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    Volume 23 Issue 5
    26 May 2018
    Research advances on target-mediated drug disposition(TMDD) models
    JI Shuangmin, ZHU Xiao, GAO Liucun, YANG Huan, GAO Chenyan
    2018, 23(5):  481-487.  doi:10.12092/j.issn.1009-2501.2018.05.001
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    Since the formal concept of target-mediated drug disposition(TMDD) was proposed by Dr.Gerhard Levy in 1994, great progress has been achieved in this area.Thanks to the development of experimental techniques,more and more data are available for the mathematical modeling of TMDD.As the rise of biologics, the application of TMDD models becomes more and more prevalent in drug development. This review introduces the development of TMDD models and discusses the application of different variants.

    Effects of IgD on the balance of Th1/Th2 and Th17/Treg subsets and transcription factors expression in human peripheral blood
    DONG Xiaojie, WU Yujing, ZHANG Jing, CHEN Wensheng, HUANG Qiong, WEI Wei
    2018, 23(5):  488-497.  doi:10.12092/j.issn.1009-2501.2018.05.002
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    AIM: To investigate the effects of immunoglobulin D (IgD) on the balance of Th1/Th2, Th17/Treg cells in healthy human T cell subsets.  METHODS: Different concentrations of IgD (final concentration of 1, 3,10 μg/mL) were added to stimulate the human peripheral mononuclear cells (PBMC). After 24 h, the expression of CD69 and CD154 and the percentage of Th1, Th2, Th17, and Treg subsets were detected by flow cytometry. The expression of nuclear transcription factors T-bet, GATA-3, Foxp3 and ROR-gammat mRNA was detected using qPCR assay. RESULTS: IgD could significantly increase the expression of CD69 and CD154(P<0.05), which are markers of activate T cells. IgD could simultaneously decrease the percentage of Th1 and Treg subsets and significantly increased the percentage of Th17 subset, but had no significant effect on Th2 subset. IgD significantly inhibited the expression of T-bet and Foxp3 mRNA and significantly promoted the expression of ROR-gammat mRNA, but had no significant effect on the expression of GATA-3 mRNA. CONCLUSION: IgD can activate T cells and induce the imbalance between Th1/Th2 and Th17/Treg subsets.

    Effects of MG-132 on cardiomyocyte apoptosis factor of CVB3 viral myocarditis in mice
    ZHANG Xinmin, CHEN Peng,YE Sheng, XIA Wujie, LI Yuechun
    2018, 23(5):  498-503.  doi:10.12092/j.issn.1009-2501.2018.05.003
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     AIM: To observe the effects of proteasome inhibitor MG-132 on myocardial cell apoptosis factor in mice with viral myocarditis, and further to explore the specific mechanisms of the ubiquitin proteasome system in the process of apoptosis in viral myocarditis.METHODS:Ninety male BALB/C mice were randomly divided into 3 groups: the normal control group (n=30), the myocarditis group (n=30), and the myocarditis +MG-132 treatment group (n=30). Intraperitoneal inoculation of coxsackievirus B3 virus (CVB3) was used to induce acute myocarditis. The treatment group was injected with proteasome inhibitor MG-132 intraperitoneally for a consecutive 7d. The control group and myocarditis group were intraperitoneally injected with DMSO solvent. The survival rate of mice, cardiac function index, pathology and the changes of cardiomyocyte apoptosis factors were observed on the 8th day. RESULTS: Compared with myocarditis group, the nuclear factor kappa B level in MG-132 treated group was significantly decreased (P<0.05), the level of Bax was significantly decreased (P<0.05), the level of Bcl-2 was significantly increased (P<0.05), and the Bcl-2/Bax ratio increased significantly (P<0.05). Compared with the myocarditis group, the MG-132 treatment group significantly reduced the cardiomyocyte apoptosis, the improvement of the hemodynamic status and the survival rate in the myocarditis mice. CONCLUSION: Proteasome inhibitor MG-132 can inhibit the apoptosis of cardiomyocytes and improve the cardiac function and survival rate in mice with acute viral myocarditis by down-regulating nuclear factor kappa B and Bax and up-regulating Bcl-2 level.

    Antitumoral effects of Sijunzi decoction on side population of SGC-7901 in nude mice and mechanism
    CHEN Shaohua, LI Nan, QIAN Jun
    2018, 23(5):  504-509.  doi:10.12092/j.issn.1009-2501.2018.05.004
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    AIM: To investigate the antitumor effect of Sijunzi decoction on side population (SP) cells and non-side population (NSP) cells of gastric cancer cell line SGC7901 in nude mice.  METHODS: Human gastric cancer cell line SGC-7901 SP cells were conventionally cultured, then, SP and NSP cells were sorted by flow cytometry. Proportion of SP cells was about 1.9%. The model of tumor-bearing mice was established and drug intervention group mice were given a gavage of Sijunzi decoction. All mice were killed after 30 days and the tumor growth curve was drawn and the tumor growth inhibition rate was measured. Tumor growth inhibition rate (IR) was calculated and apoptosis was detected by TUNEL method. RESULTS:The mean tumor volumes of SP-Drug group, NSP-Drug group were (1 348.40±103.98) mm3, (628.99±98.87) mm3, and their model group were (3 307.76±491.44) mm3, (2 202.87±67.80) mm3 (P<0.05), respectively. Tumor inhibition rate of SP-drug group and NSP-drug group were 54.69% and 60.19%, which were significantly different from the control groups (P<0.05). There was also a difference between SP group and the NSP group (P<0.05). TUNEL results showed that there were more apoptotic cells in the drug groups. The apoptosis rate of SP group and NSP group were 20.21% and 16.53%, which were obviously higher than control groups (P<0.05). CONCLUSION: Sijunzi decoction can inhibit the growth of human gastric cancer SGC-7901 SP cells in nude mice in vivo, which was probably related to induction of apoptosis in tumor cells.

    miR-200c induces resistance to doxorubicin through the Wnt/beta-catenin signaling pathway in bladder cancer cells
    LIU lei, LI Yixiao, WAN Bo, ZENG Qing
    2018, 23(5):  510-516.  doi:10.12092/j.issn.1009-2501.2018.05.005
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    AIM: To investigate the relationship between miR-200c expression and the response to DOX in bladder cancer cells. METHODS: Changes in the growthinhibitory effect of DOX on bladder cancer cells (RT4,RT112,T24 and TCCSUP) were examined after overexpression or suppression of miR-200c.The effect of miR-200c on the Wnt/beta-catenin signaling pathway were also examined to investigate whether the altered growth-inhibitory effect by miR-200c suppression was weakened after the addition of Wnt3a,a Wnt/beta-catenin signaling activator. RESULTS: RT4 and T24 cells transfected with anti-miR-200c showed significantly lower resistance to DOX. In the anti-miR-200c-transfected cells, DOX induced significantly larger numbers of apoptotic cells and S phase accumulation compared to control cells, demonstrated by Annexin V assay and flow cytometric analysis of the cell cycle, respectively. The transfected cells showed overexpression of putative target molecules including Dkk1, Kremen2 and sFRP2 and lower activation of the Wnt/beta-catenin signaling pathway.The addition of Wnt3a weakened the augmented growth-inhibitory effect of anti-miR-200c transfection. CONCLUSION: miR-200c expression correlates significantly with the growth-inhibitory effect of DOX and that activation of the Wnt/beta-catenin signaling pathway mediates the miR-200c-induced resistance to DOX in bladder cancer cell lines.

    Therapeutic effects of 1-Deoxynojirimycin in mulberry leaves on rats with diabetic nephropathy
    YAO Jia, QIAO Di, GUO Xin, CUI Changmeng
    2018, 23(5):  517-523.  doi:10.12092/j.issn.1009-2501.2018.05.006
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    AIM: To explore the effect of 1-deoxynojirimycin (DNJ) from mulberry leaves on blood glucose and kidney injury on rats with diabetic nephropathy by investigating the effect DNJ on delay the pathogenesis of diabetic nephropathy. METHODS: Diabetic nephropathy model were established by intraperitoneal injection of streptozotocin (STZ, 35 mg/kg) in male SD rats, then the animals were randomly divided into 3 groups. Rats in low and high dose DNJ groups were given 10, 25 mg/kg DNJ for 6 weeks, and no drug was given to rats in model group. SD male rats were included in experiment as normal control group. Fasting blood glucose (FBG) were detected at the 0, 4th, 6th, 12th week, and an oral glucose tolerance (OGTT) was performed at the end of 6th week after drug intervention. The body mass, urine albumin/creatinine ratio, kidney mass, serum urea nitrogen (BUN) and serum creatinine (Scr) were detected. Histopathological changes of kidney were observed by hematoxylin-eosin (HE) staining. RESULTS: Compared with model group, intragastric administration of low dose (10 mg/kg) or high dose (25 mg/kg) of DNJ reduced blood glucose at 4th and 6th week in diabetic rats, glucose tolerance was also significantly improved at 6th week. After intragastric administration of low dose (10 mg/kg) or high dose (25 mg /kg) of DNJ once daily for 6 weeks, both the renal hypertrophy index and urine albumin/creatinine ratio of rats with diabetic nephropathy were lower than that of model group. Low dose of DNJ reduced the level of Scr,while high dose of DNJ could decrease both the levels of Scr and BUN in diabetic nephropathy rats. By observing the pathological sections of renal tissue, the renal injury of rats with diabetic nephropathy were significantly attenuated with low or high dose of DNJ treatment. CONCLUSION: The DNJ extracted from mulberry leaves reduce blood glucose and attenuate renal damage in rats with diabetic nephropathy, and may delay the pathogenesis of diabetic nephropathy.

    Insights into tumor suppression mechanism of miRNA-101 in medullary thyroid carcinoma
    XU Ming, CUI Peng, YE Min, NI Xiong, WANG Tingfeng, MIN Zhijun
    2018, 23(5):  524-530.  doi:10.12092/j.issn.1009-2501.2018.05.007
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    AIM: To explore the tumor suppression mechanism of microRNA-101 in human medullary thyroid carcinoma cells (TT cells).  METHODS: The expression of microRNA-101 in tissue samples from patients with medullary thyroid carcinoma was analyzed by quantitative RT-PCR. Then TT cells were divided into two groups and transfected with miRNA-101 mimics/ negative control. Flow cytometry and Transwell assay were used to detect TT cell cycle distribution, apoptotic rate as well as cell migration. Moreover, Western blot, flow cytometry, luciferase and Transwell assays were used to predict target gene of miRNA-101 as well as its underlying mechanism. RESULTS: MiRNA-101 was significantly down-regulated in medullary thyroid carcinoma tissues. MiRNA-101 mimics' transfection significantly inhibited TT cell proliferation and migration, induced cell apoptosis comparing with negative control. Western blot and luciferase assay revealed that SOX9 gene expression was down-regulated by miRNA-101. Silencing of SOX9 by siRNA showed similar effects with miRNA-101 over-expression. CONCLUSION: MicroRNA-101 inhibits proliferation, migration and induces apoptosis of human medullary thyroid carcinoma cells by targeting SOX9 gene.

    Macrophage migration inhibitory factor protects H9c2 cardiac myocytes against hypoxia/reoxygenation injury through regulation of autophagy
    LI Jinyu, HUANG Danmei, ZHANG Yanmei, SHI Ganggang, WANG Bin
    2018, 23(5):  531-535.  doi:10.12092/j.issn.1009-2501.2018.05.008
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    AIM: To investigate the effects of macrophage migration inhibitory factor (MIF) on autophagy of H9c2 cardiac myocytes during hypoxia/reoxygenation (H/R) injury so as to explore the molecular mechanism. METHODS: The MIF mRNA-targeting siRNA was transfected to H9c2 cardiac myocytes. The H/R models of H9c2 cardiac myocytes were established. The autophagy inhibitor 3-methyladenine (3-MA) was added.The levels of MIF, LC3, Cleaved caspase-3 and mTOR protein expression in H9c2 cardiac myocytes were detected by Western blot. RESULTS: MIF siRNA transfection inhibited H/R-induced autophagy. The inhibitor of autophagy 3-MA suppressed H/R-induced autophagy and decreased apoptosis. MIF knockdown increased the expression of p-mTOR during H/R. CONCLUSION: MIF inhibits autophagy in H9c2 cardiomyocytes subjected to H/R, which is related to active mTOR protein.

    Methamphetamine dependent influenced RGS4 and mGluR5 receptor signaling in striatum of rats
    ZHAO Linbo,SUI Nianhan,LI Lihua,HONG Shijun, XING Yuming, ZHAO Yongna
    2018, 23(5):  536-540.  doi:10.12092/j.issn.1009-2501.2018.05.009
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    AIM: To investigate whether regulator of G-protein signaling 4(RGS4 ) and metabotropic receptor 5 (mGluR5) expression level changed in striatum of the methamphetamine(METH)-dependent rat and whether the changes were related to the time of METH treatment. METHODS: METH-dependent rat model of one week and two weeks were established. The expression levels of RGS4, mGluR5, Galfaq, PLCbeta1 were detected by Western blot analysis. RESULTS: Rats treated with METH of one week and two weeks spent much more time in the METH-paired chamber than NS control group, suggested that METH-dependent model has successfully established. Compared with NS control group, the expression level of RGS4 in the striatum of rats in model group was down-regulated remarkably. Furthermore, the expression level of mGluR5 and its coupling protein Galfaq, phospholipase C-beta1(PLCbeta1) were up-regulated in different degrees when compared with NS control group, and  the change is more remarkable in two weeks group than that of one week group. CONCLUSION: METH treatment down regulate the RGS4 and up regulate mGluR5 in rat striatum, and the expression level of mGluR5 coupling protein Galfaq, PLCbeta. And the longer the time of METH-dependent, the more significant the changes of RGS4, mGluR5, Galfaq, and PLCbeta1.

    Meta analysis of insulin aspart and biosynthetic human insulin for gestational diabetes mellitus
    WANG Yanqiu, JIN Yuelong, YAO Yingshui, LIU Ling, ZHU Lijun,CHANG Weiwei, CHEN Yan, ZHENG Tong, SHAO Yaojun
    2018, 23(5):  541-546.  doi:10.12092/j.issn.1009-2501.2018.05.010
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    Analysis of adverse drug events of everolimus based on US FAERS database
    LU Qing,ZENG Qingzhang, ZHOU Yaping, YU Peiming, LI Haona
    2018, 23(5):  547-551.  doi:10.12092/j.issn.1009-2501.2018.05.011
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    AIM: To reveal the rules of adverse events of everolimus and provide references for the risk control and rational clinical use of the drug by statistical analysis of adverse drug events of everolimus based on US FAERS database. METHODS: A retrospective and statistical analysis of 1 868 cases of adverse events of everolimus from FAERS database was conducted. RESULTS: Among 1 868 cases of everolimus adverse event reports, death, life danger, disability, hospitalization or duration of hospitalization amounted to 67.71%; nearly half of the reports of adverse events were from consumers, and USA, Japan, France, Germany were the most reported country; the top three clinical reported adverse events were death (382 cases, 20.45%); stomatitis (168 cases, 8.99%); malignant tumor progression (154 cases, 8.24%). CONCLUSION: The adverse reactions of everolimus is relatively serious, so close attention is required to the process of clinical use; and the number of reports of adverse events is associated with the economic level of the submitted country.

    Effects of subclinical hypothyroidism on the outcome of in vitro fertilization and embryo transfer
    HU Weihua, YAN Yongxu, RUAN Jian, HOU Wenwen
    2018, 23(5):  552-556.  doi:10.12092/j.issn.1009-2501.2018.05.012
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    AIM: To investigate the effects of in vitro fertilization (IVF) on embryo acquisition in patients with subclinical hypothyroidism.  METHODS: A total of 249 human subjects who received in vitro fertilization and embryo transfer (IVF-ET) for the first time in the reproductive medicine center of Wannan Medical College affiliated Yijishan Hospital from June 2014 to October 2017 were included and divided into two groups, with 67 cases of subclinical hypothyroidism, and 182 cases of normal thyroid function. Patients with subclinical hypothyroidism received levothyroxine sodium tablets at the beginning of treatment. Retrospective analysis was used to compare the number of retrieved oocytes, MII eggs, fertilization rate, cleavage rate, rescue ICSI rate, and high quality embryo rate between two groups. RESULTS:There were significant differences in fertilization rate, cleavage rate and salvage ICSI rate between the two groups (P<0.05), but there was no significant difference in the number of retrieved oocytes, the number of MII eggs and the rate of high quality embryos (P>0.05). CONCLUSION: Though patients with subclinical hypothyroidism received treatment to maintain TSH≤2.5 mIU/mL, they may still present lower fertilization rate, cleavage rate and higher rescue ICSI rate, hence drug maintenance is essential for subclinical hypothyroidism to maintain thyroid function.

    Effects of climen associated with goserelin on serum hormone levels of laparoscopic surgery in patients with endometriosis after laparoscopic hysterectomy
    GUI Hua, CAO Shanshan, ZHAO Qiaoyun, WANG Peihong
    2018, 23(5):  557-560.  doi:10.12092/j.issn.1009-2501.2018.05.013
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    AIM: To investigate the effects of climen associated with goserelin on serum hormone levels of laparoscopic surgery in patients with ectopic endometrium after laparoscopic hysterectomy.  METHODS: Eighty-one patients with endometriosis were divided into study group and control group. All patients were treated with laparoscopic surgery. The control group was given goserelin treatment after operation. The research group was given climen treatment based on the control group. The levels of E2, FSH, LH and CA125 were detected before and after treatment in the two groups. Adverse reactions were recorded in the two groups. The patients were followed up for 6 months after the treatment, and the pregnancy and recurrence of the two groups were recorded. RESULTS:The total effective rates of the two groups were compared. The difference was not statistically significant (P>0.05). After treatment, E2, FSH, LH, CA125 in two groups were significantly lower than those before treatment (P<0.05). After treatment, the levels of E2 and LH in the study group were significantly higher than those in the control group, and FSH was significantly lower than that in the control group. The difference was statistically significant (P<0.05). Comparison of CA125 in two groups after treatment, the difference was not statistically significant (P>0.05). The incidence of adverse reactions in the study group (9.76%) was significantly lower than that in the control group (27.50%). The difference was statistically significant (P<0.05). The recurrence rate and pregnancy rate of the study group were compared with those of the control group. The difference was not statistically significant (P>0.05). CONCLUSION: Climen associated with goserelin can significantly improve the levels of E2, LH in patients with endometriosis after laparoscopic surgery and reduce the occurrence of adverse reaction.

    Outcome of acute promyelocytic leukemia treated with low dose homoharringtonine, alltrans retinoic acid and arsenic trioxide
    CHEN Dong, LU Ying, PEI Renzhi, LOU Yinjun, WANG Jinghan, YE Peipei, ZHANG Pisheng, JIN Jie
    2018, 23(5):  561-569.  doi:10.12092/j.issn.1009-2501.2018.05.014
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    AIM: To investigate the complete remssion(CR),overall survival(OS),event free survival(EFS)and adverse events of newly diagnosised acute promyelocytic leukemia (APL) treated with low dose homoharringtonine(HHT), alltrans retinoic acid(ATRA) and arsenic trioxide(ATO), and to evaluate the efficacy treatment outcome by comparing HHT,ATRA and ATO with idarubicin(IDA), ATRA and ATO.  METHODS: A total of 145 cases (74 in HHT group, 71 in IDA group) of newly diagnosed acute promyelocytic leukemia from January 2004 to December 2013 in The First affiliated hospital of Zhejiang University School of Medicine and Yinzhou Hospital Affiliated to Ningbo University were analyzed, and were enrolled in the analyses of clinical feature, molecular biology,OS and EFS after long term follow up.RESULTS:The overall CR of 145 pations was 97.2%(141/145), the CR rate of  HTT group and IDA group was similar(98.6% vs. 95.7%,P=0.36). The interval to achieve hematological CR in two group was 32.89 and 33.3 days,the converting to PML/RARa PCR-negative from the induction therapy was 1.9 and 2.17 months respectively, similarly, there were no significant difference between the two groups (P=0.645 and 0.091, respectively). Four patients occurred early death (2.8%), 3 cases died of intracranial hemorrhage, 1 case died of respiratory distress (ARDS). With a median follow-up of 45.6 months, the two groups did not differ between the OS and EFS (P=0.9 and 0.093). A total of 13 patients relapse, including 5 cases of recurrence of molecular biology, the central nervous system relapse in 2 cases, there was no statistically significant difference of recurrence rates in the two groups (6.7% vs. 11.2%, P=0.342). And the risk group was not the factor affecting OS and EFS (P>0.05).While the incidence of hematology toxicity and grade 1 fever in HTT group were significantly lower than IDA group (P=0.003 and 0.037). And no difference was found in terms of liver dysfunction,renal dysfunction,cardiac dysfunction,and visceral bleeding, etc between two groups. CONCLUSION: Our study demonstrated comparable therapeutic effect of low dose HHT or IDA on APL,HHT was also well tolerated and had lower hematology toxicity and infection rate.

    Occurrence and clinical treatment of epilepsy associated with gene mutation in voltagegated sodium channel subtypes
    TAO Huai, XU Lujiadai, CHEN Xia
    2018, 23(5):  570-577.  doi:10.12092/j.issn.1009-2501.2018.05.015
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    Epilepsy is a common brain disease caused by abnormal discharge of brain neurons with a characteristic of short brain dysfunction. It can break out repeatedly, and has a serious influence on the health and quality of life of patients. Previous studies have found that voltagegated sodium channel subtypes (Nav1.1, Nav1.2, Nav1.3, Nav1.6, Nav1.7) expressed in the central nervous system play an important role in the pathogenesis of epilepsy, and they are targets for related antiepileptic drugs. The mutations in the encoding gene of αsubunit of these channels can cause different forms of epileptic seizures. This paper reviewed the occurrence and clinical treatment of epilepsy related with mutations in the five VGSC subtypes expressed in the central nervous system, providing basis for the studies on electrophysiology mechanism of occurrence and development of epilepsy and clinical treatment.

    Research progress in drug-induced acute kidney injury based on mitochondrial damage
    CAI Mingmin,YAO Lan,ZHANG Jingwei,ZHOU Fang,WANG Guangji
    2018, 23(5):  578-585.  doi:10.12092/j.issn.1009-2501.2018.05.016
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    Drug-induced kidney injury accounts for roughly 20% of acute kidney injury (AKI), which is likely to progress into chronic renal failure. Currently, there are no available strategies except renal replacement therapy for drug-induced AKI. Accumulating evidence highlights mitochondrial structure abnormal and dysfunction contribute greatly to the onset and progression of drug-induced AKI. This review covers the research progress on the role of mitochondrial damage in drug-induced AKI, and also proposes potential biomarkers and intervention targets, which will provide new ideas for early diagnosis and treatment of drug-induced AKI.

    Research progress of abnormally expressed lncRNAs in glioma
    GAO Yuanfeng, LI Shan, LIU Lin, OUYANG Rong
    2018, 23(5):  586-591.  doi:10.12092/j.issn.1009-2501.2018.05.017
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    With the development of whole genome and transcriptome sequencing technologies, a growing body of long noncoding RNAs (lncRNAs) has been identified. It showed that lncRNAs were important for the diagnosis, treatment and prognosis of glioma. At present, more than 20 abnormal expression lncRNAs have been identified that may play a role in glioma pathogenesis. In this paper, we reviewed those lncRNAs in glioma in hope of helping to identify potential biomarkers and improve the diagnosis and the treatment of glioma.

    Research progress in regulation of heart failure by β-adrenergic-receptor-PKA-AKAP signaling pathway
    HUANG Ting, WANG Hegui
    2018, 23(5):  592-596.  doi:10.12092/j.issn.1009-2501.2018.05.018
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    Heart failure is the final stage of the development of various cardiovascular diseases. Because of its high mortality rate and poor prognosis, it has become a major disease that endangers human life and health. In heart failure, the sympathetic system is activated and the catecholamines stimulate β-adrenergic receptor (β-AR) to increase cardiac output via Gs-AC-cAMP-PKA signaling pathway, which is beneficial in the acute phase, but chronic β-ARs stimulation eventually leads to a diminished contractile performance of the heart. A-kinase anchoring protein (AKAP) plays an important role in this pathological process, which regulates signaling pathways by anchoring PKA in specific subcellular locations. β-blockers are widely used in the treatment of heart failure, but also have a range of side effects.Therefore, novel and more targeted therapeutic treatments are needed to improve treatment of HF in the future.

    Research progress on the mechanism of traditional Chinese insects' medicine treatment of diabetic neurological complications
    XU Ming, SHEN Zheng
    2018, 23(5):  597-600.  doi:10.12092/j.issn.1009-2501.2018.05.019
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    The therapeutic effect of traditional Chinese insects' medicine treatment for diabetic neurological complications is clear,and fruitful achievements in the study of mechanism of pharmacology have been down in recent years,including metabolism,immunity,and gene level.In this paper,the traditional Chinese insects' medicine treatment of diabetic neurological complications was summarized for the further study of traditional Chinese medicine targets.