Last update 01 Nov 2024

DR4 x DR5 x VEGF

Last update 01 Nov 2024

Basic Info

Related Targets

DR4DR5VEGF

Drugs associated with DR4 x DR5 x VEGF

3-CLA

Target

DR4 x DR5 x VEGF

Mechanism

DR4 agonists [+2]

Active Org.-

Originator Org.

Adamed Sp zoo

Active Indication-

Inactive Indication

Hematologic Neoplasms [+1]

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with DR4 x DR5 x VEGF

100 Translational Medicine associated with DR4 x DR5 x VEGF

0 Patents (Medical) associated with DR4 x DR5 x VEGF

Literatures (Medical) associated with DR4 x DR5 x VEGF

01 Jun 2023·Cytotherapy

Impact of soluble tumor necrosis factor-related apoptosis-inducing ligand released by engineered adipose mesenchymal stromal cells on white blood cells.

Article

Author: Grisendi, Giulia ; Casari, Giulia ; Ceccherelli, Giovanni Battista ; Chiavelli, Chiara ; Murgia, Alba ; Baschieri, Maria Cristina ; Neri, Giovanni ; Spano, Maria Carlotta ; Masciale, Valentina ; D'Esposito, Angela ; Dall'Ora, Massimiliano ; Prapa, Malvina ; Dominici, Massimo ; Melandri, Aurora

BACKGROUND AIMSThe proapoptotic protein tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is physiologically expressed by immune cells and performs regulatory functions in infections, autoimmune diseases and cancer, where it acts as a tumor suppressor. Adipose-derived mesenchymal stromal cells (AD-MSCs) also may play immunomodulatory roles in both primary and acquired immune responses. We have previously demonstrated the efficacy of an anticancer gene therapy based on AD-MSC engineered to secrete a soluble TRAIL variant (sTRAIL) against pancreatic cancer. However, the impact of AD-MSC sTRAIL on leukocyte subsets has been not yet considered also to predict a possible immunotoxicity profile in the clinical translation of this cell-based anticancer strategy.METHODSMonocytes, polymorphonuclear cells and T lymphocytes were freshly isolated from the peripheral blood of healthy donors. Immunophenotype and functional (DR4 and DR5) and decoy (DcR1 and DcR2) TRAIL receptors were tested by flow cytometry. The viability of white blood cells treated with sTRAIL released by gene-modified AD-MSC or co-cultured with AD-MSC sTRAIL was then evaluated by both metabolic assays and flow cytometry. In addition, cytokine profile in co-cultures was analyzed by multiplex enzyme-linked immunosorbent assay.RESULTSMonocytes and polymorphonuclear cells showed high positivity for DR5 and DcR2, respectively, whereas T cells revealed negligible expression of all TRAIL receptors. Irrespective of TRAIL receptors' presence on the cell membrane, white blood cells were refractory to the proapoptotic effect displayed by sTRAIL secreted by gene-modified AD-MSC, and direct cell-to-cell contact with AD-MSC sTRAIL had negligible impact on T-cell and monocyte viability. Cytokine crosstalk involving interleukin 10, tumor necrosis factor alpha, and interferon gamma secreted by T lymphocytes and vascular endothelial growth factor A and interleukin 6 released by AD-MSC was highlighted in T-cell and AD-MSC sTRAIL co-cultures.CONCLUSIONSIn summary, this study demonstrates the immunological safety and thus the clinical feasibility of an anticancer approach based on AD-MSC expressing the proapoptotic molecule sTRAIL.

25 Mar 2023·Zhen ci yan jiu = Acupuncture research

[Effect of penetrative needling of "Zhibian" (BL54) through "Shuidao" (ST28) on expression of TRAIL and its receptors in rats with premature ovarian insufficiency].

Article

Author: Wang, Hong-Yang ; Yin, Lu-Yun ; Yan, Jing ; Jin, Xiao-Fei ; Ma, Meng-Na ; Zhao, Ji-Yu

OBJECTIVETo observe the effect of penetrative needling of "Zhibian" (BL54) through "Shuidao" (ST28) on the expressions of death receptor pathway-related protein tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors, as death receptor 4 (DR4), death receptor 5 (DR5), decoy receptor 1 (DcR1) and decoy receptor 2 (DcR2) in premature ovarian insufficiency (POI) rats, so as to explore its mechanisms underlying improvement of POI.METHODSForty female SD rats were randomly divided into blank control, model, penetrative needling and medication (estradiol valerate) groups, with 10 rats in each group. The POI model was established by intraperitoneal injection of cyclophosphamide (D1: 50 mg·kg^-1·d^-1, D2 to D15: 8 mg·kg^-1·d^-1, for a total of 15 d). After successful modeling, the rats in the penetrative needling group received penetrative needling of BL54 through ST28, with the needle retained for 30 min, once a day for a total of 4 weeks. Rats of the medication group received gavage of estradiol valerate (0.09 mg·kg^-1·d^-1) once daily for 4 weeks. After the intervention, the content of serum follicles of stimulation hormone (FSH),lateinizing hormone (LH),estradiol (E2) and vascular endothelial growth factor (VEGF) were assayed using enzyme-linked immunosorbent assay, and histopathological changes of ovarian tissue and the number of follicles were observed under light microscope after H.E. staining. The expression levels of TRAIL, DR4, DR5, DcR1, DcR2, and Fas-associated death domain (FADD) in ovarian tissues were detected using quantitative real-time PCR, and the immunoactivity of ovarian TRAIL, DR4 and DR5 detected using immunohistochemistry. The body weight and the damp weight of ovary were measured for calculating the ovarian coefficient.RESULTSCompared with the blank control group, the E2 and VEGF contents, ovarian coefficient, and the number of the primary, secondary and sinus follicles were significantly decreased (P<0.01) in the model group, whereas FSH and LH contents, the atretic follicle number, TRAIL, DR4 and DR5 immunoactivity, and the expression levels of TRAIL, DR4, DR5 and FADD mRNAs considerably increased in the model group (P<0.01). In comparison with the model group, the decrease of the VEGF content, ovarian coefficient, and the number of the primary, secondary and sinus follicles, and the increase of the atretic follicle number, TRAIL, DR4 and DR5 immunoactivity, and expression levels of TRAIL, DR4, DR5 and FADD mRNAs were reversed in both penetrative needling and medication groups (P<0.01, P<0.05). The number of primary follicles was significantly more in the medication group than in the penetrative needling group (P<0.01).CONCLUSIONPenetrative needling of BL54 and ST28 can improve ovarian weight and promote follicular development in POI rats, which may be associated with its function in down-regulating the expression of pro-apoptotic proteins TRAIL, DR4, DR5 and FADD of the death receptor pathway to inhibit apoptosis of ovarian granulosa cells.

01 Jan 2019·Chonnam Medical Journal

Therapeutic Effects of Synthetic Antimicrobial Peptides, TRAIL and NRP1 Blocking Peptides in Psoriatic Keratinocytes

Review

Author: Armstrong, Cheryl A. ; Norris, David ; Kim, Beomjoon ; Song, Peter I. ; Ryu, Sunhyo ; Broussard, Lindsey ; Youn, Chakyung ; Song, Brendon

Psoriasis is a chronic, recurrent, heterogeneous, cutaneous inflammatory skin disease for which there is no cure. It affects approximately 7.5 million people in the United States. Currently, several biologic agents that target different molecules implicated in the pathogenic processes of psoriasis are being assessed in diverse clinical studies. However, relapse usually occurs within weeks or months, meaning there is currently no cure for psoriasis. Therefore, recent studies have discovered diverse new potential treatments for psoriasis: inhibitors of bacteria such as Staphylococcus aureus, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and neuropilin 1 (NRP1). A promising approach that has recently been described involves modifying antimicrobial peptides to develop new cutaneous anti-bacterial agents that target inflammatory skin disease induced by Staphylococcus. Increased expression of TRAIL and its death receptors DR4 and DR5 has been implicated in the pathogenesis of plaque psoriasis. In addition, TRAIL has the ability to inhibit angiogenesis by inducing endothelial cell death and by negative regulation of VEGF-induced angiogenesis via caspase-8-mediated enzymatic and non-enzymatic functions. Since NRP1 regulates angiogenesis induced by multiple signals, including VEGF, ECM and semaphorins, and also initiates proliferation of keratinocytes through NF-κB signaling pathway in involved psoriatic skin, targeting NRP1 pathways may offer numerous windows for intervention in psoriasis. In this review, we will focus on the current knowledge about the emerging role of synthetic antimicrobial peptides, TRAIL and NRP1 blocking peptides in the pathogenesis and treatment of psoriasis.

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