Alauddin, M. | bioRxiv Science

bioRxiv2024

Imipridones inhibit tumor growth and improve survival in an orthotopic liver metastasis mouse model of human uveal melanoma

PurposeUveal melanoma (UM) is a highly aggressive disease with very few treatment options. We previously demonstrated that mUM is characterized by high oxidative phosphorylation (OXPHOS). Here we tested the anti-tumor, signaling and metabolic effects of imipridones, CLPP activators which reduce OXPHOS indirectly and have demonstrated safety in patients. Experimental DesignWe assessed CLPP expression in UM patient samples. We tested the effects of imipridones (ONC201, ONC212) on the growth, survival, signaling and metabolism of UM cell lines in vitro, and for therapeutic effects in vivo in UM liver metastasis models. ResultsCLPP expression was confirmed in primary and mUM patient samples. ONC201/212 treatment of UM cell lines in vitro decreased OXPHOS effectors, inhibited cell growth and migration, and induced apoptosis. ONC212 increased metabolic stress and apoptotic pathways, inhibited amino acid metabolism, and induced cell death-related lipids. ONC212 also decreased tumor burden and increased survival in vivo in two UM liver metastasis models. ConclusionImipridones are a promising strategy for further testing and development in mUM.

cancer biology↗

bioRxiv2019

DJ-1 (Park7) affects the gut microbiome, metabolites, and development of Innate Lymphoid Cells (ILCs)

The proper communication between gut and brain is pivotal for maintenance of health and dysregulation of the gut-brain axis can lead to several clinical disorders. Also, in Parkinsons disease (PD) 85% of all patients experienced constipation long before showing any signs of motor phenotypes. For differential diagnosis and when it comes to preventive treatment there is an urgent need for the identification of biomarkers indicating early disease stages long before the disease phenotype manifests. DJ-1 is a chaperon protein involved in the protection against PD and genetic mutations in this protein have been shown to cause familial PD. However, how the deficiency of DJ-1 modifies the PD risk remains incompletely understood. In the present study we provide evidence that DJ-1 is implicated in shaping the gut microbiome including their metabolite production or innate immune cells (ILCs) development. We revealed that in 4 months old mice genetic deficiency of DJ-1 leads to significantly decrease in several bacterial genera and significantly increase in two specific genera, namely Alistipes and Rikenella. DJ-1 deficient mice have a higher production of calprotectin/MCP-1 inflammatory protein - a known protein involved in colonic inflammation - and significantly higher expression of glial fibrillary acidic protein (GFAP) than control littermates. Expression of a-Synuclein, a key protein in Lewy bodies, in the colon was not significantly different between genotypes. Metabolic profiles of feces extracts analysed by H1-NMR spectroscopy showed increased short chain fatty acids (SCFAs) and decreased amino acid levels, suggesting a general switch from protein towards fibre degrading strains in DJ-1 deficient mice. We observed that Malonate - which is known to influence the immune system - has significantly higher concentrations in DJ-1 deficient mice. Moreover, DJ-1 deficient mice have high levels of the phenol derivate 3-(3-Hydroxyphenyl) propanoic acid (3-HPPA) which is a breakdown product of aromatic substrates like tyrosine, phenylalanine and polyphenols. DJ-1 deficient mice also showed significantly reduced percentage of ILCs. Thus, our data suggests that absence of DJ-1 leads to increase in gut inflammatory bacteria composition, deregulated metabolites and dysregulated innate immunity which could be a key factor in the initiation of PD disease in the gut, and potentially also in brain during disease progression.

immunology↗