NLRP3

Obesity, due to its associated chronic, systemic inflammation, increases the risk for metabolic diseases, atherosclerosis, various malignant tumors, and numerous immune-mediated disorders.With weight loss, less inflammation is expected, but adipose tissue inflammation can persist long after weight loss. One study showed that immediately after weight loss fat breakdown releases fatty acids triggering an increase in adipose tissue (AT) proinflammatory macrophages and inflammation. Over time, there is a gradual decline in inflammatory processes.The NLRP3 inflammasome and its release of pro-inflammatory cytokines, IL-1β and IL-18, by AT macrophages is essential in development of obesity-related complications. NLRP3 inhibition in a DIO mouse model protected against cardiovascular complications and fatty liver disease.Data from this review article support ZyVersa’s development of Inflammasome ASC Inhibitor IC 100 for obesity with associated comorbidities to be used as an add-on to incretin therapy. WESTON, Fla., Oct. 29, 2024 (GLOBE NEWSWIRE) -- ZyVersa Therapeutics, Inc. (Nasdaq: ZVSA, or “ZyVersa”), a clinical stage specialty biopharmaceutical company developing first-in-class drugs for treatment of inflammatory and renal diseases, highlights data from a review article published in the peer-reviewed journal, Life. The article summarizes data from 345 publications on the role of inflammasome-induced inflammation in obesity and its comorbidities, and it reinforces the need for therapeutic options to better address the inflammation. “Strong evidence that obesity treatment needs to go beyond weight loss and address the damaging inflammation leading to life-altering comorbidities is driving ZyVersa and other biopharma companies to invest in development of drugs to be used along with incretin therapy to treat inflammation,” said Stephen C. Glover, ZyVersa’s Co-founder, Chairman, CEO and President. “Studies documenting the key role of inflammasomes in triggering obesity-associated inflammation led ZyVersa to focus on this area for development of Inflammasome ASC Inhibitor IC 100. We are excited about the potential of IC 100 to effectively control the inflammation of obesity. Unlike the NLRP3 inhibitors in development, IC 100 targets ASC to inhibit multiple inflammasomes, including NLRP3 and AIM2, which are associated with obesity. More importantly, IC 100 uniquely disrupts the function of ASC specks to attenuate chronic, systemic inflammation leading to obesity comorbidities. We look forward to progressing IC 100’s obesity development program into phase 1 around mid-2025.” In the review article titled, The Interplay between Obesity and Inflammation, the authors concluded: Development of adipose tissue inflammation triggers subsequent cardiovascular events and therefore represents a major reason for the treatment of obesity.The interplay between obesity and inflammation is complex, involving a variety of cellular and humoral factors, and due to the complexity and particular features of the adipose tissue, the inflammation within may persist for long periods of time.Macrophages are the main cellular component driving adipose tissue chronic inflammation. Modulation of macrophages and their release of proinflammatory cytokines, such as NLRP3-driven IL-Iβ and IL-18, can be a key factor in medical intervention in obese patients.Understanding the pathophysiological changes in adipose tissue and the interplay with chronic inflammation can assist in the design of future studies and reveal opportunities for the development of more efficient therapies for obesity. About Inflammasome ASC Inhibitor IC 100 IC 100 is a novel humanized IgG4 monoclonal antibody that inhibits the inflammasome adaptor protein ASC. IC 100 was designed to attenuate both initiation and perpetuation of the inflammatory response. It does so by binding to a specific region of the ASC component of multiple types of inflammasomes, including NLRP1, NLRP2, NLRP3, NLRC4, AIM2, and Pyrin. Intracellularly, IC 100 binds to ASC monomers, inhibiting inflammasome formation, thereby blocking activation of IL-1β early in the inflammatory cascade. IC 100 also binds to ASC in ASC Specks, both intracellularly and extracellularly, further blocking activation of IL-1β and the perpetuation of the inflammatory response that is pathogenic in inflammatory diseases. Because active cytokines amplify adaptive immunity through various mechanisms, IC 100, by attenuating cytokine activation, also attenuates the adaptive immune response. The lead indication for IC 100 is obesity and its associated metabolic complications. To review a white paper summarizing the mechanism of action and preclinical data for IC 100, Click Here. About ZyVersa Therapeutics, Inc. ZyVersa (Nasdaq: ZVSA) is a clinical stage specialty biopharmaceutical company leveraging advanced proprietary technologies to develop first-in-class drugs for patients with inflammatory or kidney diseases with high unmet medical needs. We are well positioned in the rapidly emerging inflammasome space with a highly differentiated monoclonal antibody, Inflammasome ASC Inhibitor IC 100, and in kidney disease with phase 2 Cholesterol Efflux MediatorTM VAR 200. The lead indication for IC 100 is obesity and its associated metabolic complications, and for VAR 200, focal segmental glomerulosclerosis (FSGS). Each therapeutic area offers a “pipeline within a product,” with potential for numerous indications. The total accessible market is over $100 billion. For more information, please visit www.zyversa.com. Cautionary Statement Regarding Forward-Looking Statements Certain statements contained in this press release regarding matters that are not historical facts, are forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended, and the Private Securities Litigation Reform Act of 1995. These include statements regarding management’s intentions, plans, beliefs, expectations, or forecasts for the future, and, therefore, you are cautioned not to place undue reliance on them. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. ZyVersa Therapeutics, Inc (“ZyVersa”) uses words such as “anticipates,” “believes,” “plans,” “expects,” “projects,” “future,” “intends,” “may,” “will,” “should,” “could,” “estimates,” “predicts,” “potential,” “continue,” “guidance,” and similar expressions to identify these forward-looking statements that are intended to be covered by the safe-harbor provisions. Such forward-looking statements are based on ZyVersa’s expectations and involve risks and uncertainties; consequently, actual results may differ materially from those expressed or implied in the statements due to a number of factors, including ZyVersa’s plans to develop and commercialize its product candidates, the timing of initiation of ZyVersa’s planned preclinical and clinical trials; the timing of the availability of data from ZyVersa’s preclinical and clinical trials; the timing of any planned investigational new drug application or new drug application; ZyVersa’s plans to research, develop, and commercialize its current and future product candidates; the clinical utility, potential benefits and market acceptance of ZyVersa’s product candidates; ZyVersa’s commercialization, marketing and manufacturing capabilities and strategy; ZyVersa’s ability to protect its intellectual property position; and ZyVersa’s estimates regarding future revenue, expenses, capital requirements and need for additional financing. New factors emerge from time-to-time, and it is not possible for ZyVersa to predict all such factors, nor can ZyVersa assess the impact of each such factor on the business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward-looking statements. Forward-looking statements included in this press release are based on information available to ZyVersa as of the date of this press release. ZyVersa disclaims any obligation to update such forward-looking statements to reflect events or circumstances after the date of this press release, except as required by applicable law. This press release does not constitute an offer to sell, or the solicitation of an offer to buy, any securities. Corporate, Media, and IR Contact:Karen CashmereChief Commercial Officerkcashmere@zyversa.com786-251-9641

【导读】 过度的DNA损伤，会触发各种类型的程序性细胞死亡（PCD），但DNA损伤诱导细胞死亡的调节机制尚不完全清楚。在这项研究中，团队报道了PANoptosis，一种协调的PCD通路，包括细胞焦亡、细胞凋亡和坏死性凋亡，被DNA损伤激活。 2024年10月27日，同济大学医学院蔡振宇团队在期刊《Cell Death & Disease》上发表了题为“Sensing of endogenous retroviruses-derived RNA by ZBP1 triggers PANoptosis in DNA damage and contributes to toxic side effects of chemotherapy”的研究论文。研究结果表明，ZBP1介导的PANoptosis被DNA损伤激活，并导致基于DNA损伤的化疗的毒副作用。 ZBP1可能是一个有前途的治疗靶点， 可以减轻化疗相关的副作用。 https://www-nature-com.libproxy1.nus.edu.sg/articles/s41419-024-07175-7 关于DNA损伤 01 触发DNA损伤诱导的细胞死亡，被认为是癌症治疗（如化疗或放疗）中的重要机制 。然而，DNA损伤诱导的细胞死亡的许多方面，尚不完全清楚。 PANoptosis是一种协调的细胞死亡通路，整合了焦亡、细胞凋亡和坏死性凋亡的关键成分。ZBP1介导的PANoptisis，已被证明在感染性和炎症性疾病中起关键作用，例如，病毒和真菌感染以及感染性炎症。 ZBP1是一种胞质核酸传感器，在细胞死亡和炎症的调节中起着至关重要的作用，特别是在病毒感染和免疫应答的情况下。在无菌条件下，ZBP1已被证明可以识别ERV来源的dsRNA，以诱导坏死性凋亡和炎症。 在这项研究中，团队发现ZBP1介导的PANoptosis，被DNA损伤化合物激活。从机制上讲，ERV被DNA损伤重新激活，并作为ZBP1的配体触发PANoptosis。ZBP1介导的PANoptosis有助于化疗药物的毒性作用。这些数据表明， ZBP1可能是减轻化疗引起的副作用的潜在治疗靶点。 ZBP1介导的PANoptisis，导致小鼠化疗诱导的毒性 02 包括ETO、CDDP和5-FU在内的DNA损伤剂是癌症治疗中最有效的化疗药物之一，然而，这些有效化疗药物的临床效用，受到其毒性不良反应的剂量限制。团队发现ETO严重破坏了小肠中的隐窝和绒毛，导致WT小鼠肺中严重的血管损伤、中性粒细胞浸润和IL-6表达增加，而这些影响在ZBP1中显著减弱。与ZBP1相比，WT小鼠的ETO处理，使脾脏重量和脾脏淋巴细胞的数量显著降低。腹膜注射CDDP，还导致WT小鼠小肠隐窝丢失，肺血管损伤和中性粒细胞浸润增加，脾脏淋巴细胞数量减少，所有这些影响在ZBP1中均得到缓解。此外，与载体对照治疗相比，ETO或CDDP治疗在小鼠小肠中PLA的红色荧光信号显著增加，这表明化疗诱导的dsRNA可以在体内被ZBP1识别。这些数据表明， ZBP1驱动的PANoptosis会导致化疗诱导的小鼠毒性和炎症。 ZBP1介导的PANoptis，导致小鼠化疗诱导的毒性。 结直肠癌（CRC）患者非癌组织中的ZBP1，可感应化疗诱导的dsRNA 03 ZBP1的表达在肿瘤组织中下调。ZBP1表达在所有患者的癌细胞系中都不存在。与匹配的非癌性结肠组织相比，ZBP1在肿瘤中的表达显著降低或不存在，而Casp-6、RIPK3和MLKL的表达，在正常组织和肿瘤组织中通常相当。这些数据表明，肿瘤可能通过下调ZBP1表达，来逃避ZBP1介导的细胞死亡，并且，ZBP1驱动的PANoptisis很可能在非癌组织中被化疗激活。 一些dsRNA阳性细胞是CD45阳性，表明dsRNA是由免疫前哨细胞中的化疗诱导的。在这些化疗正常的结肠组织中，通过PLA检测到dsRNA和ZBP1之间的关联，表明化疗中的ZBP1可以感应dsRNA。团队在化疗的正常结肠组织中检测到红色荧光PLA信号，但是，在没有化疗的正常结肠组织中不存在PLA信号。这些数据表明， ZBP1可以感应化疗诱导的dsRNA，并触发CRC患者非癌组织中的PANoptosis。 ZBP1在CRC患者的非癌组织中，感应化疗诱导的dsRNA。 总结 04 1. PANoptosis与DNA损伤诱导的细胞死亡之间的关系尚未被研究，本研究发现ZBP1衍生的PANoptosis可被DNA损伤激活。 2. ZBP1通过其Zα结构域结合病毒来源的Z-RNA，触发PANoptosome复合物的组装，该复合物包含RIPK、NLRP3、ASC、Casp-6和Casp-8等关键组分。 3. ZBP1的Zα结构域能够结合左旋Z构象的核酸，对于触发炎性细胞死亡至关重要。研究提出dsRNA由DNA损伤诱导，并通过ZBP1的Zα结构域结合，对PANoptosis至关重要。 4. ZBP1介导的PANoptosis会导致化疗诱导的毒性和炎症，化疗药物如ETO、CDDP和5-FU的最佳使用受到剂量限制性副作用的限制。 5. ZBP1在肿瘤组织中的表达较低或不存在，表明ZBP1衍生的PANoptosis可能在非癌组织中被化疗激活。 6. 研究结果表明，抑制ZBP1衍生的PANoptosis可能是一种潜在的治疗方法，可以减轻化疗引起的副作用并改善癌症患者的生活质量。 参考资料： 1. Goldstein M, Kastan MB. The DNA damage response: implications for tumor responses to radiation and chemotherapy. Annu Rev Med. 2015;66:129–43. 2. Cheung-Ong K, Giaever G, Nislow C. DNA-damaging agents in cancer chemotherapy: serendipity and chemical biology. Chem Biol. 2013;20:648–59. 【关于投稿】 转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！ 转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。 热门推荐活动 点击免费报名 🕓 上海｜11月15日-16日 ▶ 2024第一届中国类器官转化医学大会 🕓 上海｜11月21日-24日 ▶ 第七届上海国际肿瘤内科学论坛 🕓 全国｜2024年12月-2025年03月 ▶ 中国转化医学产业大会 🕓 上海｜2025年02月28日-03月01日 ▶ 第四届长三角单细胞组学技术应用论坛暨空间组学前沿论坛 点击对应文字 查看详情

RICHMOND, Calif., Oct. 24, 2024 (GLOBE NEWSWIRE) -- BioAge Labs (Nasdaq: BIOA) (“BioAge”), a clinical-stage biopharmaceutical company developing therapeutic product candidates for metabolic diseases by targeting the biology of human aging, today announced that Kristen Fortney, PhD, CEO and co-founder, will present at the Jefferies London Healthcare Conference, which takes place November 19–21, 2024. The on-demand presentation will be available from through the conference site. To access the live webcast of the presentation (1:00-1:25 PM GMT on November 19), please register here. An archived replay of the webcast will be available through the Investors section of the BioAge website https://ir.bioagelabs.com for approximately 30 days following the conference. About BioAge Labs, Inc. BioAge is a clinical-stage biopharmaceutical company developing therapeutic product candidates for metabolic diseases, such as obesity, by targeting the biology of human aging. BioAge’s lead product candidate, azelaprag, is an orally available small molecule agonist of APJ that was observed to promote metabolism and prevent muscle atrophy on bed rest in a Phase 1b clinical trial. In mid-2024, BioAge initiated a Phase 2 trial of azelaprag in combination with tirzepatide for the treatment of obesity in older adults. Azelaprag has potential as an oral regimen to amplify weight loss and improve body composition in patients on obesity therapy with incretin drugs. BioAge is also developing orally available small molecule brain penetrant NLRP3 inhibitors for the treatment of diseases driven by neuroinflammation. BioAge’s preclinical programs, based on novel insights from the company’s discovery platform built on human longevity data, address key pathways in metabolic aging. ContactsPR: Chris Patil, media@bioagelabs.com IR: Elena Liapounova, ir@bioagelabs.com Partnering: partnering@bioagelabs.com Web: https://bioagelabs.com