ENT2

40Hz多感官刺激如果可以作为一种新型非侵入性策略，调节并增强脑类淋巴流动，将为相关疾病的治疗带来极大的改善。 近日，来自温州医科大学附属眼视光医院陈江帆教授的研究成果，将40Hz感官刺激促进脑内致病蛋白清除的机制进行了更新升级。他们发现40Hz光闪烁增强了脑类淋巴的流入和流出，并且发现腺苷-A2A受体（A2AR）信号传导是脑类淋巴流动增强的神经化学基础。 研究发表在Cell Discovery杂志上。 脑类淋巴系统的运转依赖于脑脊液（CSF）的流动和星形胶质细胞末端足的水通道蛋白-4（AQP4）极化，使脑脊液和间质液（ISF）进行液体交换，帮助大脑清除代谢废物。 利用荧光示踪剂，研究人员可以看到40Hz光闪烁显著增加了野生型小鼠脑脊液流动，基底前脑、前额叶、上丘和海马等区域表现出显著的脑脊液灌注速度加快，淋巴流入和流出增强。 40Hz光闪烁增强淋巴流入和流出 AQP4作为血管周围空间的外部屏障，在40Hz光闪烁30分钟后，极化显著增加，意味着更有效地定位在星形胶质细胞末端足处，有助于增强脑内的液体流动和类淋巴的废物清除功能。与此同时，小鼠的动脉血管运动和脑血流量显著增加，有助于增强类淋巴流入。 当然，研究人员也关注了小鼠的心血管健康。虽然血管运动增强，但是40Hz光闪烁没有造成小鼠的血压和心率显著上升，不会影响整体的心血管状态。 脑血流量增加 接下来，研究人员进一步探索40Hz光闪烁影响脑类淋巴流动的潜在机制。在之前的研究中，陈教授团队已经发现40Hz光闪烁可以增强胞外腺苷水平。而腺苷作为一种神经调质，在睡眠调控、心血管和炎症反应等功能中扮演着重要角色，并且与受体A2AR结合可以调节脑血流量。 因此，研究人员针对小鼠腺苷水平进行了分析。腺苷的跨膜转运依赖于两种不同的转运蛋白ENT1和ENT2。40Hz光闪烁30分钟后，小鼠脑脊液细胞外腺苷水平显著升高，脑类淋巴流动增强；分别对两种转运蛋白基因进行敲除，发现只有ENT2缺失影响了40Hz诱导的腺苷水平增加和脑类淋巴流动增强，并且在ENT2缺失小鼠中也没有发现AQP4的极化增加或者动脉血管运动增强。 ENT2缺失影响40Hz诱导的脑淋巴流动、血管运动和脑血流量增加 进一步对40Hz光闪烁诱导后的野生型小鼠大脑进行分析，可以看到全脑提取物中的ENT2密度增加以及A2AR密度增加，说明腺苷和A2AR在40Hz光闪烁促进脑类淋巴流动中的重要作用。 总的来说，研究证明40Hz光闪烁通过ENT2介导的腺苷释放和A2AR激活增强了野生型小鼠的脑类淋巴流动。 机制示意图 在多种衰老相关疾病以及神经系统疾病中，都存在脑类淋巴系统功能减退，从而导致认知能力下降和蛋白质病变。40Hz多感官刺激如果可以作为一种新型非侵入性策略，调节并增强脑类淋巴流动，将为相关疾病的治疗带来极大的改善。

*仅供医学专业人士阅读参考40Hz的神话还在继续。高频感觉刺激作为非侵入性策略，其调节大脑功能的作用正在被广泛接受。对于40Hz的光闪烁或者声音刺激在治疗阿尔茨海默病（AD）中的神奇表现，奇点糕从刚开始的大吃一惊到逐渐习惯，再之后有一阵子听不到40Hz的消息还有点想念。40Hz光闪烁治疗AD的临床试验已经在积极进行中，而对于相关机制的探索也从未停止。就在今年2月份，顶刊《自然》上的一项研究提出，40Hz多感官刺激可以促进AD小鼠脑脊液（CSF）和间质液（ISF）交换，加速淀粉样蛋白的淋巴清除。近日，来自温州医科大学附属眼视光医院陈江帆教授的研究成果，将40Hz感官刺激促进脑内致病蛋白清除的机制进行了更新升级。他们发现40Hz光闪烁增强了脑类淋巴的流入和流出，并且发现腺苷-A2A受体（A2AR）信号传导是脑类淋巴流动增强的神经化学基础。研究发表在Cell Discovery杂志上。脑类淋巴系统的运转依赖于脑脊液（CSF）的流动和星形胶质细胞末端足的水通道蛋白-4（AQP4）极化，使脑脊液和间质液（ISF）进行液体交换，帮助大脑清除代谢废物。利用荧光示踪剂，研究人员可以看到40Hz光闪烁显著增加了野生型小鼠脑脊液流动，基底前脑、前额叶、上丘和海马等区域表现出显著的脑脊液灌注速度加快，淋巴流入和流出增强。40Hz光闪烁增强淋巴流入和流出AQP4作为血管周围空间的外部屏障，在40Hz光闪烁30分钟后，极化显著增加，意味着更有效地定位在星形胶质细胞末端足处，有助于增强脑内的液体流动和类淋巴的废物清除功能。与此同时，小鼠的动脉血管运动和脑血流量显著增加，有助于增强类淋巴流入。当然，研究人员也关注了小鼠的心血管健康。虽然血管运动增强，但是40Hz光闪烁没有造成小鼠的血压和心率显著上升，不会影响整体的心血管状态。脑血流量增加接下来，研究人员进一步探索40Hz光闪烁影响脑类淋巴流动的潜在机制。在之前的研究中，陈教授团队已经发现40Hz光闪烁可以增强胞外腺苷水平。而腺苷作为一种神经调质，在睡眠调控、心血管和炎症反应等功能中扮演着重要角色，并且与受体A2AR结合可以调节脑血流量。因此，研究人员针对小鼠腺苷水平进行了分析。腺苷的跨膜转运依赖于两种不同的转运蛋白ENT1和ENT2。40Hz光闪烁30分钟后，小鼠脑脊液细胞外腺苷水平显著升高，脑类淋巴流动增强；分别对两种转运蛋白基因进行敲除，发现只有ENT2缺失影响了40Hz诱导的腺苷水平增加和脑类淋巴流动增强，并且在ENT2缺失小鼠中也没有发现AQP4的极化增加或者动脉血管运动增强。ENT2缺失影响40Hz诱导的脑淋巴流动、血管运动和脑血流量增加进一步对40Hz光闪烁诱导后的野生型小鼠大脑进行分析，可以看到全脑提取物中的ENT2密度增加以及A2AR密度增加，说明腺苷和A2AR在40Hz光闪烁促进脑类淋巴流动中的重要作用。总的来说，研究证明40Hz光闪烁通过ENT2介导的腺苷释放和A2AR激活增强了野生型小鼠的脑类淋巴流动。机制示意图在多种衰老相关疾病以及神经系统疾病中，都存在脑类淋巴系统功能减退，从而导致认知能力下降和蛋白质病变。40Hz多感官刺激如果可以作为一种新型非侵入性策略，调节并增强脑类淋巴流动，将为相关疾病的治疗带来极大的改善。参考文献：https://www.nature.com/articles/s41421-024-00701-z

- GMAB ADC demonstrated highly targeted delivery to tumor cells and durable tumor regression in preclinical model of colorectal cancer - - Results presented in a poster at the American Association for Cancer Research (AACR) Annual Meeting 2024 - HOPEWELL, N.J.--(BUSINESS WIRE)-- Gennao Bio, a privately held genetic medicines company developing first-in-class, targeted nucleic acid therapeutics, today announced new preclinical results on the application of its non-viral, cell penetrating gene monoclonal antibody (GMAB) platform technology as an antibody-drug conjugate (ADC) for the treatment of solid tumors. The data were presented in a poster at the American Association for Cancer Research (AACR) Annual Meeting 2024. Exploratory research evaluating GMAB’s ability to deliver conjugated cytotoxic payloads was conducted through Gennao’s ongoing collaboration with the laboratory of Peter M. Glazer, M.D., Ph.D., Chair of the Department of Therapeutic Radiology, Professor of Genetics and Robert E. Hunter Professor of Therapeutic Radiology at the Yale School of Medicine and co-founder of Gennao. In preclinical studies, our GMAB technology demonstrated selective delivery of payloads into tumors by targeting ENT2, a nucleoside transporter that is highly overexpressed in many tumors. ENT2 overexpression on both the plasma and nuclear membranes allows GMAB targeted therapies to internalize directly into the cytoplasm of tumor cells avoiding the endocytic pathway and traffic directly into the nucleus. In vitro studies of the GMAB ADC conjugated to exatecan, a potent topoisomerase I inhibitor, exhibited nuclear localization and activation of the DNA damage response pathway leading to tumor cell death. “The safe targeted delivery of cytotoxic drugs continues to be a challenge for the development of new ADCs. Leveraging GMAB as an ADC represents a highly differentiated approach to the delivery of drugs exclusively to tumors while avoiding harmful impact to healthy tissue. In preclinical studies, chronic treatment of the GMAB ADC demonstrated significant tumor regression and was well tolerated, providing support for the continued investigation of this novel delivery platform as an ADC,” said Dr. Glazer. In a preclinical study utilizing the DLD1 BRCA2 gene knockout xenograft mouse model of colorectal cancer, two aggressive systemic dosing regimens of the GMAB ADC were compared to exatecan alone and control. The GMAB ADC demonstrated durable tumor regression and a significant survival benefit compared to control and exatecan alone. Safety analyses showed no change in body weight throughout treatment and no change in blood chemistry markers indicative of no kidney or liver toxicity. Further, since ENT2 is also expressed in skeletal muscle, serum chemistry and analysis of muscle tissue sections demonstrated no indication of tissue damage to muscle. “These preclinical results reinforce the versatility of the GMAB platform and its ability to deliver therapeutic payloads beyond genetic medicine to targeted tissue,” Chris Duke, chief executive officer of Gennao. “Additional in vivo studies are planned through our collaboration with Yale to further optimize the GMAB ADC approach. The ability to leverage a novel antigen target, combined with GMAB’s unique biology, offers the potential to create promising novel, first-in-class treatment options for individuals living with cancer.” About Gennao Bio Gennao Bio is a genetic medicines company developing first-in-class targeted nucleic acid therapeutics utilizing its proprietary, non-viral gene monoclonal antibody (GMAB) platform technology. GMAB is an adaptive technology that uses a novel, cell-penetrating antibody to specifically deliver nucleic acid payloads to select cells while distinctly avoiding the endocytic pathway. This next-generation delivery platform is differentiated from traditional gene delivery systems, as it can rapidly and efficiently deliver multiple types of payloads for release in the cytoplasm and nucleus, allows for repeat dosing, and employs well-established antibody manufacturing processes. Gennao Bio is developing this delivery system with an initial focus on addressing significant unmet needs in skeletal muscle diseases and oncology.