作者: Ugi, Satoshi ; Yanagimachi, Tsuyoshi ; Kume, Shinji ; Nasiri, Ali ; Maegawa, Hiroshi ; Fujita, Yukihiro ; Sato, Daisuke ; Shulman, Gerald I. ; Ohgaku, Seiichiro ; Ishikado, Atsushi ; Ohashi, Natsuko ; Murata, Koichiro ; Morino, Katsutaro ; Ida, Shogo ; Shulman, Gerald I

IntroductionEndothelial cells have a crucial function in transporting and exchanging various nutrients. O-GlcNAcylation, mediated by O-GlcNAc transferase (OGT), involves the addition of N-acetylglucosamine to proteins and serves as an intracellular nutrient sensing mechanism. However, the role of O-GlcNAcylation in endothelial cells remains poorly understood.ObjectiveThis study investigated the role of O-GlcNAcylation in endothelial cells.MethodsEndothelial-cell-specific Ogt -knockout mice (Ogt-ECKO) were generated by crossing Ogt-floxed mice (Ogt-flox) with VE-Cadherin Cre ER^T2 mice. Ogt-ECKO mice and Ogt-flox control mice were subjected to a normal or high-fat diet, and their body weight, glucose metabolism, and lipid metabolism were examined.ResultsOgt-ECKO mice exhibited reduced body weight compared with Ogt-flox control mice under a high-fat diet. Lipid absorption was significantly impaired in Ogt-ECKO mice. Changes in the intercellular junctions of small intestinal lacteal endothelial cells from a button-like to a zipper-like configuration were observed. Furthermore, Ogt-ECKO mice showed decreased expression of VEGFR3. The administration of a nitric oxide donor restored lipid absorption and reversed the morphological alterations in Ogt-ECKO mice.ConclusionsThese findings demonstrate the critical role of O-GlcNAcylation in endothelial cells in lipid absorption in the intestine through the modulation of lacteal junction morphology. These results provide novel insight into the metabolic regulatory mechanisms under physiological conditions and have implications for the development of new therapeutic strategies for obesity.

2024-03-20·Journal of Society of Cosmetic Chemists of Japan

Involvement of Transglutaminase 3 (TG3) in Hair Stiffness Changing with Age by Capture of Zinc

作者: Hitomi, Kiyotaka ; Inaba, Megumi ; Ueda, Seiko

We previously reported that zinc in the cuticle of hair contributes to hair stiffness, and the age-dependent decrease in zinc is one of the reasons for the reduction in hair stiffness.From the results, we speculated that the decrease of zinc in the cuticle with aging may be caused by a decline of proteins that retain zinc in the cuticle.We extracted proteins from hair cuticle and analyzed them by mass spectrometry, revealing transglutaminase 3 (TG3) as a zinc-retaining candidate protein.The binding of TG3 to zinc was confirmed using a size fractionation column followed by ICP-MS, and the immunostaining of longitudinal sections of hair root demonstrated the presence of significant amounts of TG3 in the cuticle.Furthermore, hairs from volunteers of various ages were analyzed for the expression of TG3 mRNA in the hair roots, showing a downturn trend of the expression after their 40s and beyond.Based on the results, we concluded that the decrease of zinc in hair with aging past one's 40s is partly due to the decline of the TG3 expression that could retain zinc.In the future, the use of compounds that induce TG3 expression, could become a novel solution to maintain, or even regain hair firmness, resulting from the prevention of zinc loss with aging.

2024-03-01·Food and Chemical Toxicology

Development of an in silico evaluation system that quantitatively predicts skin sensitization using OECD Guideline No. 497 ITSv2 defined approach for skin sensitization classification

Article

作者: Asai, Takaho ; Umeshita, Kazuhiko ; Sakane, Shinji ; Sakurai, Michiko

The Integrated Testing Strategy version 2 (ITSv2) Defined Approach, which is a reliable skin sensitization hazard and multi-step risk assessment method, does not support quantitative risk assessment such as local lymph node assay EC3 values. In this study, we developed a high-performance in silico evaluation system that quantitatively predicts the EC3 values of chemical substances by combining the ITSv2 Defined Approach for hazard identification (ITSv2 HI) with machine learning models. This system uses in chemico/in vitro test data, molecular descriptors, and distance information based on read-across concepts as explanatory variables. The system achieves an R² value of 0.617 on external-validation data. Substances misclassified in ITSv2 HI are considered to have properties that do not match the correspondence between tests expressing the adverse outcome pathway assumed in the ITSv2 Defined Approach and skin sensitization. Therefore, ITSv2 HI is assumed to be correct within the applicability domains of this system. When using only substances within the applicability domains to reconstruct CatBoost models, the R² value reached 0.824 on the external-validation data, representing an improvement in system performance. The results demonstrate the utility of explanatory variables that reflect the read-across concept and the advantages of integrating multiple prediction methods.

项与 Sunstar, Inc. 相关的新闻（医药）

2023-04-25

·GlobeNewswire-Health Care

A New Herbal Medicine by Sao Thai Duong JSC SUNKOVIR Effectively Treats Covid-19, Flu, and Diseases Caused by Respiratory Virus

100% OF PATIENTS SAW NO INCREASE IN LEVEL OF SEVERITY, QUICK DECREASE IN SYMPTOMS AFTER ONLY THREE DAYS OF USEHANOI, Vietnam, April 25, 2023 (GLOBE NEWSWIRE) -- SUNKOVIR, the herbal medicine developed by Sunstar, was granted marketing authorization by the Ministry of Health of Vietnam in its decision No. 82/QD-YDCT on April 12th, 2023. In addition of being administered to Covid-19 patients, SUNKOVIR is also used in cases caused by the transmission of respiratory virus, flu. The results include a quick reduction of symptoms such as coughs, fever, difficulty in breathing, loss of sense of smell and taste, sinusitis, body ache, muscle pain, sore throat, rhinitis, headache, general fatigue, chest pain, sneezing, coldness, hoarseness, sweating, and drowsiness. It is safe for patients, children from 3 years old, on reproduction and genetics. SUNKOVIR has been officially accepted by the National Ethics Committee in Vietnam as a safe and effective product after eight clinical trials and preclinical trials taken place between January 2021 and December 2022 as well as six internal researches at Sao Thai Duong JSC. Phase III clinical trial (C573) involving 573 Covid-19 patients was carried out at two sites, the Traditional Medicine Institute of Ho Chi Minh City and the Hanoi Hospital of Traditional Medicine. The study were designed based on international scientific and ethical standards in clinical studies on COVID-19 patients in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines (ICH-GCP). The study have been published on www.clinicaltrials.gov. The research has been approved for publication on the science publications Pubmed and Phytotherapy Research of the network Scopus of Wiley (February 2023) – https://pubmed.ncbi.nlm.nih.gov/36751127/. Prior to that, the two clinical researches A66 and B100 have also been approved for publications. The first study (A66), between July and September 2021, carried out a double-blind randomized controlled trial on 66 patients. The results were published on June 22nd, 2022 - Phytotherapy research, Volume 36, Issue 7, p.2878-2888. The second study (B1000), between August and December 2021, carried out clinical research on 1,000 COVID-19 patients. The results were published on November 2022 - Phytotherapy research, letter to the editor, ptr.7668. No increase in level of severity: In the three trials, none of the 1,115 Covid-19 patients who were given SUNKOVIR experienced an increase in level of severity. It is worth noting that 6.2% and 6.0% of the unvaccinated patients; 0,5% of vaccinated patents in three studies who were not given SUNKOVIR saw an increase in the level of severity. Sharp decrease in symptoms and level of severity:SUNKOVIR resulted in a quick and sharp decrease of symptoms displayed by patients from the 3rd day.Shorten the length of treatment:In the research C573, The average time for the group given SUNKOVIR to be free from all symptoms was 7 days. The average time for the group given placebo was 11 days.Less use of medications:SUNKOVIR Capsules resulted in a sharp decrease in the use of corticoid, anticoagulant, NSAIDs, cough medicine, expectorant drug, anti- histamine, etc.Quicker in achieving a negative PCR test result:The group of patients given SUNKOVIR has a higher percentage of patients who tested negative PCR results from the 5th day than the group given placebo.Real improvement in patient wellbeing:The wellbeing of the group of patients given SUNKOVIR gradually improved as their treatment went on and was greater than that of the group given placebo.Safety:SUNKOVIR was safe to patients 3 times per day and 3 capsules each time for the duration of 14 days. Preclinical studies:SUNKOVIR produces pharmacological effects in restoring the damaged immune system at the dose of 6 or 9 capsules/day/person… SUNKOVIR does not cause acute toxicity at the dose of 156 capsules/day/person and semi-chronic toxicity at the dose of 9 and 27 capsules/day/person continuously for 30 days. The reproductive toxicity on the rats at the doses equivalent of 6 and 9 capsules/day/person, shows that there was no toxicity: to the male and female rats during their whole reproduction process.to the female rats during the pregnancy and lactation.to the development of the rats’ offspring. The genetic toxicity on bone marrow cells on the rats, which were given the equivalent of 6 and 9 capsules/day/person, showed that neither dose level caused any increase in the proportion of rats with mutations compared to the control group. The achievement of researches which has proven that Vietnamese herbal medicines are safe and effective in the fight against the Covid-19 pandemic. This result is an encouragement for Vietnamese Traditional Medicine to continue contributing to the public with valuable herbal products. Benefitting from its long history of using traditional medicine in treatment of diseases, the Association of Traditional Medicine of Vietnam with its 70.000 members, including physicians at central and regional levels, is carrying out numerous studies to evaluate the results from clinical trials of traditional medicines currently being used in Vietnam. SUNKOVIR contains 100% natural ingredients and is produced by Sao Thai Duong JSC which is a Vietnam-based science and technology company with 23 years of experience in the field of herbal medicine. The company currently has more than 300 herbal medicinal products, dietary supplements, and cosmetics which are sold widely in Vietnam and exported to the UK, USA, Europe, and China. https://www.globenewswire.com/NewsRoom/AttachmentNg/395f6850-81f1-41a3-a550-18bc8d627ab9

临床3期临床结果上市批准

2021-02-03

·药融圈

《2021中国CRO产业地图》重磅发布——国际对标和分布情况

注：本文不构成任何投资意见和建议，仅供参考用合同研究组织（CRO，Contract Research Organization）是通过合同形式为医药企业和其他医药研发机构在研发过程中提供专业化外包服务的组织或机构。CRO为医药企业提供包括新药产品开发、临床前研究及临床试验、数据管理、新药申请等技术服务，涵盖了新药研发的整个过程，并主要对新药的安全性和有效性进行检测。图1：CRO医药研发服务内容及代表性企业资料来源：美迪西招股书 01全球和国内CRO市场规模根据美国研究机构CB insights最新报告显示，2020年全球医疗/医药基金融资额达到806亿美元，创出新高，北美、欧洲和亚洲融资额都大幅增长，其中单轮融资项目超过1亿美元的有187个，打破历史记录。医疗基金的融资额大幅度上升，意味着药企的研发投入会进一步加大。图2：全球医疗/医药基金融资额资料来源：CB insights 图3：2020年全球医疗健康投融资热点区域分布图片来源：动脉橙据Evaluate Pharma数据，全球医药研发费用将从2017年的1,651亿美元增长到2024年的2,039亿美元，复合增长率为3.16%。中国医药研发投入到2021年将达到292亿美元，2016-2021年复合增长率22%左右，研发费用的持续增长为CRO行业的快速发展提供源源不断的动力。同时新药整体的成本上升和回报率的下降，推动制药企业研发外包率目前超过了50%。德勤健康解决方案中心发布的《2019医药创新回报率评价》报告指出，2019年医药行业研发的投资回报率处于2010年以来最低水平，仅为1.8%；一款新药的上市成本却增长了67%，从2010年的11.88亿美元增至2019年的19.81亿美元。每款新药上市后的销售峰值也从2018年的4.07亿美元下降至2019年的3.76亿美元，跌破4亿美元，不及2010年8.16亿美元的一半。资料来源：德勤 CRO企业在新药研发中有助于帮助制药企业降低研发成本，分散研发风险和提高研发效率。制药企业对其认可度不断的提高，选择研发外包服务的越来越多。根据Frost & Sullivan的数据统计，全球CRO行业的渗透率从2015年的43%，上升到2020年的54%左右。全球医药市场规模持续增长，研发投入的不断加大，制药企业研发外包率的上升，在研新药数量持续增长等因素共同推动了CRO行业规模的快速扩张。根据Frost & Sullivan的数据显示，2015年至2021年，全球CRO市场规模将从318.5亿美元增长到645.8亿美元，预计年复合增长率为12.8%。中国CRO市场规模将从2019年的68亿美元上升至2024年的222亿美元，年复合增长率约26.5%。国内的增速明显高于国外，未来随着国内对创新药研发的需求加速释放及更多的海外药企订单，CRO行业将迎来持续增长的黄金机遇。 02国内外CRO上市公司基本情况单从CRO业务收入来看，泰格医药2020年上半年营收14亿元左右；药明康德在2020年半年度报告，披露公司临床研究及其他 CRO 服务实现收入 49,999.77万元，同比增长5.92% 。从员工人数来看，排名靠前的药明系、康龙化成、泰格医药和凯莱英，员工人数在4000到2万多，员工人数在1000人以上的有博腾股份、睿智医药、昭衍新药和美迪西。CRO属于劳动密集型产业，员工人数的多少一般对应着公司的规模大小。从2020年前三季研发费用来看，药明康德4.75亿元排名第一，其他研发费用过亿的有凯莱英、药明生物、泰格医药和金斯瑞生物。图5：国内CRO上市公司2020年前三季基本情况注意：红色部分是2020年中报，市值按照1月22日收盘价单位：亿元资料来源：上市公司财报；药融圈整理从国内主要上市公司CRO业务布局来看，药明康德从临床前后到药物开发阶段及临床服务布局很完整；康龙化成在化合物研究和药物发现领域占据优势，具备大规模的实验室化学服务能力；泰格医药在临床CRO占据重要地位；凯莱英和博腾股份专注于药物开发阶段的工艺研发及生产业务；昭衍新药专注在安评和有效性研究方面；美迪西和睿智化学集中在临床前的化合物研究和药物发现领域；博济医药业务专注于临床期药物开发服务；成都先导更专注于药物筛选阶段方面。图6：A股主要上市公司CRO业务分布资料来源：公司财报；药融圈整理根据光大证券整理的全球CXO的数据来看，主营CRO的美国控股实验室、IQVIA在2019年营收达到700—800多亿人民币，从全球对标来看，国内的药明康德、泰格医药等CRO类公司，收入还有很大的提升空间。毛利率方面国内外CRO公司相差不大，国内公司的净利率相对较高，主要由于工程师红利导致的人力成本便宜。从员工人数和人均创收来看，国内公司还有较大提升空间，从全球CRO公司2019年营收规模来看药明康德排名第8。图7：国内外CRO相关上市公司2019年营收情况（亿人民币）图片来源：药融圈从市值来看，国内大部分CXO公司已经超过国外公司，但是营收和利润远远小于国际巨头，反应了国内证券市场投资者对CXO行业及代表性企业的看好，未来要关注业绩是否能跟上来。图8：国内外CXO相关公司经营数据对比2019 国内CRO企业分布情况从下图CRO企业分布来看，主要集中在北京、江浙沪等地。主要和沿海地区制药业发达，医药类人才聚集，跨国药企集中有关。CDMO企业分布情况请看：《2021年中国制药CDMO产业地图》。据Frost & Sullivan数据显示，国内CRO企业收入在1亿以上占5.6%，5000万到1亿占比7.1%，1000万到5000万收入占比21.7%，剩下的大部分营收在1000万以下。其中营收较高的企业都是以创新药CRO服务为主，营收较低的企业以仿制药CRO服务为主，同时也在不断转型升级中。图9：中国CRO企业营收分布情况数据来源：Frost& Sullivan ；药融圈制图未上市公司有不少特色的企业，本文仅列举少数几个。如北京的百奥赛图，该公司可以提供品系齐全的基因编辑动物模型用于基础和临床前研究，包括系列免疫检查点人源化小鼠，重度免疫缺陷B-NDG小鼠等。值得注意的是随着与祐和医药合并，公司战略转型为Biotech，未来将更聚焦于创新抗体药物研发。烟台迈百瑞生物2020年B轮融资超过5亿元人民币，拥有烟台、上海、美国圣地亚哥三个研发及生产中心，可以为全球客户提供单抗、双抗、融合蛋白、ADC等创新生物药、生物类似药的早期开发、工艺开发、临床样品生产、商业化生产、国内外IND/BLA申报等一站式、定制化服务。迈百瑞同样为荣昌制药集团下一块布局，除荣昌生物外。中国制药企业多板块布局也是一个小趋势。总部位于上海的凌凯医药是一家专业医药外包服务提供商。能提供从克级、公斤级、百公斤级和吨级医药中间体和原料药的CRO和CDMO服务，拥有江西医药中间体工厂和山东GMP工厂。目前已已积累全球超千家优质客户，并和多家知名跨国药企形成项目合作。此前与上市公司富祥药业达成战略合作。总部位于上海的有临医药专注肿瘤领域临床CRO服务，2020年完成超亿元A轮融资。有别于传统CRO模式，有临医药开发的智能化系统赋能于临床研究团队，能够远程、动态、智能化、个性化的进行多中心协同管理，大大提升了临床研究的效率和数据质量。临床CRO百花齐放，未来更侧重质量输出。上海昊航旗下的龙曦宁（上海）医药是一家专注于新药起始物料、为药企提供药物分子砌块的设计、合成以及医药中间体研发、生产的CRO/CDMO服务公司。拥有一支近百人的高素质研发团队，长期服务于日本京瓷、日星、东京化学、兼松、三友以及卡博森斯化学、桑迪亚医药、药明康德、Merck等跨国药企。医药圈内有不少这样默默耕耘的服务型企业，值得关注。则正（上海）生物科技有限公司是一家医药研发型企业，公司核心研发人员主要来自跨国企业和海外人士，致力于为海内外企业提供合规高效的新药、改良新药和仿制药研发服务，公司与临床基地合作建立了CRO服务团队。浙江湃肽生物具有年产上百公斤级多肽原料药能力，取得多项发明专利，可满足规模化药用多肽生产，目前已经为全球1000多家客户持续稳定提供多肽产品和CRO及CDMO服务。近期与华熙生物达成战略合作。苏州晶云药物目前已经提交科创板IPO，通过建立的国内首个药物晶型研发平台，致力于提高中国创新药物研发的整体实力及药品质量，并在此基础上通过资源整合、完善配套，以晶型研究为起点深入纵向发展，推出新药CMC服务，帮助全球各制药公司加速新药研发进程及提高药物的临床表现，提早在中美等地区提交新药申请并上市。地处长沙的湖南慧泽医药成立于2014年，是一家专注于创新制剂研发及早期临床试验专业服务的合同研究组织（CRO）。目前已经完成技术服务项目包括创新药I期临床试验和仿制药PK/BE试验总计超过500项。图10：2021国内CRO部分企业分布资料来源：药融圈 CRO（新药、仿制药不同阶段服务；临床前细分、临床阶段细分及SMO服务） 03总结截止到2021年1月26日，药明康德、博腾股份、美迪西、昭衍新药和康龙化成发布了2020年报预告，都保持了高速增长。从行业景气度来看，国内CRO企业市占率占全球的比例还会提升，和国外的相关公司对标来看，市值已经提前到了新的高度，营收未来还有较大的提升。目前CRO类上市公司不足20家，未来会有更多的优秀CRO企业上市。据相关统计，全国CRO企业有几百家，图中只是列举部分代表性企业，需要相对完整的CRO名单，请关注药融圈公众号并回复“药圈CRO地图”索取。分享：发送药圈CRO地图（请正确复制）至药融圈微信公众号（扫描下二维码）后台可获得全国CRO企业原文件。仅供学习交流分享，勿作他用！扫码加入“药融圈||CXO产业信息交流群” 更多药物/药企信息，请扫药融云小程序或网站www.pharnexcloud.com 参考： NMPA/CDE；药融云数据，www.pharnexcloud.com； FDA/EMA/PMDA；相关公司公开披露；上市公司财报；券商报告等等。【关于药融圈】药融圈围绕我国生物医药产业链，针对生物医药大数据、技术和资本投资、药融园(产业园)等开展系列系统性工作，促进我国生物医药产业健康发展，完善产业链，共同面对全球合作和竞争。点分享点点赞点在看