A nuclear factor-κB inhibitor, dehydroxymethylepoxyquinomicin, ameliorates GVHD in allogeneic bone marrow transplantation

Yamanouchi, Sohsaku; Adachi, Yasushi; Shimo, Tomohiko; Umezawa, Kazuo; Okigaki, Mitsuhiko; Tsuji, Shoji; Li, Ming; Takaya, Junji; Kuge, Tomohiro; Ikehara, Susumu

doi:10.1016/j.imbio.2015.05.011

Cited by 7 publications

(4 citation statements)

References 43 publications

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“…An inversely proportional relationship between spleen size and GvHD severity has been established earlier 18 . Therefore, we also measured the spleen size and weight, which was found to be significantly decreased in GvHD control group compared to WSE group ( supplementary Fig.…”

Section: Resultsmentioning

confidence: 77%

Withania Somnifera Extract Mitigates Experimental Acute Graft versus Host Disease Without Abrogating Graft Versus Leukemia Effect

Gupta,

Gohil,

Momin

et al. 2024

Cell Transplant

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Acute graft versus host disease (aGvHD) is the major contributor of nonrelapse mortality in alloHSCT. It is associated with an inflammatory immune response manifesting as cytokine storm with ensuing damage to target organs such as liver, gut, and skin. Prevention of aGvHD while retaining the beneficial graft versus leukemia (GvL) effect remains a major challenge. Withania somnifera extract (WSE) is known for its anti-inflammatory, immune-modulatory, and anticancer properties, which are appealing in the context of aGvHD. Herein, we demonstrated that prophylactic and therapeutic use of WSE in experimental model of alloHSCT mitigates aGvHD-associated morbidity and mortality. In the prophylaxis study, a dose of 75 mg/kg of WSE offered greatest protection against death due to aGvHD (hazard ratio [HR] = 0.15 [0.03-0.68], P ≤ .01), whereas 250 mg/kg was most effective for the treatment of aGvHD (HR = 0.16 [0.05-0.5], P ≤ .01). WSE treatment protected liver, gut, and skin from damage by inhibiting cytokine storm and lymphocytic infiltration to aGvHD target organs. In addition, WSE did not compromise the GvL effect, as alloHSCT with or without WSE did not allow the leukemic A20 cells to grow. In fact, WSE showed marginal antileukemic effect in vivo. WSE is currently under clinical investigation for the prevention and treatment of aGvHD.

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Section: Resultsmentioning

confidence: 77%

Withania Somnifera Extract Mitigates Experimental Acute Graft versus Host Disease Without Abrogating Graft Versus Leukemia Effect

Gupta,

Gohil,

Momin

et al. 2024

Cell Transplant

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“…Dehydroxymethylepoxyquinomicin (DHMEQ) was created as an Nf-κb inhibitor, and was also found to suppress GVHD in mice( 117 ). Tranilast, an Nf-κb and Txnip inhibitor, was found to reduce cGVHD development in MHC-matched, miHA-mismatched mice ( 118 ).…”

Section: Transcription Factors Which Separate Gvhd and Gvl Effectsmentioning

confidence: 99%

Dissecting the regulatory network of transcription factors in T cell phenotype/functioning during GVHD and GVT

Harris

Karimi

2023

Front. Immunol.

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Transcription factors play a major role in regulation and orchestration of immune responses. The immunological context of the response can alter the regulatory networks required for proper functioning. While these networks have been well-studied in canonical immune contexts like infection, the transcription factor landscape during alloactivation remains unclear. This review addresses how transcription factors contribute to the functioning of mature alloactivated T cells. This review will also examine how these factors form a regulatory network to control alloresponses, with a focus specifically on those factors expressed by and controlling activity of T cells of the various subsets involved in graft-versus-host disease (GVHD) and graft-versus-tumor (GVT) responses.

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“…But graft-versus-host disease (GVHD) is a crucial mortality factor in allogeneic bone marrow transplantation. Yamanouchi, Adachi, Kaneko, et al showed that IP administration of DHMEQ suppressed GVHD, resulting in a decreased mortality rate in a mouse bone marrow transplantation model [ 70 ]. Bone marrow cells from C57BL/6 mice (B6 mice) were transplanted into lethally irradiated BALB/c mice.…”

Section: Anti-inflammatory Activity Of Dhmeqmentioning

confidence: 99%

Inhibition of Cellular and Animal Inflammatory Disease Models by NF-κB Inhibitor DHMEQ

Ma¹,

Zhang

Sugai

et al. 2021

Cells

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General inflammatory diseases include skin inflammation, rheumatoid arthritis, inflammatory bowel diseases, sepsis, arteriosclerosis, and asthma. Although these diseases have been extensively studied, most of them are still difficult to treat. Meanwhile, NF-κB is a transcription factor promoting the expression of many inflammatory mediators. NF-κB is likely to be involved in the mechanism of most inflammatory diseases. We discovered a specific NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), about 20 years ago by molecular design from a natural product. It directly binds to and inactivates NF-κB components. It has been widely used to suppress cellular and animal inflammatory disease models and was shown to be potent in vivo anti-inflammatory activity without any toxicity. We have prepared ointment of DHMEQ for the treatment of severe skin inflammation. It inhibited inflammatory cytokine expressions and lowered the clinical score in mouse models of atopic dermatitis. Intraperitoneal (IP) administration of DHMEQ ameliorated various disease models of inflammation, such as rheumatoid arthritis, sepsis, and also graft rejection. It has been suggested that inflammatory cells in the peritoneal cavity would be important for most peripheral inflammation. In the present review, we describe the synthesis, mechanism of action, and cellular and in vivo anti-inflammatory activities and discuss the clinical use of DHMEQ for inflammatory diseases.

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A nuclear factor-κB inhibitor, dehydroxymethylepoxyquinomicin, ameliorates GVHD in allogeneic bone marrow transplantation

Cited by 7 publications

References 43 publications

Withania Somnifera Extract Mitigates Experimental Acute Graft versus Host Disease Without Abrogating Graft Versus Leukemia Effect

Withania Somnifera Extract Mitigates Experimental Acute Graft versus Host Disease Without Abrogating Graft Versus Leukemia Effect

Dissecting the regulatory network of transcription factors in T cell phenotype/functioning during GVHD and GVT

Inhibition of Cellular and Animal Inflammatory Disease Models by NF-κB Inhibitor DHMEQ

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