Biology subjects

Bjornstedt, M.

Publications and source records attributed to Bjornstedt, M..

4 recordsLinked to original sources

bioRxiv2025

Mutational insights into human kynurenine aminotransferase 1: modulation of transamination and β-elimination activities across diverse substrates

Human kynurenine aminotransferase 1 (hKYAT1) plays a crucial role in the transamination of aromatic amino acids and kynurenine. This promiscuous homodimeric enzyme transaminates various amino acids into their corresponding alpha-keto acids. Additionally, hKYAT1 is known to catalyze the beta-elimination of cysteine-S-conjugates and cysteine-Se-conjugates. In this study, we performed mutational analyses of hKYAT1, targeting its catalytic, ligand-binding, and substrate-binding sites. The transamination activity of thirteen mutant variants was systematically evaluated against sixteen different amino acid substrates, including kynurenine, selenomethionine (SeMet), and Se-methylselenocysteine (MSC), as well as for the {beta}-elimination of SeMet and MSC. Our results demonstrate that mutations of residues E27 in the catalytic site and H279 in the substrate-stabilizing site significantly enhanced the transamination of several amino acids, including phenylalanine, tryptophan, histidine, and MSC. The H279F mutation increased transamination and {beta}-elimination of MSC by two- and 1.5-fold, respectively. Furthermore, mutation at the ligand-binding residues R398 and N185 abolished the transamination activity of hKYAT1. Interestingly, none of the tested mutations affected the transamination of L-kynurenine, a natural substrate of hKYAT1. These findings provide a foundation for the rational design of selective inhibitors with potential therapeutic applications.

bioengineering↗

bioRxiv2024

Genderized Gut and Oral Microbiome Shifts: Uncovering Sex-Specific Dysbiosis in Pancreatic Cancer

BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, responsible for approximately 466,000 deaths globally in 2020. Its incidence increases by about 1% annually, with a higher occurrence in males than females. While differences in immune responses and tumor biology between sexes have been explored, the role of the microbiome in gender-specific PDAC progression is still unclear. Investigating these differences could offer crucial insights for personalized treatment strategies for males and females. MethodsThis study reanalyzed oral and gut microbiome data from BioProject: PRJNA832909, comprising 191 samples from PDAC patients and healthy controls. Using shotgun metagenomic sequencing, we examined gender-specific bacterial signatures. Alpha diversity (richness) and beta diversity (community composition) were analyzed. Differentially abundant bacterial taxa were identified via LEfSe, and gender-specific bacterial panels were validated using CombiROC. ResultsAlpha diversity analysis revealed significant differences in microbial richness, particularly between male and female PDAC patients and their healthy controls. Beta diversity demonstrated distinct microbial shifts between the PDAC and control groups across genders. LEfSe identified several pathogenic bacteria contributing to gender-specific dysbiosis, including Streptococcus, Fusobacterium, and Prevotella. Shared and sex-specific bacterial species in PDAC were highlighted through Venn diagram analysis. CombiROC validated the predictive ability of these bacterial markers, with AUC values exceeding 0.90 for both sexes. ConclusionThis study uncovered gender-specific microbial patterns in PDAC patients, potentially influenced by sex-specific immune responses. These findings provide important insights into the progression of PDAC and support sex-targeted diagnostic and therapeutic interventions. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=77 SRC="FIGDIR/small/616338v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@4b1d97org.highwire.dtl.DTLVardef@183c267org.highwire.dtl.DTLVardef@1500547org.highwire.dtl.DTLVardef@8a854c_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2021

Targeted enzyme assisted chemotherapy (TEAC) - a novel microRNA-guided and selenium-based regimen to specifically eradicate hepatocellular carcinoma

Despite progress in the treatment of non-visceral malignancies, the prognosis remains poor for malignancies of visceral organs and novel therapeutic approaches are urgently required. Here we introduce a novel therapeutic regimen by treatment with Se-methylselenocysteine (MSC) and concomitant tumor-specific induction of Kynurenine aminotransferase 1 (KYAT1) in hepatocellular carcinoma (HCC) cell lines, using either vector-based and/or lipid nanoparticle-mediated delivery of mRNA. Supplementation of MSC in KYAT1 overexpressed cells resulted in significantly increased cytotoxicity as compared to MSC alone. Furthermore, microRNA antisense targeted sites for miR122, known to be widely expressed in normal hepatocytes whilst downregulated in hepatocellular carcinoma, were added to specifically limit cytotoxicity in HCC cells, thereby limiting off-target effects. KYAT1 expression was significantly reduced in cells with high levels of miR122 supporting the concept of miR-guided induction of tumor-specific cytotoxicity. The addition of alpha-ketoacid favored the production of methylselenol, enhancing the cytotoxic efficacy of MSC in HCC cells, with no effects on primary human hepatocytes. Altogether, the proposed regimen offers great potential to safely and specifically target hepatic tumors that are currently untreatable.

cancer biology↗

bioRxiv2020

Pulmonary stromal expansion and intra-alveolar coagulation are primary causes of Covid-19 death

Most Covid-19 victims are old and die from unrelated causes. Here we present twelve complete autopsies, including two rapid autopsies of young patients where the cause of death was Covid-19 ARDS. The main virus induced pathology was in the lung parenchyma and not in the airways. Most coagulation events occurred in the intra-alveolar and not in the intra-vascular space and the few thrombi were mainly composed of aggregated thrombocytes. The dominant inflammatory response was the massive accumulation of CD163+ macrophages and the disappearance of T killer, NK and B-cells. The virus was replicating in the pneumocytes and macrophages but not in bronchial epithelium, endothel, pericytes or stromal cells. The lung consolidations were produced by a massive regenerative response, stromal and epithelial proliferation and neovascularization. We suggest that thrombocyte aggregation inhibition, angiogenesis inhibition and general proliferation inhibition may have a roll in the treatment of advanced Covid-19 ARDS.

pathology↗