver histopathological injury and the constituent ratio of significant liver histopathological injury decrease with the reduction in ALT level. A higher non-treatment threshold or ULN of ALT can help to identify the patients requiring treatment (with a higher specificity), while a lower non-treatment threshold or ULN of ALT can help to identify the patients who do not require treatment (with a higher sensitivity).
3.The effects of apigenin,an active component of Polygonati Rhizoma,on depression-like behaviors induced by hindlimb unloading simulating microgravity in rats
Xiaoni DENG ; Wenjuan ZHANG ; Hong YU ; Wenhui YANG ; Hao ZHANG ; Shuo GAO ; Airong QIAN
Space Medicine & Medical Engineering 2025;36(1):43-49
Objective To screen antidepressant-active compounds from Polygonati Rhizoma and explore their effects and possible mechanisms against depression induced by simulated weightlessness.Methods A systems pharmacology approach was used to screen potential antidepressant-active compounds and their targets from Polygonati Rhizoma.The hindlimb unloading(HLU)rat model was employed for the study.Twenty-four healthy male Sprague-Dawley rats were randomly divided into three groups:control group(administered 0.5%carboxymethylcellulose by gavage),HLU group(hindlimb unloading),and HLU+treatment group(hindlimb unloading+active compound gavage),with 8 rats in each group.After 28 days of hindlimb unloading,depressive-like behaviors in rats were evaluated using the forced swimming test and tail suspension test.Hippocampal morphology was examined with H&E staining,and GO and KEGG enrichment analyses were conducted on the targets of active compounds.Results A total of 38 active compounds were screened from Polygonati Rhizoma,among which apigenin had an oral bioavailability of 23.06%and a drug-likeness score of 0.21.Compound-target network analysis indicated that apigenin had the highest degree and betweenness centrality values,suggesting it might be the key active component with antidepressant potential in Polygonati Rhizoma.In the forced swimming and tail suspension tests,rats in the HLU group showed a significant increase in immobility time compared to the control group,indicating successful establishment of the depression model.However,compared to the HLU group,rats in the HLU plus apigenin group exhibited significantly reduced immobility time.The H&E staining results of hippocampal tissue showed a significant reduction in the number of hippocampal neurons,along with numerous shrunken neurons and small vacuoles in nerve fibers in the HLU group.In contrast,the treatment group exhibited an increased number of hippocampal neurons,with improved cellular morphology.Target enrichment analysis indicated that apigenin targets were mainly involved in the regulation of apoptosis and cancer-related signaling pathways.Conclusion Apigenin significantly improved depressive-like behaviors in rats subjected to hindlimb unloading,and it has a protective effect on hippocampal tissue.It may provide a new natural active compound for the treatment of depression caused by spaceflight-induced weightlessness.
4.Clinical application of detachable string magnetically controlled capsule endoscopy for esophageal diseases in plateau area
Xueqin MA ; Jiahui CAI ; Airong YANG ; Yingcai MA
Chinese Journal of Digestive Endoscopy 2025;42(10):828-830
To explore the diagnostic value of detachable string magnetically controlled capsule gastroscope (ds-MCE) for esophageal diseases in plateau area, clinical data of 45 patients who underwent ds-MCE at Qinghai Special Hospital of Cardio-Cerebrovascular Diseases from January 2024 to June 2024 were retrospectively analyzed to explore the application characteristics and advantages of ds-MCE. The results showed that ds-MCE examination was successfully completed in all 45 patients. Diagnosis was confirmed in 30 cases (66.67%, 30/45) including 28 cases (93.33%) of esophagitis, 8 cases (26.67%) of esophageal ulcer, 8 cases (26.67%) of esophageal varices, 5 cases (16.67%) of hiatal herniawere, 3 cases (10.00%) of esophageal polyp, 1 case (3.33%) of achalasia, 1 case (3.33%) of esophageal papilloma, and 1 case (3.33%) of lower esophageal and cardiac carcinoma. Compared with traditional endoscopy and capsule endoscopy, ds-MCE has the advantages of no need for anesthesia and high safety, which provides a new and important diagnostic option for esophageal diseases in plateau area.
5.Effects of early essential newborn care technology on the health outcomes of mothers and infants after full-term cesarean section
Jun LIU ; Dongshu ZHU ; Huan CHENG ; Airong BAO ; Hongyan DUAN ; Jialei FENG ; Huixia YANG
Chinese Journal of Modern Nursing 2023;29(3):354-358
Objective:To explore the effect of early essential newborn care technology during cesarean section on early health outcomes of mothers and infants and breast feeding.Methods:This study was a randomized controlled study. From October 2020 to August 2021, 104 delivery women and their newborns who were scheduled for full-term cesarean section in Peking University First Hospital were selected as the study subject. The subjects were randomly divided into control group and intervention group, 52 cases in each group. The control group received routine nursing of the newborn after cesarean section, while the intervention group received early essential newborn care technology after cesarean section. The amount of postpartum hemorrhage, hospital stay, Apgar score at one and five minutes after birth, the incidence of abnormal conditions within 90 minutes after birth, the time of umbilical cord shedding, the time of the first feeding sign of the newborn, the success rate of early initiation of breastfeeding and the implementation of breast feeding at discharge were compared between the two groups.Results:There was no statistical difference between the two groups in the amount of postpartum hemorrhage within two hours, the amount of postpartum hemorrhage within two to 24 hours and the number of days in hospital ( P>0.05) . There was no statistical difference between the two groups in Apgar scores at one and five min after birth ( P>0.05) . There was no statistical difference between the two groups in the occurrence of re-attraction, respiratory abnormalities, resuscitation, Neonatal Intensive Care Unit (NICU) transfer and other abnormalities within 90 minutes after birth ( P>0.05) . There was no statistical difference in the time of umbilical cord shedding between the two groups ( P>0.05) , and no umbilical infection occurred. The first foraging reflex in the intervention group was earlier than that in the control group, and the success rate of early initiation of breastfeeding was higher than that in the control group, and the differences was statistically significant ( P<0.05) . There was no statistical difference in the implementation of breast feeding between the two groups at discharge ( P>0.05) . Conclusions:It is safe and feasible to implement early essential newborn care technology during cesarean section, and it can effectively promote early initiation of breastfeeding, which is of great significance for breast feeding and has the value of clinical promotion.
6.Evaluation of therapeutic effect of calycosin on microgravity-induced muscle atrophy based on real-time shear wave elastography technology
Fan LI ; Wenjuan ZHANG ; Xiaoni DENG ; Wenhui YANG ; Hao ZHANG ; Shuo GAO ; Jiaqi ZHANG ; Xiang JIN ; Wei BAI ; Kang RU ; Xuechao LIANG ; Airong QIAN
Chinese Journal of Aerospace Medicine 2023;34(3):129-136
Objective:To investigate the protective effect of calycosin on microgravity-induced muscle atrophy by using real-time shear wave elastography (RT-SWE).Methods:The potential key active compound calycosin of anti-muscular atrophy in Astragali Radix was screened by systematic pharmacology. Eighteen healthy male Sprague-Dawley rats were divided into the control group [0.5% carboxymethyl cellulose-Na (CMC-Na) gavage], the hind limb unloading (HLU)+CMC-Na group (HLU+0.5% CMC-Na gavage), and the HLU+calycosin group (HLU+calycosin gavage) according to the method of random number table, with 6 rats in each group. After 28 d of continuous administration, the organ index, the toxicity of liver and kidney, the wet weight of soleus muscle and the ratio of muscle weight to body weight was measured, respectively. The non-invasive RT-SWE was used to evaluate the thickness and elastic modulus of rectus femoris in each group and the one-way analysis of variance was used to compare the differences among groups.Results:There was no significant difference in organ index, liver and kidney toxicity among different groups of rats (all P>0.05). There were significant differences in the weight of soleus muscle and the ratio of muscle weight to body weight among different groups of rats ( F=60.66, 56.44, both P<0.001). Compared with the HLU+CMC-Na group, the weight of soleus muscle and the ratio of muscle weight to body weight in the HLU+calycosin group increased, and the differences were significant (both P<0.01). The thickness and elastic modulus of rectus femoris of rats in different groups were significantly different ( F=35.47, 14.68, both P<0.001). Compared with the HLU+CMC-Na group, the muscle thickness and elastic modulus of rats in HLU+calycosin group were increased, and the differences were significant (both P<0.01). Conclusions:The treatment of calycosin has no side effects on rats. It can improve the thickness and elastic modulus of rectus femoris, and effectively prevent microgravity-induced muscle atrophy, which may provide a new candidate drug for astronaut muscular atrophy.
7.Evaluation of therapeutic effect of calycosin on microgravity-induced muscle atrophy based on real-time shear wave elastography technology
Fan LI ; Wenjuan ZHANG ; Xiaoni DENG ; Wenhui YANG ; Hao ZHANG ; Shuo GAO ; Jiaqi ZHANG ; Xiang JIN ; Wei BAI ; Kang RU ; Xuechao LIANG ; Airong QIAN
Chinese Journal of Aerospace Medicine 2023;34(3):129-136
Objective:To investigate the protective effect of calycosin on microgravity-induced muscle atrophy by using real-time shear wave elastography (RT-SWE).Methods:The potential key active compound calycosin of anti-muscular atrophy in Astragali Radix was screened by systematic pharmacology. Eighteen healthy male Sprague-Dawley rats were divided into the control group [0.5% carboxymethyl cellulose-Na (CMC-Na) gavage], the hind limb unloading (HLU)+CMC-Na group (HLU+0.5% CMC-Na gavage), and the HLU+calycosin group (HLU+calycosin gavage) according to the method of random number table, with 6 rats in each group. After 28 d of continuous administration, the organ index, the toxicity of liver and kidney, the wet weight of soleus muscle and the ratio of muscle weight to body weight was measured, respectively. The non-invasive RT-SWE was used to evaluate the thickness and elastic modulus of rectus femoris in each group and the one-way analysis of variance was used to compare the differences among groups.Results:There was no significant difference in organ index, liver and kidney toxicity among different groups of rats (all P>0.05). There were significant differences in the weight of soleus muscle and the ratio of muscle weight to body weight among different groups of rats ( F=60.66, 56.44, both P<0.001). Compared with the HLU+CMC-Na group, the weight of soleus muscle and the ratio of muscle weight to body weight in the HLU+calycosin group increased, and the differences were significant (both P<0.01). The thickness and elastic modulus of rectus femoris of rats in different groups were significantly different ( F=35.47, 14.68, both P<0.001). Compared with the HLU+CMC-Na group, the muscle thickness and elastic modulus of rats in HLU+calycosin group were increased, and the differences were significant (both P<0.01). Conclusions:The treatment of calycosin has no side effects on rats. It can improve the thickness and elastic modulus of rectus femoris, and effectively prevent microgravity-induced muscle atrophy, which may provide a new candidate drug for astronaut muscular atrophy.
8.Stem cell microencapsulation maintains stemness in inflammatory microenvironment.
Yajun ZHAO ; Yilin SHI ; Huiqi YANG ; Mengmeng LIU ; Lanbo SHEN ; Shengben ZHANG ; Yue LIU ; Jie ZHU ; Jing LAN ; Jianhua LI ; Shaohua GE
International Journal of Oral Science 2022;14(1):48-48
Maintaining the stemness of the transplanted stem cell spheroids in an inflammatory microenvironment is challenging but important in regenerative medicine. Direct delivery of stem cells to repair periodontal defects may yield suboptimal effects due to the complexity of the periodontal inflammatory environment. Herein, stem cell spheroid is encapsulated by interfacial assembly of metal-phenolic network (MPN) nanofilm to form a stem cell microsphere capsule. Specifically, periodontal ligament stem cells (PDLSCs) spheroid was coated with FeIII/tannic acid coordination network to obtain spheroid@[FeIII-TA] microcapsules. The formed biodegradable MPN biointerface acted as a cytoprotective barrier and exhibited antioxidative, antibacterial and anti-inflammatory activities, effectively remodeling the inflammatory microenvironment and maintaining the stemness of PDLSCs. The stem cell microencapsulation proposed in this study can be applied to multiple stem cells with various functional metal ion/polyphenol coordination, providing a simple yet efficient delivery strategy for stem cell stemness maintenance in an inflammatory environment toward a better therapeutic outcome.
Anti-Bacterial Agents/pharmacology*
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Capsules/pharmacology*
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Cell Differentiation
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Cell Encapsulation
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Cells, Cultured
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Ferric Compounds/pharmacology*
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Osteogenesis/physiology*
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Periodontal Ligament
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Polyphenols/pharmacology*
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Stem Cells
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Tannins/pharmacology*
9.Application of narrow band imaging-magnifying endoscopy to the further assessment of gastric low-grade intraepithelial neoplasia in biopsy
Liujing NI ; Jinzhou ZHU ; Liting XI ; Yi YANG ; Chenyan YU ; Chentao ZOU ; Chao WANG ; Airong WU
Chinese Journal of Digestive Endoscopy 2021;38(12):1013-1017
Objective:To evaluate narrow band imaging-magnifying endoscopy (NBI-ME) for the further assessment of lesions of low-grade intraepithelial neoplasia (LGIN) in the gastric biopsy.Methods:Data of 180 patients who underwent NBI-ME before endoscopic submucosal dissection (ESD) for biopsy of gastric LGIN at the First Affiliated Hospital of Soochow University from January 2017 to October 2020 were analyzed retrospectively. Taking the pathological results after ESD as the gold standard, the sensitivity, the specificity, the positive predictive value, the negative predictive value, and the accuracy of NBI-ME in predicting the pathological upgrading of gastric LGIN lesions after ESD were calculated, and the receiver operator characteristic (ROC) curve was drawn.Results:Among 180 gastric LGIN lesions, 115 (63.89%) were pathological upgraded and 65 (36.11%) were not after ESD. There were 10 missed diagnoses, 19 misdiagnoses, and 151 correct diagnoses in NBI-ME examination before ESD. The sensitivity, the specificity, the positive predictive value, the negative predictive value, and the accuracy of NBI-ME in predicting the pathological upgrading of gastric LGIN lesions after ESD were 91.3% (105/115), 70.8% (46/65), 84.7% (105/124), 82.1%(46/56) and 83.9% (151/180), respectively. The area under the ROC curve was 0.810 (95% CI: 0.737-0.883). Conclusion:Further NBI-ME examination of gastric LGIN lesions diagnosed by biopsy pathology can accurately predict whether the lesions have pathological upgrading after ESD, which is of important guiding significance for the patients to choose the treatment strategy of further follow-up or endoscopic resection.
10.Study on the Association of Synergistic Effects of Wuzhi Capsules on Tacrolimus with CYP3A5*3 Gene Polymorphism
Yan YANG ; Huawen XIN ; Fei LIU ; Lei XIONG ; Weiliang LI ; Airong YU
China Pharmacy 2017;28(5):581-585
OBJECTIVE:To investigate the association of synergistic effects of Wuzhi capsules on tacrolimus with CYP3A5*3 (6986A>G,rs776746) gene polymorphisms. METHODS:One hundred and severty patients underwent renal transplantation receiving tacrolimus maintenance therapy after surgery were selected from our hospital during Jan. 1997-Dec. 2015,and then divided into Wuzhi capsules(+)group(74 cases)and Wuzhi capsules(-)group(96 cases)according to the use of Wuzhi capsules. Both groups received tacrolimus+mycophenolate mofetil+prednisone;Wuzhi capsules (+)group was additionally given Wuzhi capsules,one capsule each time,bid,for more than 12 months. Trough concentration of tacrolimus was detected by CMIA 0,1,3,6,12 months after medica-tion,and the blood concentrations(C0/D)were calculated at different time points after correcting daily dose. CYP3A5*3 gene polymor-phisms was detected by PCR-RFLP. The association of C0/D value with gene polymorphism was investigated by analysis of covariance. RESULTS:Among 170 patients,there were 65 cases of CYP3A5 GG genotype,83 cases of AG genotype and 22 cases of AA geno-type;genotype frequencies were 38.2%,48.8% and 12.9%,which was in line with Hardy-Weinberg balance (P>0.05). There was statistical significance in the distribution frequencies of GG,AG+AA genotype between Wuzhi capsules(+)group and Wuzhi capsules (-)group (P<0.05). After 1 month of medication,C0/D of tacrolimus in GG genotype was significantly higher in Wuzhi capsules (+)group than in Wuzhi capsules(-)group. After 1,3,6,12 months of medication,C0/D of tacrolimus in AG+AA genotype was sig-nificantly higher in Wuzhi capsules(+)group than in Wuzhi capsules(-)group,with statistical significance(P<0.05). There was no statistical significance in C0/D of tacrolimus in GG genotype between 2 groups after 3,6,12 months of treatment(P>0.05). CON-CLUSIONS:Wuzhi capsules can increase C0/D of tacrolimus in CYP3A5*3 AG+AA genotype,but have no significant effect on C0/D of tacrolimus in GG genotype;CYP3A5*3 genotype should be considered when using Wuzhi capsules as synergist of tacrolimus.

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