Serine synthesis via reversed SHMT2 activity drives glycine depletion and acetaminophen hepatotoxicity in MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one-third of the global population. Understanding the metabolic pathways involved can provide insights into disease progression and treatment. Untargeted metabolomics of livers from mice with early-stage steatosis uncovered decreased methylated metabolites, suggesting altered one-carbon metabolism. The levels of glycine, a central component of one-carbon metabolism, were lower in mice with hepatic steatosis, consistent with clinical evidence. Stable-isotope tracing demonstrated that increased serine synthesis from glycine via reverse serine hydroxymethyltransferase (SHMT) is the underlying cause for decreased glycine in steatotic livers. Consequently, limited glycine availability in steatotic livers impaired glutathione synthesis under acetaminophen-induced oxidative stress, enhancing acute hepatotoxicity. Glycine supplementation or hepatocyte-specific ablation of the mitochondrial SHMT2 isoform in mice with hepatic steatosis mitigated acetaminophen-induced hepatotoxicity by supporting de novo glutathione synthesis. Thus, early metabolic changes in MASLD that limit glycine availability sensitize mice to xenobiotics even at the reversible stage of this disease.

Reovirus infection of tumor cells reduces the expression of NKG2D ligands, leading to impaired NK-cell cytotoxicity and functionality.

In recent years, reoviruses have been of major interest in immunotherapy because of their oncolytic properties. Preclinical and clinical trials, in which reovirus was used for the treatment of melanoma and glioblastoma, have paved the way for future clinical use of reovirus. However, little is known about how reovirus infection affects the tumor microenvironment and immune response towards infected tumor cells. Studies have shown that reovirus can directly stimulate natural killer (NK) cells, but how reovirus affects cellular ligands on tumor cells, which are ultimately key to tumor recognition and elimination by NK cells, has not been investigated. We tested how reovirus infection affects the binding of the NK Group-2 member D (NKG2D) receptor, which is a dominant mediator of NK cell anti-tumor activity. Using models of human-derived melanoma and glioblastoma tumors, we demonstrated that NKG2D ligands are downregulated in tumor cells post-reovirus-infection due to the impaired translation of these ligands in reovirus-infected cells. Moreover, we showed that downregulation of NKG2D ligands significantly impaired the binding of NKG2D to infected tumor cells. We further demonstrated that reduced recognition of NKG2D ligands significantly alters NK cell anti-tumor cytotoxicity in human primary NK cells and in the NK cell line NK-92. Thus, this study provides novel insights into reovirus-host interactions and could lead to the development of novel reovirus-based therapeutics that enhance the anti-tumor immune response.

Fatty liver-mediated glycine restriction impairs glutathione synthesis and causes hypersensitization to acetaminophen.

Non-alcoholic fatty liver disease (NAFLD) affects nearly one third of the population worldwide. Understanding metabolic pathways involved can provide insights into disease progression. Untargeted metabolomics of livers from mice with early-stage steatosis indicated a decrease in methylated metabolites suggesting altered one carbon metabolism. The levels of glycine, a central component of one carbon metabolism, were lower in steatotic mice, in line with clinical evidence. Isotope tracing studies demonstrated that increased synthesis of serine from glycine is the underlying cause for glycine limitation in fatty livers. Consequently, the low glycine availability in steatotic livers impaired glutathione (GSH) synthesis under oxidative stress induced by acetaminophen (APAP), enhancing hepatic toxicity. Glycine supplementation mitigated acute liver damage and overall toxicity caused by APAP in fatty livers by supporting de novo GSH synthesis. Thus, early metabolic changes in NAFLD that lead to glycine depletion sensitize mice to xenobiotic toxicity even at a reversible stage of NAFLD.

Thorium complexes possessing expanded ring N-heterocyclic iminato ligands: synthesis and applications.

Six and seven membered N-heterocyclic iminato ligands (L) are introduced allowing access a new class of Th(iv) complexes of the type Cp*2Th(L)(CH3). These complexes were studied in the Tishchenko reaction. Stoichiometric reactions together with kinetic and thermodynamic studies permit us to propose a plausible mechanism.