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Granzyme B, Human, 1.3_960 U_ml, ELISA Kit, includes Mab coating Ab, control, standard, Biotin secondary, HRP_Streptavidin, buffer, substrate (No plate)

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[#CLBM1936] Granzyme B, Human, 1.3_960 U_ml, ELISA Kit, includes Mab coating Ab, control, standard, Biotin secondary, HRP_Streptavidin, buffer, substrate (No plate)


CLBM1936 | Granzyme B, Human, 1.3_960 U_ml, ELISA Kit, includes Mab coating Ab, control, standard, Biotin secondary, HRP_Streptavidin, buffer, substrate (No plate), kit
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(1) Epsin15 Homology Domains: Role in the Pathogenesis of Pulmonary Arterial Hypertension.[TOP]

Pubmed ID :30333761
Publication Date : //
Intersectin-1s (ITSN) deficiency and expression of a biologically active ITSN fragment, result of granzyme B cleavage under inflammatory conditions associated with pulmonary arterial hypertension (PAH), are characteristics of lung tissue of human and animal models of PAH. Recently, we have shown that this ITSN fragment comprising two Epsin15 homology domains (EH) triggers endothelial cell (EC) proliferation and the plexiform arteriopathy in PAH. Limited evidence also indicates that the EH domains of endocytic proteins such as ITSN, upregulate compensatory endocytic pathways in cells with impaired vesicular trafficking. Thus, we sought to investigate whether the EH may be involved in this compensatory mechanism for improving the EC endocytic dysfunction induced by ITSN deficiency and possibly contribute to PAH pathogenesis. We used stably-transfected human pulmonary artery ECs expressing the Myc-EH (EC) and ITSN knockout heterozygous mice (K0 ) transduced with the Myc-EH, in conjunction with functional assays: the biotin assay for caveolae internalization and 8 nm gold (Au)- and dinitrophenylated (DNP)-albumin perfusion of murine lung microvasculature. Pulmonary artery ECs of PAH patients (EC), ITSN knockdown ECs (EC), the monocrotaline (MCT)-induced mouse and rat models of PAH, as well as untreated animals, served as controls. ELISA via streptavidin-HRP or anti-DNP antibody (Ab), applied on ECs and lung lysates indicated greater than 30% increase in biotin internalization in EC compared to EC. Despite their endocytic deficiency, EC internalized biotin similar to EC which is twofold higher compared to EC. Moreover, the lung microvascular bed of Myc-EH-transduced mice and MCT-treated animals showed greater than twofold increase in DNP-BSA transendothelial transport, all compared to untreated controls. Electron microscopy (EM) revealed the increased occurrence of non-conventional endocytic/transcytotic structures (i.e., caveolae clusters, tubulo-vesicular and enlarged endocytic structures, membranous rings), usually underrepresented. Most of these structures were labeled by Au-BSA, consistent with their involvement in the transendothelial transport. Furthermore, ITSN deficiency and EH expression alter the subcellular localization of the EH-binding protein 1 (EHBP1) and cortical actin organization, altogether supporting the increase occurrence/trafficking of the alternative endocytic structures. Thus, the EH by shifting the physiological vesicular (caveolae) transport toward the alternative endocytic pathways is a significant contributor to the dysfunctional molecular phenotype of EC.

Authors : Predescu Dan, Qin Shanshan, Patel Monal, Bardita Cristina, Bhalli Rabia, Predescu Sanda,

(2) Granzyme B is an essential mediator in CD8+ T cell killing of infected cells.[TOP]

Pubmed ID :30323022
Publication Date : //
There is established evidence that cytotoxic CD8+ T cells are important mediators of immunity against the bovine intracellular protozoan parasite However, the mechanism by which the specific CD8+ T cells kill parasitized cells is not understood. Although the predominant pathway used by human and murine CD8+ T cells to kill pathogen-infected cells is granule exocytosis, involving release of perforin and granzyme B, there is to date a lack of published information on the biological activities of bovine granzyme B. The present study set out to define the functional activities of bovine granzyme B and determine its role in mediating killing of -parasitized cells. DNA constructs encoding functional and non-functional forms of bovine granzyme B were produced and the proteins expressed in Cos-7 cells were used to establish an enzymatic assay to detect and quantify expression of functional granzyme B protein. Using this assay, the levels of killing of different -specific CD8+ T cell clones were found to be significantly correlated with levels of granzyme B protein, but not mRNA transcript, expression. Experiments using inhibitors specific for perforin and granzyme B confirmed that CD8+ T cell killing of parasitized cells is dependent on granule exocytosis and specifically granzyme B. Further studies showed that granzyme B-mediated death of parasitized cells is independent of caspases and that granzyme B activates the pro-apoptotic molecule Bid.

Authors : Yang Jie, Pemberton Alan, Morrison W Ivan, Connelley Tim,

(3) Stimulation of natural killer cells with rhCD137 ligand enhances tumor-targeting antibody efficacy in gastric cancer.[TOP]

Pubmed ID :30321186
Publication Date : //
Although many anticancer agents for gastric cancer have been developed, the prognosis for many patients remains poor. Recently, costimulatory immune molecules that reactivate antitumor immune responses by utilizing the host immune system have attracted attention as new therapeutic strategies. CD137 is a costimulatory molecule that reportedly potentiates the antitumor activity of tumor-targeting monoclonal antibodies (mAbs) by enhancing antibody-dependent cellular cytotoxicity. However, it remains unclear whether CD137 stimulates tumor-regulatory activity in gastric cancer. In this study, we investigated the antitumor effects of CD137 stimulation on gastric cancer cells administered tumor-targeting mAbs. Our results showed that human natural killer (NK) cells were activated by expressing CD137 after encountering trastuzumab-coated gastric cancer cells, and that stimulation of activated NK cells in the presence of trastuzumab and recombinant human CD137 ligand (rhCD137L) enhanced cytotoxicity and release of cytokines (IFN-γ, TNF, granzyme A, or granzyme B) as compared with activated NK cells with trastuzumab alone (p < 0.05). By combination treatment with rhCD137L, similar effects were obtained regarding cancer cell cytotoxicity in the presence of cetuximab (p < 0.01). Moreover, we revealed that CD137 expression was dependent upon the affinity between the Fc portion of the antibodies and FcγRIIIa of NK cells based on results indicating that human IgG1 and IgG3 subclasses enhanced CD137 expression (p < 0.001). These results confirmed that FcγRIIIA polymorphisms (158 V/V) enhanced CD137 expression to a greater degree than 158 F polymorphisms (p = 0.014). Our results suggested that CD137 stimulation could promote the effects of tumor-targeting mAbs in gastric cancer, and that further investigation of antibody binding affinity and in vivo activities might improve therapeutic strategies related to the treatment of gastric cancer patients.

Authors : Misumi Toshihiro, Tanabe Kazuaki, Fujikuni Nobuaki, Ohdan Hideki,

(4) Granzyme B-loaded, cell-selective penetrating and reduction-responsive polymersomes effectively inhibit progression of orthotopic human lung tumor in vivo.[TOP]

Pubmed ID :30312720
Publication Date : //
The clinical use of protein therapeutics with intracellular targets is hampered by its in vivo fragility and low cell permeability. Here, we report that cell-selective penetrating and reduction-responsive polymersomes (CPRPs) mediate high-efficiency targeted delivery of granzyme B (GrB) to orthotopic human lung tumor in vivo. Model protein studies using FITC-labeled cytochrome C (FITC-CC) revealed efficient and high protein loading up to 17.2 wt% for CPRPs. FITC-CC-loaded CPRPs exhibited a small size of 82-90 nm, reduction-responsive protein release, as well as greatly enhanced internalization and cytoplasmic protein release in A549 lung cancer cells compared with the non-targeted FITC-CC-loaded RPs control. GrB-loaded CPRPs showed a high potency toward A549 lung cancer cells with a half maximal inhibitory concentration (IC) of 20.7 nM. Under the same condition, free GrB was essentially non-toxic. Importantly, installing cell-selective penetrating peptide did not alter the circulation time but did enhance tumor accumulation of RPs. Orthotopic A549-Luc lung tumor-bearing nude mice administered with GrB-loaded CPRPs at a dosage of 2.88 nmol GrB equiv./kg showed complete tumor growth inhibition with little body weight loss throughout the treatment period, resulting in significantly improved survival rate over the non-targeted and non-treated controls. These cell-selective penetrating and reduction-responsive polymersomes provide a targeted protein therapy for cancers.

Authors : Yang Weijing, Wei Yaohua, Yang Liang, Zhang Jian, Zhong Zhiyuan, Storm Gert, Meng Fenghua,

(5) Aged human skin accumulates mast cells with altered functionality which localise to macrophage and VIP nerve fibres.[TOP]

Pubmed ID :30291626
Publication Date : //
Skin health declines with age and this is partially attributed to immunosenescence. Mast cells (MCs) are innate immune cells which coordinate tissue immune responses integral to skin homeostasis and disease.

Authors : Pilkington S M, Barron M J, Watson R E B, Griffiths C E M, Bulfone-Paus S,

(6) Immunohistochemical Profiling of Canine Intestinal T-Cell Lymphomas.[TOP]

Pubmed ID :30278836
Publication Date : //
Human enteropathy-associated T-cell lymphoma (EATL) is classified into 2 distinct subgroups based on their phenotypes (type I and type II). Canine intestinal T-cell lymphoma can be morphologically classified into large and small cell lymphomas (LCL and SCL, respectively). Their association with human EATL or immunohistochemical and biological features has not been well characterized. In this study, the immunohistochemical profiles of 17 cases of LCL and 33 cases of SCL were evaluated with markers used for human EATL classification. Morphologically, LCL was characterized by sheet-like proliferation of large to moderately sized neoplastic lymphocytes, with scant clear cytoplasm and pleomorphic, irregularly shaped nuclei containing distinctive nucleoli and scattered chromatin. In contrast, SCL was characterized by the proliferation of monomorphic small neoplastic lymphocytes, accompanied by infiltration of nonneoplastic plasma cells. Interestingly, 8 cases demonstrated mixed LCL and SCL morphologies. Granular cytoplasmic expression of granzyme B was observed in most LCL and SCL cases. Membranous expression of CD56 was demonstrated in only 2 of 17 LCL and 0 of 33 SCL cases. Coexpression of CD20 by neoplastic T cells was observed in more SCL cases (16/33; 48%) than LCL cases (1/17; 6%). The CD56-positive cells in 2 cases were negative for CD20. Although canine LCL shares common features with human EATL type I, canine SCL cells and human EATL type II differ in their immunophenotype. Canine intestinal T-cell lymphoma had a homogeneous immunophenotype regardless of cell morphology. The findings of this study may indicate large cell transformation of SCL rather than 2 distinct entities.

Authors : Matsumoto Isao, Nakashima Ko, Goto-Koshino Yuko, Chambers James Kenn, Tsujimoto Hajime, Nakayama Hiroyuki, Uchida Kazuyuki,

(7) EF Hand Domain Family Member D2 Is Required for T Cell Cytotoxicity.[TOP]

Pubmed ID :30275048
Publication Date : //
Programmed cell death 1 (PD-1) is a major coinhibitory receptor and a member of the immunological synapse (IS). To uncover proteins that regulate PD-1 recruitment to the IS, we searched for cytoskeleton-related proteins that also interact with PD-1 using affinity purification mass spectrometry. Among these proteins, EF hand domain family member D2 (EFHD2), a calcium binding adaptor protein, was functionally and mechanistically analyzed for its contribution to PD-1 signaling. EFHD2 was required for PD-1 to inhibit cytokine secretion, proliferation, and adhesion of human T cells. Interestingly, EFHD2 was also required for human T cell-mediated cytotoxicity and for mounting an antitumor immune response in a syngeneic murine tumor model. Mechanistically, EFHD2 contributed to IS stability, lytic vesicles trafficking, and granzyme B secretion. Altogether, EFHD2 is an important regulator of T cell cytotoxicity and further studies should evaluate its role in T cell-mediated inflammation.

Authors : Peled Michael, Dragovich Matthew A, Adam Kieran, Strazza Marianne, Tocheva Anna S, Vega Irving E, Mor Adam,

(8) Bortezomib improves adoptive carbonic anhydrase IX‑specific chimeric antigen receptor‑modified NK92 cell therapy in mouse models of human renal cell carcinoma.[TOP]

Pubmed ID :30272343
Publication Date : //
Adoptive chimeric antigen receptor (CAR) T or NK cells offer new options for cancer treatment. Clinical results indicate that CAR‑modified T cell (CAR‑T) therapy has curative therapeutic efficacy for hematological malignancies. However, the efficacy of the therapy in most solid tumors, including advanced renal cell carcinoma (RCC), remains highly limited. New regimens, including combination of CAR‑T cells with chemical drugs, must be studied to enhance the therapeutic efficacy of CAR‑T or NK cells for solid tumors. In the present study, a carbonic anhydrase IX (CAIX)‑specific third‑generation CAR was transduced into NK92 cells by lentiviral vectors. The immune effects, including cytokine release and cytotoxicity, of the CAR‑NK92 cells against CAIX‑positive RCC cells were evaluated in vitro. Combination therapeutic effects of bortezomib and CAR‑NK92 cells were analyzed in a mouse model with human RCC xenografts. The results revealed that CAIX‑specific CAR‑NK92 cells specifically recognized in vitro cultured CAIX‑positive RCC cells and released cytokines, including IFN‑γ, perforin and granzyme B, and exhibited specific cytotoxicity. The cytotoxicity of the CAR‑NK92 cells was enhanced after treating RCC cells with bortezomib in vitro. The suppressive efficacy of bortezomib combined with CAR‑NK92 cells against established CAIX‑positive tumor xenografts was more significant than that of the monotherapy with either CAR‑NK92 cells or bortezomib. Therefore, bortezomib can enhance the effects of the CAR‑NK92 cells against RCC in vitro and in vivo. This study provided an experimental basis for the novel clinical regimen of CAIX‑specific CAR‑modified NK or T cells for the treatment of RCC.

Authors : Zhang Qing, Xu Jinjing, Ding Jiage, Liu Hongyan, Li Huizhong, Li Hailong, Lu Mengmeng, Miao Yangna, Wang Zhenzhen, Fu Qiang, Zheng Junnian,

(9) PEGylated meloxicam-loaded nanocapsules reverse in vitro damage on caspase activity and do not induce toxicity in cultured human lymphocytes and mice.[TOP]

Pubmed ID :30257340
Publication Date : //
Meloxicam is an anti-inflammatory drug that has a potential protective effect in many common diseases. However, this molecule is quickly eliminated from the body due to it short half-life. One way to overcome this problem is to incorporate meloxicam into lipid-core nanocapsules which may increase it anti-inflammatory effects. In view of this, the objective of this work was to evaluate the potential toxicity and safety of these novel nanomaterials both in vitro and in vivo. Here, we evaluated the effects of uncoated meloxicam-loaded nanocapsules (M-NC), uncoated and not loaded with meloxicam or blank (B-NC), PEGylated meloxicam-loaded lipid-core nanocapsules (M-NCPEG), blank PEGylated lipid-core nanocapsules (B-NCPEG) and free meloxicam (M-F) in vitro through the analysis of cell viability, caspase activity assays and gene expression of perforin and granzyme B. Meanwhile, the in vivo safety was assessed using C57BL/6 mice that received nanocapsules for seven days. Thus, no change in cell viability was observed after treatments. Furthermore, M-NC, M-NCPEG and M-F groups reversed the damage caused by HO on caspase-1, 3 and 8 activities. Overall, in vivo results showed a safe profile of these nanocapsules including hematological, biochemical, histological and genotoxicity analysis. In conclusion, we observed that meloxicam nanocapsules present a safe profile to use in future studies with this experimental protocol and partially reverse in vitro damage caused by HO.

Authors : Nishihira Vivian S K, Fontana Barbara D, Ianiski Francine R, de Almeida Hemilaine S, Posser Christopher P, Dias Juliane B, Parodi Crystian B, Piva Manoela M, Gris Anderson, Mendes Ricardo E, Duarte Marta M M F, Sagrillo Michele R, Luchese Cristiane, Rech Virginia C, Vaucher Rodrigo A,

(10) Siglec-7 engagement by GBS β-protein suppresses pyroptotic cell death of natural killer cells.[TOP]

Pubmed ID :30254166
Publication Date : //
Natural killer (NK) cells are innate immune lymphocytes that recognize and destroy abnormal host cells, such as tumor cells or those infected by viral pathogens. To safely accomplish these functions, NK cells display activating receptors that detect stress molecules or viral ligands displayed at the cell surface, balanced by inhibitory receptors that bind to self-molecules. To date, such activating and inhibitory receptors on NK cells are not known to recognize bacterial determinants. Moreover, NK cell responses to direct interactions with extracellular bacteria are poorly explored. In this study, we observed the human neonatal pathogen group B (GBS) can directly engage human NK cells. The interaction was mediated through the B6N segment of streptococcal β-protein, binding to the inhibitory receptor Siglec-7 via its amino-terminal V-set domain. Unlike classical Siglec binding, the interaction is also independent of its sialic acid recognition property. In contrast to WT GBS, mutants lacking β-protein induced efficient pyroptosis of NK cells through the NLRP3 inflammasome, with production and secretion of the proinflammatory cytokine IL-1β and dissemination of the cytotoxic molecule granzyme B. We postulate that GBS evolved β-protein engagement of inhibitory human Siglec-7 to suppress the pyroptotic response of NK cells and thereby block recruitment of a broader innate immune response, i.e., by "silencing the sentinel."

Authors : Fong Jerry J, Tsai Chih-Ming, Saha Sudeshna, Nizet Victor, Varki Ajit, Bui Jack D,