galectin-3

帕金森病（PD）是一种影响中枢神经系统的退行性疾病，在美国大约有100万人受到它的影响，而预计到2042年，全球的患者人数可能会攀升至1290万。作为仅次于阿尔茨海默病的第二大神经退行性疾病，帕金森病主要影响老年人群，在85至89岁年龄段达到发病高峰，并且男性比女性更容易患病。 在临床上，帕金森病患者会经历多种运动和非运动症状，这些症状给他们的日常生活带来了诸多不便。病理特征上，帕金森病表现为黑质区域神经元的丧失，导致纹状体内的多巴胺含量减少，并伴有中脑区域出现的路易小体。 虽然高龄被认为是帕金森病的主要风险因素之一，但生活方式的选择，如饮食习惯，以及环境暴露也同样在疾病的发展过程中扮演了重要角色。在过去十年里，遗传学研究揭示了一些与家族性帕金森病相关的罕见基因突变，并通过大规模全基因组关联研究GWAS）发现了散发性帕金森病的多基因背景。尽管已知的遗传变异解释了大约22%的遗传易感性，但至今为止确认的遗传位点只能解释其中的一小部分。 为了填补这一空白，需要更多的病例研究。此外，理解帕金森病风险变异的功能影响对于确定潜在的治疗目标至关重要。然而，尽管人类遗传学在药物研发中用于识别和验证靶标，但GWAS信号往往不能明确指出致病基因。 蛋白质组学研究可以补充这一不足，因为它能帮助我们了解帕金森病风险变异的功能效应，并可能识别出治疗目标和潜在生物标志物。蛋白质不仅是细胞结构的基础，也是许多调节过程的关键参与者，它们的作用不仅取决于其数量，还包括其相互作用、运输以及翻译后的修饰。因此，蛋白质组学研究具有巨大的潜力，可以作为生物标志物、治疗目标及疾病进程监测的工具。 近期的技术进步使得大规模的人群蛋白质组学研究成为可能，例如英国生物银行制药蛋白质组学项目（UKB-PPP），就为研究基因-蛋白质相互作用提供了新的机会。 图片来源：https://doi.org/10.1038/s41467-024-50718-x 近日，来自美国的研究者们在Nat Commun杂志上发表了题为“Proteogenomic network analysis reveals dysregulated mechanisms and potential mediators in Parkinson's disease”的文章，这项研究通过蛋白质基因组网络分析揭示了帕金森病中的失调机制和潜在的介质，有助于我们更好地理解帕金森病中的基因-蛋白质动态，并为识别与GWAS信号相关的潜在介质提供了范例。 蛋白质基因组网络分析 图片来源：https://doi.org/10.1038/s41467-024-50718-x 在这项研究中，研究者开发了一个三相系统级蛋白质基因组学分析框架来表征疾病相关蛋白质和失调机制。蛋白质基因组学分析确定了577种丰富帕金森病相关途径的蛋白质，如细胞因子受体相互作用和溶酶体功能，以及9种在疾病发病机制中具有潜在作用的蛋白，包括LGALS3、CSNK2A1、SMPD3、STX4、APOA2、PAFAH1B3、LDLR、HSPB1、BRK1。 蛋白质基因组网络分析揭示了帕金森病的失调机制和潜在的介质示意图 图片来源：https://doi.org/10.1038/s41467-024-50718-x 综上所述，通过整合UkB蛋白质基因组数据，研究者们创建了一个网络模型，以描绘基因组-蛋白质组的关系及其相互作用。这种综合方法为理解帕金森病及其他复杂疾病的遗传驱动蛋白破坏提供了一个全面的视角，并为进一步研究这些受影响的蛋白质奠定了基础。 参考文献： Abolfazl Doostparast Torshizi et al. Proteogenomic network analysis reveals dysregulated mechanisms and potential mediators in Parkinson's disease. Nat Commun. 2024 Jul 31;15(1):6430. doi: 10.1038/s41467-024-50718-x. 本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！ 点击下方「阅读原文」，前往生物谷官网查询更多生物相关资讯~

BOSTON, Aug. 28, 2024 (GLOBE NEWSWIRE) -- Galecto, Inc. (NASDAQ: GLTO), a clinical-stage biotechnology company focused on the development of novel treatments for cancer and fibrosis, today announced that it will implement a 1-for-25 Reverse Stock Split of its common stock (the “Reverse Stock Split”), effective at 5:00 p.m. Eastern Time on Thursday, August 29, 2024. The Reverse Stock Split, which was approved by shareholders at the company’s Annual Meeting of Stockholders on June 20, 2024, is primarily intended to bring the company into compliance with the minimum bid price requirement for maintaining its listing on The Nasdaq Capital Market. Beginning with the opening of trading on Friday, August 30, 2024, the company’s common stock will trade on the Nasdaq Capital Market on a split-adjusted basis under the existing symbol “GLTO” and a new CUSIP number 36322Q 206. At the effective time of the Reverse Stock Split, every twenty-five (25) shares of the company’s issued and outstanding common stock will be automatically converted into one (1) issued and outstanding share of common stock without any change in the par value of $0.00001 per share. This will reduce the company’s number of shares of outstanding common stock from approximately 27.1 million shares to approximately 1.1 million shares. The total authorized number of shares will not be reduced. Proportional adjustments will be made to the number of shares of common stock issuable upon exercise of the company’s outstanding stock options and restricted stock units, as well as the applicable exercise price of the stock options. No fractional shares of common stock will be issued as a result of the Reverse Stock Split. In lieu of issuing fractional shares, shareholders of record who otherwise would be entitled to receive fractional shares will be entitled to rounding up of the fractional share to the nearest whole number. The Reverse Stock Split impacts all holders of the company’s common stock proportionally and will not impact any shareholder’s percentage ownership of common stock (except for immaterial adjustments that may result from the treatment of fractional shares). Computershare Inc. is acting as exchange agent for the Reverse Stock Split. Registered shareholders holding pre-split shares of the company's common stock are not required to take any action to receive post-split shares. Shareholders owning shares via a broker, bank, trust or other nominee will have their positions automatically adjusted to reflect the Reverse Stock Split, subject to such broker's particular processes, and will not be required to take any action in connection with the Reverse Stock Split. Additional information about the Reverse Stock Split can be found in Galecto’s definitive proxy statement (Form DEF 14A) filed with the U.S. Securities and Exchange Commission (the "SEC") on April 29, 2024. About GalectoGalecto is a clinical stage company incorporated in the U.S. that is developing small molecule-based inhibitors of galectin-3 and LOXL2. Galecto has multiple Phase 2 clinical opportunities in fibrosis and cancer, including (i) an orally active LOXL2 inhibitor (GB2064) for the treatment of myelofibrosis; (ii) an orally active galectin-3 inhibitor (GB1211) for the treatment of liver cirrhosis; and (iii) an orally active galectin-3 inhibitor (GB1211) in combination with a checkpoint inhibitor for various oncology indications. In September 2023, Galecto announced that it initiated a process to evaluate strategic alternatives. As part of this ongoing strategic review process, Galecto continues to explore potential strategic alternatives that include, without limitation, a stock or asset acquisition, merger, business combination, liquidation, dissolution or other transactions. Forward-Looking StatementsCertain statements in this press release are forward-looking statements that involve a number of risks and uncertainties. Such forward-looking statements include statements regarding the timing of the implementation of the Reverse Stock Split and our compliance with the continued listing requirements of The Nasdaq Capital Market, our compliance with the continued listing requirements of The Nasdaq Capital Market and our plans and expectations regarding our strategic alternative review process that we announced in September 2023 and the timing and success of such process, including the completion of a potential transaction. Such forward-looking statements include statements about Galecto’s focus, plans for clinical development, product candidates and pipeline. The words “may,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “estimate,” “predict,” “project,” “potential,” “continue,” “target” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. For such statements, Galecto claims the protection of the Private Securities Litigation Reform Act of 1995. Actual events or results may differ materially from Galecto's expectations. Factors that could cause actual results to differ materially from the forward-looking statements include risks and uncertainties related to the development of Galecto’s product candidates and their therapeutic potential, having adequate funds and their use, and those disclosed in Galecto’s filings with the Securities and Exchange Commission (SEC), including, but not limited to, Galecto’s Annual Report on Form 10-K, as filed with the SEC on March 8, 2024. These forward-looking statements represent Galecto's judgment as of the time of this release. Galecto disclaims any intent or obligation to update these forward-looking statements, other than as may be required under applicable law. For more information, contact: Galecto, Inc. Hans Schambye, CEO +45 70 70 52 10 Investors/USMedia/EUAshley R. RobinsonSandya von der Weidarr@lifesciadvisors.com svonderweid@lifesciadvisors.com +1 617 430 7577+41 78 680 0538

*仅供医学专业人士阅读参考我们都知道，身体是具有很强的调节修复能力的。对于多发性硬化症患者来说，免疫系统异常，对髓鞘进行攻击导致髓鞘损伤或破坏（原发性脱髓鞘），从而影响神经系统功能。在脱髓鞘发生后，神经系统也自发启动了髓鞘再生过程，使少突胶质细胞祖细胞（OPC）分化为成熟的少突胶质细胞，并在轴突周围产生新的髓鞘。但是随着年龄增长，髓鞘再生不能完全覆盖受损髓鞘，最终导致患者病程进展加快。找到年龄相关的髓鞘再生调控通路，并逆转衰老相关退化，是再生医学领域的重要研究课题。慕尼黑工业大学的MIKAEL SIMONS及其团队在2018年发现，在衰老小鼠中，大量含有胆固醇的髓鞘碎片影响了小胶质细胞的代谢，脂质代谢受损，从而阻碍衰老状态下的组织再生。但是依然没能详细描述其中的潜在机制。近日，MIKAEL SIMONS团队再次在《免疫》杂志上发文，发现了促进衰老中枢神经系统髓鞘再生的方法。他们发现，小胶质细胞中的两种组蛋白去乙酰化酶（HDAC1/2）是调控衰老小鼠髓鞘再生能力的关键，条件性删除HDAC1/2可以恢复衰老小鼠的髓鞘再生能力。研究人员还发现了训练先天免疫促进髓鞘再生的方法。给髓鞘损伤小鼠注射减毒卡介苗（BCG），可以使脑内髓系细胞的表观遗传重编程，促进髓鞘碎片的清除和病变恢复。为了对比年轻小鼠和衰老小鼠在大脑脱髓鞘损伤后小胶质细胞的不同反应，研究人员使用3月龄和15月龄小鼠，分别诱导小鼠大脑白质的局灶性脱髓鞘病变，脱髓鞘在4-7天内完成，大脑自发的修复过程在14至21天（dpi）达到高峰。在诱导注射7天（dpi）时对病变小鼠的白质束进行单核RNA测序。分析结果显示，年轻小鼠的小胶质细胞中与脂质代谢、先天免疫反应和吞噬作用相关的基因表达活跃，意味着在脱髓鞘修复过程有更强的免疫和代谢反应能力，而衰老小鼠小胶质细胞的相关转录反应不足。脱髓鞘损伤后年轻和衰老小鼠小胶质细胞/巨噬细胞基因表达差异鉴于染色质可及性对基因的正常表达至关重要，因此研究人员分析了衰老小鼠的染色质的可及性。他们发现，衰老小鼠染色质的可及性较年轻小鼠降低，尤其是参与先天免疫反应、脂质代谢、细胞定位和组织代谢的相关基因。这些年龄相关的表观遗传变化影响衰老小鼠小胶质细胞的活化和髓鞘脂质清除，导致髓鞘再生能力下降。BCG疫苗已经被证明可以引起免疫细胞的表观遗传变化，通过激活和重新编程先天免疫系统，增强机体对多种病原体的抵抗力。为了能够让衰老小鼠的小胶质细胞产生年轻时的促再生反应，研究人员向衰老小鼠注射BCG疫苗，尝试用先天免疫训练方案进行表观遗传重编程。与对照组相比，BCG小鼠小胶质细胞/巨噬细胞染色质蛋白组H3K27ac标记显著富集，H3K4me3标记也有所增加。这些表观遗传学变化，意味着染色质可及性增加。相应地，研究人员确实观察到与先天免疫反应、脂质代谢、炎症和干扰素反应相关基因的转录水平增加。卡介苗免疫促进老年小鼠脱髓鞘损伤后病变恢复接下来，研究人员验证了先天免疫训练的效果。在病变诱导前一个月，向老年小鼠注射BCG疫苗或生理盐水，之后在4dpi和14dpi时观察小鼠病变和恢复情况。第4dpi时，BCG处理组和对照组小鼠脱髓鞘病变大小相似，但是BCG小鼠的小胶质细胞/巨噬细胞表现出更高的反应性，MAC2+IBA1+和MHCII+IBA1+细胞比例增加；14dpi时，BCG小鼠的病变体积已经小于对照组小鼠，并且成熟少突胶质细胞比例增加，再生功能得到恢复；同时，BCG小鼠的髓鞘碎片清除和脂质代谢也得到明显改善。小胶质细胞中HDAC1/2缺失可改善老年小鼠的髓鞘再生研究人员还发现，与年轻小鼠相比，衰老小鼠小胶质细胞中的组蛋白去乙酰化酶1（HDAC1）和组蛋白去乙酰化酶2（HDAC2）活性显著增加，经BCG处理的小鼠HDAC1和HDAC2活性又略有降低。特异性敲除小鼠的HDAC1/2，可以观察到脱髓鞘小鼠的病变体积减少，少突胶质细胞数量增加，表明HDAC1/2缺失改善了小胶质细胞的再生反应。虽然BCG接种可以增强衰老小鼠的髓鞘再生，但是在HDAC1/2缺失小鼠中，BCG的先天免疫训练反应失效，表明BCG诱导的先天免疫训练是通过调控HDAC1/2来实现的。总的来说，研究找到了衰老相关的小胶质细胞功能的调控因子，并且证明可以通过先天免疫重编程来预防这种衰老相关的功能衰退。参考文献：Tiwari V, Prajapati B, Asare Y, et al. Innate immune training restores pro-reparative myeloid functions to promote remyelination in the aged central nervous system[J]. Immunity, 2024.本文作者丨王雪宁