Sepsis is a life-threatening condition involving a dysregulated immune response to infectious agents that cause injury to host tissues and organs. Current treatments are limited to early administration of antibiotics and supportive care. While appealing, the strategy of targeted inhibition of individual molecules in the inflammatory cascade has not proved beneficial. Non-targeted, systemic immunosuppression with steroids has shown limited efficacy and raises concern for secondary infection. Iminosugars are a class of small molecule glycomimetics with distinct inhibition profiles for glycan processing enzymes based on stereochemistry. Inhibition of host endoplasmic reticulum resident glycoprotein processing enzymes has demonstrated efficacy as a broad-spectrum antiviral strategy, but limited consideration has been given to the effects on host glycoprotein production and consequent disruption of signalling cascades. This work demonstrates that iminosugars inhibit dengue virus, bacterial lipopolysaccharide and fungal antigen-stimulated cytokine responses in human macrophages. In spite of decreased inflammatory mediator production, viral replication is suppressed in the presence of iminosugar. Transcriptome analysis reveals the key interaction of pathogen-induced endoplasmic reticulum stress, the resulting unfolded protein response and inflammation. Our work shows that iminosugars modulate these interactions. Based on these findings, we propose a new therapeutic role for iminosugars as treatment for sepsis-related inflammatory disorders associated with excess cytokine secretion.
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http://dx.doi.org/10.1111/imm.13393 | DOI Listing |
Front Immunol
January 2025
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
The innate immune system promptly detects and responds to invading pathogens, with a key role played by the recognition of bacterial-derived DNA through pattern recognition receptors. The Z-DNA binding protein 1 (ZBP1) functions as a DNA sensor inducing type I interferon (IFN) production, innate immune responses and also inflammatory cell death. ZBP1 interacts with cytosolic DNA via its DNA-binding domains, crucial for its activation.
View Article and Find Full Text PDFTzu Chi Med J
August 2024
Department of Pediatrics, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan.
Endoplasmic reticulum (ER) is a crucial organelle associated with cellular homeostasis. Accumulation of improperly folded proteins results in ER stress, accompanied by the reaction involving triggering unfolded protein response (UPR). The UPR is mediated through ER membrane-associated sensors, such as protein kinase-like ER kinase (PERK), inositol-requiring transmembrane kinase/endoribonuclease 1α, and activating transcription factor 6 (ATF6).
View Article and Find Full Text PDFFood Chem X
January 2025
Hubei Key Laboratory of Edible Wild Plants Conservation & Utilization, College of Life Sciences, Hubei Normal University, Huangshi 435002, China.
The study aimed to assess the oxidative modification behavior of bovine myofibrillar proteins (MPs) cysteines (Cys) by hydroxyl radical (·OH) through the construction of an in vitr Fenton reaction system. The ·OH generated by the Fenton reaction induced large-scale oxidative modification of Cys, and redox proteomics identified a total of 1192 differential oxidation sites (Dos), 59 Dos were located in the MPs structure. The Cys of actin (17 Dos), myosin/myomesin (16 Dos), tenascin (12 Dos) and sarcomere (10 Dos) in the MPs structure showed active oxidative modification behavior towards ·OH, especially with the "-C-X-X-X-X-W-" structure amino acid sequence showed high sensitivity.
View Article and Find Full Text PDFUltrason Sonochem
January 2025
Department of Food Engineering, Heilongjiang Key Laboratory of Food Science and Engineering, Heilongjiang Key Laboratory of Grain Food and Comprehensive Processing, Harbin University of Commerce, Harbin 150028, Heilongjiang, China. Electronic address:
Heat facilitates aggregation and gel formation of soybean proteins. Ultrasonic reduces the size of protein aggregates. This study examined the impact of glycinin (11S) subunits on soybean lipophilic proteins (SLPs) gel formation and underlying mechanisms.
View Article and Find Full Text PDFZool Res
January 2025
National Key Laboratory for Swine Genetic Improvement and Germplasm Innovation, Ministry of Science and Technology of China, Jiangxi Agricultural University, Nanchang, Jiangxi 330045, China.
Pigeons and certain other avian species produce a milk-like secretion in their crop sacs to nourish offspring, yet the detailed processes involved are not fully elucidated. This study investigated the crop sacs of 225-day-old unpaired non-lactating male pigeons (MN) and males initiating lactation on the first day after incubation (ML). Using RNA sequencing, ribosome profiling, and single-cell transcriptome sequencing (scRNA-seq), we identified a significant up-regulation of genes associated with ribosome assembly and protein synthesis in ML compared to MN.
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