A Speedy Route to Multiple Highly Potent SARS-CoV-2 Main Protease Inhibitors

The COVID-19 pathogen, SARS-CoV-2, requires its main protease (SC2MPro) to digest two of its translated polypeptides to form a number of mature proteins that are essential for viral replication and pathogenesis. Inhibition of this vital proteolytic process is effective in preventing the virus from replication in infected cells and therefore provides a potential COVID-19 treatment option. Guided by previous medicinal chemistry studies about SARS-CoV-1 main protease (SC1MPro), we have designed and synthesized a series of SC2MPro inhibitors that contain {beta}-(S-2-oxopyrrolidin-3-yl)-alaninal (Opal) for the formation of a reversible covalent bond with the SC2MPro active site cysteine C145. All inhibitors display high potency with IC50 values at or below 100 nM. The most potent compound MPI3 has as an IC50 value as 8.5 nM. Crystallographic analyses of SC2MPro bound to 7 inhibitors indicated both formation of a covalent bond with C145 and structural rearrangement from the apoenzyme to accommodate the inhibitors. Virus inhibition assays revealed that several inhibitors have high potency in inhibiting the SARS-CoV-2-induced cytopathogenic effect in both Vero E6 and A549 cells. Two inhibitors MP5 and MPI8 completely prevented the SARS-CoV-2-induced cytopathogenic effect in Vero E6 cells at 2.5-5 M and A549 cells at 0.16-0.31 M. Their virus inhibition potency is much higher than some existing molecules that are under preclinical and clinical investigations for the treatment of COVID-19. Our study indicates that there is a large chemical space that needs to be explored for the development of SC2MPro inhibitors with extreme potency. Due to the urgent matter of the COVID-19 pandemic, MPI5 and MPI8 may be quickly advanced to preclinical and clinical tests for COVID-19.

Comparison of long-term outcomes between endoscopic submucosal dissection and surgery on treatment of early esophagogastric junction adenocarcinoma / 中华消化内镜杂志

Objective:To evaluate the long-term efficacy of endoscopic submucosal dissection (ESD) and surgical resection on the treatment of early esophagogastric junction (EGJ) adenocarcinoma.Methods:A retrospective analysis was performed on the data of 166 consecutive cases with early EGJ adenocarcinoma in Digestive Endoscopy Center and Department of General Surgery of Shanxi Provincial People′s Hospital from January 2004 to June 2018. Their preoperative assessment conformed to the absolute and expanded criteria of ESD, and postoperative pathological assessment accorded with the absolute and expanded criteria of curative resection. Patients were divided into the ESD group (n=77) and the surgical resection group (n=89), and the recent results (curative resection rate and complications) and long-term results (cumulative survival rate) were compared between the two groups.Results:In the ESD group, 65 (84.4%) patients met the absolute criteria of ESD treatment and 12 (15.6%) patients met the expanded criteria. In the surgical resection group, 60 (67.4%) patients met the absolute criteria of ESD and 29 (32.6%) patients met the expanded criteria. The difference in the composition of ESD criteria was statistically significant between the two groups ( P=0.011). Other baseline indicators showed no significant difference between the two groups ( P > 0.05). In the ESD group, the overall resection rate was 98.7% (76/77), the complete resection rate was 94.8% (73/77), and the curative resection rate was 93.5% (72/77). In the surgical resection group, the curative resection rate was 100.0% (89/89). The difference in the curative resection rate between the two groups was not statistically significant ( P=0.05). In the ESD group, there were 3 (3.9%) cases of intraoperative bleeding, 1 (1.3%) case of early postoperative bleeding, and 2 (2.6%) cases of intraoperative perforation. In the surgical resection group, there was 1 (1.1%) case of intraoperative bleeding, 4 (4.5%) cases of postoperative bleeding, and 2 (2.2%) cases of postoperative anastomotic leakage. There was no death or local recurrence occurred in the both groups within 1 month after treatment. The median follow-up time was 89.3 months (ranged 72.5-105.7 months) in the ESD group and 82.3 months (ranged 69.6-101.0 months) in the surgical treatment group, respectively. There was no tumor-related death or recurrence occurred in the two groups during follow-up. The 5-year survival rate in the ESD group and the surgical resection group was 94.8% (73/77) and 96.6% (86/89), respectively. The difference in the cumulative survival rate was not significant between the two groups ( P=0.648). Subgroup analysis showed that there was no significant difference in the cumulative survival rate between patients receiving ESD and those receiving surgical resection who met the absolute criteria of ESD ( P=0.449) and met ESD expanded criteria ( P=0.505). Conclusion:For EGJ adenocarcinoma conforming to the ESD treatment absolute and expanded criteria, ESD may be an alternative treatment option to surgery with the comparable long-term outcomes.

Recent research progress on swainsonine / 中国兽医学报

Locoweeds are presently defined as those species of the genera Oxytropis and Astragalus (family Leguminosae) that specifically contain the key toxic constituent,swainsonine.After ingesting locoweeds,livestock can develop poisoning disease characterized by chronic dysfunction of the nervous system,which causes severe economic losses to the pastoral areas.In addition,swainsonine has attracted a great attention from toxicology and medicine fields,due to its dual role of toxicity and pharmacological activity.This review not only summarizes the latest research progress of toxicity and its poisoning mechanism,pharmacological activity,source,and biosynthesis pathway of swainsonine,but also speculates the possible regulatory enzymes involved in the synthesis pathway.Moreover,the future research on swainsonine is also looked ahead,which provide references for the prevention and treatment of locoism.

Effects of madder on bone biomechanical property in rats / 生物医学工程学杂志

Bones are stained into red color with feeding madder, but we do not know whether the fed madder can change the bone biomechanical properties and bone mineral contents in animals. In this research, we established a rat model with feeding madder. The bone biomechanical properties were detected by universal material mechanics, bone mineral contents were detected by inductively coupled plasma mass spectrometry and spectrometer, and red color material in bone was analyzed by high performance liquid chromatography. The results showed that bone biomechanical parameters in femur diaphysis in the 10% and 15% group rats were significantly higher than those in the control group after feeding madder for 6 months. The level of calcium, magnesium and zinc in femur diaphysis in 10% and 15% group rats were higher than those in the control group after feeding madder for 6 months. However, it was shown that the kidney congestion and hyperemia and the level of blood urea nitrogen and creatinine in the 15% group rats were significantly different compared to those in the control group rats after feeding madder for 6 months. The red colored material in bone is related to alizarin analyzed with high-performance liquid chromatography. The conclusion could be drawn that feeding 10% madder in diet was not toxic to the rats fed for 6 months, and it could improve bone biomechanical properties and increase bone mineral elements.

Pathogenesis and preventive treatment for animal disease due to locoweed poisoning.

Locoweeds are perennial herbaceous plants included in Astragalus spp. and Oxytropis spp. that contain the toxic indolizidine alkaloid swainsonine. The livestock that consume locoweed feeding can suffer from a type of toxicity called "locoism." There are aliphatic nitro compounds, selenium, selenium compounds and alkaloids in locoweed. The toxic component in locoweeds has been identified as swainsonine, an indolizidine alkaloid. Swainsonine inhibits lysosomal α-mannosidase and mannosidase II, resulting in altered oligosaccharide degradation and incomplete glycoprotein processing. As a result, livestock that consume locoweeds exhibit several symptoms, including dispirited behavior, staggering gait, chromatopsia, trembling, ataxia, and cellular vacuolar degeneration of most tissues by pathological observation. Locoism results in significant annual economic losses. Recently, locoweed populations have increased domestically in China and abroad, resulting in an increase in the incidence of poisoning. Therefore, in this paper, we review the current research on locoweed, including on species variation, pathogenesis, damage and poisoning prevention measures.

Treatment of 234 Cases of Dementia due to Cerebrovascular Disease by Acupoint Injection / 针灸推拿医学（英文版）

Objective To observe the effect of acupoint-injection on vascular dementia. Methods 1 ml of cytidine diphosphocholine was injected into Baihui ( GV 20) and Fengchi (GB 20, bilateral) respectively. 234 patients were treated. Results and conclusion: 49 cases were cured, 150 cases got improve, 35 cases had ineffectiveness, the total utility rate was 85.0%, so acupoint-injecting cytidine diphosphocholine is a utility method healing vascular dementia.