INTRODUCTIONThe inhibition of melanoma adhesion through adhesion molecules, such as integrins and E-cadherin, may represent a promising strategy for managing melanoma metastasis. Compounds, namely l-kynurenine (L-kyn) and quinolinic acid (Quin), previously displayed anti-cancer effects at half-maximal inhibitory concentration (IC₅₀) against B16 F10 melanoma cells in vitro. However, the role of these compounds in B16 F10 melanoma cell adhesion, migration and apoptosis remain unknown.METHODSPost-exposure to the compounds, flow cytometry was used to analyse the expression of very late antigen-5 (VLA-5), E-cadherin and cleaved caspase-3 in B16 F10 melanoma and RAW 264.7 murine macrophage cells. An adhesion assay was used to quantify the adhesion of both cell lines to vitronectin. A scratch migration assay was used to measure the possible inhibition of cell migration in B16 F10 cells in response to L-kyn and Quin.RESULTSIn both B16 F10 and RAW 264.7 cells, neither L-kyn nor Quin induced significant effects on VLA-5 expression or cell adhesion to vitronectin. In B16 F10 cells, both L-kyn and Quin elevated E-cadherin expression and displayed a trend of suppressed migration. However, only L-kyn elevated E-cadherin in RAW 264.7 cells. L-kyn induced apoptosis by elevating cleaved caspase-3 expression in both cell lines.CONCLUSIONL-kyn and Quin demonstrated promising antimetastatic effects in their ability to elevate E-cadherin expression and induce apoptosis in B16 F10 melanoma cells. However, these effects did not occur in response to vitronectin or VLA-5 integrin alterations. Furthermore, it cannot be excluded that L-kyn also induced apoptosis in RAW 264.7 cells. As such, these effects should be confirmed in additional control cell lines and substantiated with in vivo models.

01 Oct 2024·Physiological Reports

Fructose‐1,6‐bisphosphate reverses hypotensive effect caused by L‐kynurenine in Wistar male rats

Article

Author: Becker, Tiago ; Catarina, Anderson Velasque ; Nunes, Fernanda Bordignon ; Branchini, Gisele ; de Oliveira, Jarbas Rodrigues ; Caceres, Rafael Andrade ; Ferreira, Luis Fernando ; Costa, Bruna Pasqualotto ; Fernandes, Renata Streck ; Rigatto, Katya ; Machado, Kleiton Lima De Godoy

AbstractHypotension is one of the main characteristics of the systemic inflammation, basically caused by endothelial dysfunction. Studies have shown that the amino acid L‐kynurenine (KYN) causes vasodilation in mammals, leading to hypotensive shock. In hypotensive shock, when activated by the KYN, the voltage‐gated potassium channel encoded by the family KCNQ (Kv7) gene can cause vasodilation. Fructose‐1,6‐bisphosphate (FBP) it is being considered in studies an anti‐inflammatory, antioxidant, immunomodulator, and a modulator of some ion channels (Ca2+, Na+, and K+). We analyzed the effects of KYN and FBP on mean blood pressure (MBP), systolic and diastolic (DBP) blood pressure, and heart rate variability (HRV) in Wistar rats. Results demonstrated that the administration of KYN significant decreased MBP, DBP, and increased HRV. Importantly, the FBP treatment reversed the KYN effects on MBP, DBP, and HRV. Molecular Docking Simulations suggested that KYN and FBP present a very close estimated free energy of binding and the same position into structure of KCNQ4. Our results did demonstrate that FBP blunted the decrease in BP, provoked by KYN. Results raise new hypotheses for future and studies in the treatment of hypotension resulting from inflammation.

01 Aug 2024·European Journal of Pharmacology

β-arrestin2 is indispensable for the antidepressant effects of fluoxetine via inhibiting astrocytic pyroptosis in chronic mild stress mouse model for depression

Article

Author: Sun, Yiming ; Liu, Hao ; Yang, Daofeng ; Yuan, Hongwei ; Song, Lele ; Liu, Zhe ; Yang, Rong ; Yu, Nengyi ; Xu, Jingxuan ; Cai, Hui ; Sun, Lejie ; Ma, Chengyao

β-arrestin2 is a versatile protein for signaling transduction in brain physiology and pathology. Herein, we investigated the involvement of β-arrestin2 in pharmacological effects of fluoxetine for depression. A chronic mild stress (CMS) model was established using wild-type (WT) and β-arrestin2^-/- mice. Behavioral results demonstrated that CMS mice showed increased immobility time in the tail suspension test and forced swimming test, elevated concentrations of pro-inflammatory factors in peripheral blood, increased expression of pyroptosis-related proteins, and increased co-labeling of glial fibrillary acidic protein and Caspase1 p10 in the hippocampus compared to the CON group. Treatment with fluoxetine (FLX) ameliorated these conditions. However, compared with the β-arrestin2^-/- CMS group, these results of the β-arrestin2^-/- CMS + FLX group showed no significant changes. These results suggested that the above effects of FLX could be eliminated by knocking out β-arrestin2. Mass spectrometry implying that FLX promoted the binding of β-arrestin2 to the NLRP2 inflammasome of depressed mice. Subsequently, the results of the cellular experiments suggested that the 5HT_2B receptor antagonist may attenuate L-kynurenine + ATP-induced cell pyroptosis by attenuating NLRP2 binding to β-arrestin2. We further found that the lack of β-arrestin2 eliminated the anti-pyroptosis effect of fluoxetine. In conclusion, β-arrestin2 is an essential protein for fluoxetine to alleviate pyroptosis in the hippocampal astrocytes of CMS mice. Mechanistically, we found that the 5-HT_2BR-β-arrestin2-NLRP2 axis is vital for maintaining the antidepressant effects of fluoxetine.

News (Medical) associated with L-kynurenine

23 Jun 2022

·www.biospace.com

Kynos builds out senior management team with appointment of Dr Alison Strutt, a seasoned biotech and ex-GSK executive, as CFO

Dr Alison Strutt joins Kynos senior management team as CFO Brings extensive strategic, transactional, and operational experience in biotech and large pharma to the Kynos leadership team Edinburgh, UK – 23 June 2022 – Kynos Therapeutics Ltd (Kynos or the Company), an immune-metabolic company with world-leading expertise in the kynurenine pathway and kynurenine 3-monooxygenase (KMO) biology today announced the appointment of Dr Alison Strutt as Chief Finance Officer (CFO). Alison Strutt is a seasoned healthcare finance executive with extensive strategic, transactional and operational experience. She will combine her current role as Chief Operating Officer at NodThera Inc. whilst supporting Kynos Therapeutics as CFO. She formerly held a number of senior finance roles at GSK, including as Chief of Staff to the Chief Finance Officer, where she was responsible for transforming GSK’s financial reporting processes and organisation as well as leading local completions of the global Novartis transaction. Alison also served as CFO of GSK’s drug discovery group, where she established the Tres Cantos Open Lab and Catalyst Science Park at GSK’s UK flagship R&D site. Prior to time at GSK, Alison led the UK M&A life sciences team at Deloitte in London. She holds a Ph.D. in chemistry and physical chemistry from the University of Wales, Cardiff and is a Fellow of the Institute of Chartered Accountants for England and Wales. Welcoming Alison to the company, CEO of Kynos Therapeutics, Damian Mole said, “Alison is an exceptional addition to the Kynos leadership team, and we are delighted to have been able to attract her to the Company. Kynos is rapidly building momentum towards the clinic, and Alison’s experience across large pharma and biotech covers finance at the operational level as well as a strategic outlook. This breadth of skill and experience will support Kynos to achieve the strong position that we are aiming for in the near future.” Alison Strutt, CFO of Kynos Therapeutics, said, “I am very excited to be getting involved in Kynos at this critical point in its journey, and I am really looking forward to working with the leadership team and the Board to help create a leading company in immunometabolic medicine.” Caption: Dr Alison Strutt, Chief Finance Officer (CFO), Kynos Therapeutics -Ends- About Kynos Therapeutics – www.kynostx.com Kynos Therapeutics is developing an innovative portfolio of first-in-class medicines where there is an unmet medical need for new therapies. It is a spin-out from the University of Edinburgh commercialising a decade of drug discovery research on kynurenine 3-monooxygenase (KMO), a pivotal enzyme in the kynurenine pathway of tryptophan metabolism. Its innovative pipeline of first-in-class KMO inhibitors across key indications in inflammation, immunity and metabolism, was originally co-developed through a collaboration between GSK and the University of Edinburgh and is now exclusively licensed to Kynos. Based in Edinburgh, UK, the company is financed by equity investment from Epidarex Capital, IP Group plc and Scottish Enterprise as well as a grant from Innovate UK. Follow us on LinkedIn and Twitter For further information please contact: At the Company Professor Damian Mole, CEO of Kynos Therapeutics E: media@kynostx.com Media enquiries Sue Charles, Charles Consultants T: +44 (0)7968 726585 E: sue@charles-consultants.com

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