Transcriptomic Characterization of Inhalation Phosphine Toxicity in Adult Male Sprague-Dawley Rats (16,500 ppm x min)
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ABSTRACT: Phosphine (PH3) is a highly toxic, corrosive, flammable, heavier-than-air gas that is a commonly used fumigant. Although the mechanism of toxicity is unclear, PH3 is thought to be a metabolic poison. PH3 exposure induces multi-organ toxicity and no effective antidotes or therapeutics have been identified. To better characterize the mechanism(s) driving PH3-induced toxicity we have performed transcriptomic analysis on conscious adult male Sprague-Dawley rats following whole-body inhalation exposure to phosphine gas at three concentrations. PH3 exposure induced concentration- and time-dependent changes in gene expression across multiple tissues.
Project description:Phosphine (PH3) is a highly toxic, corrosive, flammable, heavier-than-air gas that is a commonly used fumigant. Although the mechanism of toxicity is unclear, PH3 is thought to be a metabolic poison. PH3 exposure induces multi-organ toxicity and no effective antidotes or therapeutics have been identified. To better characterize the mechanism(s) driving PH3-induced toxicity we have performed transcriptomic analysis on conscious adult male Sprague-Dawley rats following whole-body inhalation exposure to phosphine gas at three concentrations. PH3 exposure induced concentration- and time-dependent changes in gene expression across multiple tissues.
Project description:Phosphine (PH3) is a highly toxic, corrosive, flammable, heavier-than-air gas that is a commonly used fumigant. Although the mechanism of toxicity is unclear, PH3 is thought to be a metabolic poison. PH3 exposure induces multi-organ toxicity and no effective antidotes or therapeutics have been identified. To better characterize the mechanism(s) driving PH3-induced toxicity we have performed transcriptomic analysis on conscious adult male Sprague-Dawley rats following whole-body inhalation exposure to phosphine gas at three concentrations. PH3 exposure induced concentration- and time-dependent changes in gene expression across multiple tissues.
Project description:Pancreatic cancer is projected to become the second leading cause of cancer-related deaths globally by 2030, yet effective therapeutic options remain limited. Within the pancreatic cancer tumor microenvironment (TME), tumor-associated macrophages (TAMs) secrete interleukin-1 beta (IL-1β), promoting cancer progression while suppressing type I interferons (IFN-I), which is critical for effective tumor treatment. Utilizing the convolutional neural network (CNN)-based DLINP model developed in our laboratory, we identified Co68—an effective metal catalyst featuring a Phosphine-Nitrogen-Phosphine (PNP)-chelated CoCl₂ complex—as a promising candidate to modulate these immune pathways. In preclinical animal models, Co68 demonstrated superior antitumor efficacy compared to the STING agonist DMXAA and showed enhanced therapeutic effects when combined with PD-1 blockade. Single-cell RNA sequencing (scRNA-seq) revealed that Co68 reprograms TAMs to express interferon-stimulated genes (ISGs), attenuates pro-inflammatory cytokine secretion, and disrupts the IL-1β-PGE2 feedback loop, thereby facilitating the recruitment of NK and cytotoxic CD8+ T cells into the TME. Mechanistically, Co68 activates the IFN-I signaling pathway through the TLR4-TRIF-IFN-I axis and weakens inflammation via the TLR4-SYK-STAT1 pathway. Collectively, these findings highlight the therapeutic potential of Co68, derived from PNP-pincer chemistry, to reshape immune dynamics within the pancreatic cancer TME, positioning it as a promising candidate for innovative immunotherapy strategies.
Project description:Pancreatic cancer is projected to become the second leading cause of cancer-related deaths globally by 2030, yet effective therapeutic options remain limited. Within the pancreatic cancer tumor microenvironment (TME), tumor-associated macrophages (TAMs) secrete interleukin-1 beta (IL-1β), promoting cancer progression while suppressing type I interferons (IFN-I), which is critical for effective tumor treatment. Utilizing the convolutional neural network (CNN)-based DLINP model developed in our laboratory, we identified Co68—an effective metal catalyst featuring a Phosphine-Nitrogen-Phosphine (PNP)-chelated CoCl₂ complex—as a promising candidate to modulate these immune pathways. In preclinical animal models, Co68 demonstrated superior antitumor efficacy compared to the STING agonist DMXAA and showed enhanced therapeutic effects when combined with PD-1 blockade. Single-cell RNA sequencing (scRNA-seq) revealed that Co68 reprograms TAMs to express interferon-stimulated genes (ISGs), attenuates pro-inflammatory cytokine secretion, and disrupts the IL-1β-PGE2 feedback loop, thereby facilitating the recruitment of NK and cytotoxic CD8+ T cells into the TME. Mechanistically, Co68 activates the IFN-I signaling pathway through the TLR4-TRIF-IFN-I axis and weakens inflammation via the TLR4-SYK-STAT1 pathway. Collectively, these findings highlight the therapeutic potential of Co68, derived from PNP-pincer chemistry, to reshape immune dynamics within the pancreatic cancer TME, positioning it as a promising candidate for innovative immunotherapy strategies.
Project description:Pancreatic cancer is projected to become the second leading cause of cancer-related deaths globally by 2030, yet effective therapeutic options remain limited. Within the pancreatic cancer tumor microenvironment (TME), tumor-associated macrophages (TAMs) secrete interleukin-1 beta (IL-1β), promoting cancer progression while suppressing type I interferons (IFN-I), which is critical for effective tumor treatment. Utilizing the convolutional neural network (CNN)-based DLINP model developed in our laboratory, we identified Co68—an effective metal catalyst featuring a Phosphine-Nitrogen-Phosphine (PNP)-chelated CoCl₂ complex—as a promising candidate to modulate these immune pathways. In preclinical animal models, Co68 demonstrated superior antitumor efficacy compared to the STING agonist DMXAA and showed enhanced therapeutic effects when combined with PD-1 blockade. Single-cell RNA sequencing (scRNA-seq) revealed that Co68 reprograms TAMs to express interferon-stimulated genes (ISGs), attenuates pro-inflammatory cytokine secretion, and disrupts the IL-1β-PGE2 feedback loop, thereby facilitating the recruitment of NK and cytotoxic CD8+ T cells into the TME. Mechanistically, Co68 activates the IFN-I signaling pathway through the TLR4-TRIF-IFN-I axis and weakens inflammation via the TLR4-SYK-STAT1 pathway. Collectively, these findings highlight the therapeutic potential of Co68, derived from PNP-pincer chemistry, to reshape immune dynamics within the pancreatic cancer TME, positioning it as a promising candidate for innovative immunotherapy strategies.
Project description:Carbonyl sulfide (COS) is a novel grain fumigant, introduced in 1993 as a substitute to methyl bromide and phosphine for managing stored-grain pests. While COS has demonstrated high toxicity and broad efficacy against various stored-product pests, including Tribolium castaneum, the mechanisms underlying its toxicity in insects remain largely unexplored. To elucidate the molecular basis of COS toxicity in insects, we analyzed the transcriptome to investigate gene expression in the malpighian tubules and fat body tissues of adult T. castaneum upon COS fumigation. Our analysis identified 3,034 and 2,973 differentially expressed genes (DEGs) in the malpighian tubules and fat body, respectively. Several DEGs associated with insecticide detoxification, mitochondrial functions, and carbonic anhydrase (CA) activity were significantly expressed between the COS-treated and control groups. The functional annotation and pathway analyses using Gene Ontology (GO) terms and KEGG for these DEGs identified categories related to binding, catalytic activity, cellular and biological processes, cellular anatomical entity and xenobiotic metabolism pathways. We validated 23 DEGs, which revealed consistent gene expression levels with those of transcriptomic analysis. Furthermore, we analysed the impact of acetazolamide, a CA inhibitor, on the survival rates of T. castaneum larvae and adults following COS exposure, implying that acetazolamide likely reduces COS toxicity through CA inhibition. This study presents the first comparative transcriptome investigation of the malpighian tubules and fat body in T. castaneum, enhancing our understanding of the molecular basis of COS toxicity and its potential as an effective alternative for control of this significant agricultural pest.