[6]‐Gingerol impedes 7,12‐dimethylbenz(a)anthracene‐induced inflammation and cell proliferation‐associated hamster buccal pouch carcinogenesis through modulating Nrf2 signaling events

2020 ◽  
Author(s):  
Yugang Sun ◽  
Jinmin Ren ◽  
Fang Wang
Keyword(s):  
Cell Proliferation ◽  
Hamster Buccal Pouch ◽  
Signaling Events

The JAK1/JAK2 Inhibitor Ruxolitinib Substantially Affects NK Cell Biology

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 16-16 ◽  
Author(s):  
Kathrin Schönberg ◽  
Janna Rudolph ◽  
Isabelle Cornez ◽  
Peter Brossart ◽  
Dominik Wolf
Keyword(s):  
Flow Cytometry ◽  
Cell Proliferation ◽  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Granzyme B ◽  
Receptor Activation ◽  
Jak2 Inhibitor ◽  
Signaling Events ◽  
Ifn Γ

Abstract Introduction We recently demonstrated that ruxolitinib (INCB018424), the first approved JAK1/JAK2 inhibitor for treatment of myelofibrosis (MF), exerts potent anti-inflammatory activity. This may at least in part explain higher infection rates observed in ruxolitinib-treated patients. NK cells are critical for cancer-immune surveillance and cytokine-mediated signals are central for proper NK cell activation. We here aimed to characterize in detail the effects of JAK1/2 inhibition on human NK cells. Methods Highly purified CD56+ NK cells were isolated from human peripheral buffy coats by magnetic bead isolation and subsequently exposed to increasing concentrations of ruxolitinib (0.1-10 µM). Cytokine (1000U/ml IL-2, 25ng/ml IL-15)-induced NK cell proliferation was analyzed by CFSE dilution. Phenotypic and functional NK cell activation markers (NKp46, NKG2D, Granzyme B, CD16, and CD69) were analyzed by flow cytometry (including CD107a expression for degranulation). NK cell function was tested by flow-cytometry-based killing assays and quantification of IFN-γ production upon stimulation with either MHC class I-deficient K562 target cells or cytokines (IL-12, IL-18). In addition, phenotypic and functional analyses were also tested during NK receptor activation via plate-bound activating NKp46 antibodies. Signaling events were analyzed by Western Blot analysis to detect phosphorylation of JAK1 and JAK2 as well as by applying phospho-flow technology to evaluate ruxolitinib-mediated changes of cytokine-dependent signalling cascades (pS6, pSTAT1, pSTAT3, pSTAT5, pERK, pAKT, pP38, and pZAP70). Results Our results demonstrate provide first evidence that ruxolitinib profoundly affects cytokine-induced NK cell activation. This includes a significant and dose-dependent reduction of NK cell proliferation, reduced induction of activation-associated surface markers (including NKp46, NKG2D, Granzyme B, CD16, CD69) as well as impaired killing activity against the classical NK target cell line K562. In addition, all main functional activities of NK cells are down-regulated as shown by reduced cytotoxic capacity, impaired degranulation and IFN-γ production. After wash-out, the inhibitory effects of ruxolitinib on NK cells are fully reversible, as shown by proper re-activation by cytokines. In contrast to cytokine-mediated NK cell activation, stimulation via the NK-specific receptor NKp46 are not affected by ruxolitinib. Of note, ruxolitinib does not affect NK cell viability. On a molecular level, phospho-flow analyses revealed that cytokine associated signaling events, such as phosphorylation of STAT5 and S6 were dose-dependently reduced by ruxolitinib in primary human NK cells. Conclusions Ruxolitinib strongly inhibits NK cell activation leading to impaired proliferation and functional activity. Experiments verifying these effects in patients are currently ongoing and will be presented at the meeting. Our findings may have important clinical implications, when considering the application of ruxolitinib as GvHD therapy, because NK cells are critically involved in the GvL effect after allogeneic stem cell transplantation. Disclosures: Wolf: Novartis: Honoraria, Research Funding.

Geraniol modulates cell proliferation, apoptosis, inflammation, and angiogenesis during 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis

2012 ◽  
Vol 369 (1-2) ◽  
pp. 17-25 ◽  
Author(s):  
Veerasamy Vinothkumar ◽  
Shanmugam Manoharan ◽  
Ganapathy Sindhu ◽  
Madhavan Ramados Nirmal ◽  
Venkatesan Vetrichelvi
Keyword(s):  
Cell Proliferation ◽  
Hamster Buccal Pouch

scholarly journals Inhibition of Cell Proliferation by a Unique Lysophosphatidic Acid, PHYLPA, Isolated from Physarum polycephalum: Signaling Events of Antiproliferative Action by PHYLPA.

1993 ◽  
Vol 18 (5) ◽  
pp. 363-370 ◽  
Author(s):  
Kimiko Murakami-Murofushi ◽  
Kazuhiko Kaji ◽  
Kazutaka Kano ◽  
Mitsugu Fukuda ◽  
Masaki Shioda ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Lysophosphatidic Acid ◽  
Physarum Polycephalum ◽  
Antiproliferative Action ◽  
Signaling Events

scholarly journals XB130 Mediates Cancer Cell Proliferation and Survival through Multiple Signaling Events Downstream of Akt

PLoS ONE ◽  
2012 ◽  
Vol 7 (8) ◽  
pp. e43646 ◽  
Author(s):  
Atsushi Shiozaki ◽  
Grace Shen-Tu ◽  
Xiaohui Bai ◽  
Daisuke Iitaka ◽  
Valentina De Falco ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cancer Cell ◽  
Cancer Cell Proliferation ◽  
Signaling Events ◽  
Multiple Signaling

scholarly journals HIP-55 Is Important for T-Cell Proliferation, Cytokine Production, and Immune Responses

2005 ◽  
Vol 25 (16) ◽  
pp. 6869-6878 ◽  
Author(s):  
Jin Han ◽  
Jr-Wen Shui ◽  
Xuejun Zhang ◽  
Biao Zheng ◽  
Shuhua Han ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Knockout Mice ◽  
Cytokine Production ◽  
Adaptor Protein ◽  
T Cell Proliferation ◽  
Tcr Signaling ◽  
Signaling Events

ABSTRACT Engagement of the T-cell receptor (TCR) triggers a series of signaling events that lead to the activation of T cells. HIP-55 (SH3P7 or mAbp1), an actin-binding adaptor protein, interacts with and is tyrosine phosphorylated by ZAP-70, which is a crucial proximal protein tyrosine kinase for TCR signaling. HIP-55 is important for JNK and HPK1 activation induced by TCR signaling. In this study, we report the generation and characterization of HIP-55 knockout mice. We found that HIP-55 knockout mice were viable and fertile but showed decreased body weight and increased occurrence of death within the first 4 weeks after birth. The lymphoid organs in HIP-55 knockout mice showed cellularity and T-cell development comparable to that of the wild-type mice. HIP-55 knockout T cells displayed defective T-cell proliferation, decreased cytokine production, and decreased up-regulation of the activation markers induced by TCR stimulation. TCR internalization was slightly increased in HIP-55 knockout T cells. These phenotypes were accompanied by reduced immune responses, including antigen-specific antibody production and T-cell proliferation in HIP-55 knockout mice. The TCR-induced signaling events, including LAT/phospholipase Cγ1 phosphorylation and HPK1/JNK activation, were partially defective in HIP-55 knockout T cells. These results demonstrate the importance of HIP-55 as an adaptor protein in the TCR signaling and immune system.

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