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Journal of International Pharmaceutical Research

1958  to  Present  ISSN: 1674-0440

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Leucine-rich repeat kinase 2 inhibitor as Parkinson′s disease novel therapeutics:research advances

Xiaoyu ZHAN ; Xuhong REN ; Xinhua HE

Journal of International Pharmaceutical Research.2016;(1):97-103,133. doi:10.13220/j.cnki.jipr.2016.01.014

Parkinson′s disease(PD)is a common disease caused by multiple factors and characterized by pathological degen?eration in the dopaminergic neural system. Based on its pathogenic factors,PD can be divided into several subtypes,so it is essential to develop therapeutic agents based on the main pathogenic factor of each subtype of PD. Recently it is confirmed that the mutation of leucine-rich repeat kinase 2(LRRK2)gene leads to increased activity of the LRRK2 notably,and then causes neurodegeneration. Thus developing LRRK2 inhibitors to modulate the kinase activity will be a novel therapy for the PD subtype which is caused by LRRK2 gene mutation. LRRK2,either a kinase or a GTPase,has two drug binding sites. Therefore,two types of LRRK2 inhibitors are being studied,one is the kinase inhibitor and the other is GTPase inhibitor. This paper summarizes the recent progress in the dis?covery and development of LRRK2 inhibitors.

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Gut microbiota and Alzheimer′s disease

Tongju LI ; Yang ZHAO ; Guoming DONG ; Dexian JIA ; Baiping MA

Journal of International Pharmaceutical Research.2016;(1):15-19,32. doi:10.13220/j.cnki.jipr.2016.01.003

Gut microbiota(GM)consists of a complex community of microorganism species that live in the digestive tracts of animals including humans. Dysbiosis is believed to involve in the development of some diseases. Recently dysbiosis in the patients with Alzheimer′s disease(AD)and AD rat models was reported. GM may influence the pathogenesis and development of AD in several ways. Some neurotoxic substances produced by GM can invade into the brain via circulation and impair the neural functions. These sub?stances include ammonia,cyanobacteria-producedβ-N-methylamino-L-alanine,saxitoxin,anatoxin-αand amyloid. The decrease in brain-derived neurotrophic factor(BDNF)in hippocampus and cerebral cortex induced by dysbiosis contributes to the cognitive dys?function. Dysbiosis related endotoxin can induce inflammation,which is one important risk factor for obesity,insulin resistance(IR) and type 2 diabetes mellitus(TIDM). AD and diabetes have good correlation and similarity. Probiotics,prebiotics and Chinese herbal medicines can rebuild GM and have been reported to ameliorate the memory loss of AD patients or model rats. However ,whether and how their preventative and therapeutic effects on AD mediated by GM are worthy of further investigation.

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Protective effect of Ento-Ⅰplastic against cerebral ischemia-reperfusion injury in rats

Fanmao JIN ; Zhixue ZHANG ; Yin WANG ; Hairong ZHAO ; Youyun YANG ; Xi HUANG ; Chenggui ZHANG

Journal of International Pharmaceutical Research.2016;43(3):504-508,528. doi:10.13220/j.cnki.jipr.2016.03.019

Objective To research the protective effect of Ento-Ⅰagainst cerebral ischemia-reperfusion injury in rats,and to evaluate its analgesic and anticoagulating effects in mice. Methods The ischemic model was established with line embolism to block the middle cerebral artery of male rats. The 56 rats were randomly assigned into 7 groups of sham-operation,blank-matrix,nor?
mal saline,Ento-Ⅰplastic of 3 doses(6.67,3.33,1.67 mg/kg),and ozagrel sodium(8.3 mg/kg,ip). The effect of Ento-Ⅰplastic on anti-cerebral ischemia was measured by nervous function scores and the areas of cerebral infarction were determined by TTC staining for the calculation of cerebral infarction rates. The analgesic effect of Ento-Ⅰplastic was determined with acetic acid-induced twisting experiment. Sixty KM mice were randomly allocated into blank-matrix,aspirin,aspirin-plastic,and Ento-Ⅰplastic of 3 doses(5,10 and 20 mg/kg),the number of mouse twisting were recorded right after intraperitoneal injection of 0.7%acetic acid solution at the time of 1 h after the last administration. Moreover,the anticoagulant activity of Ento-Ⅰplastic was tested by glass capillary method. Re?sults The results of acetic acid-induced twisting experiment displayed that Ento-Ⅰplastic of all 3 dose groups(5,10 and 20 mg/kg) could significantly reduce the number of body torsion and increase the inhibitory rates of twisting,compared with that of blank matrix group(the inhibitory rates of twisting for 3 dose groups were 21.79%,48.89%,and 56.15%,respectively),with dose-response man?ner. According to the results of glass capillary test,the clotting time of mouse blood could be significantly prolonged by mid-(10 mg/kg)and low-dose(5 mg/kg)of Ento-Ⅰplastic with corresponding clotting time of(155.20±54.19)s and(155.80±73.84)s,compared with normal saline group at(92.10 ± 24.61)and blank-matrix group at(80.40 ± 48.09,P<0.05). The experiment results of the isch?emia-reperfusion injury by line embolism method in rats exhibited that Ento-Ⅰplastic in mid-dose(3.33 mg/kg)could significantly re?duce the neurological scores after 24 h of reperfusion injury,from(2.33 ± 0.52)of normal saline group to(1.00 ± 0.00)of mid-dose group(P<0.01). The results from TTC staining revealed that the cerebral infarction rates of normal saline group and blank-matrix group were(24.89±7.24)%and(27.72±7.89)%,respectively,whereas those of 6.67 mg/kg and 3.33 mg/kg group of Ento-Ⅰplastic were(14.01±2.65)%and(14.73±4.94)%,respectively. Compared to the 2 negative-control groups,both the high-and mid-dose of Ento-Ⅰplastic could significantly reduce the cerebral infarction rates after ischemic reperfusion injury in rats (P<0.01). Conclu?sion Ento-Ⅰplastic demonstrates strong analgesic and anticoagulant effects,and could substantially reduce the neurological scores and reduce cerebral infarction rates for ischemia-reperfusion injured rats. These are likely to be the mechanism of action for Ento-Ⅰplastic realizing its anti-cerebral ischemia effect.

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Progress in the application of metabonomics technology in toxicology research

Xianzhong YAN ; Bo SUN ; Xiangbo DU

Journal of International Pharmaceutical Research.2014;(4):379-392,399. doi:10.13220/j.cnki.jipr.2014.04.001

Metabonomics is a new member in the omics field following the development of genomics, transcriptomics and proteomics, with its research object being the collection of metabolites-metabolome, the downstream products of life. Even with the development of past decade, there are still many problems to be solved in the area of experimental techniques, data analysis and results annotation. Any xenobiotics would cause the disturbance of homeostasis of organisms, resulting in the changes of metabolites. Consequently, toxicology is one of the major application areas of metabolomics, and is the earliest one. Metabolomics has been widely used in the early toxicological screening of leads, preclinical and clinical toxicology of drugs in animals and human, as well as in surrogate models such as cell lines and zebrafish. Annotation techniques for metabolic data have also been developed. In this paper, the development of metabolomic techniques and its application in toxicology are reviewed.

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Preventive effect of Senecio cannabifolius Less.Ⅱon perfluoroisobutylene inhalation-induced acute lung injury in rats

Jiadan SUN ; Xiaobo WANG ; Shuang JIANG ; Ronggang XI ; Ye TIAN

Journal of International Pharmaceutical Research.2014;(4):444-448,472. doi:10.13220/j.cnki.jipr2014.04.011

Objective To preliminarily investigate the effect and possible mechanisms of Senecio cannabifolius Less.Ⅱ(FHC-Ⅱ) on perfluoroisobutylene (PFIB) inhalation-induced acute lung injury. Methods Totally 156 rats were randomly assigned to three groups: the control group, the PFIB group and the FHC-Ⅱ prevention group, with 32, 62 and 62 rats in each group respectively. The FHC-Ⅱprevention group were given FHC-Ⅱthree times per day at the dosage of 340 mg/kg before PFIB exposure. 1 h after the last time of FHC-Ⅱ administration, the FHC-Ⅱ prevention group were exposured to gaseous PFIB (0.2 mg/L) for 10 minutes in a static whole-body exposure inhalation system. The survival rate of the rats were recorded at 1, 2, 4, 8, 16, 24, 48 and 72 h post PFIB exposure;the lung index and total protein content in bronchoalveolar lavage fluid (BALF) were measured at 1 h, 2 h, 4 h, 8 h, 16 h and 24 h; IL-1β and IL-8 in sera were assayed by enzyme-linked immunosorbent assay (ELISA) at 1, 2, 4, 8 and 16 h post PFIB exposure and the histopathological examination of the lung tissue was performed at 8 h post PFIB exposure. Results FHC-II significantly reduced the content of the total protein in BALF, lung index and the levels of IL-1β and IL-8 in aera as well, and dramatically alleviated the histopathological changes in the lung tissue. Conclusion FHC-Ⅱ demonstrates some preventive effect on PFIB inhalation-induced acute lung injury in rats.

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Change in expression of interleukin-17 in C57 mice′s spinal cord injury area

Shiyuan DENG ; Zhuoqiang WANG ; Zhen XU ; Chao MA

Journal of International Pharmaceutical Research.2014;(6):698-702,706. doi:10.13220/j.cnki.jipr.2014.06.016

Objective To investigate the mechanism of expression of interlenkin (IL)-17 in C57 mice′s spinal cord clamp area,and to provide new targets for clinical treatment of spinal cord injury (SCI). Methods Male C57BL/6 mice were randomly divided into three groups. In the spinal cord injury group,mice were made into spinal cord clamp model. In the sham surgery group, the dura was cut without injuring the spinal cord. The IL-17 neutralizing antibody group received IL-17 neutralizing antibody injection through the cadual vein at 1 hour after the spinal cord clamp . Mouse scale for locomotion (BMS)was applied to evaluate the mice's behavior change of hindlimb in 1-7 days,the real time fluorescent quantitative PCR was used to detect the change in the expression of spinal cord injury district TNF-αmRNA each time,HE staining was conducted to detect the morphological changes of spinal cord injury of the sham surgery group,the spinal cord injury group and the IL-17 neutralizing antibody group at the 7th days. Results After spinal cord injury,the mice's BMS score were 9 in the sham surgery group;in the model of spinal cord injury group,the mice's BMS score were 0 on the 1st day,and 2.9 on the 7th day. In the IL-17 neutralizing antibody group,the mice's BMS score were 0 on the 1st day,and 3.5 on the 7th day. The expression of IL-17 mRNA in the injury area peaked at the 3rd hour,which showed statistical difference when compared with sham surgery group (P<0.05),and then decreased. In other times,it had no statistical difference when compared with sham surgery group (P>0.05),and the expression of IL-17 mRNA reduced the lowest levels on the 7th day. The 7th day following spinal cord injury,mice's spinal cord tissue was complete normal in the sham surgery group. In the spinal cord injury group,a large number of mice's nerve cells were necrotic, a lot of cells formed vacuolated. In the IL-17 neutralizing antibody group, part of mice's nuclear neurons were shrinking, cells formed vacuolated, but part of cells remained morphologically complete. Conclusion IL-17 is involved in secondary immune inflammatory process of spinal cord injury, it may be targets for intervention in the treatment of spinal cord injury.

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Complement system and tumor:research progress Complement system and tumor:research progress

Chang NING ; Wenwei CHEN ; Yan LI ; Guojiang CHEN

Journal of International Pharmaceutical Research.2014;(5):516-520,521. doi:10.13220/j.cnki.jipr.2014.05.002

Complement system is an important component of innate immunity and has been recognized as an effective means to inhibit tumor. However,in last decades,accumulating studies showed unexpected results that the complement components and their activation products could promote development of malignancies by secreting growth factors,activating signal pathway and promoting tumor angiogenesis. Herein,the relationship between the complement system and tumor is reviewed.

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Simultaneous determination of five furostanol saponins in rhizome and fibrous root of Anemarrhena asphodeloides Bge. by HPLC-CAD

Fengxia MA ; Xinguang SUN ; Jie ZHANG ; Zhen LONG ; Yang ZHAO ; Chunni ZHANG ; Fangxu WANG ; Shuchen LIU ; Baiping MA

Journal of International Pharmaceutical Research.2017;44(6):642-646. doi:10.13220/j.cnki.jipr.2017.06.033

Objective To develop a method for the determination of five furostanol saponins(timosaponin N,timosaponin L, timosaponin BⅡ,25R-timosaponin BⅡ,and 25S-officinalisnin-Ⅰ)in rhizome and fibrous root of Anemarrhena asphodeloides Bge. by HPLC with the charged aerosol detector(CAD). Methods The analysis was performed on TechMate C18-ST-II(250 mm×4.6 mm,5μm)with acetonitrile:water(22:78,V/V),the flow rate of 1.0 ml/min and column temperature at 30℃. The Corona parameters were as follows:sampling rate 10 Hz,filter 5 s,and the nebulizer temperature 55℃. Results The approach showed good linearity for five saponins. The correlation coefficients(r2)for calibration curves varied from 0.9992 to 0.9998. The limits of detection(LOD)were 0.28,0.92,0.92,0.92 and 0.92 ng for five steroidal saponins,respectively. The limits of quantitation(LOQ)were found to be 0.92, 2.77,2.77,2.77 and 2.76 ng,respectively. RSD calculated from peak area of precision,repeatability and stability in 48 h were all less than 3.0%. The average recoveries of timosaponin N,timosaponin L,timosaponin BⅡ,25R-timosaponinBⅡ,and 25S-officinalis-nin-Ⅰwere 98.17%,101.37%,98.53%,97.63%,and 98.17%,respectively. Conclusion The developed method is accurate,reli-able,which could be applied to the quality control of multiple components in A. asphodeloides Bge.

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Lignan constituents and activities of Linum usitatissimum L. above ground

Xiang CHEN ; Jingming JIA ; Yu YANG ; Nengjiang YU

Journal of International Pharmaceutical Research.2017;44(6):590-594. doi:10.13220/j.cnki.jipr.2017.06.023

Objective To investigate the chemical constituents and activities of Linum usitatissimum L.aboveground. Meth-ods The chemical constituents were separated through silica gel,ODS,Sephadex LH-20,and semi-preparative RP-HPLC chroma-tography and identified by optical rotation and spectroscopic analysis. All of the isolates were evaluated for their inhibitory activities by the luciferase assay. Results Eight dibenzylbutyrolactone lignans were separated from L. usitatissimum and identified as(-)-hinoki-nin(1),(-)-bursehernin(2),(-)-dimethylmatairesinol(3),(-)-yatein(4),(-)-thujaplicatin trimethyl ether(5),nemerosin (6),(+)-E-7,8-dehydromatairesinol dimethyl ether(7),and E-7,8-dehydrothujaplicatin trimethyl ether(8),respectively. Conclu-sion Compounds 7 and 8 were isolated from L. usitatissimum for the first time,and NMR spectral data of compound 8 were reported for the first time. Compounds 1 and 3 showed moderate inhibitory activities on IL-6/STAT3 signaling pathway with IC50 values of 42.12 and 43.43μmol/L,respectively.

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Hemin-air,an efficient catalytic-oxidation system for disulfide formation in linaclotide synthesis

Weiwei GE ; Jing CHEN ; Ye ZHANG ; Liang ZONG ; Ming ZHANG ; Junjun DONG

Journal of International Pharmaceutical Research.2017;44(6):585-589. doi:10.13220/j.cnki.jipr.2017.06.022

Objective To use hemin as a catalyst in the formation of disulfide bonds in the synthesis of linaclotide. Methods The linaclotide peptide was synthesized by the standard 9-fluorenylmethyl(Fmoc)solid-phase synthetic strategy. Wang resin and Trt-protected cysteine were used in the synthesis. Hemin was used in random oxidation of line linaclotide. The result was compared with those of air,dimethyl sulfoxide(DMSO),and I2 oxidation systems. Results and Conclusion Hemin is a highly effective catalyst for disulfide bond formation in linaclotide synthesis. It overcomes some disadvantages in oxidation reactions with conventional oxidative re-agents,and supplies a convenient way for the synthesis of peptide with concentrated disulfide bonds.

Country

China

Publisher

ElectronicLinks

http://gjyxyjzz.juqk.net/

Editor-in-chief

E-mail

guol@nic.bmi.ac.cn

Abbreviation

Journal of International Pharmaceutical Research

Vernacular Journal Title

国际药学研究杂志

ISSN

1674-0440

EISSN

Year Approved

2013

Current Indexing Status

Suspended(2024)

Start Year

1958

Description

1958-1960:药学文摘; 1963:医学文摘第三分册(药学); 1966-1973:停刊; 1974-1978:国外医学参考资料·药学分册; 1979-2006:国外医学·药学分册; 2007-:国际药学研究杂志

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