Author: Zhou, Xiying ; Wang, Yujiao ; Wu, Yifan ; Li, Jingjing ; Li, Shang ; Zhai, Junyu ; Yang, Lexin ; Yu, Juanjuan ; Du, Yanzhi ; Chen, Zi-Jiang ; Jiang, Hongwei ; Wang, Cong

Dysregulated amino acid metabolism is a key contributor to polycystic ovary syndrome (PCOS). This cross-sectional study revealed that serum levels of L-kynurenine (L-Kyn) were significantly elevated in women with PCOS, whereas pyridoxal 5'-phosphate (PLP) levels were markedly reduced. Moreover, human serum L-Kyn levels exhibited a positive correlated with low-density lipoprotein cholesterol (LDL-C) and a negative correlation with high-density lipoprotein cholesterol (HDL-C). Additionally, letrozole (LET) induced PCOS-like mice displayed increased hepatic L-Kyn levels. Mechanistically, both in vivo and in vitro experiments demonstrated that the upregulation of indoleamine 2,3-dioxygenase (IDO1) activates the aryl hydrocarbon receptor (AHR) - proprotein convertase subtilisin/kexin type 9 (PCSK9) pathway in the liver of PCOS-like mice, thereby contributing to dyslipidemia. Treatment with epacadostat, an inhibitor of the enzyme IDO1, or PLP, a cofactor for L-Kyn catabolism, effectively restored ovarian function, improved glucose tolerance, and ameliorated lipid profile abnormalities in PCOS-like mice.

01 May 2025·International Immunopharmacology

L-Kynurenine regulates immune response in ICIs-associated myocarditis via JAK/STAT pathway

Article

Author: Pan, Jianan ; Cheng, Leilei ; Zhang, Yerui ; Zhang, Shilong ; Zhang, Jian ; Zhang, Hui ; He, Xiaozhen ; Chen, Yifan ; Zhou, Yan ; Li, Huishan

BACKGROUNDImmune checkpoint inhibitors associated drug-induced myocarditis (ICIAM) is a - myocarditis characterized by the infiltration of immune cells into cardiac. However, the mechanisms are unknown and effective drug therapies are lacking in clinical practice. This study aims to explore the relationship between plasma metabolites and the treatment of ICIAM.METHODSHuman plasma metabolites were analyzed using untargeted metabolomics for characteristic metabolites. For in vivo experiments, Male Balb/c mice were divided into six groups: PBS, L-Kynurenine, cTNI+PD-1 inhibitor (ICIs), ICIs+L-Kynurenine, ICIs+RO8191, ICIs+RO8191+L-Kynurenine. On day 21 post-modeling, echocardiography, ELISA and histopathology were employed to evaluate the therapeutic effect of L-Kynurenine. Flow cytometry was used to determine the proportion of immune cells in the heart and spleen. Bulk-RNAseq was conducted to analyze differential genes, and q-PCR, immunofluorescence and western blot were performed for validation experiments.RESULTSUntargeted metabolomics verified that indoleamine 2,3 dioxygenase-1 (IDO1)-derived L-Kynurenine level was higher in the serum of ICIAM compared to non-ICIAM patients. Meanwhile, in vitro and in vivo experiments showed that L-Kynurenine exhibited a therapeutic ability in ICIAM by inhibiting the pro-inflammatory polarization of immune cells and the secretion of pro-inflammatory cytokines. Mechanistically, L-Kynurenine improved cardiac functions majorly by the inhibition of the JAK1/STAT3 signaling pathway.CONCLUSIONL-Kynurenine exhibits significant therapeutic potential in ICIAM. The multi-roles of L-Kynurenine in regulating immune responses make it possible to be used as a targeted drug for ICIAM therapy.

01 Apr 2025·CNS Neuroscience & Therapeutics

Gut Microbial Tryptophan Metabolism Is Involved in Post‐Cardiac Arrest Brain Injury via Pyroptosis Modulation

Article

Author: Hu, Wei ; Yu, Shuhang ; Xi, Shaosong ; Wu, Chenghao ; Zheng, Zhipeng ; Diao, Mengyuan ; Wang, Shuai ; Cao, Yang ; Zhang, Mao ; Zhu, Ying

ABSTRACTAimsPost‐cardiac arrest brain injury (PCABI) is a leading cause of death in cardiac arrest/cardiopulmonary resuscitation (CA/CPR) victims and long‐term disability in CA/CPR survivors. Despite previous evidence indicating that the microbiota‐gut‐brain axis is critically involved in many neurological disorders, no research has hitherto established a connection between the gut microbiota and PCABI through this axis. This study aims to explore the biological roles of microbial tryptophan metabolites in the progression of PCABI.MethodsTo achieve this, we pretreated rats with a cocktail of broad‐spectrum antibiotics (Abx) to eradicate the gut microbiota before establishing a 7‐min asphyxia‐CA/CPR model.ResultsRemarkably, the 24‐h survival rate and neurological outcomes improved in Abx/CPR rats. Fecal 16s rDNA sequencing and PICRUSt2 analysis revealed that Abx reshaped the microbial community and elevated the proportion of microbial tryptophan metabolism in rats. Metabolomic profiling suggested that Abx shifted the phenotype of microbial tryptophan metabolism from the indole pathway to the kynurenine pathway, thereby increasing the levels of the neuroprotective metabolite kynurenine in the feces, circulation, and ultimately the brain. Furthermore, the hippocampal expression of aryl hydrocarbon receptor (AhR), an endogenous receptor of kynurenine, was upregulated in Abx/CPR rats. In vitro experiments further demonstrated that the neuroprotective effects of kynurenine are AhR‐dependent and that AhR activation could negatively regulate the NLRP3 protein expression. Supporting this, results from qRT–PCR, immunohistochemistry, and immunofluorescence in the rat cerebral cortex exhibited that L‐kynurenine inhibited NLRP3‐induced pyroptosis.ConclusionsOur study provides a direct clue to the essential participation of the microbiota‐gut‐brain axis in the progression of PCABI. It demonstrates that kynurenine might attenuate PCABI by inhibiting NLRP3‐induced pyroptosis.

100 Deals associated with L-kynurenine

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KEGG	Wiki	ATC	Drug Bank
-	L-kynurenine	-	DB02070

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Indication	Highest Phase	Country/Location	Organization	Date
Headache	Phase 1	Denmark	Danish Headache Center	01 Mar 2017

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