Pilot single-arm open label study to assess the effectiveness of topical amlexanox in promoting wound healing and collagen 7 expression in patients with Dystrophic Epidermolysis bullosa

Start Date01 May 2021

Sponsor / Collaborator-

NCT01975935 / CompletedPhase 2IIT

Clinical Protocol to Investigate the Efficacy of Amlexanox vs. Placebo for Treatment of Glucose and Lipid Abnormalities in Obese Type 2 Diabetics

This study involves research about an investigational medicine called Amlexanox. The reason for this study is to find out how Amlexanox can improve type 2 diabetes, insulin resistance, obesity and non-alcoholic fatty liver disease (NAFLD). In this study, Amlexanox is considered to be investigational (not approved by the Food and Drug Administration [FDA]) for type 2 diabetes, insulin resistance, obesity and non-alcoholic fatty liver disease (NAFLD). This is a placebo controlled study. There is a 50-50 chance that the patient may either receive the study drug, Amlexanox, or a placebo (sugar pill). Neither the patient or the study doctors will know if the patient is receiving the study drug or placebo.

Start Date01 Jan 2014

Sponsor / Collaborator

University of Michigan

NCT01842282 / TerminatedPhase 2IIT

Clinical Protocol to Investigate the Efficacy of Amlexanox for Treatment of Glucose and Lipid Abnormalities in Obese Type 2 Diabetics

This study involves the use of a research drug, Amlexanox, for the treatment of type 2 diabetes, insulin resistance, obesity and non-alcoholic fatty liver disease (NAFLD). Amlexanox is taken orally in a pill three times a day. The investigators plan to continue therapy for a period of 12 weeks followed by a follow-up 4 weeks after therapy ends. The investigators will evaluate the changes in metabolic parameters (e.g. blood cholesterol, liver function, insulin resistance) and body composition characteristics (e.g. the pattern of fat distribution in the body). Seven eligible subjects in this study will also be evaluated for a change in liver disease by a liver biopsy.

Start Date19 Jul 2013

Sponsor / Collaborator

University of Michigan

100 Clinical Results associated with IKKε x TBK1

100 Translational Medicine associated with IKKε x TBK1

0 Patents (Medical) associated with IKKε x TBK1

273

Literatures (Medical) associated with IKKε x TBK1

16 Sep 2024·Journal of natural medicines

Azamollugin, a mollugin derivative, has inhibitory activity on MyD88- and TRIF-dependent pathways.

Article

Author: Nishino, Hitomi ; Morita, Hiroshi ; Kaneda, Toshio ; Hirasawa, Yusuke ; Takahashi, Kazunori ; Nakajima, Yuki ; Nugroho, Alfarius Eko

Previously, we reported that azamollugin, an aza-derivative of mollugin, exhibited potent inhibitory activity on NO production in LPS-stimulated RAW 264.7 cells. Further investigations in this study revealed that azamollugin not only suppressed iNOS gene expression regulated by NF-κB, but also inhibited LPS-induced IFN-β expression, which is known to be regulated by IRF3. Azamollugin exhibited an inhibitory activity on LPS-induced IRAK1 activation, suggesting inhibitory effect on the MyD88-dependent pathway. Furthermore, azamollugin inhibited LPS-induced phosphorylation of IRF3 and its upstream factor, TBK1/IKKε, suggesting an inhibitory effect on the TRIF-dependent pathway via TLR4. In addition, azamollugin also suppressed poly(I:C)-induced phosphorylation of TBK1 and IRF3, suggesting an inhibitory effect on the TRIF-dependent pathway via TLR3. These results suggest that azamollugin has inhibitory activity against both the MyD88-dependent and TRIF-dependent pathways, respectively.

01 Sep 2024·iScience

IKKɛ induces STING non-IFN immune responses via a mechanism analogous to TBK1

Article

Author: Lahoud, Mireille H. ; Saunders, Tahnee L ; Lane, Rachael M. ; Tullett, Kirsteen M ; Saunders, Tahnee L. ; Crack, Peter J. ; Lawlor, Kate E. ; Kile, Benjamin T ; Sivamani, Jananipriya ; O’Keeffe, Meredith ; Lane, Rachael M ; Lahoud, Mireille H ; Wakim, Linda M. ; Balka, Katherine R ; Lawlor, Kate E ; Crack, Peter J ; Tailler, Maximilien ; Venkatraman, Rajan ; Magill, Zoe ; Wong, Wilson ; Balka, Katherine R. ; De Nardo, Dominic ; O'Keeffe, Meredith ; Wakim, Linda M ; Kile, Benjamin T. ; Tullett, Kirsteen M.

The cGAS-STING pathway responds to cytosolic DNA to elicit host immunity to infection. The activation of stimulator of interferon genes (STING) can trigger a number of critical cellular responses including inflammation, noncanonical autophagy, lipid metabolism, senescence, and cell death. STING-mediated immunity through the production of type I interferons (IFNs) and nuclear factor kappa B (NF-κB)-driven proinflammatory cytokines is primarily driven via the effector protein TBK1. We have previously found that IκBα kinase epsilon (IKKε), a homolog of TBK1, can also facilitate STING-NF-κB responses. Therefore, a thorough understanding of how IKKε participates in STING signaling is essential. Here, we used a combination of genetic and biochemical approaches to provide mechanistic details into how IKKε confers non-IFN (e.g., NF-κB and MAPK) STING responses in macrophages, including in the absence of TBK1. We demonstrate a conserved mechanism of STING binding between TBK1 and IKKε. These findings strengthen our understanding of cGAS-STING signaling and the preservation of host immunity in cases of TBK1-deficiency.

08 Aug 2024·bioRxiv : the preprint server for biology

TBK1 and IKKε protect target cells from IFNγ-mediated T cell killing via an inflammatory apoptotic mechanism.

Article

Author: Dong, Haidong ; Chan, Mark ; Pandey, Akhilesh ; Hsu, Michelle A ; Bogunovic, Dusan ; Sun, Nicholas D ; Krogman, Erica N ; Ting, Adrian T ; Rogers, Laura M ; Guttormson, Matthew C ; Chawla, Yogesh ; Carr, Allison R ; Zhong, Jun

Cytotoxic T cells produce interferon gamma (IFNγ), which plays a critical role in anti-microbial and anti-tumor responses. However, it is not clear whether T cell-derived IFNγ directly kills infected and tumor target cells, and how this may be regulated. Here, we report that target cell expression of the kinases TBK1 and IKKε regulate IFNγ cytotoxicity by suppressing the ability of T cell-derived IFNγ to kill target cells. In tumor targets lacking TBK1 and IKKε, IFNγ induces expression of TNFR1 and the Z-nucleic acid sensor, ZBP1, to trigger RIPK1-dependent apoptosis, largely in a target cell-autonomous manner. Unexpectedly, IFNγ, which is not known to signal to NFκB, induces hyperactivation of NFκB in TBK1 and IKKε double-deficient cells. TBK1 and IKKε suppress IKKα/β activity and in their absence, IFNγ induces elevated NFκB-dependent expression of inflammatory chemokines and cytokines. Apoptosis is thought to be non-inflammatory, but our observations demonstrate that IFNγ can induce an inflammatory form of apoptosis, and this is suppressed by TBK1 and IKKε. The two kinases provide a critical connection between innate and adaptive immunological responses by regulating three key responses: (1) phosphorylation of IRF3/7 to induce type I IFN; (2) inhibition of RIPK1-dependent death; and (3) inhibition of NFκB-dependent inflammation. We propose that these kinases evolved these functions such that their inhibition by pathogens attempting to block type I IFN expression would enable IFNγ to trigger apoptosis accompanied by an alternative inflammatory response. Our findings show that loss of TBK1 and IKKε in target cells sensitizes them to inflammatory apoptosis induced by T cell-derived IFNγ.Short SummaryIn the absence of TBK1 and IKKε, target cells are killed by T cells in an IFNγ-dependent manner. In TBK1 and IKKε-deficient cells, IFNγ induces RIPK1-dependent death, as well as hyper-induction of NFκB-dependent inflammatory genes. This suggests that any inhibition of TBK1/IKKε to block type I IFN expression will result in the demise of the cell accompanied by an alternate inflammatory program.

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