更新于：2024-05-01

CD86

分化群86

更新于：2024-05-01

基本信息

别名

B7-2抗原、Activation B7-2 antigen、B-lymphocyte antigen B7-2

+ [11]

简介

Receptor involved in the costimulatory signal essential for T-lymphocyte proliferation and interleukin-2 production, by binding CD28 or CTLA-4. May play a critical role in the early events of T-cell activation and costimulation of naive T-cells, such as deciding between immunity and anergy that is made by T-cells within 24 hours after activation (PubMed:7527824). Also involved in the regulation of B cells function, plays a role in regulating the level of IgG(1) produced. Upon CD40 engagement, activates NF-kappa-B signaling pathway via phospholipase C and protein kinase C activation (By similarity). (Microbial infection) Acts as a receptor for adenovirus subgroup B. Interferes with the formation of CD86 clusters, and thus acts as a negative regulator of T-cell activation.

关联

项与 CD86 相关的药物

Belatacept

贝拉西普

靶点

CD80 x CD86

作用机制

CD80抑制剂 [+1]

在研机构

Bristol-Myers Squibb Pharma EEIG [+2]

原研机构

Bristol Myers Squibb Co.

在研适应症

肾移植排斥反应 [+2]

非在研适应症

抗体介导的排斥反应 [+7]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2011-06-15

Abatacept

阿巴西普

靶点

CD80 x CD86

作用机制

CD80调节剂 [+1]

在研机构

Bristol Myers Squibb Co. [+2]

原研机构

Bristol Myers Squibb Co.

在研适应症

急性移植物抗宿主病 [+16]

非在研适应症

斑秃 [+18]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2005-12-23

Belatacept biosimilar(Suzhou Alphamab)

贝拉西普生物类似药 (苏州康宁杰瑞)

靶点

CD80 x CD86

作用机制

CD80抑制剂 [+1]

在研机构

苏州康宁杰瑞生物科技有限公司 [+1]

原研机构

苏州康宁杰瑞生物科技有限公司

在研适应症

类风湿关节炎 [+1]

非在研适应症-

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

348

项与 CD86 相关的临床试验

NCT06291103 / Not yet recruiting临床2/3期IIT

Screening for Subclinical Antibody Mediated Rejection and Efficacy of Belatacept in the Context of de Novo Donor Specific Antibody After Kidney Transplantation (BELA-M-R)

Antibody mediated rejection (ABMR) is a major cause of graft loss after kidney transplantation (KT) and is mainly associated with preformed anti-HLA donor specific antibodies (DSAs) (phenotype 1) or de novo DSAs (dnDSAs) (phenotype 2). Preexisting DSA-associated ABMR have superior graft survival compared with dnDSA-associated ABMR, which could partly be explained by the fact that patients with de novo DSA-associated ABMR have biopsy later, when graft dysfunction and/or proteinuria are already present. ABMR is a progressive process with an early stage called subclinical ABMR (sABMR), in which histological lesions are present in the kidney graft without clinical graft dysfunction. These early lesions are now well recognized as risk factors for transplant glomerulopathy and poor graft survival in phenotype 1 ABMR (ref 5). The impact of sABMR associated with dnDSA at any time post-transplant has been less studied and reported. Recently, we published a retrospective multicenter study within the Spiesser Group that included 123 patients without graft dysfunction who underwent graft biopsy because of the presence of dnDSA (One Lambda, MFI > 1000). Performing a kidney graft biopsy after dnDSA indentification without renal dysfunction leads to the diagnosis of active sABMR in 35 % of cases. Nevertheless, we did not observe any effect of standard of care treatment in active sABMR. Very recently, an expert consensus for the recommended treatment for ABMR after KT was published. They concluded the clear lack of evidence but a standard of care for ABMR was nevertheless defined. Therefore, we propose to evaluate a new strategy for active sABMR, testing a conversion from calcineurin inhibitor (CNI) to belatacept associated with the recently recommended standard of care (SOC) compared to continuing CNI. Belatacept might help to manage nonadherence, decrease the toxicity of CNI on an endothelium already affected by microvascular inflammation, and reduce DSA titers.
The monitoring of dnDSA after KT and an indication graft biopsy in case of appearance, even in the absence of graft dysfunction, is not part of a routine clinical practice in all KT centers. This strategy could be a valuable option, in order to begin treatment of ABMR before graft dysfunction occurs, and therefore to improve prognosis associated with phenotype 2 ABMR. Parajuli et al.4 suggested that early diagnosis and treatment of sABMR with SOC, using DSA monitoring may improve outcomes after KT, but this is a retrospective and no-randomized study. This study will be the first prospective randomized study in the context of de novo DSA. We will evaluate a new combination of treatment for ABMR in the context of dnDSA with subclinical lesions and in the same time may help to determine the real incidence of sABMR in KT recipients with subclinical dnDSA. The use of belatacept in the context of sABMR to improve the non-adherence and to decrease the endothelial toxicity had never been evaluated in a prospective way.

开始日期2025-01-01

申办/合作机构

University Hospital

NCT06291077 / Not yet recruiting临床4期IIT

Comparison of the Effects of Belatacept and Anticalcineurins on Endothelial Function in Renal Transplant Patients <BELAFENDO>

Kidney transplantation is the standard treatment for patients with end-stage renal failure.
However, anticalcineurin inhibitors, the most widely used immunosuppressants, are involved in the occurrence of cardiovascular events, a major cause of premature death in these patients. They play an important role in the occurrence of endothelial dysfunction and increased arterial stiffness by decreasing the synthesis of nitric oxide (NO), promoting intrarenal arterial vasoconstriction and stimulating the production of pro-inflammatory cytokines. leading to the development of hypertension and chronic graft dysfunction.
Belatacept, a more recently developed immunosuppressant and co-stimulation signal inhibitor, has shown an anti-rejection effect similar to cyclosporine with a better cardiovascular tolerance profile. Preliminary studies are contradictory on the influence of Belatacept on arterial stiffness. Furthermore, to date, no study has evaluated the impact of Belatacept on vasomotor endothelial function in humans, an indicator of NO bioavailability. The interest of this study is to demonstrate that patients taking Belatacept have an improvement in vascular function compared to patients taking anticalcineurins in order to consider an earlier change in immunosuppressive strategy in the event of vascular damage.

开始日期2025-01-01

申办/合作机构

University Hospital

NCT04344873 / Not yet recruiting早期临床1期IIT

Impact of T Cells on Age-related Vascular Dysfunction: A Translational Approach

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States and other industrialized societies, and advanced age is the major risk factor for development of CVD. Advancing age appears to exert its pathological influence primarily via adverse functional and structural effects on arteries. Aging is associated with increased stiffness (reduced compliance) of large elastic arteries and impaired arterial endothelial function that is characterized by reductions in nitric oxide (NO)- mediated endothelium-dependent dilation (EDD). While several changes to arteries may contribute to age-associated increases in CVD risk; the development of endothelial dysfunction and stiffening of the large elastic arteries are among the most important contributors. Both are predictors of CV events and clinical CVD with increasing age. Although the importance of endothelial dysfunction and arterial stiffening with age are well established, the initiating events of these deleterious changes are elusive.

开始日期2024-05-01

申办/合作机构

University of Utah

[+1]

100 项与 CD86 相关的临床结果

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100 项与 CD86 相关的转化医学

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0 项与 CD86 相关的专利（医药）

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11,657

项与 CD86 相关的文献（医药）

2024-05-01·Carbohydrate polymers

An arabinose-rich heteropolysaccharide isolated from Belamcanda chinensis (L.) DC treats liver cancer by targeting FAK and activating CD40

Article

作者: Zhao, Yinan ; Hou, Jiantong ; Liu, Yuhui ; Xu, Jing ; Guo, Yuanqiang

An undisclosed polysaccharide, BCP80-2, was isolated from Belamcanda chinensis (L.) DC. Structural investigation revealed that BCP80-2 consists of ten monosaccharide residues including t-α-Araf-(1→, →3,5)-α-Araf-(1→, →5)-α-Araf-(1→, →4)-β-Xylp-(1→, →3)-α-Rhap-(1→, →4)-β-Manp-(1→, t-β-Glcp-(1→, →6)-α-Glcp-(1→, t-β-Galp-(1→, and→3)-α-Galp-(1→. In vivo activity assays showed that BCP80-2 significantly suppressed neoplasmic growth, metastasis, and angiogenesis in zebrafish. Mechanistic studies have shown that BCP80-2 inhibited cell migration of HepG2 cells by suppressing the FAK signaling pathway. Moreover, BCP80-2 also activated immunomodulation and upregulated the secretion of co-stimulatory molecules CD40, CD86, CD80, and MHC-II. In conclusion, BCP80-2 inhibited tumor progression by targeting the FAK signaling pathway and activating CD40-induced adaptive immunity.

2024-02-29·Heliyon

Use of the improved tug-of-war acupuncture for promoting cartilage repair by inducing macrophage polarization in knee osteoarthritis.

Article

作者: Jun Yan ; Suying Jiang ; Junjie Ma ; Xuan Zhou ; Mei Zhao ; Jinliang Huang ; Huimeng Zhu ; Bingyao Huang ; Ermei Li ; Hong Chang

Introduction:

Knee osteoarthritis (KOA) is a type of joint disease causing degenerative changes that are challenging to treat. The improved tug-of-war acupuncture (BHZF) can improve joint pain in KOA. However, the associated mechanism has not been validated.

Methods:

The KOA rabbit model was established. After the surgery, the improved BHZF was provided as an intervention, and the animals were euthanized after 2 weeks. Histopathological changes in the synovium and cartilage were observed on hematoxylin & eosin staining and Safranin O-Fast Green staining. Synovial fluid and serum samples were collected to assess the presence of cytokines using the enzyme-linked immunosorbent assay. The expression of M1 macrophage (CD86) and M2 macrophage (ARG1) markers in the cartilage and synovium was detected via immunohistochemistry and immunofluorescence assays.

Results:

The improved BHZF could reduce KOA-related pain and inhibit joint swelling. Further, it significantly maintained the morphology of articular chondrocytes in KOA and reduced the decomposition of the cartilage matrix. Then, it significantly reduced the expression of CD86-positive cells (P < 0.05), and increased the expression of ARG1-positive cells in the cartilage and synovium (P < 0.05). Moreover, it significantly decreased the expression of inflammatory factors interleukin (IL)-1 beta and tumor necrosis factor-alpha in the serum and synovial fluid (P < 0.05), and significantly increased the expression levels of anti-inflammatory cytokines IL-4 and IL-10 (P < 0.05).

Conclusions:

The improved BHZF can relieve pain and improve cartilage damage by regulating macrophage polarization in KOA.

2024-02-23·Cancer immunology research

ILT2 and ILT4 drive myeloid suppression via both overlapping and distinct mechanisms.

Article

作者: Jane Tian ; Amir M Ashique ; Sabrina Weeks ; Tian Lan ; Hong Yang ; Hung-I H Chen ; Christina Song ; Kikuye Koyano ; Kalyani Mondal ; Daniel Tsai ; Isla Cheung ; Mehrdad Moshrefi ; Avantika Kekatpure ; Bin Fan ; Betty Li ; Samir Qurashi ; Lauren Rocha ; Jonathan Aguayo ; Col Rodgers ; Marchelle Meza ; Darren Heeke ; Sara M Medfisch ; Chun Chu ; Shelley Starck ; Nandini Pal Basak ; Satish Sankaran ; Mohit Malhotra ; Suzanne Crawley ; Thomas-Toan Tran ; Dana Y Duey ; Carmence Ho ; Igor Mikaelian ; Wenhui Liu ; Lee B Rivera ; Jiawei Huang ; Kevin J Paavola ; Kyle O'Hollaren ; Lisa K Blum ; Vicky Y Lin ; Peirong Chen ; Anjushree Iyer ; Sisi He ; Julie M Roda ; Yan Wang ; James Sissons ; Alan K Kutach ; Daniel D Kaplan ; Geoffrey W Stone

Solid tumors are dense three-dimensional (3D) multi-cellular structures that enable efficient receptor-ligand trans interactions via close cell-cell contact. Immunoglobulin-like transcript (ILT)2 and ILT4 are related immune suppressive receptors that play a role in the inhibition of myeloid cells within the tumor microenvironment. The relative contributions of ILT2 and ILT4 to immune inhibition in the context of solid tumor tissue has not been fully explored. We present evidence that both ILT2 and ILT4 contribute to myeloid inhibition. We found that while ILT2 inhibits myeloid cell activation in the context of trans-engagement by MHC-I, ILT4 efficiently inhibits myeloid cells in the presence of either cis- or trans-engagement. In a 3D spheroid tumor model, dual ILT2/ILT4 blockade was required for optimal activation of myeloid cells, including the secretion of CXCL9 and CCL5, upregulation of CD86 on dendritic cells, and downregulation of CD163 on macrophages. Humanized mouse tumor models showed increased immune activation and cytolytic T cell activity with combined ILT2 and ILT4 blockade, including evidence of the generation of immune niches, which have been shown to correlate with clinical response to immune checkpoint blockade. In a human tumor explant histoculture system, dual ILT2/ILT4 blockade increased CXCL9 secretion, downregulated CD163 expression, and increased the expression of M1 macrophage, IFN-γ, and cytolytic T cell gene signatures. Thus, we have revealed distinct contributions of ILT2 and ILT4 to myeloid cell biology and provide proof-of-concept data supporting the combined blockade of ILT2 and ILT4 to therapeutically induce optimal myeloid cell reprogramming in the tumor microenvironment.

143

项与 CD86 相关的新闻（医药）

2024-04-05

·佰傲谷BioValley

肿瘤中的关键炎症通路

J Hematol Oncol.(一) 类花生酸(Eicosanoid)信号通路：二十烷基硫酸酯信号通路在生理过程和病理过程中都起着关键作用，通过类花生酸将炎症与癌症联系起来。二十碳多不饱和脂肪酸(PUFAs)是由20碳多不饱和脂肪酸(PUFAs)氧化而成的具有高度生物活性的衍生物，可通过环氧合酶(COX)、脂氧合酶(LOX)和细胞色素P450途径产生。COX途径产生前列腺素(PGs)和血栓素A(TXs)，而LOX途径则产生白三烯(LTs)和脂氧素(LXs)。COX信号通路COX家族中，COX-2的表达会受到早期炎症(proinflammatory)的上调，并被发现和调控多种肿瘤的进展相关。在炎症反应的早期阶段，COX-2衍生的PG被认为具有促炎功能。前列腺素D2、前列腺素E2、前列腺素F2α、前列腺素I2和血栓素A2是通过COX通路衍生的五种关键 PG。COX/PEG2COX-2/CSK3β信号还和上皮-间充质转化有关，通过抑制GSK3β来促进E-钙粘蛋白、β-连环蛋白和p120连环蛋白的蛋白质稳定性。抑制COX-2可以下调E-钙黏蛋白导致细胞死亡。PGE2通过其两种E-前列腺素受体EP2和EP4提供信号传导来塑造DC功能。EP4调节CD80、CD86、CD83、MHC II等激活标志物上调以及IL-10和IL-23的产生，引导cDC2成熟，促进T细胞扩增，形成抑制性而非促炎性T细胞群富集。PGE2还可能通过E2调节NK细胞合成IFN-γ来诱导免疫抑制，从而促进肿瘤的发生。肿瘤来源的前列腺素E2(PGE2)介导MDSC分化和获得促肿瘤特征。在PGE2暴露期间，EP2/4联合阻断M-MDSCs可防止这些抑制特征的发生。双重 EP2/EP4 PGE2受体拮抗剂增加了肿瘤微环境淋巴细胞浸润，并显着降低了多种肿瘤模型中的疾病负担。前列腺素D2则是COX-2的另一种代谢物，可能在慢性炎症和癌症中发挥双重作用。PGD2与其受体PTGDR2之间的相互作用抑制了胃癌细胞的自我更新，并减弱了胃癌的生长和转移。脂氧合酶(LOX)信号通路LOX通路负责将花生四烯酸代谢为白三烯，包括白三烯A4(LTA4)、LTB4和LTD4等。炎症细胞(包括白细胞、巨噬细胞和肥大细胞)是白三烯的主要来源。抑制LTB4受体可抑制炎症相关肿瘤的进展，LTD4则在肝细胞癌和慢性乙型肝炎患者的循环中上调。LOX途径主要包括5-LOX、12-LOX和15-LOX。5-LOX在上皮性癌和淋巴瘤中高度表达，具有促血管生成和促肿瘤活性。12-LOX通过激活整合素连接的激酶/NF-κB途径来促进肿瘤的生长。而15-LOX的代谢产物被发现能增强肿瘤相关炎症，既有促肿瘤作用又有抗肿瘤作用。另一种由LOX衍生的类花生酸脂毒素(lipoxins， LXs)则具有抗肿瘤作用。在前列腺癌中，LXA4通过抑制METTL3和或FPR2/IRF4途径，以促进巨噬细胞M2样极化。LXA4对炎性巨噬细胞极化的抑制作用与p-NF-κB p65和IRF5活性的下调有关，从而降低了LPS诱导的M1巨噬细胞通过FPR2/IRF5信号通路的表型和功能极化。 J Hematol Oncol.(二)JAK/STAT信号通路STAT3在炎症反应和肿瘤进展中发挥着广泛的作用。多种生长因子和细胞因子参与典型的STAT3通路，调节细胞分化、血管生成和肿瘤形成。IL-6和STAT3是启动肿瘤的肠上皮细胞生存和增殖所必需的。此外，在设计肠道的肿瘤如前列腺癌中，肠道生物失调增加了肠道通透性，肿瘤内的内毒素通过NF-κB/IL 6/STAT3轴促进了肿瘤的进展。Int Immunopharmacol.影响JAK/STAT通路的药物种类复杂，包括植物化学物质、合成药物和生物分子等等。Int Immunopharmacol.(三)金属代谢铁和ROS氧化还原铁代谢失调是肿瘤细胞的一个重要标志，在肿瘤细胞中，恶性肿瘤细胞需要大量的铁来生存和增殖。细胞色素P450酶、一氧化氮合酶、NADPH氧化酶和脂氧合酶等铁依赖性酶参与ROS的产生。同时，谷胱甘肽过氧化物酶GPX4是一种铁死亡的中枢抑制剂，GPX4利用还原性谷胱甘肽将活性的PUFA-PL-OOH还原为非活性和非致死性的PUFA-PL-OH。抑制Gpx4可通过诱导铁性死亡而增强治疗的抗肿瘤效应。十年铁死亡：双向调控与药物开发锌和NF-κB通路锌与许多炎症性细胞因子的产生和信号传递有关。当对应激刺激做出急性反应时，血浆锌浓度迅速下降。人体的锌代谢与ZIP8等锌转运蛋白的活性密切相关。在感染过程中，激活的NF-κB增加ZIP8的表达，ZIP8定位于细胞膜并调节锌的摄取。锌抑制了IKKβ的活性，从而减弱了炎症反应。参考文献：1.Wang M, Chen S, He X, Yuan Y, Wei X. Targeting inflammation as cancer therapy. J Hematol Oncol. 2024 Mar 22;17(1):13. doi: 10.1186/s13045-024-01528-7.2.Balamurugan K,et al.Stabilization of E-cadherin adhesions by COX-2/GSK3β signaling is a targetable pathway in metastatic breast cancer. JCI Insight. 2023 Mar 22;8(6):e156057. doi: 10.1172/jci.insight.156057.3.Cuenca-Escalona J,et al.PGE2-EP4 signaling steers cDC2 maturation toward the induction of suppressive T-cell responses. Eur J Immunol. 2024 Mar;54(3):e2350770. doi: 10.1002/eji.202350770.4.Francica BJ,et al.Dual Blockade of EP2 and EP4 Signaling is Required for Optimal Immune Activation and Antitumor Activity Against Prostaglandin-Expressing Tumors. Cancer Res Commun. 2023 Aug 8;3(8):1486-1500. doi: 10.1158/2767-9764.CRC-23-0249.5.Yuan J, et al. Lipoxin A4 regulates M1/M2 macrophage polarization via FPR2-IRF pathway. Inflammopharmacology. 2022 Apr;30(2):487-498. doi: 10.1007/s10787-022-00942-y.6.Wang Y,et al. Deciphering JAK/STAT signaling pathway: A multifaceted approach to tumorigenesis, progression and therapeutic interventions. Int Immunopharmacol. 2024 Mar 22;131:111846. doi: 10.1016/j.intimp.2024.111846.·····

免疫疗法

2024-03-25

·GlobeNewswire-Health Care

Linkage of Cancer and Lupus in Gliomas Patients

AGOURA HILLS, Calif., March 25, 2024 (GLOBE NEWSWIRE) -- Oncotelic Therapeutics, Inc (OTCQB:OTLC) announced today the peer reviewed publication of Transforming Growth Factor Beta 2 (TGFB2) mRNA Levels, in Conjunction with Interferon-Gamma Receptor Activation of Interferon Regulatory Factor 5 (IRF5) and Expression of CD276/B7-H3, Are Therapeutically Targetable Negative Prognostic Markers in Low-Grade Gliomas: Past, Present, and Future Strategies in the Treatment and Management of Gliomas. Dr. Vuong Trieu, CEO and Chairman of Oncotelic, stated, ”Our R&D team has discovered crosstalk between the TGF-β and IFN signaling pathways, linking gliomas and Systemic Lupus Erythematosus (SLE). This publication has identified IRF5 as a common target for both diseases, opening up a new avenue for combating cancer,” Our findings place IRF5 at the intersection of inflammation and cancer. Understanding the role of IRF5 in both SLE and cancer opens an avenue for targeting IRF5 or its downstream pathways. This could offer new strategies for treating SLE and various cancers by modulating the immune response. The article can be accessed for free online: https://www.mdpi.com/2072-6694/16/6/1202 Abstract: Gliomas develop in the central nervous system from the glial cells that support it. Low-grade gliomas (LGGs) are characterized by a reduced number of immune cells infiltrating the tumor, requiring immune-boosting therapies to release the immunosuppressive environment of the tumor. We conducted a bioinformatics-led study to evaluate the prognostic impact of cell surface receptor markers for tumor-associated macrophages (TAMs) that produce transforming growth factor beta (TGFB) ligands and interferon-gamma receptor activation to maintain the tumor microenvironment in an immunosuppressed state. Detailed investigation of messenger RNA levels and their impact on OS in LGG patients demonstrated that low mRNA levels of a specific TGFB ligand, TGFB2, and the receptor along with the signaling molecules from interferon-gamma receptor activation (IFNGR2, IRF1, IRF5, and STAT1) result in improved survival of LGG patients. LGG patients expressing high levels of TGFB2 and IFNGR2 are over-represented in IDH wild-type tumor samples, suggesting that TGFB2 and IFNGR2 mRNA can be therapeutically targeted in these high-risk patients. Furthermore, demethylation of TFGB2, IFNGR2, IRF1, IRF5, STAT1, and CD276 genes also results in worse survival outcomes, pointing to a molecular mechanism that increases the negative prognostic effects of increased mRNA levels of these target genes. We observed that significant upregulation of mRNA expression levels for three TAM markers, MSR1/CD204, CD86, and CD68, suggested that TGFB2 is pivotal in establishing a pro-tumorigenic TME in gliomas mediated through TAMs. Interestingly, a tumor-associated antigen CD276/B7-H3 mRNA expression increased in tumor tissue, giving further insights into the roles of macrophages and tumor cells in the immunosuppressive TME. Therefore, to improve OS in LGG patients, combination therapies must target TGFB2 and IFN-γ activation (via IRF5 inhibition) or immune therapies targeted against CD276/B7-H3 About Oncotelic Oncotelic (f/k/a Mateon Therapeutics, Inc.), was formed in the State of New York in 1988 as OXiGENE, Inc., was reincorporated in the State of Delaware in 1992, and changed its name to Mateon Therapeutics, Inc. in 2016, and Oncotelic Therapeutics, Inc. in November 2020. Oncotelic is seeking to leverage its deep expertise in oncology drug development to improve treatment outcomes and survival of cancer patients with a special emphasis on rare pediatric cancers. Oncotelic has rare pediatric designation for Diffuse Intrinsic Pontine Glioma (“DIPG” through OT-101) through its 45% joint venture, GMP Biotechnology Limited, melanoma (through CA4P), and Acute Myeloid Leukemia (through OXi 4503). Oncotelic acquired PointR Data Inc. in November 2019 to build an AI driven biotechnology company. Further, Oncotelic acquired AL-101, during the 4th quarter of 2021, for the intranasal delivery of apomorphine. We intend to develop AL-101 for the treatment of Parkinson Disease, erectile dysfunction, female sexual disorder and hypoactive sexual desire disorder. All these ailments have a very large population suffering from them and there is a need for treatments for each. For more information on AL-101, refer to our Annual Report on Form 10-K/A filed with the SEC on April 19, 2023. Oncotelic's Cautionary Note on Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements, other than statements of historical facts, included in this communication regarding strategy, future operations, future financial position, prospects, plans and objectives of management are forward-looking statements. Words such as "may", "expect", "anticipate" "hope", "vision", "optimism", "design", "exciting", "promising", "will", "conviction", "estimate," "intend," "believe", "quest for a cure of cancer", "innovation-driven", "paradigm-shift", "high scientific merit", "impact potential" and similar expressions are intended to identify forward-looking statements. Forward looking statements contained in this press release include, but are not limited to, statements about future plans related to the operations of the JV, taking the JV into an initial public offering or the success thereof, the progress, timing of clinical development, scope and success of future clinical trials, the reporting of clinical data for the Company’s product candidates and the potential use of the Company's product candidates to treat various cancer indications as well as obtaining required regulatory approval to conduct clinical trials and upon granting of approval by the regulatory agencies, the successful marketing of the products; building and the success of our nanoparticle platform and the related success of launching the platform, the development of the Company’s AI suite including but not limited to AI Chatbots, the public access to the Company’s AI suite, the success of the development of the AI suite or any other AI technologies and whether if any or portion thereof the Company’s AI suite or technologies will be commercialized and launched for sale. 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Forward-looking statements are based on expectations and assumptions as of the date of this press release. Except as required by law, the company does not assume any obligation to update forward-looking statements contained herein to reflect any change in expectations, whether because of new information, future events, or otherwise. Contact Information: For Oncotelic Therapeutics, Inc.:Investor Relationsir@oncotelic.com

并购免疫疗法

2024-03-19

·生物探索

JEV | 东南大学邱海波/巢杰发现败血症相关急性肺损伤的致病新机理

引言急性肺损伤(ALI)/急性呼吸窘迫综合征(ARDS)是一种常见的危及生命的综合征，目前尚无有效的药物治疗。败血症相关性ARDS是ARDS的主要类型，其致死率高于其他类型。细胞外囊泡(EVs)被认为是炎症性疾病发展中的新型介质。之前的研究表明，内皮细胞来源的EVs (EC-EVs)在ALI/ARDS的发展中起着至关重要的作用，但其机制仍不清楚。2024年3月15日，东南大学邱海波及巢杰共同通讯在Journal of Extracellular Vesicles在线发表题为“Endothelial cell-derived extracellular vesicles expressing surface VCAM1 promote sepsis-related acute lung injury by targeting and reprogramming monocytes”的研究论文，该研究发现循环EC-EVs的数量在败血症中增加，通过靶向单核细胞并将其重编程为促炎巨噬细胞，加剧了肺损伤。生物信息学分析和进一步的机制研究表明，败血症期间在EC-EVs上过表达的血管细胞粘附分子1 (VCAM1)通过与单核细胞表面而非组织巨噬细胞表面的整合素亚单位α 4 (ITGA4)相互作用激活NF-κB通路，从而调节单核细胞分化。这种作用可以通过降低EC-EVs中的VCAM1水平或阻断单核细胞上的ITGA4来减弱。此外，在败血症相关性ARDS患者中，VCAM1+ EC-EVs的数量显著增加。这些发现不仅揭示了先前未确定的败血症相关ALI/ARDS机制，而且为其精确治疗提供了潜在的新靶点和策略。急性肺损伤(ALI)/急性呼吸窘迫综合征(ARDS)是一种常见的呼吸危重综合征，由直接肺损伤(如肺炎、误吸)或非肺损伤(如败血症、创伤)引起，死亡率为35%至46% 。败血症相关性ARDS是ARDS的主要类型，其致死率高于其他类型。ARDS的本质是一种压倒性的、不受控制的炎症反应，其特征是炎症细胞大量浸润、细胞因子风暴形成、肺毛细血管通透性增加和肺水肿。尽管自1967年首次报道以来，在了解ARDS的发病机制方面取得了进展，但目前ARDS的治疗主要依赖于机械通气的支持性治疗，缺乏特异性和有效的药物治疗。这些治疗不能从根本上阻断疾病进展并改善患者的预后。因此，迫切需要探索新的靶点来抑制炎症级联反应的扩增。单核-巨噬细胞系统在ALI/ARDS的发生和发展中起着核心作用促炎型(M1型)和抗炎型(M2型)巨噬细胞失衡是ARDS发生的主要原因之一，其中M1巨噬细胞作为促炎表型，可促进ARDS的发生。巨噬细胞根据来源可分为组织常驻巨噬细胞(TR-Mφs)和单核细胞源性巨噬细胞(Mo-Mφs)。当感染发生时，经典Ly6Chigh单核细胞迁移到肺部并分化为Mo-Mφs以取代TR-Mφs。之前的大多数研究都将两者结合起来分析，认为它们在疾病中发挥着相同的功能。然而，最近越来越多的研究证明了两者之间意想不到的功能异质性。在SARS-CoV-2感染引起的ARDS中，Mo-Mφs驱动炎症反应，并且比TR-Mφs经历更显著的重编程，其中细胞表型因转录组变化而改变。在铜绿假单胞菌诱导的ALI小鼠模型中，Mo-Mφs与肺中其他细胞群(包括TR-Mφs)相比，M1巨噬细胞标志物(CD86、MHCII和iNOS)的表达更高。动物实验表明，外周血单核细胞的消耗可以降低ALI 。这些发现强烈提示Mo-Mφs在ARDS中起关键作用。在肺性ARDS中，单核细胞的募集和分化主要由肺泡细胞释放的趋化因子介导，这些趋化因子被病原体相关分子模式(pathogen-associated molecular patterns, PAMPs)或损伤相关分子模式(damage-associated molecular patterns, DAMPs)激活。然而，在非肺脓毒症相关的ARDS中，单核细胞在肺泡缺乏PAMPs和DAMPs的情况下从外周循环迁移到肺并分化为巨噬细胞的机制仍未得到充分研究。最近，新出现的证据表明，细胞外囊泡(EVs)参与调节免疫细胞功能和介导各种炎症性疾病的发展。EVs是脂质双层封闭囊泡，在正常和病理条件下几乎所有细胞类型都能释放，具有长距离细胞间通讯功能，稳定性好，作用持续时间长。有报道称，EVs介导肝脏疾病中单核细胞的募集和分化并在ARDS的发展中发挥作用。研究表明，与健康受试者相比，ARDS患者循环中内皮细胞源性细胞外囊泡(EC-EVs)的数量显著增加。早期对体外灌注人肺模型的研究发现，大肠杆菌诱导的体外人ALI模型的灌注液中的EVs主要来源于内皮细胞；将这些EVs注射到naïve人体肺部导致ALI，阻断EVs摄取后ALI降低。EC-EVs在败血症相关ALI/ARDS中的作用示意图（Credit: Journal of Extracellular Vesicles）该研究发现肺外败血症期间循环EC-EVs数量显著增加。值得注意的是，这些EC-EVs被单核细胞优先摄取，并在肺中被重编程为促炎巨噬细胞，导致细胞因子风暴和更多炎症细胞的浸润，从而加剧肺损伤。然而，这些EVs对肺TR-Mφs没有影响。生物信息学分析和进一步的机制研究表明，败血症期间在EC-EVs上过表达的VCAM1通过与单核细胞表面的ITGA4而不是TR-Mφs相互作用激活NF-κB通路，从而重新编程单核细胞(图10)。此外，在临床水平上，作者证实了VCAM1+ EC-EV在脓毒症相关ARDS患者中显著升高，这可能作为脓毒症患者ARDS发展的潜在生物标志物和靶点。这些发现不仅揭示了先前未确定的败血症相关ALI/ARDS机制，而且为其精确治疗提供了潜在的新靶点和策略。原文链接https://isevjournals.onlinelibrary.wiley.com/doi/full/10.1002/jev2.12423责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述

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