Monash University

从使用药物到滥用药物的道路始于遗传和环境因素造成的脆弱性背景。物质使用障碍(Sud)是一个总称，定义了一种因反复滥用某种物质而导致临床上显著损害的慢性疾病；实际上，是一种物质成瘾。 从使用药物到滥用药物的道路始于遗传和环境因素造成的脆弱性背景。物质使用障碍(Sud)是一个总称，定义了一种因反复滥用某种物质而导致临床上显著损害的慢性疾病；实际上，是一种物质成瘾。 SSD一般可分为三个阶段：全神贯注/期待、狂欢/醉酒和退缩/消极情绪。滥用的主要成瘾物质分为尼古丁、酒精、大麻、类阿片、镇静剂和兴奋剂。 图片来源：https://pubmed.ncbi.nlm.nih.gov/37679998/ 近日，来自莫纳什大学的研究者们在Br J Pharmacol杂志上发表了题为“Molecular and structural insights into the 5-HT2C receptor as a therapeutic target for substance use disorders”的文章，该研究揭示了5-HT2C受体作为药物使用障碍治疗靶点的分子和结构研究。 物质使用障碍(SUD)是一种慢性疾病，持续滥用某种物质会导致生理和心理变化，并经常改变认知和社会行为。目前的治疗方法包括心理治疗和药物治疗；然而，高复发率揭示了这些治疗方法的缺点。 5-羟色胺2C受体(5-HT2C受体)的信号、表达谱和神经功能使其成为治疗SUD的候选分子。最近，广泛作用于5-HT2受体的迷幻剂已显示出治疗SUD的潜力，涉及5-HT2C受体。现代迷幻运动重新点燃了人们对5-HT2C受体的兴趣，导致了许多新的研究，特别是结构分析。 本文就5HT2C受体功能调控的结构、分子和细胞机制作一综述。这为它们在SUD中的作用提供了临床前和临床证据的基础，并突出了未来探索的潜力。 5-HT2C受体激活下游的细胞内通路 图片来源：https://pubmed.ncbi.nlm.nih.gov/37679998/ 5-HT2C是治疗肥皂症的一个有趣的治疗靶点，因为它在与疾病相关的关键大脑区域中的表达和活动情况。因此，疾病背景在RNA编辑表达谱和预测功能结果中起着重要作用。虽然这种受体的激动剂并不缺乏，但很少有人成功地用于肥皂泡的治疗，可能是因为难以管理的靶向和靶向外的副作用；包括迷幻剂。 GPCR结构生物学的最新进展将为靶向5HT2C受体的治疗提供新的见解和方法，并可包含该受体的独特特征，包括RNA编辑的异构体和多效性偶联。下一代受体和异构体选择性5-HT2C受体疗法的阶段现在已经准备就绪，用于SUD及以后的治疗。（生物谷 Bioon.com） 参考文献 Maleesha Ubhayarathna et al. Molecular and structural insights into the 5-HT2C receptor as a therapeutic target for substance use disorders. Br J Pharmacol. 2023 Sep 7. doi: 10.1111/bph.16233.

肺动脉高压(PAH)是一种罕见但致命的疾病，其特征是炎症、血管重构和血管收缩。目前的血管扩张剂治疗可以降低肺动脉压(PAP)，但不能降低死亡率。 肺动脉高压(PAH)是一种罕见但致命的疾病，其特征是炎症、血管重构和血管收缩。目前的血管扩张剂治疗可以降低肺动脉压(PAP)，但不能降低死亡率。G蛋白偶联的甲酰肽受体(FPR)介导血管扩张和炎症消退，这些作用可能有益于PAH。研究者利用小鼠精密肺切片(PCLS)研究了偏向于FPR的激动剂化合物17b(Cmpd17b)在肺血管中的扩张剂和抗炎作用。 图片来源：https://pubmed.ncbi.nlm.nih.gov/37696768/ 近日，来自莫纳什大学的研究者们在Br J Pharmacol杂志上发表了题为“Flucloxacillin worsens while imipenem-cilastatin protects against vancomycin induced kidney injury in a translational rat model”的文章，该研究首次提供了靶向FPR的证据，使用一种有偏见的激动剂，同时靶向血管功能和炎症，支持基于FPR的药物治疗PAH的发展。 研究者使用8周龄雄性和雌性C57BL/6小鼠的PCLS，用5-羟色胺预收缩肺内动脉，以测定对FPR激动剂Cmpd17b和Cmpd43以及标准护理西地那非、伊洛前列素和利奥昔格特的浓度-反应曲线。 Cmpd17b介导的松弛作用于±fpr受体拮抗剂或药物抑制剂，以及经肿瘤坏死因子-α或内毒素处理的PCLS。测定经肿瘤坏死因子-α和内毒素处理后的PCLS±Cmpd17b细胞因子的释放。 Cmpd17b可引起浓度依赖性的血管扩张，其作用强度为iloprost>Cmpd17b=riociguat>Cmpd43=Sildenaven。Cmpd17b可被FPR1拮抗剂环孢素-H抑制，但不能被sGC、NOS或COX的抑制剂抑制。在炎症条件下，Cmpd17b的疗效和效力保持不变，而伊洛前列素和西地那非的效果较差。此外，Cmpd17b通过FPR2抑制PAH相关细胞因子的分泌。 血管扩张剂对FPR激动剂Cmpd17b和Cmpd43以及标准护理血管扩张剂西地那非、利奥昔古特和伊洛前列斯特的反应 图片来源：https://pubmed.ncbi.nlm.nih.gov/37696768/ 对Cmpd17b的血管扩张，但不是标准护理血管扩张剂，在炎症条件下保持不变，并额外抑制PAH相关细胞因子的释放。本研究首次提供了靶向FPR的证据，使用一种有偏见的激动剂，同时靶向血管功能和炎症，支持基于FPR的药物治疗PAH的发展。（生物谷 Bioon.com） 参考文献 William R Studley et al. The small-molecule formyl peptide receptor biased agonist, Compound 17b, is a vasodilator and anti-inflammatory in mouse precision-cut lung slices. Br J Pharmacol. 2023 Sep 1. doi: 10.1111/bph.16231.

NEW YORK, Sept. 26, 2023 (GLOBE NEWSWIRE) -- Mesoblast Limited (Nasdaq:MESO; ASX:MSB), global leader in allogeneic cellular medicines for inflammatory diseases, today announced that independent Director Jane Bell AM has been appointed Chair of the Mesoblast Board Audit and Risk Committee. Ms Bell joined the Board in August 2022, and is a banking and finance lawyer with 30 years of corporate finance expertise focussing on international investment transactions in the United States, Canada, Australia and the United Kingdom, including funds management, mergers, acquisitions, and divestments. The Board thanked retiring Director and Chair of Audit and Risk Committee Mr Michael Spooner for his many years of dedicated service and contributions, and wished him well in his future endeavours. Commenting on her appointment as Chair of the Audit and Risk Committee, Ms Bell said, “My major focus will be to oversee and support management’s ongoing implementation of the Company’s cost containment and cash preservation initiatives. As outlined by Chief Executive Silviu Itescu very recently, the Company is targeting a 23% reduction (US$15 million) in annual net operating cash for FY2024 and a 40% annualized reduction in payroll by February 2024 which includes base salaries, short-term incentive payments and contractor fees. As important will be my focus on supporting the Chief Executive and management in the parallel pursuit of corporate initiatives to strengthen the balance sheet of the Company, including royalty monetization and strategic partnerships.” Ms Bell is currently Chair of the Audit and Risk Committee of publicly-listed biotechnology company Amplia Therapeutics, and serves as Chair of the Audit Committee and Deputy Chair of Monash Health, Australia’s largest and most diverse public health service delivering more than 3.46 million episodes of care across an extensive network of hospitals, rehabilitation, aged care, community health and mental health facilities. From 2014 until 2021 she was a director of U Ethical, Australia’s first ethical funds manager with over $1.2B of funds under management, and a member of both its Audit and Investment Committees. She has been a former Chair of Melbourne Health as well as of Advisory Groups for the Royal Australian and New Zealand College of Obstetricians and Melbourne Genomics Health Alliance, and has been a director of Hudson Institute of Medical Research and Chair of its Intellectual Property and Commercialization Committee. Ms Bell holds a Master of Laws from King’s College (London), Bachelor of Laws University of Melbourne, and Bachelor of Economics Monash University. In 2023 Ms Bell was appointed a Member of the Order of Australia (AM) for her significant service to governance in the medical research, healthcare and not-for-profit sectors. About Mesoblast Mesoblast (the Company) is a world leader in developing allogeneic (off-the-shelf) cellular medicines for the treatment of severe and life-threatening inflammatory conditions. The Company has leveraged its proprietary mesenchymal lineage cell therapy technology platform to establish a broad portfolio of late-stage product candidates which respond to severe inflammation by releasing anti-inflammatory factors that counter and modulate multiple effector arms of the immune system, resulting in significant reduction of the damaging inflammatory process. Mesoblast has a strong and extensive global intellectual property portfolio with protection extending through to at least 2041 in all major markets. The Company’s proprietary manufacturing processes yield industrial-scale, cryopreserved, off-the-shelf, cellular medicines. These cell therapies, with defined pharmaceutical release criteria, are planned to be readily available to patients worldwide. Mesoblast is developing product candidates for distinct indications based on its remestemcel-L and rexlemestrocel-L allogeneic stromal cell technology platforms. Remestemcel-L is being developed for inflammatory diseases in children and adults including steroid refractory acute graft versus host disease, biologic-resistant inflammatory bowel disease, and acute respiratory distress syndrome. Rexlemestrocel-L is in development for advanced chronic heart failure and chronic low back pain. Two products have been commercialized in Japan and Europe by Mesoblast’s licensees, and the Company has established commercial partnerships in Europe and China for certain Phase 3 assets. Mesoblast has locations in Australia, the United States and Singapore and is listed on the Australian Securities Exchange (MSB) and on the Nasdaq (MESO). For more information, please see www.mesoblast.com, LinkedIn: Mesoblast Limited and Twitter: @Mesoblast Forward-Looking StatementsThis press release includes forward-looking statements that relate to future events or our future financial performance and involve known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to differ materially from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. We make such forward-looking statements pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 and other federal securities laws. Forward-looking statements should not be read as a guarantee of future performance or results, and actual results may differ from the results anticipated in these forward-looking statements, and the differences may be material and adverse. Forward-looking statements include, but are not limited to, statements about: the initiation, timing, progress and results of Mesoblast’s preclinical and clinical studies, and Mesoblast’s research and development programs; Mesoblast’s ability to advance product candidates into, enroll and successfully complete, clinical studies, including multi-national clinical trials; Mesoblast’s ability to advance its manufacturing capabilities; the timing or likelihood of regulatory filings and approvals, manufacturing activities and product marketing activities, if any; the commercialization of Mesoblast’s product candidates, if approved; regulatory or public perceptions and market acceptance surrounding the use of stem-cell based therapies; the potential for Mesoblast’s product candidates, if any are approved, to be withdrawn from the market due to patient adverse events or deaths; the potential benefits of strategic collaboration agreements and Mesoblast’s ability to enter into and maintain established strategic collaborations; Mesoblast’s ability to establish and maintain intellectual property on its product candidates and Mesoblast’s ability to successfully defend these in cases of alleged infringement; the scope of protection Mesoblast is able to establish and maintain for intellectual property rights covering its product candidates and technology; estimates of Mesoblast’s expenses, future revenues, capital requirements and its needs for additional financing; Mesoblast’s financial performance; developments relating to Mesoblast’s competitors and industry; and the pricing and reimbursement of Mesoblast’s product candidates, if approved. You should read this press release together with our risk factors, in our most recently filed reports with the SEC or on our website. Uncertainties and risks that may cause Mesoblast’s actual results, performance or achievements to be materially different from those which may be expressed or implied by such statements, and accordingly, you should not place undue reliance on these forward-looking statements. We do not undertake any obligations to publicly update or revise any forward-looking statements, whether as a result of new information, future developments or otherwise. Release authorized by the Chief Executive. For more information, please contact: Corporate Communications / InvestorsMediaPaul HughesBlueDot MediaT: +61 3 9639 6036Steve DabkowskiE: investors@mesoblast.comT: +61 419 880 486 E: steve@bluedot.net.au