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Amlexanox
Published in Anton C. de Groot, Monographs in Contact Allergy, 2021
Amlexanox is an anti-allergic and anti-inflammatory drug. It is a strong inhibitor of histamine release and a competitive inhibitor of leukotriene. In a mucoadhesive oral paste, this agent has been clinically proven to abort the onset, accelerate healing and resolve the pain of aphthous ulcers (canker sores). Tablets have been on the market since 1987 in Japan and are used for the treatment of asthma and allergic rhinitis. Amlexanox is (or was) also available as ophthalmic solution for allergic conjunctivitis and as nasal douche for treatment of allergic rhinitis (1, 2). Probably, the ophthalmic solution is not used anymore, but the oral paste and tablets appear to be available in some countries (drugs.com).
AK-1, a Sirt2 inhibitor, alleviates carbon tetrachloride-induced hepatotoxicity in vivo and in vitro
Published in Toxicology Mechanisms and Methods, 2020
Zixiong Zhou, Jing Qi, Jong-Won Kim, Myung-jo You, Chae Woong Lim, Bumseok Kim
Primary mouse hepatocytes were cultured in 96-well plates (1 × 104 cells/well). At ∼80% confluence, the cells were incubated overnight with various concentrations of amlexanox for 24 h. For LDH assay, hepatocytes were removed from the culture medium by centrifugation at about 250 g, prior to the determination of LDH activity. Cell death was evaluated using a cytotoxicity detection kit (Sigma-Aldrich), based on the measurement of the activity of Lactate dehydrogenase (LDH) released from the cytosol into the culture medium, following the manufacturer’s instruction. The absorbance of the sample was measured at a wavelength of 490 nm by EMax spectrophotometry (Molecular Devices). For MTT assay (Promega, Madison, WI), viable adherent cells were stained with a 15 μL dye solution at 37 °C in a humidified CO2 incubator. After 2 h, 100 μL stop solution was added to each well, and the absorbance of the sample was quantified at a wavelength of 570 nm by EMax spectrophotometry (Molecular Devices).
Translational readthrough inducing drugs for the treatment of inherited retinal dystrophies
Published in Expert Review of Ophthalmology, 2020
Christopher M Way, Dulce Lima Cunha, Mariya Moosajee
PTC-containing transcripts are typically degraded by NMD, reducing their availability. Therefore, inhibition of NMD is proposed to increase mRNA stability and as a consequence, increase the amount of substrate for TRIDs to target. Caffeine inhibits NMD through the inhibition of SMG1 kinase [35,36] (Figure 2(c)). It alone has been shown to rescue the phenotype in fibroblasts carrying a PTC seen in the muscular dystrophy Ullrich’s disease, by increasing mRNA and protein levels of the defective collagen VI α2 [37]. NMDI1 is a tetracyclic compound that traps UPF1 in a hyperphosphorylated state, preventing downstream interactions with SMG5 [38] (Figure 2(d)). It is specific for NMD, does not affect translation efficiency and is non-cytotoxic [38]. In a mouse model of Mucopolysacchardisosis I-Hurler syndrome (MPS I-H) that carries the knock-in Idua p.W392* mutation, NMDI1 application with gentamicin resulted in greater readthrough and functional enzymatic activity than gentamicin alone [39]. However, NMDI1 synthesis is inefficient and technically difficult. In contrast, VG1, a structural analogue of NMDI1 with similar inhibition capability, is more easily produced and shows an improved yield [40]. Its mechanism of action is currently unknown but its application to IRDs is awaited. Amlexanox is a compound with both readthrough and NMD inhibition properties. It has been reported as a combined therapy option for PTCs causing cystic fibrosis (CF) and recessive dystrophic epidermolysis bullosa, showing increased levels of full-length proteins compared to G418 and PTC124 alone [41,42].
TANK-binding kinase 1 as a novel therapeutic target for viral diseases
Published in Expert Opinion on Therapeutic Targets, 2019
As a critical kinase in innate immunity, TBK1 activity must be tightly controlled to eliminate the virus effectively. TBK1 will be an ideal target to develop antiviral drugs. However, aberrant activation of TBK1 may cause several side effects of systemic immunity, such as obesity, autoimmunity diseases, chronic inflammation, and cancer. Up to now, multiple small molecule inhibitors targeting TBK1 are developed and exhibit potential roles in a variety of aberrant TBK1 activity related disorders. BX795 and CYT387 are representative potent TBK1 inhibitors [107–109]. BX795 possesses antitumor activity in human oral squamous cell carcinoma through inhibiting TBK1-mediated apoptosis and mitotic phase arrest [107]. CYT387 impairs the growth and cytokine secretion of Kras-driven murine lung cancer cells and IKBKE-driven breast cancer cells [108,109]. Amlexanox, a selective TBK1/IKKε inhibitor, improves insulin sensitivity both in obese mice model and type 2 diabetes patients [110,111]. Considering amlexanox also used as the clinic treatment of aphthous ulcers and asthma, it may be safe to certain extent. Recently, we reported that ML323, as a selective inhibitor of USP1-UAF1 deubiquitinase complex, could inhibit TBK1 deubiquitination and promote its protein degradation [55]. Accordingly, ML323 attenuated viral infection induced IFN-β expression and enhanced viral replication both in vitro and in vivo [55]. These results suggested ML323 as a promising candidate for the intervention of the diseases caused by excessive TBK1 activation and IFN-β expression, such as rheumatoid arthritis and systemic lupus erythematosus.