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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the COVID-19 pandemic, is rapidly evolving. Due to the limited efficacy of vaccination in prevention of SARS-CoV-2 transmission and continuous emergence of variants of concern (VOC), including the currently most prevalent Delta variant, orally bioavailable and broadly efficacious antiviral drugs are urgently needed. Previously we showed that adenosine analogue 69-0 (also known as GS-441524), possesses potent anti-SARS-CoV-2 activity. Herein, we report that esterification of the 5-hydroxyl moieties of 69-0 markedly improved the antiviral potency. The 5-hydroxyl-isobutyryl prodrug, ATV006, showed excellent oral bioavailability in rats and cynomolgus monkeys and potent antiviral efficacy against different VOCs of SARS-CoV-2 in cell culture and three mouse models. Oral administration of ATV006 significantly reduced viral loads, alleviated lung damage and rescued mice from death in the K18-hACE2 mouse model challenged with the Delta variant. Moreover, ATV006 showed broad antiviral efficacy against different mammal-infecting coronaviruses. These indicate that ATV006 represents a promising oral drug candidate against SARS-CoV-2 VOCs and other coronaviruses.
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Objective:To investigate the effect of phacoemulsification using different corneal micro-incision sizes on the postoperative corneal healing.Methods:A non-random controlled study was performed.Seventy-six patients (76 eyes) with age-related cataract who underwent phacoemulsification and cataract extraction combined with intraocular lens (IOL) implantation in Yanbian University Hospital from May 2016 to May 2017 were enrolled.The subjects were divided into 2.2 mm incision group (37 eyes) and 1.8 mm incision group (39 eyes) according to corneal incision size.The intraoperative cumulative dissipated energy (CDE) and ultrasound time of the two groups were measured and compared.The corneal incision structure and corneal thickness of operative eyes were measured by anterior segment optical coherence tomography before surgery and at postoperative 1 day, 1 week and 1 month.The corneal endothelial cells count, the central corneal thickness (CCT), and the corneal volume in the central corneal diameters of 3.0 mm (CV3) and 10.0 mm (CV10) were measured by Pentacam.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of the Yanbian University Hospital (No.2015153), and written informed consent was obtained from all subjects before surgery.Results:There were statistically significant differences in the corneal endothelial cells count, CCT, CV3, CV10, and corneal thickness at epithelial side of the incision between pre-operation and post-operation in each group ( Ftime=17.717, 67.356, 17.577, 13.559, 80.076; all at P<0.01).But there was no statistically significant difference in the indexes between the two groups ( Fgroup=0.788, 0.706, 3.692, 4.341, 4.182; all at P>0.05).The number of corneal endothelial cells in the two groups was gradually decreased after surgery, and was significantly reduced at one month after surgery in comparison with the pre-operation, and the differences were statistically significant (both at P<0.05).At 1 day after surgery, the CCT, CV3, CV10, and corneal thickness at epithelial side of the incision in the two groups were increased significantly in comparison with the pre-operation and the differences were statistically significant (all at P<0.05), and the differences were not statistically significant between preoperative and postoperative 1 week or 1 month (all at P>0.05).With time going by, the indexes were back to normal gradually.The incidence of endothelial gaping and dislocation at the corneal incision in the 1.8 mm incision group was 12.8% (5/39) and 5.1% (2/39), which were significantly higher than 0.0% (0/37) and 2.7% (1/37) in the 2.2 mm incision group, and the differences were statistically significant ( χ2=5.078, P=0.024; χ2=0.295, P=0.590).At 1 day after surgery, corneal thickness at the endothelial side in the 1.8 mm incision group was significantly thicker than that in the 2.2 mm incision group, and the difference was statistically significant ( P=0.042), and the corneal thickness at endothelial side of the incision was positively correlated with CDE in the two groups ( r=0.231, P=0.025; r=0.347, P=0.003). Conclusions:Compared with 2.2 mm incision, 1.8 mm corneal incision results in higher incidence of endothelial gaping and dislocation at the corneal incision, greater corneal thickness at endothelial side of the incision and slower recovery.
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The outbreak of coronavirus disease 2019 (COVID-19) rapidly spreads across worldwide and becomes a global pandemic. Remdesivir is the only COVID-19 treatment approved by U.S. Food and Drug Administration (FDA); however, its effectiveness is still under questioning as raised by the results of a large WHO Solidarity Trial. Herein, we report that the parent nucleotide of remdesivir, GS-441524, potently inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Vero E6 and other cells. It exhibits good plasma distribution and longer half-life (t1/2=4.8h) in rat PK study. GS-441524 is highly efficacious against SARS-CoV-2 in AAV-hACE2 transduced mice and murine hepatitis virus (MHV) in mice, reducing the viral titers in CoV-attacked organs, without noticeable toxicity. Given that GS-441524 was the predominant metabolite of remdesivir in the plasma, the anti-COVID-19 effect of remdesivir may partly come from the effect of GS-441524. Our results also supported that GS-441524 as a promising and inexpensive drug candidate in the treatment of COVID-19 and future emerging CoVs diseases.
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In all of the clinical trials for COVID-19 conducted thus far and among those ongoing involving chloroquine or hydroxychloroquine, the drug substance used has invariably been chloroquine (CQ) diphosphate or hydroxychloroquine (HCQ) sulfate, i.e., the phosphoric or sulfuric acid salt of a racemic mixture of R- and S-enantiomer (50/50), respectively. As a result, the clinical outcome from previous CQ or HCQ trials were, in fact, the collective manifestation of both R and S- enantiomers with inherent different pharmacodynamic and pharmacokinetic properties, and toxicity liabilities. Our data for the first time demonstrated the stereoselective difference of CQ and HCQ against live SARS-CoV-2 virus in a Biosafety Level 3 laboratory. S-chloroquine (S-CQ) and S-hydroxychloroquine (S-HCQ) significantly more active against SARS-CoV-2, as compared to R-CQ and R-HCQ, respectively. In addition, Mpro, as one of the critical enzymes for viral transcription and replication, also exhibited an enantioselective binding affinity toward the S-enantiomers. The most significant finding from this study is the pronounced difference of the two enantiomers of CQ and HCQ observed in hERG inhibition assay. The IC50 value of S-HCQ was higher than 20 M against hERG channel, which was much less active over all tested CQ and HCQ compounds. Moreover, S-HCQ alone did not prolong QT interval in guinea pigs after 3 days and 6 days of administration, indicating a much lower cardiac toxicity potential. With these and previous findings on the enantio-differentiated metabolism, we recommend that future clinical studies should employ S-HCQ, substantially free of the R-enantiomer, to potentially improve the therapeutic index for the treatment of COVID-19 over the racemic CQ and HCQ.
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Objective @#To explore the association between coffee intake and all cancer mortality in East Asian populations. @*Methods @#We searched literatures which assessed the relationship between coffee intake and cancer mortality in Asian populations published by December 10th,2018 from China National Knowledge Infrastructure,Wanfang Database,VIP Database and PubMed. We conducted category and dose-response meta-analyses using Stata 15.0. @*Results @#A total of 335 relevant articles were retrieved; five articles were finally included in the meta-analyses,of which four were carried out in Japanese population and one in Singaporean Chinese population. The total sample size of the five articles was 361 802,and the number of deaths from cancer was 17 664. The results showed that coffee intake reduced the risk of all cancer mortality in East Asian populations(RR=0.93,95%CI:0.87-0.99). There was no statistical significant association between coffee intake and all cancer mortality in East Asian men(RR=0.94,95%CI:0.77-1.15). Among East Asian women,coffee consumption reduced the risk of all cancer mortality by 12%(RR=0.88,95%CI:0.81-0.95). All cancer mortality risk decreased with the increase of coffee intake,and reached the lowest point at one and a half cups of coffee per day(RR=0.92,95%CI:0.86-0.98). @*Conclusion @#Coffee intake reduced the risk of all cancer mortality in East Asian populations,which was obviously found in East Asian women. Drinking one and a half cups of coffee a day had the lowest risk of all cancer mortality.
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Objective To study the effect and mechanisms of chloride channel blocker 5-Nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) on thansforming growth factor β1 (TGF-β1) induced human conjunctival fibroblasts (HConF) fibrosis.Methods Cell counting kit (CCK-8) was used to screen out the optimal TGF-β1 treatment time and the optimal NPPB concentration.The cells were divided into control group,TGF-β1 treatment group and TGF-β1+NPPB group.Cell proliferation and cell cycle were detected by CCK-8 and flow cytometer,respectively.Cell migration ability were observed by scratch and transwell migration assays.Western blot and Real time-PCR were used to detect the expression of collagen Ⅰ (COL-Ⅰ),fibronectin (FN) and α-smooth muscle actin (α-SMA).The phosphorylation level of PI3K and Akt were measured by Western blot.Results TGF-β1 promotes cell proliferation in a time-dependent manner.There was no statistically significant difference in A values between 48 hours and 72 hours after TGF-β1 treatment (P =0.064).Forty-eight hours was selected as the most appropriate time for TGF-β1 treatment.NPPB inhibited HConF cell proliferation in a concentration-dependent manner.Compared with the control group,the proliferation A values of cells in the 50 mol/L and 100 mol/L NPPB groups were significantly reduced (P =0.020,0.000),and 100 mol/L was selected as the optimal concentration of NPPB.The cell proliferation A value,migration area and migration cell number of TGF-β1 +NPPB group were significantly lower than those of TGF-β1 treatment group (all at P<0.05).Compared with the control group and TGF-β1 +NPPB group,the proportion of G1 phase cells in the TGF-β1 treatment group was reduced,and the proportion of cells in the S phase and G2/M phase were increased,with statistically significant differences between them (all at P < 0.05).The protein and mRNA expression of α-SMA,COL-Ⅰ and FN in the TGF-β1 treatment group were higher than those in the control group and TGF-β1+NPPB group,with statistically significant differences between them(all at P<0.05);the ratios of p-PI3K/PI3K and p-Akt/Akt in the TGF-β1 treatment group were significantly higher than those in the control group and TGF-β1 +NPPB group,with statistically significant differences between them (all at P<0.05).Conclusions NPPB may inhibit TGF-β1 induced HConF fibrosis process by inhibiting phosphorylation of PI3K and Akt.
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Objective To explore the expression of chemokine receptor 6 (CCR6) and T helper cell 17 (Th-17) in the epithelial cells and tears in diabetic patients with dry eye disease.Methods Prespective study was performed.Ninety-one type 2 diabetic patients with dry eye disease and 102 normal subjects were involved from January to July in 2017 in Affiliated Hospital of Yanbian University.Ocular Surface Disease Index (OSDI)questionnaire survey score,Break-up time of tear film (BUT),Schirmer Ⅰ test (S Ⅰ t) and fluorescein corneal stainning (FLS) were performed on both groups.The conjunctival epithelial cells of both groups were obtained by impression cytology.The expression of the chemokine receptors (CCR) 4,CCR5 and CCR6 in conjunctival epithelial cells and the number of Th-17 cells in tears were detected by flow cytometry.This study was approved by the ethics committee of Affiliated Hospital of Yanbian University (2014053),and all the patients signed informed consent.Results The OSDI questionnaire scores,BUT,S Ⅰ t and FLS were significantly different between diabetic dry eye group and normal control group (all at P<0.05).The ratio of CCR4+ CD4+ T cells,CCR5+ CD4+ T cells and CCR6+CD4 +Tcells was (1.1±0.9)%,(2.1±1.7)% and (5.2±2.4)% in the normal control group,(1.2±0.8)%,(9.5±5.3)% and (19.2±5.7)% in the diabetic dry eye group,respectively.The ratios of CCR5+CD4+ T cells and CCR6+CD4+ T cells in the diabetic dry eye group were significantly higher than those in the normal control group (both at P<0.05).The proportion of Th-17 cell in tears of diabetic dry eye group was significantly higher than that in the normal control group (P<0.001).Conclusions CCR5,CCR6 and Th-17 cells may play a key role in the pathogenesis of diabetic patients with dry eye.
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Background The incidence of dry eye is gradually increasing,and the aging of population is one of factors.Researches showed that the change of tear film stability leads to shift of corneal refractive power, which probably affects the measurement of intraocular lens (IOL) power.The influence of dry eye on the calculation of IOL power is worth paying close attention.Objective This study was to investigate the influence of dry eye on the accuracy of IOL power calculation in age-related cataractous patients.Methods A non-randomized controlled clinical study was performed.Two hundred and sixteen eyes of 216 cataract patients were enrolled in Yanbian Eye Ear Nose and Throat Hospital from May 2013 to February 2014.The visual acuity, intraocular pressure, break up time of tear film (BUT),Schirmer Ⅰ test (S] t) and corneal fluorescein staining were examined in all the eyes,and then the patients were assigned to mild dry eye group (73 eyes), severe dry eye group (68 eyes) and non-dry eye control group (75 eyes).The axial length (AL) and anterior chamber depth (ACD) were measured using IOL Master for the calculation of IOL power and K value (corneal curvature).Phacoemulsification with IOL implantation was performed on all the eyes,and the refractive power was measured with KR 8100 automatic optometry 2 months after operation.The mean absolute refractive error (MARE) between actual refraction and predicted refraction was calculated, and percentage of eyes in different refractive error ranges was compared between the dry eye group and non-dry eye control group.The correlations of dry eye-related parameters with peroperative K value and refractive error were analyzed.This study was approved by the Ethics of Yanbian University,and written informed consent was obtained from each subject prior to entering the cohort.Results No significant differences were found in age, gender, AL,ACD and MARE among the mild dry eye group,severe dry eye group and non-dry eye control group (all at P>0.05), and significant differences in BUT,S Ⅰ t and corneal fluorescein staining scores were found among these three groups (F=5.460,4.521,3.572, all at P<0.05).The K values were (43.59± 1.39) , (44.66± 1.53) and (43.42± 1.32) D in the mild dry eye group,severe dry eye group and non-dry eye control group,and the K value in the severe dry eye group was significantly higher than that in the non-dry eye control group (P =0.012).The percentage of eyes with +0.50-+0.75 D deviation was significantly elevated(28.8% versus 13.3%), and that with-0.50--0.75 D deviation was significantly declined (17.3% versus 28.0%) in the dry eye group compared with non-dry eye control group (x2 =4.513 ,P=0.032;x2 =4.236,P=0.037).A negative correlation was found between BUT and K value (r=-0.204,P=0.011).Conclusions Dry eye affects the accuracy of the determination of IOL power.Compared with the preoperative refraction predictive value,the postoperative refraction shift toward hyperopia.
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Medical function experimental science in the medical education reform has been a hot spot in recent years. The set-up and adjustment of the curriculum is a very important step in teaching reform and one of the major issues in the research and study of medical education. In the article, it explores the initial ideas for curriculum reform, such as optimization of the course content, reform of teaching methods and means, improving student achievement evaluation system, and other aspects, to promote the development and improvement on curriculum construction in functional experimental science of medical colleges.
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Objective To study the therapeutic effect of catgut net wrapping for preservation of the injured spleen.Methods Catgut net wrapping method was used to preserve the injured spleen,and the clinical material of those patients treated by the wrapping method was retrospectively evaluated.Results Ultimate spleen recovery was achieved in each case of 15 patients without postoperative bleeding observed,any abscess formation,or complications related to the use of catgut net wrapping.The patients were discharged after 10 to 14 hospital dayS.Two-week-fol-low-up results showed this therapeutic opinion is safe.Conclusion As a means of preserving the injured spleen,the catgut net wrapping method was simple,safe,and efficacious.
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Aim To study the effect of [P-(1-Benzotriazole methl)-Benylacrylic acid sodium,abbreviated for BMBS] on experimental arrhythmias. Methods Arrhythmias models induced by drugs in animals were used to observe the effect of BMBS on experimental arrhythmias. Results BMBS 25,12.5 mg?kg -1 iv markedly increased the dose of aconitine for inducing Ventricular premature beats (VP), ventricular tachycardia (VT) and ventricular fibrillation (VF) in rats, as well as that of ouabain for inducing VP, VT, VF and cardiac arrest (CA) in guinea pigs. Also, it postponed the onset time and shortened the duration of arrhythmias induced by barium chloride in rats and decreased the number of animals showing biphasic arrhythmias. Conclusion BMBS has significant effect on experimental arrhythmias.
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Object To study the standard operating procedure (SOP) for Alisma plantago aquatica L. so as to make its high quality, high yield and public nuisance free, and correspond to international standards, then enter into world market. Methods The historical culture, essential ecological environment, species resources and seed selection for the plant were investigated, the content of index components and active components in the plant was determined. Results The traditional cultural manner was improved and SOP for the plant was set up. Conclusion The plant cultured under SOP is excellent.
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Objective To observe the effects of wogonin on lipopolysaccharide(LPS-induced) proinflammatory cytokine production in activated microglia.Methods By using LPS-induced microglia activation model,nitric oxide(NO),tumor necrosis factor-alpha(TNF-?) and interleukin-6(IL-6) secreted by extracellular fluid were measured by ELISA.Results Microglia markedly produced NO,TNF-? and IL-6 in response to LPS.Wogonin,administered at 20-30 ?mol/L,significantly reduced the production of NO,TNF-? and IL-6 in microglia.Conclusion Wogonin has an inhibitory effect on the production of proinflammatory cytokines.