Cytotechnology, Journal Year: 2025, Volume and Issue: 77(1)
Published: Jan. 3, 2025
Language: Английский
Journal for ImmunoTherapy of Cancer, Journal Year: 2023, Volume and Issue: 11(3), P. e006481 - e006481
Published: March 1, 2023
Background and aims Macrophage innate immune response plays an important role in tumorigenesis. However, the mechanism of macrophage STING signaling modulating tumor microenvironment to suppress growth at secondary sites remains largely unclear. Methods expression was assessed liver samples from patients with colorectal cancer (CRC) metastasis. Global or myeloid stimulator interferon gene (STING)-deficient mice, NOD-like receptor protein 3 (NLRP3)-deficient wild-type (WT) mice were subjected a mouse model CRC metastasis by intrasplenic injection murine colon carcinoma cells (MC38). Liver non-parenchymal including macrophages natural killer (NK) isolated for flow cytometry analysis. Bone marrow-derived pretreated MC38 co-cultured splenic NK vitro studies. Results Significant activation detected adjacent tissues intrahepatic macrophages. STING-deficient had exacerbated shorten survival, decreased infiltration impaired antitumor function cells. Depletion WT animals increased their metastatic burden, while no significant effects observed mice. contributed secretion interleukin (IL)-18 IL-1β macrophages, which optimized activity promoting 4-1BBL 4-1BB cells, respectively. Moreover, treatment activated NLRP3 signaling, inhibited depletion. Myeloid deficiency burden suppressed its agonist effectively SITNG-deficient Conclusions We demonstrated that promoted NLRP3-mediated IL-18 production optimize via co-stimulation 4-1BBL/4-1BB.
Language: Английский
Citations
53
Military Medical Research, Journal Year: 2024, Volume and Issue: 11(1)
Published: May 29, 2024
Abstract Mitochondria, the most crucial energy-generating organelles in eukaryotic cells, play a pivotal role regulating energy metabolism. However, their significance extends beyond this, as they are also indispensable vital life processes such cell proliferation, differentiation, immune responses, and redox balance. In response to various physiological signals or external stimuli, sophisticated mitochondrial quality control (MQC) mechanism has evolved, encompassing key like biogenesis, dynamics, mitophagy, which have garnered increasing attention from researchers unveil specific molecular mechanisms. this review, we present comprehensive summary of primary mechanisms functions regulators involved major components MQC. Furthermore, critical regulated by MQC its diverse roles progression systemic diseases been described detail. We discuss agonists antagonists targeting MQC, aiming explore potential therapeutic research prospects enhancing stabilize function.
Language: Английский
Citations
30
Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)
Published: Jan. 9, 2024
Abstract Background Intracellular DNA-sensing pathway cGAS-STING, inflammasomes and pyroptosis act as critical natural immune signaling axes for microbial infection, chronic inflammation, cancer progression organ degeneration, but the mechanism regulation of crosstalk network remain unclear. Main body abstract Cellular stress disrupts mitochondrial homeostasis, facilitates opening permeability transition pore leakage DNA to cell membrane, triggers inflammatory responses by activating cGAS-STING signaling, subsequently induces activation onset pyroptosis. Meanwhile, inflammasome-associated protein caspase-1, Gasdermin D, CARD domain ASC potassium channel are involved in regulating pathway. Importantly, this has a cascade amplification effect that exacerbates immuno-inflammatory response, worsening pathological process autoimmune diseases. Given importance innate immunity, it is emerging new avenue explore mechanisms multiple disease pathogenesis. Therefore, efforts define strategies selectively modulate different settings have been or ongoing. In review, we will describe how mechanistic understanding driving possible therapeutics targeting network, focusing on interacting regulatory proteins, pathways, hub between inflammasomes, Short conclusion This review aims provide insight into roles pyroptosis, highlight some promising directions future research intervention.
Language: Английский
Citations
28
MedComm, Journal Year: 2024, Volume and Issue: 5(8)
Published: Aug. 1, 2024
Abstract Macrophages are versatile immune cells with remarkable plasticity, enabling them to adapt diverse tissue microenvironments and perform various functions. Traditionally categorized into classically activated (M1) alternatively (M2) phenotypes, recent advances have revealed a spectrum of macrophage activation states that extend beyond this dichotomy. The complex interplay signaling pathways, transcriptional regulators, epigenetic modifications orchestrates polarization, allowing respond stimuli dynamically. Here, we provide comprehensive overview the cascades governing focusing on roles Toll‐like receptors, signal transducer activator transcription proteins, nuclear microRNAs. We also discuss emerging concepts metabolic reprogramming trained immunity, contributing their functional adaptability. Macrophage plasticity plays pivotal role in repair regeneration, macrophages coordinating inflammation, angiogenesis, matrix remodeling restore homeostasis. By harnessing potential novel therapeutic strategies targeting polarization could be developed for diseases, including chronic wounds, fibrotic disorders, inflammatory conditions. Ultimately, deeper understanding molecular mechanisms underpinning will pave way innovative regenerative medicine engineering approaches.
Language: Английский
Citations
28
Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(3)
Published: March 14, 2024
Abstract Recently, innate immunity and inflammation were recognized as the key factors for acute kidney injury (AKI) caused by sepsis, which is closely related to high mortality. Stimulator of interferon genes (STING) has emerged a critical component immune inflammatory responses. However, role STING in pathogenesis septic AKI remains unclear. This study demonstrated that was significantly activated tubular cells induced lipopolysaccharide (LPS) vivo vitro. Tubule-specific knockout attenuated LPS-induced renal dysfunction pathological changes. Mechanistically, pathway promotes NOD-like receptor protein 3 (NLRP3) activation. triggers endoplasmic reticulum (ER) stress induce mitochondrial reactive oxygen species (mtROS) overproduction, enhancing thioredoxin-interacting activation association with NLRP3. Eventually, NLRP3 inflammasome leads cell pyroptosis. revealed STING-regulated network further identified STING/ER stress/mtROS/NLRP3 axis an emerging contributing damage AKI. Hence, targeting may be promising therapeutic strategy preventing
Language: Английский
Citations
25
Redox Biology, Journal Year: 2024, Volume and Issue: 71, P. 103114 - 103114
Published: March 5, 2024
Non-alcoholic fatty liver disease (NAFLD) is a chronic worldwide. Numerous evidence has demonstrated that metabolic reprogramming serves as hallmark associated with an elevated risk of NAFLD progression. Selenoprotein W (SelW) extensively expressed hepatic selenoprotein plays crucial role in antioxidant function. Here, we first SelW significantly distinct factor the tissue patients through Gene Expression Omnibus (GEO) database. Additionally, loss alleviated steatosis induced by high-fat diet (HFD), and was accompanied regulation inflammatory pathways verified transcriptomic analysis. Moreover, co-immunoprecipitation (CO-IP), liquid chromatography-tandem mass spectrometry (LC-MS), laser scanning confocal microscopy (LSCM) molecular docking analysis were subsequently implemented to identify Pyruvate Kinase M2 (PKM2) potential interacting protein SelW. Meanwhile, modulated PKM2 translocation into nucleus trigger transactivation HIF-1α, further mediating mitochondrial apoptosis, eventually resulting damage, ROS excessive production mtDNA leakage. mito-ROS accumulation activation NLRP3 inflammasome-mediated pyroptosis, thereby facilitating extracellular leakage mtDNA. The escaped then evokes cGAS-STING signaling pathway macrophage, thus inducing shift macrophage phenotype. Together, our results suggest promotes hepatocyte apoptosis pyroptosis regulating activate cGAS/STING macrophages, exacerbating progression NAFLD.
Language: Английский
Citations
21
Burns & Trauma, Journal Year: 2024, Volume and Issue: 12
Published: Jan. 1, 2024
Abstract Background Ensuring the survival of distal end a random flap during hypoperfusion (ischaemia) is difficult in clinical practice. Effective prevention programmed cell death potential strategy for inhibiting ischaemic necrosis. The activation stimulator interferon genes (STING) pathway promotes inflammation and leads to death. epidermal growth factor family member neuregulin-1 (NRG1) reduces by activating protein kinase B (AKT) signalling pathway. Moreover, AKT negatively regulates STING activity. We aimed verify efficacy NRG1 injection protecting against Additionally, we investigated whether effectively enhances ischemic pyroptosis necroptosis through suppression. Methods A random-pattern skin model was generated on backs C57BL/6 mice. area determined. blood supply vascular network assessed laser Doppler flow analysis. Cluster differentiation 34 immunohistochemistry (IHC) haematoxylin eosin (H&E) staining sections revealed microvessels. Transcriptome sequencing analysis mechanism which flaps. levels angiogenesis, oxidative stress, necroptosis, indicators associated with pathways flaps were examined IHC, immunofluorescence Western blotting. Packaging adeno-associated virus (AAV) used activate Results promoted An increased subcutaneous neovascularization found after application NRG1. Transcriptomic gene ontology enrichment level detection indicated that activity reduced group. phosphorylation forkhead box O3a (FOXO3a) treatment. expression induced AAV reversed therapeutic effect ability phosphorylate AKT-FOXO3a, inhibit promote abolished inhibitor MK2206. Conclusions inhibits AKT-FOXO3a suppress survival.
Language: Английский
Citations
19
Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)
Published: Feb. 4, 2025
Abstract As a highly complex organ with digestive, endocrine, and immune-regulatory functions, the liver is pivotal in maintaining physiological homeostasis through its roles metabolism, detoxification, immune response. Various factors including viruses, alcohol, metabolites, toxins, other pathogenic agents can compromise function, leading to acute or chronic injury that may progress end-stage diseases. While sharing common features, diseases exhibit distinct pathophysiological, clinical, therapeutic profiles. Currently, contribute approximately 2 million deaths globally each year, imposing significant economic social burdens worldwide. However, there no cure for many kinds of diseases, partly due lack thorough understanding development these Therefore, this review provides comprehensive examination epidemiology characteristics covering spectrum from conditions manifestations. We also highlight multifaceted mechanisms underlying initiation progression spanning molecular cellular levels networks. Additionally, offers updates on innovative diagnostic techniques, current treatments, potential targets presently under clinical evaluation. Recent advances pathogenesis hold critical implications translational value novel strategies.
Language: Английский
Citations
3
Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)
Published: Feb. 7, 2025
Mitochondrial dysfunction is a pivotal instigator of neuroinflammation, with mitochondrial DNA (mtDNA) leakage as critical intermediary. This review delineates the intricate pathways leading to mtDNA release, which include membrane permeabilization, vesicular trafficking, disruption homeostatic regulation, and abnormalities in dynamics. The escaped activates cytosolic sensors, especially cyclic gmp-amp synthase (cGAS) signalling inflammasome, initiating neuroinflammatory cascades via pathways, exacerbating spectrum neurological pathologies. therapeutic promise targeting discussed detail, underscoring necessity for multifaceted strategy that encompasses preservation homeostasis, prevention leakage, reestablishment dynamics, inhibition activation sensors. Advancing our understanding complex interplay between neuroinflammation imperative developing precision interventions disorders.
Language: Английский
Citations
3
Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)
Published: Jan. 17, 2025
Drug resistance is a common challenge in clinical tumor treatment. A reduction drug sensitivity of cells often accompanied by an increase autophagy levels, leading to autophagy-related resistance. The effectiveness combining chemotherapy drugs with inducers/inhibitors has been widely confirmed, but the mechanisms are still unclear. Ferroptosis and pyroptosis can be affected various types autophagy. Therefore, ferroptosis have crosstalk via autophagy, potentially switch cell death under certain conditions. As two forms inflammatory programmed death, different effects on inflammation, cGAS-STING signaling pathway also involved. it plays important role progression some chronic diseases. This review discusses relationship between pyroptosis, attempts uncover reasons behind evasion nature
Language: Английский
Citations
2