Translational research : the journal of laboratory and clinical medicine
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Human immunodeficiency virus type 1 (HIV-1) infection is a chronic disease without a known cure. The advent of effective antiretroviral therapy (ART) has enabled people with HIV (PWH) to have significantly prolonged life expectancies. As a result, morbidity and mortality associated with HIV-1 infection have declined considerably. ⋯ We also delineate the current literature on inflammasomes and the therapeutic targeting strategies aimed at the NLRP3 inflammasome to moderate HIV-1 infection-associated inflammation. Here we describe the NLRP3 inflammasome as a key pathway in developing novel therapeutic targets to block HIV-1 replication and HIV-1-associated inflammatory signaling. Controlling the inflammatory pathways is critical in alleviating the morbidities and mortality associated with chronic HIV-1 infection in PWH.
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Neurodegenerative diseases are characterized by a dysregulated neuro-glial microenvironment, culminating in functional deficits resulting from neuronal cell death. Inflammation is a hallmark of the neurodegenerative microenvironment and despite a critical role in tissue homeostasis, increasing evidence suggests that chronic inflammatory insult can contribute to progressive neuronal loss. Inflammation has been studied in the context of neurodegenerative disorders for decades but few anti-inflammatory treatments have advanced to clinical use. ⋯ We discuss inflammasome-driven pyroptotic processes highlighting the potential utility of evaluating extracellular inflammasome-related proteins in the context of biomarker discovery. We complete the report by pointing out gaps in our understanding of intracellular modifiers of inflammasome activity and mechanisms regulating the resolution of inflammasome activation. The literature review and perspectives provide a conceptual platform for continued analysis of inflammation in neurodegenerative diseases through the study of inflammasomes and pyroptosis, mechanisms of inflammation and cell death now recognized to function in multiple highly prevalent neurological disorders.
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Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths in the world. Inflammation is often an underlying risk factor for developing CRC. Maintaining gut homeostasis and balancing inflammation is therefore critical to prevent CRC development. ⋯ Furthermore, IRF1, a key regulator of some inflammasomes and PANoptosomes, has been implicated in CRC. It is therefore critical to consider the role of inflammasomes in effector cytokine-dependent and -independent protection as well as their role in PANoptosis to modulate CRC for therapeutic targeting. Here, we discuss the mechanisms of inflammasome activation, the functions of inflammasomes in CRC, and current obstacles and future perspectives in inflammasome and CRC research.
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KRAS mutation is a common driver in solid tumors, and KRAS-mutated tumors are relatively resistant to radiotherapy. Therefore, we investigated the combined effect of radiation and KRAS-MEK inhibitors (AMG510 and trametinib) in KRAS-mutated tumors. The expression of programmed death-ligand 1 (PD-L1), major histocompatibility complex (MHC) class I molecules, and cytokines in KRAS-mutated cell lines was assessed using flow cytometry, western blot analysis, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay. ⋯ The combination of trametinib and radiation controlled tumor growth and induced more infiltration of CD4+ and CD8+ T cells in vivo, wherein tumor inhibition function and the survival period of mice could be reduced by CD8+ and/or CD4+ T cell depletion. The expression levels of immune-related genes also increased in the combination therapy group. Our results indicate that KRAS-MEK inhibitors in combination with radiotherapy can enhance antitumor immunity, providing new therapeutic strategies for KRAS-mutated tumors.
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Overactive inflammatory responses are central to the pathophysiology of many hemolytic conditions including sickle cell disease. Excessive hemolysis leads to elevated serum levels of heme due to saturation of heme scavenging mechanisms. Extracellular heme has been shown to activate the NLRP3 inflammasome, leading to activation of caspase-1 and release of pro-inflammatory cytokines IL-1β and IL-18. ⋯ Some clinical studies indicate there is a benefit to blocking the NLRP3 inflammasome pathway in patients with sickle cell disease and other hemolytic conditions. However, a thorough understanding of the mechanisms of heme-induced inflammasome activation is needed to fully leverage this pathway for clinical benefit. This review will explore the mechanisms of heme-induced NLRP3 inflammasome activation and the role of this pathway in hemolytic conditions including sickle cell disease.