作者: Shkhyan, Ruzanna ; Chuong, Cheng-Ming ; Van der Horst, Robert ; Banks, Nicholas ; Evseenko, Denis ; Liu, Nancy Q ; Flynn, Candace ; Harn, Hans I-Chen ; Bajaj, Paul ; Lamoure, Emma ; York, Jesse ; Hurtig, Mark S ; Sarkar, Arijita ; Lozito, Thomas ; Vadivel, Kanagasabai ; Van Handel, Benjamin ; Tassey, Jade ; Lee, Siyoung ; Lieberman, Jay R ; Li, Jinxiu

Adult mammals are incapable of multitissue regeneration, and augmentation of this potential may shift current therapeutic paradigms. We found that a common co-receptor of interleukin 6 (IL-6) cytokines, glycoprotein 130 (gp130), serves as a major nexus integrating various context-specific signaling inputs to either promote regenerative outcomes or aggravate disease progression. Via genetic and pharmacological experiments in vitro and in vivo, we demonstrated that a signaling tyrosine 814 (Y814) within gp130 serves as a major cellular stress sensor. Mice with constitutively inactivated Y814 (F814) were resistant to surgically induced osteoarthritis as reflected by reduced loss of proteoglycans, reduced synovitis, and synovial fibrosis. The F814 mice also exhibited enhanced regenerative, not reparative, responses after wounding in the skin. In addition, pharmacological modulation of gp130 Y814 upstream of the SRC and MAPK circuit by a small molecule, R805, elicited a protective effect on tissues after injury. Topical administration of R805 on mouse skin wounds resulted in enhanced hair follicle neogenesis and dermal regeneration. Intra-articular administration of R805 to rats after medial meniscal tear and to canines after arthroscopic meniscal release markedly mitigated the appearance of osteoarthritis. Single-cell sequencing data demonstrated that genetic and pharmacological modulation of Y814 resulted in attenuation of inflammatory gene signature as visualized by the anti-inflammatory macrophage and nonpathological fibroblast subpopulations in the skin and joint tissue after injury. Together, our study characterized a molecular mechanism that, if manipulated, enhances the intrinsic regenerative capacity of tissues through suppression of a proinflammatory milieu and prevents pathological outcomes in injury and disease.

2019-07-01·Journal of Colloid and Interface Science2区 · 化学

Destabilizing Pickering emulsions using fumed silica particles with different wettabilities

2区 · 化学

Article

作者: Griffith, Christopher ; Daigle, Hugh

HYPOTHESISWhereas hydrophobic colloidal particles are known to destabilize foams and emulsions stabilized with surfactants, their use for destabilizing Pickering emulsions is unexplored. Pickering emulsions differ from surfactant-stabilized emulsions because they are stabilized with colloidal particles that are adsorbed to the oil/water interface, which provide a steric barrier to droplet coalescence. This can make Pickering emulsions very stable, but it can also make their subsequent destabilization difficult. The hypothesis of this work is that destabilizing a Pickering emulsion should be possible with colloidal particles provided they are sufficiently hydrophobic, which will enable the particles to dewet an emulsion film and induce coalescence.EXPERIMENTSA model oil-in-water Pickering emulsion was stabilized with polyethylene glycol-modified silica nanoparticles and its stability was assessed by centrifugation and by stirring on a stir plate. Three different fumed silica particles, A200 (bare, hydrophilic), R816 (hexadecylsilane modified, intermediate hydrophobicity), and R805 (octadecylsilane modified, hydrophobic), were added to the emulsion and stirred to evaluate their ability to macroscopically induce coalescence. Optical microscopy was used to visualize the interaction between the model Pickering emulsion and the three different fumed silica particles.RESULTSThe results from this work show there is a strong correlation between the wettability of a fumed silica particle and its ability to destabilize a model Pickering emulsion, with more hydrophobic particles showing a greater tendency to coalesce the Pickering emulsion. The hydrophilic and partially hydrophobic particles, at all concentrations tested, were unable coalesce the model Pickering emulsion. This was because the particles were almost immediately wetted by the continuous phase of the emulsion, which prevented any interactions between the emulsified oil drops and the silica particle surface. The hydrophobic fumed silica particles coalesced 60% of the emulsified oil with just 0.01 wt% added fumed silica, which further increased to 85% with 0.05 wt% added silica.

2007-06-01·Reproduction in Domestic Animals3区 · 农林科学

Measurement of Ovine Pregnancy‐Associated Glycoprotein (PAG) During Early Pregnancy in Lacaune Sheep

3区 · 农林科学

Article

作者: J Sulon ; AV Alvarez-Oxiley ; O Szenci ; A Karen ; Y Cognié ; JF Beckers ; N Melo de Sousa ; B El Amiri

ContentsThis study describes ovine pregnancy‐associated glycoprotein (ovPAG) concentrations in 20 Lacaune sheep during early pregnancy. Measurements were performed by using semi‐purified ovPAG as standard, tracer and immunogens for antibody production in rabbits. Antisera R780 (against ovPAG57+59kDa) and R805 (against ovPAG558+61kDa) were used respectively in RIA‐780 and RIA‐805. Blood samples were collected at days 0, 18, 20, 22 and 25 after artificial insemination. From day 18 after breeding onward, the mean ovPAG concentration was significantly higher (p < 0.001) in plasma samples from pregnant ewes (n = 17) than in non‐pregnant ones (n = 3). The specific activity of the tracer was 11 760 Ci/mmol in RIA‐780 and 14 900 Ci/mmol in RIA‐805. The minimal detection limits for RIA‐780 and RIA‐805 were 0.2 ng/ml and 0.3 ng/ml, respectively. The intra‐assay CV of samples with low (1.0 ng/ml), medium (2.5 ng/ml) and high (4.0 ng/ml) PAG concentrations were 3%, 6% and 9% for RIA‐780 and 8%, 9% and 5% for RIA‐805. The inter‐assay CV in the same samples were 13%, 12% and 7% for RIA‐780 and 13%, 11% and 5% for RIA‐805. The recovery was higher than 95% in both assays. No cross‐reaction was observed with members of aspartic proteinase family as well as with other tested proteins. In both RIA‐780 and RIA‐805, inhibition of the binding of the tracer by antisera was parallel between standard curve and serial dilutions of pregnant ewe samples. In conclusion, the two homologous RIA systems are suitable for early quantification of ovPAG concentrations in ewe plasma samples from day 18 after breeding.

项与 CX-011 相关的新闻（医药）

2023-03-24

·药明康德

前沿 | 显著改善关节疼痛变形！《科学》子刊新发现即将迈入临床

▎药明康德内容团队编辑关节中的软骨侵蚀和炎症是引起骨关节炎（osteoarthritis）的原因，患者的关节时常感到僵硬和疼痛。随着平均寿命的延长，罹患骨关节炎的人数预计也将会增多，然而直至目前为止仍没有治愈这种疾病的方法。然而这周刊登在《科学》子刊Science Translational Medicine上的论文可能会改变这一现状，来自南加州大学（USC）的研究团队发现其药品R805/CX-011可有效减少大鼠与狗的骨关节炎症状与炎症严重程度并加强组织再生。目前USC研究团队已与Carthronix公司达成合作，将在今年进行此药物用以治疗骨关节炎的临床1/2a期试验。R805是一种能够调控gp130蛋白的小分子。gp130蛋白能够在生物体遭受感染时募集白细胞来对抗外来侵袭物。然而，此蛋白也召唤免疫细胞对我们自己关节的软骨碎片产生有害的反应，因而导致关节过度炎症——骨关节炎的产生。科学家们发现，gp130蛋白中的酪氨酸814（Y814）是炎症信号调节的关键。带有Y814失活的小鼠对于手术诱导的骨关节炎具有抵抗力，小鼠的蛋白多糖水平下降减少，且其滑膜炎和滑膜纤维化获得改善。这类小鼠在皮肤受伤时还表现出增强的再生而非修复性反应。此外，当在小鼠皮肤伤口局部给予R805时可引起毛囊新生和真皮再生增强。而当对内侧半月板撕裂的大鼠以及具关节镜下半月板松解的狗，在关节内给予R805时也可观察到显著骨关节炎外观的缓解。在一项模拟人类双盲临床试验的实验当中，研究人员发现与安慰剂组相较，R805在三种不同剂量下皆具效力，并产生剂量依赖效应。实验动物的关节疼痛得到缓解，其关键结构与功能也获得改善。图片来源：123RF“我们看到了药物对于关节疼痛、结构和功能的深远效力。”论文的通讯作者，也是USC骨外科教授的Denis Evseenko博士说道。随着这项发现的人体临床试验即将启动，让我们期待这些在动物身上所观察到的疗效也能在人类当中获得印证，以促进创新骨关节炎疗法的诞生，造福更多的疾病患者。药明康德为全球生物医药行业提供一体化、端到端的新药研发和生产服务，服务范围涵盖化学药研发和生产、生物学研究、临床前测试和临床试验研发、细胞及基因疗法研发、测试和生产等领域。如您有相关业务需求，欢迎点击下方图片填写具体信息。▲如您有任何业务需求，请长按扫描上方二维码，或点击文末“阅读原文/Read more”，即可访问业务对接平台，填写业务需求信息▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料：[1] Shkhyan, Ruzanna et al. “Inhibition of a signaling modality within the gp130 receptor enhances tissue regeneration and mitigates osteoarthritis.” Science translational medicine vol. 15,688 (2023): eabq2395. doi:10.1126/scitranslmed.abq2395[2] Potential relief for osteoarthritis moves to clinical trial after animal studies. Retrieved March 24, 2023 from https://keck.usc.edu/potential-relief-for-osteoarthritis-moves-to-clinical-trial-after-animal-studies/[3] New osteoarthritis drug curbs symptoms in animals, researchers gear up for clinical trial. Retrieved March 24, 2023 from https://www.fiercebiotech.com/research/new-osteoarthritis-drug-curbs-symptoms-animals-researchers-gear-clinical-trial免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

基因疗法临床研究核酸药物

100 项与 CX-011 相关的药物交易

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