Intelligent nanotherapeutic strategies for the delivery of CRISPR system

CRISPR, as an emerging gene editing technology, has been widely used in multiple fields due to its convenient operation, less cost, high efficiency and precision. This robust and effective device has revolutionized the development of biomedical research at an unexpected speed in recent years. The development of intelligent and precise CRISPR delivery strategies in a controllable and safe manner is the prerequisite for translational clinical medicine in gene therapy field. In this review, the therapeutic application of CRISPR delivery and the translational potential of gene editing was firstly discussed. Critical obstacles for the delivery of CRISPR system in vivo and shortcomings of CRISPR system itself were also analyzed. Given that intelligent nanoparticles have demonstrated great potential on the delivery of CRISPR system, here we mainly focused on stimuli-responsive nanocarriers. We also summarized various strategies for CIRSPR-Cas9 system delivered by intelligent nanocarriers which would respond to different endogenous and exogenous signal stimulus. Moreover, new genome editors mediated by nanotherapeutic vectors for gene therapy were also discussed. Finally, we discussed future prospects of genome editing for existing nanocarriers in clinical settings.

Species distribution and antifungal susceptibility of fungi originating from positive blood cultures in Guangdong, 2019-2021 / 中国热带医学

@#Abstract: Objective　To investigate the species distribution and the antifungal susceptibility of fungi originating from positive blood cultures in Guangdong, so as to provide a basis for the rational use of antifungal drugs in clinical fungal bloodstream infections. Methods All data were collected for retrospective study from monitoring units of the Guangdong Fungal Disease Surveillance Network between 2019-2021, including clinical characteristics, species distribution and antifungal susceptibility. Results A total of 3 589 fungi strains were isolated, most of which were Candida spp. (86.5%, 3 105/3 589). The most common species was Candida albicans (36.6%, 1 315/3 589), followed by Candida tropicalis (17.4%, 1 626/3 589) and Candida parapsilosis (14.5%, 520/3 589). There were 42.1%(1 512/3 589) of strains isolated from ICU. The proportions of Candida albicans strains were 40.0%-50.0% among ICU, general surgery, organ transplantation and emergency department. Candida tropicalis (60.0%, 144/240) was the most common species in hematology department. Both Cryptococcus neoformans (35.4%, 69/195) and Talaromyces marneffei (35.9%,70/195) were common in infection department. All of the Candida isolates were of wild-type (WT) phenotype to amphotericin B. Resistance rates of caspofungin and micafungin for Candida spp. ranged from 0.0% to 4.2%. The resistance rates of Candida tropicalis to fluconazole and voriconazole were 42.3% and 38.9%, which were significantly higher than other common Candida spp. The cryptococcus neoformans strains were totally of WT phenotype to fluconazole and voriconazole. Conclusions Candida albicans is the most common species originating from positive blood cultures in Guangdong Province. Common Candida strains are highly sensitive to echinocandins and amphotericin B. Candida tropicalis has a high resistance rate to triazole drugs.

Short needling for knee osteoarthritis with blood stasis obstruction and its effect on serum inflammatory factors / 中国针灸

OBJECTIVE@#To compare the clinical efficacy and its effect on serum levels of tumor necrosis factor α(TNF-α), interleukin 1β(IL-1β), interleukin 6 (IL-6) and prostaglandin E2 (PGE2) between short needling (close-to-bone needling) and conventional acupuncture for knee osteoarthritis (KOA) with blood stasis obstruction.@*METHODS@#A total of 68 KOA patients with blood stasis obstruction were randomized into a short needling group (34 cases, 3 cases dropped off) and a conventional acupuncture group (34 cases, 3 cases dropped off). The same acupoints (Dubi [ST 35], Neixiyan [EX-LE 4], Binzhong [Extra], Liangqiu [ST 34], etc. on the affected side) were selected in the two groups. In the short needling group, short needling technique was adopted, the needles were slowly inserted and the needle bodies were shaken, thus gradually penetrated to the bone. In the conventional acupuncture group, conventional acupuncture was adopted, the needles were penetrated to the muscle. After qi-arrival, Dubi (ST 35) and Neixiyan (EX-LE 4), Zusanli (ST 36) and Liangqiu (ST 34) were connected with CMNS6-1 electronic acupuncture instrument, with disperse-dense wave, 2 Hz/10 Hz in frequency, the current intensity was based on patients' feeling, the needles were retained for 30 min, at the same time, the knee joint was irradiated for 30 min with a special electromagnetic wave apparatus in the two groups. Once every other day, 3 times a week for 4 weeks. Before and after treatment, the Western Ontario and McMaster Universities osteoarthritis index (WOMAC) score, knee joint pain visual analogue scale (VAS) score, inflammatory response related indexes (serum TNF-a, IL-1β, IL-6 and PGE2) and knee joint ultrasound were observed，and the clinical effect was evaluated in the two groups.@*RESULTS@#After treatment，the pain, stiffness, function scores and total scores of WOMAC were decreased as compared with those before treatment in the two groups (P<0.05), except for the pain score, the changes of above scores in the short needling group were greater than the conventional acupuncture group (P<0.05). After treatment, the VAS scores, serum levels of TNF-a, IL-1β, IL-6, PGE2 and knee joint synovium thickness, intra-articular effusion were decreased as compared with those before treatment in the two groups (P<0.05), the levels of TNF-a, IL-1β, IL-6 in the short needling group were lower than the conventional acupuncture group (P<0.05). The total effective rate in the short needling group was 87.1% (27/31), which was superior to 83.9% (26/31) in the conventional acupuncture group (P<0.05).@*CONCLUSION@#Short needling could improve the knee joint function, relieve the pain and inflammatory response, improve the knee joint synovium inflammatory response, reduce the knee joint intra-articular effusion for KOA patients, its effect is better than conventional acupuncture.

Therapeutic prospect of tetrandrine against SARS-CoV-2 based on its pulmonary pharmacology and exposure character / 药学学报

As the main active compound of Stephania tetrandra S. Moore, tetrandrine (TET) has been used to treat silicosis for nearly 50 years. TET has clear therapeutic effect on pulmonary fibrosis and lung cancer. A recent study suggests that TET may inhibit the replication of SARS-CoV-2 by blocking the two-pore channel 2 (TPC2), revealing its potential as a natural medicine to treat COVID-19. To explore the material basis of TET targeting lung efficacy and its potential toxicity, available literatures related to the pharmacological activity on pulmonary, dosage, toxicity and pharmacokinetics of TET are systemically reviewed. The prospect and current problems of TET to be a therapeutic agent for COVID-19 are further investigated on this basis.

A modified beagle model of inducible atrial fibrillation using a right atrium pacemaker

Abstract Objective: To modify the chronic atrial fibrillation of atrial tachycardia pacing in beagles with a homemade pacemaker placed outside the body and to evaluate connective tissue growth factor and fibrosis of atrial tissue in our modified atrial tachycardia pacing beagle model. Methods: Twelve adult beagles of either sex were randomly divided into an atrial tachycardia pacing group and a control group (n=6 in each group). We performed the temporary pacemaker implantation at the right atrial appendage and put the pacemaker into the pocket of dog clothing in the atrial tachycardia pacing group. After eight weeks of atrial tachycardia pacing, the electrocardiography, transthoracic echocardiography, hematoxylin-eosin staining, and Masson's staining of the right atrial appendages were performed along with the immunohistochemistry, quantitative real-time polymerase chain reaction, and Western blot analysis of connective tissue growth factor, collagen I, and collagen III. Results: In the atrial tachycardia pacing group, atrial fibrillation was induced in five beagles (83.3%); the left atrium enlarged significantly; more canines had mitral regurgitation; and the Masson's staining, quantitative real-time polymerase chain reaction, and Western blot results demonstrated more obvious fibrosis of the left atrium. Conclusion: The modified beagle model of atrial fibrillation using a right atrium pacemaker outside the body was effective, increased connective tissue growth factor and collagen I messenger ribonucleic acid overexpression, and induced atrial fibrosis.

Experimental study on radiation damage of125I seeds implanted in canine gastric wall tissue

Objective: The objective of the study was to investigate the radiation damage to125 I seeds implanted in canine gastric wall tissue. Materials and Methods: Eight beagles were randomly assigned to either the treatment or control group, with four beagles per group. For each beagle in the treatment group, six125 I seeds were implanted in the gastric wall in two rows, spaced at 1.0 cm, with a seed activity of 0.5 mCi and a half-life of 60.2 d. For each beagle in the control group, six 125 I seeds were similarly implanted as a cold source. After implantation, the beagles were scanned by computed tomography (CT) (slice thickness: 2 mm), the region of interest was labeled along the seed boundaries, and postoperative doses were verified. One beagle per group was sacrificed at the 1, 2, 3, and 4 half-lives to be used as gross specimens for observing histological and ultrastructural changes using light microscopy and electron microscopy, respectively. Results: Beagles from the treatment group who had125 I radioactive seeds implanted in their stomach walls had the most radiation damage after two half-lives, damage repair began after three half-lives, and the damage was stabilized and further repaired after four half-lives. In the control group, only mild inflammatory reactions were observed around the seeds. Conclusion: Appropriate and well-planned implantation of125 I radioactive seeds in beagle stomach walls is safe and reliable

Novel small molecule retrograde transport blocker confers post-exposure protection against ricin intoxication

Ricin is a highly toxic type 2 ribosome-inactivating protein (RIP) which is extracted from the seeds of castor beans. Ricin is considered a potential bioterror agent and no effective antidote for ricin exists so far. In this study, by structural modification of a retrograde transport blocker Retro-2, a series of novel compounds were obtained. The primary screen revealed that compound has an improved anti-ricin activity compare to positive control. pre-exposure evaluation in Madin-Darby Canine Kidney (MDCK) cells demonstrated that is a powerful anti-ricin compound with an EC of 41.05 nmol/L against one LC (lethal concentration, 5.56 ng/mL) of ricin. Further studies surprisingly indicated that confers post-exposure activity against ricin intoxication. An study showed that 1 h post-exposure administration of can improve the survival rate as well as delay the death of ricin-intoxicated mice. A drug combination of with monoclonal antibody mAb4C13 rescued mice from one LD (lethal dose) ricin challenge and the survival rate of tested animals is 100%. These results represent, for the first time, indication that small molecule retrograde transport blocker confers both and post-exposure protection against ricin and therefore provides a promising candidate for the development of anti-ricin medicines.

Histone deacetylase: a potential target for the treatment of atrial fibrillation / 中国胸心血管外科临床杂志

@#Atrial fibrillation is a common arrhythmia associated with high mortality and morbidity, and the current treatment of atrial fibrillation is still limited. Histone deacetylase (HDAC) plays an important role in the pathophysiology of cardiovascular disease and promotes the occurrence of atrial fibrillation. Inhibition of HDAC may be a new therapeutic strategy through the regulation of atrial remodeling. Therefore, we reviewed the research progress of the HDAC and atrial fibrillation.

Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods

SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths. There are currently no registered therapies for treating coronavirus infections. Because of time consuming process of new drug development, drug repositioning may be the only solution to the epidemic of sudden infectious diseases. We systematically analyzed all the proteins encoded by SARS-CoV-2 genes, compared them with proteins from other coronaviruses, predicted their structures, and built 19 structures that could be done by homology modeling. By performing target-based virtual ligand screening, a total of 21 targets (including two human targets) were screened against compound libraries including ZINC drug database and our own database of natural products. Structure and screening results of important targets such as 3-chymotrypsin-like protease (3CLpro), Spike, RNA-dependent RNA polymerase (RdRp), and papain like protease (PLpro) were discussed in detail. In addition, a database of 78 commonly used anti-viral drugs including those currently on the market and undergoing clinical trials for SARS-CoV-2 was constructed. Possible targets of these compounds and potential drugs acting on a certain target were predicted. This study will provide new lead compounds and targets for further and studies of SARS-CoV-2, new insights for those drugs currently ongoing clinical studies, and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections.

Safety of the removal of pericardial and mediastinal drain within a different drainage volume after cardiac valvular replacement surgery: A case control study / 中国胸心血管外科临床杂志

@#Objective To assess the safety of the removal of pericardial and mediastinal drain within different drainage volume after cardiac valvular replacement surgery. Methods Between July 2013 and July 2017, 201 patients with rheumatic heart disease (CHD) were treated with valve replacement in our hospital, including 57 males and 144 females, aged 15 to 72 years. They were divided into two groups according to the amount of 24-h drainage before the drain removal: a group one with 24-h drainage volume≤50 ml (n=127) and a group two with 24-h drainage volume>50 ml (n=74). The postoperative hospital stay and the incidence of severe complications between the two groups were compared. Results There was no difference between the two groups in the baseline information or the incidence of severe pericardial effusion and tamponade, while the group two tended to have a shorter length of hospital stay after surgery (8.0 dvs.7.5 d, P=0.013). Conclusion In CHD patients undergoing valvular surgery, compared with a relatively low amount of drainage before the drain removal, drawing the tube at a greater amount of drainage (24-h drainage volume>50 ml) will shorten the length of hospital stay after cardiac surgery while incidence of severe complications remains the same.

Research progress of new anti-influenza drugs / 中华实用儿科临床杂志

Influenza virus,as the root cause of public health problems,is mainly transmitted by aerosols with high infectivity and high mortality,which seriously endangers human health.Moreover,influenza viruses mutate rapidly,and existing drugs are constantly appearing resistant,it is urgent to develop new anti-influenza drugs.Now,the anti-influenza drugs with different targets from the 2 aspects of viral targets and host targets are introduces,and focus on the research progress of new anti-influenza drugs.

Establishment and application of animal infection model of Zika virus / 国际药学研究杂志

Zika virus (ZIKV) is closely related to severe neurological diseases such as neonatal microcephaly and GuillainBarre syndrome. As a new emergent infectious disease, the investigation on animal infection model of ZIKV has become a research hotspot. Establishment of animal infection models, an indispensable phase in drug and vaccine research and development, is of great significance to the study of viral pathogenesis and pathogen-host interaction. Based on the different diseases and adverse outcomes caused by the ZIKV infection, this paper reviews the current animal infection models of ZIKV and their applications in medical research, focusing on the lethal infection model, nervous system damage model and reproductive system damage model.

Synthesis and optical characteristics of near infrared-Ⅱ fluorescent molecule CH1055 / 国际药学研究杂志

Objective To optimize the synthetic method for the fluorescent molecule CH1055 and perform a preliminary study on its water solubility and optical properties. Methods Starting from triphenylamine and benzothiadiazole, the desired products were synthesized via a series of reactions, such as Vilsmeier-Haack reaction, acylation, catalytic hydrogenation, bromination, condensation, silylation protection, Suzuki coupling, nitrification and reduction. The structures of the intermediates and targeted compound were confirmed by MS and1 H NMR. At the same time, the key reaction steps were optimized, and the solubility and optical properties of CH1055 were investigated both in vitro and in vivo. Results After improvement of the synthetic method, the total yield increased from 9.13％ in the literature to 12.1％ in the present study. The PEGylated product improved water solubility by about 300 times. At the wavelength of 750 nm long excitation light, CH1055 had better imaging characteristics than the traditional Cy5.5. Conclusion The present method for the CH1055 synthesis has appeared to be cheaper in cost, easy to operate, and higher in yield. After PEGylation modification, the water solubility of the target compound was greatly improved, which was highly advantageous to the development of a water-soluble NIR-Ⅱ fluorescent molecule. CH1055 showed excellent imaging properties in the long wavelength range, which implicated a new potential application of the fluorescent molecule.

Efficacy analysis of three-dimensional and two-dimensional laparoscopic repairs of gastroduodenal perforation / 中华消化外科杂志

Objective To compare the clinical efficacy of three-dimensional (3D) and two-dimensional (2D) laparoscopic repairs of gastroduodenal perforation.Methods The retrospective cohort study was conducted.The clinicopathological data of 92 patients who underwent laparoscppic repair of gastroduodenal perforation from July 2014 to December 2017 in the Ganzhou People's Hospital were collected.Forty-four patients undergoing 3D laparoscopic repair and 48 patients undergoing 2D laparoscopic repair were respectively allocated into the 3D and 2D groups.Observation indicators:(1) comparisons of intra-and post-operative recovery;(2) postoperative drug sensitivity test and pathological examination;(3) follow-up.Follow-up using outpatient examination and telephone interview was performed to detect complications after discharging from hospital up to August 2018.Measurement data with normal distribution were represented as x-±s and comparison between groups was analyzed using t test.Measurement data with skewed distribution were described as M (range).Comparison between groups of count data was analyzed using the chi-square test.Results (1) Comparison of intra-and post-operative recovery:92 patients underwent successfully laparoscopic gastroduodenal perforation,without conversion to open surgery or perioperative death.The operation time,time of pathological tissue extract at the perforation,time of perforation repair,volume of intraoperative blood loss and time of initial anal exsufflation were respectively (60± 8)minutes,(36± 6) seconds,(137±12)seconds,(9.0±2.2)mL,(23.8±2.8)hours in the 3D group and (70±9)minutes,(39±6) seconds,(143±14) seconds,(10.3±2.5) mL,(25.9±4.8) hours in the 2D group,with statistically significant differences between groups (t =5.795,2.779,2.215,7.740,2.570,P＜0.05).Three patients in the 3D group were complicated with pulmonary infection,localized atelectasis and delirium.Two patients in the 2D group were complicated with pulmonary infection and heart failure.Patients with complications between groups were improved by symptomatic and supporting treatment.There was no statistically significant difference in cases with postoperative complications between groups (x2 =0.010,P＞ 0.05).(2) Postoperative drug sensitivity test and pathological examination:the ascites culture of peritoneal effusion in the 2 groups was positive,and drug susceptibility results were obtained.No malignant cells at the perforation were found in pathological examination.(3) Follow-up:84 patients were followed up for 1-12 months,with a median time of 3 months.There was no related complication after discharging from hospital.Conclusion Compared with 2D laparoscopic repair of gastroduodenal perforation,3D laparoscopic repair of gastroduodenal perforation not only is safe and feasible,but also has advantages of shorter operation time,perforation repair time and time of pathological tissue extract at the perforation,less volume of intraoperative blood loss and shorter time of initial anal exsufflation.

Anti-Zika virus:research advances / 国际药学研究杂志

Zika virus(ZIKV)is an arbovirus transmitted mainly through Aedes aegypti,which is associated with adult Guil-lain-Barré syndrome and microcephaly,as well as other neurological deficits in the neonate.On Feb.1,2016,the outbreak of ZIKV disease was regarded as an international public health emergency by WHO,and anti-ZIKV has become a worldwide medical chal-lenge.There are currently no vaccines and specific antiviral therapeutics available for ZIKV.In this paper,the possible pathogenesis of ZIKV and the new progress in the treatment drugs are reviewed.

Syntheses of dimorpholine benzothiazole-phenylurea selective PI3Kβ inhibitors / 国际药学研究杂志

Objective To investigate and optimize the syntheses of dimorpholine benzothiazole-phenylurea selective PI3Kβinhibitors. Methods With 2,4,6-three bromine aniline as the raw material,all the target compounds were prepared through thiophos?gene,cyclization,Buchwald-Hartwig cross coupling reaction and Suzuki coupling. The structures of intermediates and target com?pounds were characterized by MS and 1H NMR spectra. Results Six derivatives were synthesized. Compared with the method report?ed in the literature,the total yield of this new synthesis method increased from 16.2%to 26.9%. Conclusion The raw materials of op?timized synthesis method are cheap and easy to obtain,and the reaction operation steps are simplified. The post-processing process avoids steps of column chromatography and improves the experimental efficiency.

Ricin and its antidote agents:research advances / 国际药学研究杂志

Ricin is a highly toxic plant protein produced by the seeds of the castor plant. It belongs to the ribosome inactivat-ing proteins(RIP)family and causes cell death by inhibiting the protein synthesis activity of ribosome. Ricin takes a unique pathway calledretrograde trafficking pathwayto enter the cytosol,where it interacts with ribosome and then exerts its inhibitory activity. No effective antidote agents have been developed for the treatment of ricin poisoning. In this paper,the structure,cell trafficking process, toxicological mechanism and the research progress in ricin antitoxin agents are reviewed.

Outcomes of 25-gauge vitrectomy with air tamponade for idiopathic macular hole repair surgery / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To evaluate the anatomic and visual outcomes of 25-gauge vitrectomies combined with air tamponade for the treatment of idiopathic macular hole (IMH).METHODS: Thirty eyes of 27 patients with IMH were included in this prospective interventional study.All patients underwent 25-gauge pars plana vitrectomy (PPV) combined with phacoemulsification and air tamponade.Best corrected visual acuity (BCVA, logMAR), perimetry and multifocal electroretinography (mfERG) were conducted before and after the operation.Anatomical changes were evaluated with optical coherence tomography (OCT).RESULTS: The macular holes closed successfully in 28 eyes after the primary vitrectomy.The mean BCVA improved from 0.72±0.22 logMAR preoperatively to 0.29±0.18 logMAR postoperatively (P<0.001).In the visual field of central 10°, the average mean deviation (MD) decreased from-3.59±1.83 dB preoperatively to-2.51±1.36 dB postoperatively (P<0.001) and the average pattern standard deviation (PSD) decreased from 1.86±0.68 dB preoperatively to 1.33±0.32 dB postoperatively (P=0.001).The retinal response densities of mfERG in the foveal and perifoveal area increased significantly, and implicit times of rings 4-6 prolonged significantly (P<0.05).The symptom duration and baseline N1 amplitude densities at ring 1 had a significant impact on postoperative BCVA (P<0.001, P=0.001, respectively).CONCLUSION: The 25-gauge PPV and air tamponade with 1 day prone positioning produce favorable anatomic and functional outcomes.

Trachoma rapid assessment of children aged 1 to 9 years in Hainan Province of China / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To investigate the incidence of trachoma in children aged 1 to 9y in Hainan Province and determine high-risk trachoma endemic and non-endemic areas in Hainan, and thus provide evidence for developing trachoma control and prevention therapy.METHODS:The areas of investigation were chosen on the basis of past literatures, expert interviews and survey on the spot.In 2013, Hainan Provincial Office of Blindness Prevention carried out the survey in 7 counties including Dongfang City, Wuzhishan City, Ledong County, Baisha County, Baoting County, Lingao County and Changjiang County.In these districts, 356 pupils including 192 boys and 164 girls were examined, their age ranging from 1 to 9 and their average age being 7 years old.The targeted students received the trachoma rapid assessment by the adoption of simplified trachoma classification system which was recommended by the World Health Organization.RESULTS: No case of active trachoma was found among the 356 students.CONCLUSION:The prevalence rate of trachoma in children under 9 years is less than 5% in Hainan Province.Active trachoma is not a public health issue in Hainan Province.

The effect and mechanism of capsaicin prevented acute gastric mucosal injury by indomethacin / 实用医学杂志

Objective The study of capsaicin (CAP) on the effect and mechanism of indomethacin induced acute gastric mucosal injury in different period.Methods 80 SD rats were randomly divided into 8 groups with 10 rats in each group.The experiment was completed in two phases,and the Ⅰ period was 2 weeks,the Ⅱ period was 4 weeks.The Ⅰ period including group A1 (control group),group B1 (model group),group C1 (CAP group),group D1 (CAP + indomethacin group).The grouping method of the two periods were the same.The rats' gastric mucosa were damaged by indomethacin,and then killed the rats 4 hours later.Last,astric juice was collected to determine the total acidity of gastric acid,counted thegastric mucosal injury index,observed the gastric mucosa pathological injury,detected the expression of TRPV 1、CGRP、MDA、SOD and PGI2.Results The Ⅰ period:the gastric mucosa of group A1 and C1 had no damage.Group D1 compared with group B1,there was no significant difference in gastric mucosa injury (P ＞ 0.05),total acidity decreased significantly (P ＜ 0.05),MDA was no significant difference (P ＞ 0.05),SOD、PGI2 increased significantly (P ＜ 0.05),the expression of TRPV1、CGRP increased significantly (P ＜ 0.05).The Ⅱperiod:the gastric mucosa of group A2 and C2 had no damage.Group D2 compared with group B2,the gastric mucosa injury were significantly reduced (P ＜ 0.05),total acidity decreased significantly (P ＜ 0.05),MDA decreased significantly (P ＜ 0.05),SOD、PGI2 increased significantly (P ＜ 0.05),the expression of TRPV1、CGRP increased significantly (P ＜ 0.05).Conclusion There was no damage to the general morphology and histology of gastricmucosa in rats by intragastric CAP 1 mg/(kg· d) for 2 weeks and 4 weeks.2.It could prevent that indomethacininduced acute gastric mucosal injury in rats by pretreated with CAP 1 mg(kg· d) for 4weeks.