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.

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.

Epidemiological characteristics of cerebral palsy in twelve province in China / 中华实用儿科临床杂志

Objective To investigate the epidemiological characteristics of cerebral palsy(CP)in children aged 1-6 years in China,including the incidence,prevalence,type of CP,etiology,prevention and rehabilitation status. Methods The survey was carried out by standard questionnaires,multi-center collaboration,stratified-cluster ran-dom sampling method.The surveyed adopted the following principles:streets in the city and villages in the rural areas, and the number of the urban and rural children was the same,and the proportion of children in each age group was balanced.The investigation areas included provinces and autonomous regions,including Heilongjiang,Beijing,Henan, Shandong,Shanxi,Shaanxi,Anhui,Hunan,Guangxi,Guangdong,Chongqing and Qinghai,and 323 858 children were in-vestigated.Results The incidence of CP was 2.48‰(155/62 591 cases),and the prevalence was 2.46‰(797/323 858 cases)(1-6 years old).The prevalence varied in different regions,in which the highest prevalence was 5. 40‰(54/9 998 cases)in Qinghai province,and the lowest prevalence was 1.04‰(47/45 133 cases)in Shandong province.The prevalence of the males(2.64‰,461/174 391 cases)was higher than that of the females(2.25‰, 336/149 467 cases),and the difference was statistically significant(P<0.05).The types of CP were spastic type (58.85%,469/797 cases),mixed type(13.17%,105/797 cases),dyskinetic(9.79%,78/797 cases),hypotonic (8.28%,66/797 cases),ataxia(6.25%,52/797 cases)and rigid(3.39%,27/797 cases)respectively in 797 CP children.The first three risk factors for CP were long -term exposure to harmful physical factors during pregnancy, whether there were birth defects among the three generations of relatives of the children,such as children's peers, parents or grandparents,whether there were birth defects among the children's peers,parents or grandparents,and neonatal jaundice or persistent jaundice.Among 797 CP children,79.67% of the children with CP were timely detected and treated in the local hospitals,while the other 19.93% of them were not timely treated.The places which could give them timely detection and early diagnosis and treatment were general hospitals(42.97%),Maternity and Infant Hospitals (27.03%)and Children's Hospitals(20.31%). The main rehabilitation methods for 797 children with CP were 34.58% in the hospitals or rehabilitation centers,31.61% in the communities(including at home),33.80% mainly in the medical institution,and in the communities they could also receive partially rehabilitation services. Conclusions The prevalence of CP in China is coincident with international levels.The prevalence rate of CP in males is higher than that in females.The types of CP distribution are accorded with international distribution characteristics.There were still some children with CP who could not receive timely detection and treatment.Rehabilitation at the medical institutions is the chief way and proper rehabilitation guidance should be carried out in the communities.

Screening for selective TGF-βⅠinhibitors and structure-activity relationship analysis / 国际药学研究杂志

Objective To screen for selective transforming growth factor β(TGF-β)inhibitors from the compound library, and analyze their structure-activity relationship. Methods The inhibiting activities of 170 compounds to TGF-βpathway were evaluat-ed by the SMAD3 luciferase reporter system;the positive hits were examined for their selectivity towards activin receptor like kinase (ALK)4、ALK5 or ALK7 by a molecule based screening system composed of SMAD3,ATP and the purified kinase domain for ALK4, ALK5 or ALK7;the EGFP-SMAD2 fusion protein redistribution assay was used to confirm the inhibiting effects of positive hits. The structure-activity relationship was analyzed by comparing the docking module of SB431542 with ALK5 kinase domain. Results Fif-teen compounds were found capable of inhibiting luciferase expression downstream of SMAD3 with≥25%inhibitory rate;several of them showed different selectivity towards ALK4,ALK5 and ALK7. Compound 63 selectively inhibited the activity of ALK4 and ALK7 with IC500.234 and 0.370μmol/L,respectively,while compound 64 showed inhibiting activity towards all three kinases with the IC50 values 10,6 and 85 nmol/L for ALK4、ALK5 and ALK7,respectively. In addition,compounds 63 and 64 further inhibited the TGF-β1 induced EGFP-SMAD2 nuclear translocation,with the IC50 values of 0.45 and 6.30μmol/L,respectively. The MTT anti-proliferative assay indicated that compounds 63 and 64 exerted these activities at non-toxic concentrations. The analysis of structure-activity rela-tionship indicated that the compounds sharing a core structure,the 1,2,4-triarylimizazole or 1,3,5-triarylpyrazoline,with the 3,4 methyoenedioxyphenyl,6-methylpyridine and 4-aminocarboxyl substitution groups tended to exhibit better activities. Conclusion The two potent TGF-βpathway inhibitors,63 and 64 are identified through this screening project,of which,63 selectively inhibited the ALK4 and ALK7 activity,while 64 showed inhibiting activity towards all three tested types of ALKs.

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.

Clinical treatment and small molecular drugs for anti MERS-CoV:research advances / 国际药学研究杂志

Middle East respiratory syndrome (MERS) is a viral respiratory infection caused by the newly identified MERS-CoV, which was first discovered in Saudi Arabia in 2012. Although most cases of MERS have occurred in Middle East, cases also have been reported in Europe, the USA and Asia in people who travelled from the Middle East or their contacts. The most recent outbreak was in South Korea with over dozens of cases, wherein, one case imported into mainland China via Hong Kong. No specific drug treatment exists for MERS now. Supportive treatment, aiming to prevent complications, supporting the function of respiratory, circulatory and renal, was the mainstay of management. In this paper, the reported clinical treatment, the research progress of potential targets and small molecule drugs for anti MERS-CoV were reviewed.

Research Progress of Plant Polyphenols for Improving Cognitive Function / 世界科学技术-中医药现代化

Plant polyphenols are a group of naturally occurring phytochemicals which are present in high amounts in plants and are the most abundant dietary antioxidants. Epidemiological and animal model researches have indicated that polyphenols can improve cognitive function. The mechanism for polyphenols to improve cognitive function has been extensively studied and may be owing to antioxidant, anti-imflammatory, neuroprotective, cerebrovascular blood flow increasing activities, and etc. Nowadays, the plant polyphenols and its benefits to cognitive function have become a hot research topic. In this article, we reviewed the latest progress from the structure and origin of phenolic compound, as well as its effect and action mechanism on cognitive function.

RELN Gene Single Nucleotide Polymorphism Related with Clinical Features of Autism / 中国康复理论与实践

@#Objective To investigate the relationship between RELN gene single nucleotide polymorphism (SNP) and childhood autism in Jiamusi, Heilongjiang. Methods Polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) was used to determine allele and genotype of SNP (exon 6) of RELN in 30 children with autism and 30 normal children. Autism Behavior Checklist (ABC) was used to evaluate the children. Results There was a significant difference in the distribution of the allelic frequencies and genotype in exon 6 between these groups (P<0.05). There was a significant difference in the communication factors between patients with genotype of A/A and A/G or A/A and G/G (P<0.05), as well as in the total scores of ABC between A/G and G/G (P<0.05). Conclusion The SNP of RELN (exon 6) associated with the childhood autism. There is a more serious communication disorder in children with genotype of G/G, A/G than that of A/A.

Effects of Atorvastatin Pretreatment on Spinal Cord Ischemia-reperfusion Injury of Rabbits / 中国康复理论与实践

@#ObjectiveTo explore the atorvastatin impact of pretreatment on spinal cord ischemia-reperfusion injured model of rabbits.MethodsThe animal model was induced by occlusion abdominal aorta. Spinal cord was performed for 45 min ischemia and neuronal function was evaluated at 2 h, 6 h, 12 h, and 24 h after reperfusion. The contents of malonydialdehyde (MDA), superoxide dismutase (SOD) and myeloperoxidase (MPO) were assayed 24 h after reperfusion.ResultsThe neuronal function decreased significantly 12 h and 24 h after reperfusion. The activity of SOD significantly enhanced, MDA contents and the activity of MPO decreased at medium-dose and high-dose atorvastatin.ConclusionAtorvastatin has protective effect on the spinal cord ischemia-reperfusion injury of rabbits.