A novel synthetic derivative of melatonin, 5-hydroxy-2’-isobutyl-streptochlorin (HIS), inhibits inflammatory responses via regulation of TRIF-dependent signaling and inflammasome activation

Shim, Do-Wan; Shin, Hee Jae; Han, Jiwon; Ji, Young-Eun; Jang, Cheol-Hun; Koppula, Sushruta; Kang, Tae-Bong; Lee, Kwang-Ho

doi:10.1016/j.taap.2015.02.006

Cited by 35 publications

(27 citation statements)

References 46 publications

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“…Melatonin or its derivative has been reported to exert various biological activities like anti-oxidative6789, anti-inflammatory10111213 and anti-apoptotic141516 effects. Recently, melatonin is widely used to protect organs against endogenous damage due to its lack of toxicity.…”

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confidence: 99%

Melatonin prevents acute kidney injury in severely burned rats via the activation of SIRT1

Bai

Gao

et al. 2016

Sci Rep

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Acute kidney injury (AKI) is a common complication after severe burns. Melatonin has been reported to protect against multiple organ injuries by increasing the expression of SIRT1, a silent information regulator that regulates stress responses, inflammation, cellular senescence and apoptosis. This study aimed to investigate the protective effects of melatonin on renal tissues of burned rats and the role of SIRT1 involving the effects. Rat severely burned model was established, with or without the administration of melatonin and SIRT1 inhibitor. The renal function and histological manifestations were determined to evaluate the severity of kidney injury. The levels of acetylated-p53 (Ac-p53), acetylated-p65 (Ac-p65), NF-κB, acetylated-forkhead box O1 (Ac-FoxO1), Bcl-2 and Bax were analyzed to study the underlying mechanisms. Our results suggested that severe burns could induce acute kidney injury, which could be partially reversed by melatonin. Melatonin attenuated oxidative stress, inflammation and apoptosis accompanied by the increased expression of SIRT1. The protective effects of melatonin were abrogated by the inhibition of SIRT1. In conclusion, we demonstrate that melatonin improves severe burn-induced AKI via the activation of SIRT1 signaling.

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confidence: 99%

Melatonin prevents acute kidney injury in severely burned rats via the activation of SIRT1

Bai

Gao

et al. 2016

Sci Rep

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“…Since CSF or plasma levels of IFN-1 were not measured in our patient either before or during treatment with MT we can not affirm that the improvement obtained has been due to the blockade of IFN-1, but a recent study utilizing a novel MT derivative which possessess stronger anti-inflammatory properties than the physiological hormone, demonstrated that its potent effects are exerted via the regulation of IFN-dependent signaling patway from Toll-like receptors [55]. Moreover, we treated a women with rheumatoid arthritis, an autoimmune disease with interferon-signature, with 100 mg/day of MT and one month after beginning the treatment her joint pains had disappeared and plasma markers of inflammation were fully normalised, something that had never happened during the long time that she had been treated with immunosuppressants or corticoids (unpublished data).…”

Section: Discussionmentioning

confidence: 74%

A Rare Case of Aicardi-Goutières Syndrome Who Showed a Positive Evolution after Being Treated with Growth Hormone, High Doses of Melatonin and Neurorehabilitation

Devesa¹,

Alonso²,

Porto³

et al. 2017

Preprint

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1) Background:The Aicardi-Goutières syndrome (AGS) is a rare congenital disease which courses with severe psychomotor delay in neurodevelopment. We studied a 3-years and 4-months old child with very important growth and weight affectation, microcephaly and loss of his developmental skills from 16-months of age, in which previous metabolic and genetic studies discarded any abnormality. Therefore diagnosis was cerebral palsy of unknown etiology. He presented spastic paraparesia, poor fine motricity, cognitive impairment and absence of oral communication. One year after discharge, a de novo mutation was detected in a single nucleotide in the gene IFIH1: c.2317G>C, being then diagnosed of AGS. 2) Methods: Blood analysis showed very low IGF-1 and slightly elevated liver transaminases. Treatment consisted in GH (0.04 mg/kg/day), melatonin (20 mg/day, and after 3-months 50 mg/day), and daily intense neurorehabilitation (5 days/week). Tests for evaluating childhood developmental milestones (GMFM-88, BDIST and the WeeFim test) were carried out every 3-months. 3) Results: The equivalent age at admission (10-months) increased to 24-months at discharge. There were clear improvements in spasticity, fine motor function, swallowing, cognition and autonomy as well as in communication, growth and weight. 4) Conclusion: Most likely melatonin blocked or decreased the interferon signature, allowing GH and neurorehabiltation to act on neurodevelopment.

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“…5) HIS was synthesized as described previously. 12) Indole-3-carboxylic acid, atenolol, metoprolol, nadolol, propranolol, ranitidine, verapamil, chloramphenicol, hydrochlorothiazide, ketoprofen, glipizide, reduced nicotinamide adenine dinucleotide phosphate (NADPH), uridine 5′-diphosphoglucuronic acid (UDPGA), 3′-phosphoadenosine-5′-phosphosulfate (PAPS), dimethyl sulfoxide (DMSO), D-α-tocopherol polyethylene glycol 1000 succinate, L-α-phosphatidylcholine, dodecane, ethanol and Kolliphor ® EL were purchased from Sigma-Aldrich (U.S.A.). Pooled male CD-1 MLMs and pooled male CD-1 mouse liver S9 fractions were purchased from BD Biosciences (U.S.A.).…”

Section: Methodsmentioning

confidence: 99%

“…10) Streptochlorin contains a privileged scaffold of 5-(3-indolyl) oxazole, which is incorporated in many natural products, including pimprinine, labradorin, martefragin A and almazole C. 11) Efforts have been made to synthesize derivatives to improve its efficacy. [12][13][14] Among them 5-hydroxy-2′-isobutyl-streptochlorin (HIS) has demonstrated effective anti-inflammatory activities.…”

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confidence: 99%

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Pharmacokinetics and Metabolism of Streptochlorin and Its Synthetic Derivative, 5-Hydroxy-2′-isobutyl Streptochlorin, in Mice

Zhou

Choi

Kim

et al. 2018

Biological & Pharmaceutical Bulletin

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The purpose of this study was to investigate the pharmacokinetics and metabolism of streptochlorin and its derivative 5-hydroxy-2′-isobutyl streptochlorin (HIS) in mice. Plasma concentration of streptochlorin declined rapidly resulting in a high sustemic plasma clearance (CL p ) (5.8 1.7 L/h/kg), a large volume of distribution (V ss ) (1.4 0.9 L/kg) and a short half-life (t 1/2 ) (0.4 0.1 h) after a single intravenous administration (5 mg/kg). Oral bioavailability (F) was 10.3 3.4% after a single oral administration (10 mg/kg). HIS also showed a rapid plasma decline with a high CL p (11.3 8.8 L/h/kg), a high V ss (0.8 1.0 L/kg) and a short t 1/2 (0.070 0.004 h) following intravenous administration. It was not detected in plasma after oral administration. Metabolic stability studies using mouse liver microsomes and S9 fractions predicted a high hepatic clearance for both compounds, consistent with the in vivo data. Metabolite identification studies revealed three metabolic pathways for streptochlorin: monooxygenation, glucuronidation of the indole moiety and oxidative opening of the 4-chlorooxazole ring. HIS was metabolized via monooxygenation of the isobutyl chain and glucuronidation of the indole ring. These results may aid in structural optimization to mitigate the metabolic liability of streptochlorin.Key words streptochlorin; 5-hydroxy-2′-isobutyl streptochlorin; pharmacokinetics; metabolism Terrestrial organisms have been a rich source of natural products for drug discovery and development for thousands of years. Since the mid-twentieth century, studies have shown that marine creatures, especially microbes, have provided many bioactive compounds with novel structures. These include compounds such as ziconotide which is an analgesic agent for severe and chronic pain treatment, trabectedin, an anticancer drug, and eribulin for metastatic breast cancer and liposarcoma treatment.

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A novel synthetic derivative of melatonin, 5-hydroxy-2’-isobutyl-streptochlorin (HIS), inhibits inflammatory responses via regulation of TRIF-dependent signaling and inflammasome activation

Cited by 35 publications

References 46 publications

Melatonin prevents acute kidney injury in severely burned rats via the activation of SIRT1

Melatonin prevents acute kidney injury in severely burned rats via the activation of SIRT1

A Rare Case of Aicardi-Goutières Syndrome Who Showed a Positive Evolution after Being Treated with Growth Hormone, High Doses of Melatonin and Neurorehabilitation

Pharmacokinetics and Metabolism of Streptochlorin and Its Synthetic Derivative, 5-Hydroxy-2′-isobutyl Streptochlorin, in Mice

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A novel synthetic derivative of melatonin, 5-hydroxy-2’-isobutyl-streptochlorin (HIS), inhibits inflammatory responses via regulation of TRIF-dependent signaling and inflammasome activation

Cited by 35 publications

References 46 publications

Melatonin prevents acute kidney injury in severely burned rats via the activation of SIRT1

Melatonin prevents acute kidney injury in severely burned rats via the activation of SIRT1

A Rare Case of Aicardi-Gouti&egrave;res Syndrome Who Showed a Positive Evolution after Being Treated with Growth Hormone, High Doses of Melatonin and Neurorehabilitation

Pharmacokinetics and Metabolism of Streptochlorin and Its Synthetic Derivative, 5-Hydroxy-2′-isobutyl Streptochlorin, in Mice

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A Rare Case of Aicardi-Goutières Syndrome Who Showed a Positive Evolution after Being Treated with Growth Hormone, High Doses of Melatonin and Neurorehabilitation