Vascular dementia (VaD) ranks as the second most prevalent form of dementia and poses a considerable global health challenge. Icariin has been recognized for its robust neuroprotective effects in combating VaD. Nonetheless, the underlying mechanisms have not been fully elucidated. An integrated approach involving network pharmacology, molecular docking, and molecular dynamics simulations (MDS) was employed to systematically investigate the potential pharmacological actions of Icariin in counteracting VaD. The AGE/RAGE pathway was identified as a promising anti-inflammatory pathway. A chronic cerebral hypoperfusion mouse model was utilized to establish VaD. Both Icariin and FP S-ZM1 (a RAGE inhibitor) were administered through oral gavage and intraperitoneal injection, respectively. The Morris water maze (MWZ) was used to evaluate cognitive functions. Moreover, immunofluorescence, RT-qP CR, and Western blot analyses were carried out to evaluate the effects of FP S-ZM1 on neuroinflammation. Network analysis identified 14 crucial targets and highlighted the AGE-RAGE signaling cascade in diabetic complications as the foremost KEGG pathway with potential anti-neuroinflammatory property. MDS results suggested a stable binding of the RAGE-Icariin complex. Remarkably, Icariin was found to effectively mitigate cognitive deficits in VaD mice, which was correlated with the upregulation of the P I3K/AKT pathway and downregulation of the JNK/cJUN signaling cascade. Critically, co-administration of FP S-ZM1 enhanced Icariin's ameliorative effects on cognitive deficits, owing to bolstered anti-neuroinflammatory action. This study unveils the potential of Icariin in alleviating cognitive dysfunction and neuroinflammation in VaD, which may be attributed to the modulation of the AGE/RAGE pathway.Communicated by Ramaswamy H. Sarma.

2024-12-01·PHYTOMEDICINE

Geniposide ameliorates diabetic nephropathy in type 2 diabetic mice by targeting AGEs-RAGE-dependent inflammatory pathway

Article

作者: Ni, Ying ; Chen, Chao ; Zhang, Wensheng ; Dong, Zhaoqi ; Zhu, Dina ; Wang, Lei

BACKGROUND:

Diabetic nephropathy (DN) is a prevalent complication of diabetes mellitus and the primary cause of morbidity and mortality in end-stage renal disease. The receptor for advanced glycation end products (RAGE) plays a crucial role in mediating AGE-triggered inflammation, which has been implicated in DN pathogenesis. While geniposide, a natural compound, has demonstrated anti-inflammatory and hypoglycemic properties, its potential to mitigate AGE-induced renal inflammation and consequently impede DN progression remains unexplored.

PURPOSE:

The objective of this study was to ascertain whether geniposide is a novel natural AGEs-RAGE blocker and to investigate its protective effect on renal DN in type 2 diabetic mice.

METHODS:

Binding affinity between geniposide and RAGE was assessed using MicroScale Thermophoresis (MST), molecular docking, and co-immunoprecipitation. RAGE was then subjected to knockdown and overexpression in cellular experiments to evaluate geniposide's effects on AGE-induced inflammatory responses and the RAGE pathway. Finally, db/db mice were employed to validate the renoprotective effects of geniposide in DN.

RESULTS:

Geniposide exhibited higher binding affinity to RAGE's V domain than AGEs, competitively inhibiting AGEs-RAGE interaction through hydrogen bonding. It suppressed RAGE expression and RAGE-dependent inflammatory responses to AGEs, comparable to RAGE siRNA effects. In RAGE-overexpressing cells, geniposide further inhibited AGEs-induced ERK1/2 and NFκB P65 activation, reducing inflammatory marker levels. Long-term oral administration of geniposide to db/db mice improved plasma creatinine, urea, and proteinuria levels, ameliorated pathological changes, and downregulated inflammatory factors such as TNF-α and IL-1β. Moreover, it dose-dependently attenuated enhanced renal expression of RAGE, phosphorylated ERK1/2, IκB-α, and NF-κB P65.

CONCLUSION:

Geniposide effectively attenuates AGEs-induced RAGE activation by directly blocking AGEs-RAGE signal transduction, thereby mitigating inflammatory responses. These findings suggest that geniposide has potential as a high-affinity RAGE antagonist, potentially playing a crucial role in the treatment of DN.

2024-10-01·AGING CELL

Lens capsule advanced glycation end products induce senescence in epithelial cells: Implications for secondary cataracts

Article

作者: Nam, Mi‐Hyun ; Wormstone, Yvette M. ; Cooksley, Grace ; Nahomi, Rooban B. ; Rankenberg, Johanna ; Nagaraj, Ram H. ; Wormstone, I. Michael ; Smith, Andrew J. O.

Abstract:

Posterior capsule opacification (PCO) is a common complication after cataract surgery. Residual lens epithelial cells (LECs) on the anterior lens capsule, after cataract surgery, migrate to the posterior lens capsule and undergo transdifferentiation into myofibroblast‐like cells. Those cells synthesize excessive amounts of extracellular matrix and contribute to fibrosis during PCO. Cellular senescence, a phenomenon that increases with aging, has been implicated in several fibrotic diseases. Here, we have investigated the prevalence of senescent LECs within the lens posterior capsule and the ability of advanced glycation end products (AGEs) in lens capsules to induce senescence, contributing to PCO. Aged lens capsules from pseudophakic human cadaver eyes showed the presence of senescent LECs. In human capsular bags, LECs showed an age‐dependent increase in senescence after 28 days of culture. Human LECs cultured on aged lens capsules for 3 days underwent senescence; this effect was not seen in LECs cultured on young lens capsules. Human LECs cultured on an AGE‐modified extracellular matrix (ECM‐AGEs) showed an AGE‐concentration‐dependent increase in the expression of senescence markers and reactive oxygen species (ROS) levels. Treatment with a RAGE antagonist and ROS inhibitor reduced the expression of senescence and fibrotic markers. Additionally, conditioned media from ECM‐AGEs‐treated cells induced the expression of fibrotic markers in naïve LECs. Together, these suggest that AGEs in the capsule induce senescence of LECs, which triggers the mesenchymal transition of neighboring non‐senescent LECs and contributes to PCO.

项与 VG-301 相关的新闻（医药）

2023-10-12

·生物制药小编

论溶瘤病毒公司的共性

近几年来，溶瘤病毒可能是除了CAR-T之外设计上最为花哨的存在，例如分泌表达的蛋白从最开始的时候T-VEC用的GM-CSF，到现在大量涌入的各类细胞因子，趋化因子，多肽，抑制免疫检查点的单抗，双抗，花样是层出不穷，方法是日新月异。溶瘤病毒在设计思路不断内卷，追求疗效优异的同时，还有着许多与知名药物，如CAR-T，K药联合使用加强疗效，探索给药窗口，给药恰当时间的各类探索。扩展阅读：溶瘤病毒新产品设计越来越“花哨”本文选取了思路相对较为接近的三家企业，复诺健，滨会生物，亦诺微医药三家的异同进行简析。单纯疱疹病毒的改造由于本文选取的这三家企业都采用的是单纯疱疹病毒作为溶瘤病毒的载体。因此先行了解单纯疱疹病毒的特性相当重要。单纯疱疹病毒(Herps simplex virus，HSV)是一种长约154kb的双链DNA病毒，可在受染宿主细胞核中复制。而采用的HSV载体具有以下优点：①宿主细胞广泛；②病毒滴度高；③外源基因容量大。但是HSV载体的缺点在于它的毒性——其中一些它表达的蛋白可能产生毒性，而HSV本身也是一种神经嗜好的病毒。因此对于HSV的改造许多都是围绕HSV一些毒性蛋白，例如剃除神经毒因子ICP34.5后能够靶向肿瘤，剔除ICP47后能够增强免疫等等。有趣的是，尽管目前常用到的是HSV载体是HSV-1（I型野生型HSV），这三家中只有滨会生物特别去开发了II型HSV。滨会生物开发II型HSV的原因在于克服HSV-1生产周期长、溶瘤活性不足的缺点，开发HSV-II能够减少生产周期、增加溶瘤活性。复诺健：溶瘤病毒+mRNA从管线而言，复诺健的所有管线基本上都是建立在IL-12-IL-15-IL-15Rα表达框的基础上的各类添加，这也是复诺健的核心有效载荷。可以看到目前临床进度最快的VG161就是在这个基础上加了能够表达抑制PD-L1的多肽，也因此VG161也是可以联合BMS的O药，恒瑞的卡瑞利珠单抗，做出基于PD-1抑制剂+PD-L1/IL-12-IL-15-IL-15Rα溶瘤病毒的组合。而在这个基础上还有更深一步的补强，VG161本身采用的是ICP34.5减毒骨架，后续复诺健还开发了一种转录翻译双重调控TTDR非减毒骨架。减毒和非减毒毕竟是双刃剑，减毒了担心疗效，非减毒担心安全。虽然专利未公开但根据该公司官网显示，结合创始人贾为国博士的相关文献可以进行合理的推测。复诺健的做法可能是通过提高选择性，避免对非肿瘤细胞的杀伤。这种TTDR骨架在原本骨架不去减毒的基础上去结合肿瘤抑制性miRNA。例如在2013年的一项研究中，正常细胞中的miRNA-145表达量很高，研究人员就将miRNA-145靶序列的多拷贝整合到必需IE基因如感染细胞蛋白27 (ICP27)或感染细胞蛋白4 (ICP4)的3′-UTR中，而miRNA-145靶序列整合到基因组后，溶瘤病毒就难以在正常细胞中的miRNA复制了。因此可以产生选择性靶向。而在非减毒骨架技术的背景下，复诺健又开发了VG201和VG203。VG201则是能够靶向CEA，VG203能够通过肿瘤特异性的CXCR4来启动，VG301则在VG201技术的基础上更进一步，甚至能分泌双抗达成CEACAM6xCD3 T细胞接合器的组合。而除了目前已知的溶瘤病毒管线之外，该公司还有开发预防猴痘和新冠的mRNA疫苗以及针对HER2激活免疫的mRNA疫苗。未来也许看到该公司mRNA+溶瘤病毒的组合。亦诺微医药：溶瘤病毒+外泌体亦诺微医药可能是这三家中玩得最花的。最开始设计的MVR-T3011倒也还好，后续的T7011不仅能够表达趋化因子和CAR-T靶点，更是找上了CAR-T联合治疗，思路相当有趣。亦诺微MVR-T3011的研究在于oHSV作为载体表达IL-12和PD-1抗体，思路上和复诺健的VG161类似，这也是亦诺微医药此前就已经开发的临床管线MVR-T3011（下图为其结构）。此前MVR-T3011就已经展现了相当不错的疗效。而MVR-T7011则在此基础上进一步进行开发。由于已经有一些将腺病毒或工程化溶瘤痘苗病毒用作溶瘤标记的先例，因此亦诺微医药的研究人员在发现CD19/BCMA双靶点CAR-T无论临床前还是临床后都展现出了对复发和难治性多发性骨髓瘤较好的治疗效果后（所有5名患者对治疗均有反应:1名患者达到sCR，3名达到VGPR，1名达到PR），便决定将CD19和BCMA作为作为靶标。由于oHSV递送至肿瘤的CD19和BCMA对于CAR T细胞治疗这个过程是至关重要的。在CAR T细胞到达靶向肿瘤细胞之前，输注的CAR T细胞需要先从血流到达实体肿瘤区域，渗透到肿瘤基质中，并进一步增加免疫渗透的可用性。而肿瘤细胞中OVs的感染将改变TME中细胞因子或趋化因子的表达谱，从而为肿瘤组织中最佳的CAR T细胞外显率和浸润提供更多的机会。而这里的细胞因子IL-12和趋化因子CCL5正是为此而设。而PD-1/PD-L1则是著名的免疫检查点，将帮助CAR T细胞压倒由PD-1/PD-L1信号通路诱导的抑制，从而减少CAR T细胞的耗竭。因此在MVR-T3011已经具有IL-12，PD-1的情况下，需要在MVR-T3011上插入CD19-BCMA-CCL5.而研究人员通过把截短的CD19和BCMA以及趋化因子CCL5基因插入MVR-T3011的UL37和UL38位点，并借助细菌人工染色体(BAC)技术，T7011被设计成能够选择性感染大范围的实体瘤并驱动CAR靶向肿瘤抗原的肿瘤特异性表达。而上述的三个基因CD19，BCMA，CCL5，串联表达在一个开放阅读框(ORF)中，并采用HSV立即早期(IE)启动子控制下的自剪切多肽T2A。这种构建方式能够在病毒进入肿瘤后快速表达CD19、BCMA以及CCL5。而进入后，截短的非信号CD19和BCMA可以作为CAR靶递送到肿瘤细胞表面，并且CCL5将在溶瘤病毒介导的肿瘤溶解之前释放到TEM中以浸润CAR T细胞。图：T7011的结构另外根据该公司官网展示，该公司还有一款临床前项目T8011，不过T8011目前其设计和思路尚且不明，仅仅知道其针对血液瘤，不过既然编号在7011之后，那和T7011设计思路也可能相关。而在T系列之外，亦诺微还有专门针对胶质母细胞瘤的MVR-C5252（结构如前面图所示，与T3011类似）。胶质母细胞瘤作为脑癌具有特殊的地位，HSV本身是一种神经嗜好的病毒，但是此前用于大脑疗效方面普遍不理想。但C5252的研究却表明与现有的oHSV-1病毒相比，缺失两份拷贝的γ34.5基因和反向内部重复区的oHSV-1，在针对脑肿瘤方面，相对于非脑肿瘤而言，具有出乎意料优越的抗肿瘤活性。当然，亦诺微医药也没有死磕溶瘤病毒，在溶瘤病毒之外还有外泌体技术，目前可查证的是一款工程化外泌体，通过外泌体来包含靶向HER2 mRNA的miRNA进行给药，未来可能可以看到这款外泌体+溶瘤病毒的组合，这和复诺健开发的激活针对HER2免疫的mRNA疗法也有异曲同工之妙。滨会生物：HSV II+细胞治疗如前文所提的那样，滨会生物开发了II型HSV BS001，不过BS001虽然是HSV II型，但设计理念还是借鉴了T-VEC，选择了和T-VEC相似的敲除蛋白ICP47和ICP34.5，并在ICP34.5敲除点位插入了和T-VEC相似的GM-CSF。而另外一款BS006则被设计成能够分泌的PD-L1xCD3的Bite双抗。此外，在去年时滨会生物首创性地提出将SIRPα抗体与溶瘤病毒联用，可能已有相关联合临床进行。从该公司管线来看，该公司尚有VAK细胞治疗管线，适应症为肿瘤胸腹水。VAK技术指的是(Virus activated killer)技术。它是将经病毒oHSV2激活的免疫细胞回输病人体内，从而发挥抗肿瘤作用。一些癌症病人自身免疫细胞功能低下或对癌细胞耐受，病毒可有效激活这些免疫细胞(经VAK技术激活的免疫细胞简称为VAK细胞)，使其发挥强大肿瘤杀伤作用，且VAK细胞在杀伤癌细胞的同时，促进肿瘤相关抗原的释放，有利于诱导特异性抗肿瘤免疫反应。小编总结总的来说，这三家公司对于溶瘤病毒的设计思路虽然各有差别，但总归是越来越复杂，毕竟HSV载体本身能够装载30kb甚至超过30kb的基因组的这个性质给了改装很大的空间。当然技术上的越复杂意味着工艺上的越困难，这对于溶瘤病毒来说也是重要的挑战。另外，这些溶瘤病毒企业都有在溶瘤病毒之外的布局，这也一定程度上反映了溶瘤病毒目前的状况——作为单药使用的效果仍待提高，产品联用是目前的主流。参考来源：Li JM, Kao KC, Li LF, Yang TM, Wu CP, Horng YM, Jia WW, Yang CT. MicroRNA-145 regulates oncolytic herpes simplex virus-1 for selective killing of human non-small cell lung cancer cells. Virol J. 2013 Jul 22;10:241.各公司官网及其专利

细胞疗法信使RNA免疫疗法

2023-10-10

·生物谷

梅奥医学中心发现可以预测死亡风险的五种衰老标志物

该研究通过对1923名65岁及以上、基线时无或有一种慢性疾病的患者进行了中位时间为6.3年的随访，发现与死亡风险增加最密切相关的五种衰老生物标志物是GDF15、RAGE、VEGFA、PARC和MMP2 细胞衰老是人类衰老以及多种年龄相关疾病发生的重要原因，衰老细胞会随着年龄的增长而积累，并在患有疾病或功能障碍的人体组织中富集，包括骨骼肌、肺、大脑、脂肪组织、骨以及肾脏等器官中。 2023年1月，来自西班牙奥维耶多大学肿瘤研究所和法国巴黎大学的科学家在 Cell 期刊发表了题为：Hallmarks of aging: An expanding universe 的综述论文。该综述在之前的基础上首次创造性的提出了衰老的十二个标志，对理解衰老的发生、发展以及如何干预衰老过程意义巨大。这十二个衰老标志包括：基因组不稳定、端粒损耗、表观遗传改变、蛋白质稳态丧失、大自噬失能、营养感应失调、线粒体功能障碍、细胞衰老、干细胞耗竭、细胞间通讯改变、慢性炎症和生态失调。衰老另外一个重要组成成分是衰老相关分泌表型（SASP），SASP是指衰老细胞表达和分泌多种细胞外调节剂的能力，包括细胞因子、趋化因子、蛋白酶、生长因子和生物活性脂质等。已有研究表明SASP浓度和衰老程度息息相关，但是SASP中的成份能否预测老年人的死亡率目前尚不清楚。 2023年10月6日，美国梅奥医学中心的 Jennifer L. St. Sauver 教授团队在 Aging Cell 期刊发表了题为：Biomarkers of cellular senescence and risk of death in humans 的论文。该研究评估了28种SASP蛋白的血浆水平与死亡风险之间的关系，发现了与死亡风险增加最密切相关的五种衰老生物标志物是GDF15、RAGE、VEGFA、PARC和MMP2。本研究数据来自梅奥诊所生物库，该数据库由57000名成年志愿者组成，包括24244名65岁以上的老人。其中1923位65岁及以上老人最终被纳入研究，包括1066名女性和857名男性。 68%的研究参与者在基线时没有慢性疾病，32%有一种疾病，随访持续时间的中位数是6.3年，有283例死亡。其中年龄较大和男性与死亡风险增加相关。然而，与没有慢性病的人相比，在基线时患有一种慢性病的人在随访期间死亡的可能性更小。研究人员随后使用LASSO回归对年龄、性别、种族和慢性疾病的存在进行调整后，发现14种衰老生物标志物的血浆水平与死亡风险增加相关，其中与死亡率关联最强的五个生物标记为GDF15、RAGE、VEGFA、PARC和MMP2。最后，研究人员研究了这五种标志物在男性和女性中的表现是否相同。结果发现，在男性中GDF15、VEGFA、RAGE、PARC与死亡率密切相关；而在女性中GDF15、VEGFA、PARC和TNFR1与女性死亡率密切相关。总的来说，该研究通过对1923名65岁及以上、基线时无或有一种慢性疾病的患者进行了中位时间为6.3年的随访，发现与死亡风险增加最密切相关的五种衰老生物标志物是GDF15、RAGE、VEGFA、PARC和MMP2。这些发现也表明细胞衰老的生物标志物有预测老年人临床健康的价值。

临床研究

2023-02-08

·virogin.com

New Research Progress on VG301 Development

About History Our Leadership Team Scientific Advisory Board Technology Oncolytic Virotherapy mRNA Platform saRNA Prime-Boost Approach Pipeline Clinical Trials Strategy & Milestones VG161 VG201 Publications Careers Investors Media History Our Leadership Team Scientific Advisory Board Oncolytic Virotherapy mRNA Platform saRNA Prime-Boost Approach saRNA Strategy & Milestones VG161 VG201 About History Our Leadership Team Scientific Advisory Board Technology Oncolytic Virotherapy mRNA Platform saRNA Prime-Boost Approach Pipeline Clinical Trials Strategy & Milestones VG161 VG201 Publications Careers Investors Media History Our Leadership Team Scientific Advisory Board Oncolytic Virotherapy mRNA Platform saRNA Prime-Boost Approach saRNA Strategy & Milestones VG161 VG201 About History Our Leadership Team Scientific Advisory Board Technology Oncolytic Virotherapy mRNA Platform saRNA Prime-Boost Approach Pipeline Clinical Trials Strategy & Milestones VG161 VG201 Publications Careers Investors Media History Our Leadership Team Scientific Advisory Board Oncolytic Virotherapy mRNA Platform saRNA Prime-Boost Approach saRNA Strategy & Milestones VG161 VG201 About History Our Leadership Team Scientific Advisory Board Technology Oncolytic Virotherapy mRNA Platform saRNA Prime-Boost Approach Pipeline Clinical Trials Strategy & Milestones VG161 VG201 Publications Careers Investors Media History Our Leadership Team Scientific Advisory Board Oncolytic Virotherapy mRNA Platform saRNA Prime-Boost Approach saRNA Strategy & Milestones VG161 VG201 February 8, 2023 Virogin’s R&D team announced good news just after New Year’s Eve in 2023. Virogin’s global R&D team released the preprint of “HSV-1 Oncolytic Virus Targeting CEACAM6-Expressing Tumors Using a Bispecific T Cell Engager” on BioRxiv. This article focuses on the latest research progress of the company’s newest generation of oncolytic virus product VG301 (product code “VG21306”) that demonstrates the robust research capabilities of Virogin’s global R&D team in the field of oncolytic viruses. Oncolytic virotherapy is a potent weapon in cancer therapy. Virogin developed the novel VG301 (VG21306) oncolytic virus based on the TTDR HSV-1 virus backbone with the addition of a bispecific T-cell engager targeting CD3 and CEACAM6. VG301 locally expresses T-cell engager in the tumor mass, which not only tackles the problem of solid tumor penetration for bispecific antibodies, but also mitigates the systemic risk of on-target, off-tumor toxicity. In the research article, both in vitro and in vivo testing demonstrated VG301’s expression of a functional T-cell engager capable of binding CD3 and CEACAM6. The addition of bispecific antibodies is shown to enhance anti-tumor efficacy of oncolytic viruses against CEACAM6 overexpressing tumors cells. Even for tumor cells lacking CEACAM6 expression, the T cell engager as oncolytic virus payload was shown to induce bystander killing and engage exhausted T cells, therefore inducing tumor cell death. In terms of safety, the bispecific antibodies expressed locally demonstrate no binding to normal tissue, nor leakage into the bloodstream. Figure 1: Effect of VG21306 (VG301) in A549-CEACAM6-knockout (red dye) and T cell (green dye) co-culture system. Figure 2: VG301 enhances T-cell activation in animal studies. Figure 3: Detection of UCHT-2-03 engager in tumor and circulating blood indicates payload engager is only restricted to the injected tumors. Research evidence points out that VG301, as Virogin’s next-generation oncolytic virus, is designed to target CEACAM6-expressing tumors through T-cell engager payloads. Besides offering the full therapeutic benefits of an Oncolytic Virus, this new Oncolytic Virus offers extra efficacy by expressing the T-cell engager in the tumor microenvironment. “The expression of T-cell engager by our oncolytic virus is a manifestation of Virogin’s strategy to remodel anti-viral immunity into anti-tumor immunity. This is the next-generation product after the TTDR (Transcriptional and Translational Dual-Regulated) oncolytic virus,” said Dr. William Wei-Guo Jia, Chief Scientific Officer of Virogin Biotech. Intratumoral replication of Oncolytic Virus will induce T cell infiltration, but the main function of those T cells is to attack virus-infected cells in the tumor mass. Using T-cell engager expressed by the Oncolytic Virus can redirect these T cells to target the non-infected tumor cells, therefore achieving the anti-tumor efficacy. Oncolytic virus with T-cell engager payload platform established by Virogin is highly tumor-specific and reduces systemic toxicity of traditional bispecific T-cell engager antibody treatments, thus yielded unique and promising results for immuno-oncotherapy. Link to the Article: HSV-1 Oncolytic Virus Targeting CEACAM6-Expressing Tumors Using a Bispecific T-Cell Engager | bioRxiv About Virogin Biotech: Virogin is developing two different platforms that are highly complementary: an oncolytic HSV-1 platform armed with multiple therapeutic payloads and genomic regulation to increase oncolytic effect and modulate the tumor microenvironment; and a discovery-stage mRNA tumor vaccine platform consisting of tumor vaccines to be used in combination with oncolytic viruses to augment anti-tumor activity.

疫苗临床研究免疫疗法信使RNA

100 项与 VG-301 相关的药物交易

登录后查看更多信息