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Background: Kidneys are at risk from drug-induced toxicity, with a significant proportion of acute kidney injury (AKI) linked to medications, particularly cisplatin. Existing cytoprotective drugs for cisplatin-AKI carry side effects, prompting a search for better biological therapies. Mesenchymal Stem Cells (MSCs) are under consideration given their regenerative properties, yet their clinical application has not achieved their full potential, mainly due to variability in the source of MSC tested. In addition, translating treatments from rodent models to humans remains challenging due to a lack of standardized dosing and understanding potential differential responses to cisplatin between animal strains. Method: In the current study, we performed a time-course analysis of the effect of cisplatin across different mouse strains and evaluated gender related differences to create a robust preclinical model that could then be used to explore the therapeutic efficacy of different sources of MSCs for their ability to reverse AKI. Result: Our data indicated that different mouse strains produce differential responses to the same cisplatin dosing regimen. Despite this, we did not observe any gender-related bias towards cisplatin nephrotoxicity. Furthermore, our time-course analysis identified that cisplatin-induced inflammation was driven by a strong CXCL1 response, which was used as a putative biomarker to evaluate the comparative therapeutic efficacy of different MSC sources in reversing AKI. Our data indicates that UC-MSCs have a stronger anti-inflammatory effect compared to BM-MSCs and AD-MSCs, which helped to ameliorate cisplatin-AKI. Conclusion: Overall, our data underscores the importance of using an optimized preclinical model of cisplatin-AKI to test different therapies. We identified CXCL1 as a potential biomarker of cisplatin-AKI and identified the superior efficacy of UC-MSCs in mitigating cisplatin-AKI. [ABSTRACT FROM AUTHOR]

Graft versus host disease (GVHD) is one of the most serious complications following stem cell transplant in children and is a major cause of morbidity and mortality. Corticosteroids remain the mainstay of treatment, and although a majority of children respond to systemic steroids, those refractory to or dependent upon corticosteroids suffer from complications secondary to long-term steroid administration. This problem has prompted consideration of steroid-sparing treatment strategies, although the time to clinical remission can be variable. Intraarterial corticosteroid delivery has been used in adults as a rescue therapy in steroid-resistant patients, but its use in children has been limited. We investigated the feasibility of intraarterial steroid administration into the bowel and/or liver in a cohort of six pediatric patients with acute GVHD. All patients successfully underwent treatment with no serious adverse effects. Five of five (100%) patients with gastrointestinal bleeding due to GVHD had rapid symptom improvement by 48 h, which was durable up to three weeks. Three of four (75%) patients with hepatic GVHD had improved cholestasis following intraarterial steroid administration. Our experience with this small cohort preliminarily demonstrated the feasibility and safety of intraarterial steroid administration in children with acute GVHD. This approach warrants consideration as a rescue therapy in steroid-refractory cases and as a "bridge" therapy for children with severe acute GVHD who are transitioning to steroid-sparing regimens. [ABSTRACT FROM AUTHOR]

Hexavalent chromium [Cr(VI)] damages DNA and causes cancer, but it is unclear which DNA damage responses (DDRs) most critically protect cells from chromate toxicity. Here, genome-wide quantitative functional profiling, DDR measurements and genetic interaction assays in Schizosaccharomyces pombe reveal a chromate toxicogenomic profile that closely resembles the cancer chemotherapeutic drug camptothecin (CPT), which traps Topoisomerase 1 (Top1)-DNA covalent complex (Top1cc) at the 3’ end of single-stand breaks (SSBs), resulting in replication fork collapse. ATR/Rad3-dependent checkpoints that detect stalled and collapsed replication forks are crucial in Cr(VI)-treated cells, as is Mus81-dependent sister chromatid recombination (SCR) that repairs single-ended double-strand breaks (seDSBs) at broken replication forks. Surprisingly, chromate resistance does not require base excision repair (BER) or interstrand crosslink (ICL) repair, nor does co-elimination of XPA-dependent nucleotide excision repair (NER) and Rad18-mediated post-replication repair (PRR) confer chromate sensitivity in fission yeast. However, co-elimination of Tdp1 tyrosyl-DNA phosphodiesterase and Rad16-Swi10 (XPF-ERCC1) NER endonuclease synergistically enhances chromate toxicity in top1Δ cells. Pnk1 polynucleotide kinase phosphatase (PNKP), which restores 3’-hydroxyl ends to SSBs processed by Tdp1, is also critical for chromate resistance. Loss of Tdp1 ameliorates pnk1Δ chromate sensitivity while enhancing the requirement for Mus81. Thus, Tdp1 and PNKP, which prevent neurodegeneration in humans, repair an important class of Cr-induced SSBs that collapse replication forks. [ABSTRACT FROM AUTHOR]

Heavy metals and metalloids such as cadmium [Cd(II)] and arsenic [As(III)] are widespread environmental toxicants responsible for multiple adverse health effects in humans. However, the molecular mechanisms underlying metal-induced cytotoxicity and carcinogenesis, as well as the detoxification and tolerance pathways, are incompletely understood. Here, we use global fitness profiling by barcode sequencing to quantitatively survey the Schizosaccharomyces pombe haploid deletome for genes that confer tolerance of cadmium or arsenic. We identified 106 genes required for cadmium resistance and 110 genes required for arsenic resistance, with a highly significant overlap of 36 genes. A subset of these 36 genes account for almost all proteins required for incorporating sulfur into the cysteine-rich glutathione and phytochelatin peptides that chelate cadmium and arsenic. A requirement for Mms19 is explained by its role in directing iron-sulfur cluster assembly into sulfite reductase as opposed to promoting DNA repair, as DNA damage response genes were not enriched among those required for cadmium or arsenic tolerance. Ubiquinone, siroheme, and pyridoxal 59-phosphate biosynthesis were also identified as critical for Cd/As tolerance. Arsenic-specific pathways included prefoldin-mediated assembly of unfolded proteins and protein targeting to the peroxisome, whereas cadmium-specific pathways included plasma membrane and vacuolar transporters, as well as Spt-Ada-Gcn5-acetyltransferase (SAGA) transcriptional coactivatorthat controls expression of key genes required for cadmium tolerance. Notable differences are apparent with corresponding screens in the budding yeast Saccharomyces cerevisiae, underscoring the utility of analyzing toxic metal defense mechanisms in both organisms. [ABSTRACT FROM AUTHOR]

Systemic steroid exposure, while useful for the treatment of acute flares in inflammatory bowel disease (IBD), is associated with an array of side effects that are particularly significant in children. Technical advancements have enabled locoregional intraarterial steroid delivery directly into specific segments of the gastrointestinal tract, thereby maximizing tissue concentration while limiting systemic exposure. We investigated the feasibility of intraarterial steroid administration into the bowel in a cohort of nine pediatric patients who had IBD. This treatment approach provided symptom relief in all patients, with sustained relief (>2 weeks) in seven out of nine; no serious adverse effects occurred in any patient. In addition, we identified patterns of vascular morphologic changes indicative of a vasculopathy within the mesenteric circulation of inflamed segments of the bowel in pediatric patients with Crohn's disease, which correlated with disease activity. An analysis of publicly available transcriptomic studies identified vasculitis-associated molecular pathways activated in the endothelial cells of patients with active Crohn's disease, suggesting a possible shared transcriptional program between vasculitis and IBD. Intraarterial corticosteroid treatment is safe and has the potential to be widely accepted as a locoregional approach for therapy delivery directly into the bowel; however, this approach still warrants further consideration as a short-term "bridge" between therapy transitions for symptomatic IBD patients with refractory disease, as part of a broader steroid-minimizing treatment strategy. [ABSTRACT FROM AUTHOR]

Pancreatic β cells are central to glycemic regulation through insulin production. Studies show autophagy as an essential process in β cell function and fate. Autophagy is a catabolic cellular process that regulates cell homeostasis by recycling surplus or damaged cell components. Impaired autophagy results in β cell loss of function and apoptosis and, as a result, diabetes initiation and progress. It has been shown that in response to endoplasmic reticulum stress, inflammation, and high metabolic demands, autophagy affects β cell function, insulin synthesis, and secretion. This review highlights recent evidence regarding how autophagy can affect β cells' fate in the pathogenesis of diabetes. Furthermore, we discuss the role of important intrinsic and extrinsic autophagy modulators, which can lead to β cell failure. [ABSTRACT FROM AUTHOR]