Did you mean: proptosis
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Heliyon May 2024Lung cancer is the leading cause to induce cancer-related mortality. Effective biomarkers for prediction the occurrence of lung cancer is urgently needed. Our previous...
OBJECTIVES
Lung cancer is the leading cause to induce cancer-related mortality. Effective biomarkers for prediction the occurrence of lung cancer is urgently needed. Our previous studies indicated that pyroptosis-related cytokines TNF-α, IFN-γ, MIP-1α, MIP-1β, MIP-2 and IP-10 is important to influence the efficacy of chemotherapy drug in lung cancer tissues. But the role of pyroptosis-related cytokines in prediction the occurrence of lung cancer is still unknown.
METHODS
Blood samples were collected from 258 lung cancer patients at different stage and 80 healthy volunteers. Serum levels of pyroptosis-related cytokines including TNF-α, IFN-γ, MIP-1α, MIP-1β, MIP-2 and IP-10 were measured by Cytometric Bead Array (CBA). ROC curve was performed to evaluate the cut-off value and diagnosis value for prediction and diagnosis of lung cancer.
RESULTS
Compared with control group, the levels of IP-10, MIP-1α, MIP-1β, MIP-2 and TNF-α were significantly higher in lung cancer patients (45.5 (37.1-56.7): 57.2 (43.0-76.5), 34.4 (21.8-75.2): 115.4 (96.6-191.2), 49.3 (25.6-78.7): 160.5 (124.9-218.6), 22.6 (17.8-31.2): 77.9 (50.1-186.5), 3.80 (2.3-6.2): 10.3 (5.7-16.6)), but the level of IFN-γ was decreased in the patients (12.38 (9.1-27.8): 5.9 (3.5-9.7)). All the above cytokines were significantly associated with the diagnosis of lung cancer, and the AUC values of IFN-γ, IP-10, MIP-1α, MIP-1β, MIP-2, and TNF-α were 0.800, 0.656, 0.905, 0.921, 0.914, and 0.824. And the AUC can rise to 0.986 after combining the above factors, and the sensitivity and specificity also up to 96.7 % and 93.7 %, respectively. Additionally, TNF-α (r = 0.400, P < 0.01), MIP-2 (r = 0.343, P < 0.01), MIP-1α (r = 0.551, P < 0.01) and MIP-1β (r = 0.403, p < 0.01) were positively associated with occurrence of lung cancer, but IFN-γ (r = -0.483, p < 0.01) was negatively associated with occurrence of lung cancer. As far as the potential of early diagnosis of lung cancer, TNF-α (AUC = 0.577), MIP-1α (AUC = 0.804) and MIP-1β (AUC = 0.791) can predict the early stage of lung cancer, and combination of the above three cytokines has a better predictive efficiency (AUC = 0.854).
CONCLUSION
Our study establishes a link between the levels of IP-10, MIP-1α, MIP-1β, MIP-2, TNF-α and IFN-γ and diagnosis of lung cancer. Besides, we observed a synergistic effect of these five pyroptosis-related cytokines in diagnosing lung cancer patient, suggesting their potential as biomarkers for lung cancer diagnosis. Moreover, the combination of TNF-α, MIP-1α and MIP-1β are also potential predictors for the early diagnosis of lung cancer.
PubMed: 38813211
DOI: 10.1016/j.heliyon.2024.e31399 -
Cell Death Discovery May 2024Acute cerebral ischemia has a high rate of disability and death. Although timely recanalization therapy may rescue the ischemic brain tissue, cerebral...
Acute cerebral ischemia has a high rate of disability and death. Although timely recanalization therapy may rescue the ischemic brain tissue, cerebral ischemia-reperfusion injury has been shown to limit the therapeutic effects of vascular recanalization. Protein HAX-1 has been reported as a pro-survival protein that plays an important role in various disorders, particularly in association with the nervous system. However, the effects and mechanisms of HAX-1 in cerebral IR injury have yet to be elucidated. So, we aimed to investigate the effect of HAX-1 on microglial pyroptosis and explore its potential neuroprotective effects in ischemia-reperfusion injury. Our results show that the expression of HAX-1 decreased after cerebral IR injury, accompanied by an increase in pyroptosis pathway activation. In addition, HAX-1 could inhibit microglial pyroptosis both in vivo and in vitro and reduce the release of inflammatory mediators. The above neuroprotective effects might be partially mediated by inhibiting of interaction of NLRP3 and ASC through competitive binding, followed by the attenuation of NLRP3 inflammasome formation. In conclusion, Our findings support that HAX-1 exhibits a protective role in cerebral I/R injury, and further study on HAX-1 expression regulation will contribute to cerebral infarction therapy.
PubMed: 38811533
DOI: 10.1038/s41420-024-02005-3 -
Poultry Science May 2024Duck hepatitis A virus 1 (DHAV-1) is the primary cause of duck viral hepatitis, leading to sudden mortality in ducklings and significant economic losses in the duck...
Duck hepatitis A virus 1 (DHAV-1) is the primary cause of duck viral hepatitis, leading to sudden mortality in ducklings and significant economic losses in the duck industry. However, little is known about how DHAV-1 affects duckling liver at the molecular level. We conducted an analysis comparing the expression patterns of mRNAs and miRNAs in DHAV-1-infected duckling livers to understand the underlying mechanisms and dynamic changes. We identified 6,818 differentially expressed mRNAs (DEGs) and 144 differentially expressed microRNAs (DEMs) during DHAV-1 infection. Functional enrichment analysis of DEGs and miRNA target genes using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed their potential involvement in innate antiviral immunity, mitophagy, and pyroptosis. We constructed coexpression networks of mRNA-miRNA interactions and confirmed key DEMs (novel-mir333, novel-mir288, novel-mir197, and novel-mir71) using RT-qPCR. Further investigation demonstrated that DHAV-1 activates the RLRs signaling pathway, disrupts mitophagy, and induces pyroptosis. In conclusion, DHAV-1-induced antiviral immunity is closely linked to mitophagy, suggesting it could be a promising therapeutic target.
PubMed: 38810565
DOI: 10.1016/j.psj.2024.103839 -
Frontiers in Cell and Developmental... 2024Sporadic inclusion body myositis (sIBM) is a distinct subcategory of Idiopathic Inflammatory Myopathies (IIM), characterized by unique pathological features such as... (Review)
Review
Sporadic inclusion body myositis (sIBM) is a distinct subcategory of Idiopathic Inflammatory Myopathies (IIM), characterized by unique pathological features such as muscle inflammation, rimmed vacuoles, and protein aggregation within the myofibers. Although hyperactivation of the immune system is widely believed as the primary cause of IIM, it is debated whether non-immune tissue dysfunction might contribute to the disease's onset as patients with sIBM are refractory to conventional immunosuppressant treatment. Moreover, the findings that mitochondrial dysfunction can elicit non-apoptotic programmed cell death and the subsequent immune response further support this hypothesis. Notably, abnormal mitochondrial structure and activities are more prominent in the muscle of sIBM than in other types of IIM, suggesting the presence of defective mitochondria might represent an overlooked contributor to the disease onset. The large-scale mitochondrial DNA deletion, aberrant protein aggregation, and slowed organelle turnover have provided mechanistic insights into the genesis of impaired mitochondria in sIBM. This article reviews the disease hallmarks of sIBM, the plausible contributors of mitochondrial damage in the sIBM muscle, and the immunological responses associated with mitochondrial perturbations. Additionally, the potential application of mitochondrial-targeted chemicals as a new treatment strategy to sIBM is explored and discussed.
PubMed: 38808223
DOI: 10.3389/fcell.2024.1403463 -
Frontiers in Aging Neuroscience 2024As the global population ages, the incidence of elderly patients with dementia, represented by Alzheimer's disease (AD), will continue to increase. Previous studies have... (Review)
Review
As the global population ages, the incidence of elderly patients with dementia, represented by Alzheimer's disease (AD), will continue to increase. Previous studies have suggested that β-amyloid protein (Aβ) deposition is a key factor leading to AD. However, the clinical efficacy of treating AD with anti-Aβ protein antibodies is not satisfactory, suggesting that Aβ amyloidosis may be a pathological change rather than a key factor leading to AD. Identification of the causes of AD and development of corresponding prevention and treatment strategies is an important goal of current research. Following the discovery of soluble oligomeric forms of Aβ (AβO) in 1998, scientists began to focus on the neurotoxicity of AβOs. As an endogenous neurotoxin, the active growth of AβOs can lead to neuronal death, which is believed to occur before plaque formation, suggesting that AβOs are the key factors leading to AD. PANoptosis, a newly proposed concept of cell death that includes known modes of pyroptosis, apoptosis, and necroptosis, is a form of cell death regulated by the PANoptosome complex. Neuronal survival depends on proper mitochondrial function. Under conditions of AβO interference, mitochondrial dysfunction occurs, releasing lethal contents as potential upstream effectors of the PANoptosome. Considering the critical role of neurons in cognitive function and the development of AD as well as the regulatory role of mitochondrial function in neuronal survival, investigation of the potential mechanisms leading to neuronal PANoptosis is crucial. This review describes the disruption of neuronal mitochondrial function by AβOs and elucidates how AβOs may activate neuronal PANoptosis by causing mitochondrial dysfunction during the development of AD, providing guidance for the development of targeted neuronal treatment strategies.
PubMed: 38808033
DOI: 10.3389/fnagi.2024.1400544 -
Heliyon May 2024Electroacupuncture (EA) is an effective alternative for the treatment of functional dyspepsia (FD). It reduces low-grade duodenal inflammation and improves the symptoms...
Electroacupuncture (EA) is an effective alternative for the treatment of functional dyspepsia (FD). It reduces low-grade duodenal inflammation and improves the symptoms of FD by downregulating the expression of NF-κB p65 and NLRP3, but its mechanism needs to be elucidated. To examine the regulatory effect of electroacupuncture (EA) on intestinal flora and NF-κB p65/NLRP3 pyroptosis pathway in FD rats. The FD rat model was established via multi-factor stress intervention for two weeks. The rats were randomly divided into the NC group, model group, NF-kB inhibitor group (NF-κB inhibitor BAY 11-7082 was administered), EA group, and EA + NF-kB inhibitor group. After 14 days of treatment, the rats were sacrificed, and the protein and mRNA levels of NF-κB p65, IκB, and NLRP3 in the duodenum were evaluated by Western blotting assays and real-time fluorescent quantitative PCR. The Illumina MiSeq sequencing platform was used to analyze the V4 region of the 16S rRNA gene of intestinal flora and predict functional genes. The concentration of short-chain fatty acids (SCFAs) in feces was assessed by metabolomics. EA can decrease low-grade duodenal inflammation and promote gastrointestinal motility in FD rats. This effect is mediated by inhibition of the NF-κB p65/NLRP3 pyroptosis pathway, an increase in the alpha and beta diversity of gut microbiota in the duodenum, an increase in the abundance of beneficial bacteria at the phylum and genus levels, and an increase in the content of SCFAs. The protective effect of EA against FD might involve multiple hierarchy and pathways. EA may remodel intestinal flora by inhibiting the NF-κB p65/NLRP3 pyroptosis pathway, thereby improving low-grade duodenal inflammation in FD rats.
PubMed: 38807876
DOI: 10.1016/j.heliyon.2024.e31197 -
Journal of Biomedical Research May 2024The intestinal mucosal barrier serves as a vital guardian for gut health, maintaining a delicate equilibrium between gut microbiota and host immune homeostasis. Recent...
The intestinal mucosal barrier serves as a vital guardian for gut health, maintaining a delicate equilibrium between gut microbiota and host immune homeostasis. Recent studies have found the intricate roles of Gasdermin D (GSDMD), a key executioner of pyroptosis downstream of the inflammasome, within the intestine, including controlling colitis in intestinal macrophage and the regulatory function in goblet cell mucus secretion. Thus, the exact role and nature of GSDMD's regulatory function in maintaining intestinal immune homeostasis and defending against pathogens remain elucidation. Here, we uncover that GSDMD plays a key role in defending against intestinal infection, with high expression in intestinal epithelial and lamina propria myeloid cells. Our results show that GSDMD specifically acts in intestinal epithelial cells to fight the infection, independently of its effects on antimicrobial peptides or mucin secretion. Instead, the resistance is mediated through GSDMD's N-terminal fragments, highlighting its importance in intestinal immunity. However, the specific underlying mechanism of GSDMD N-terminal activity in protection against intestinal bacterial infections still needs further study to clarify in the future.
PubMed: 38807373
DOI: 10.7555/JBR.38.20240041 -
Clinical and Translational Medicine Jun 2024Although numerous studies have indicated that activated pyroptosis can enhance the efficacy of antitumour therapy in several tumours, the precise mechanism of pyroptosis...
BACKGROUND
Although numerous studies have indicated that activated pyroptosis can enhance the efficacy of antitumour therapy in several tumours, the precise mechanism of pyroptosis in colorectal cancer (CRC) remains unclear.
METHODS
Pyroptosis in CRC cells treated with antitumour agents was assessed using various techniques, including Western blotting, lactate dehydrogenase release assay and microscopy analysis. To uncover the epigenetic mechanisms that regulate NLRP3, chromatin changes and NLRP3 promoter histone modifications were assessed using Assay for Transposase-Accessible Chromatin using sequencing and RNA sequencing. Chromatin immunoprecipitation‒quantitative polymerase chain reaction was used to investigate the NLRP3 transcriptional regulatory mechanism. Additionally, xenograft and patient-derived xenograft models were constructed to validate the effects of the drug combinations.
RESULTS
As the core molecule of the inflammasome, NLRP3 expression was silenced in CRC, thereby limiting gasdermin D (GSDMD)-mediated pyroptosis. Supplementation with NLRP3 can rescue pyroptosis induced by antitumour therapy. Overexpression of HDAC2 in CRC silences NLRP3 via epigenetic regulation. Mechanistically, HDAC2 suppressed chromatin accessibility by eliminating H3K27 acetylation. HDAC2 knockout promotes H3K27ac-mediated recruitment of the BRD4-p-P65 complex to enhance NLRP3 transcription. Inhibiting HDAC2 by Santacruzamate A in combination with classic antitumour agents (5-fluorouracil or regorafenib) in CRC xenograft-bearing animals markedly activated pyroptosis and achieved a significant therapeutic effect. Clinically, HDAC2 is inversely correlated with H3K27ac/p-P65/NLRP3 and is a prognostic factor for CRC patients.
CONCLUSION
Collectively, our data revealed a crucial role for HDAC2 in inhibiting NLRP3/GSDMD-mediated pyroptosis in CRC cells and highlighted HDAC2 as a potential therapeutic target for antitumour therapy.
HIGHLIGHTS
Silencing of NLRP3 limits the GSDMD-dependent pyroptosis in colorectal cancer. HDAC2-mediated histone deacetylation leads to epigenetic silencing of NLRP3. HDAC2 suppresses the NLRP3 transcription by inhibiting the formation of H3K27ac/BRD4/p-P65 complex. Targeting HDAC2 activates pyroptosis and enhances therapeutic effect.
Topics: Pyroptosis; Colorectal Neoplasms; Humans; NLR Family, Pyrin Domain-Containing 3 Protein; Histone Deacetylase 2; Mice; Animals; Intracellular Signaling Peptides and Proteins; Antineoplastic Agents; Cell Line, Tumor; Gasdermins; Phosphate-Binding Proteins
PubMed: 38804602
DOI: 10.1002/ctm2.1692 -
Frontiers in Immunology 2024Atherosclerosis, a leading cause of global cardiovascular mortality, is characterized by chronic inflammation. Central to this process is the NOD-like receptor pyrin...
INTRODUCTION
Atherosclerosis, a leading cause of global cardiovascular mortality, is characterized by chronic inflammation. Central to this process is the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, which significantly influences atherosclerotic progression. Recent research has identified that the olfactory receptor 2 (Olfr2) in vascular macrophages is instrumental in driving atherosclerosis through NLRP3- dependent IL-1 production.
METHODS
To investigate the effects of Corilagin, noted for its anti-inflammatory attributes, on atherosclerotic development and the Olfr2 signaling pathway, our study employed an atherosclerosis model in ApoE mice, fed a high-fat, high-cholesterol diet, alongside cellular models in Ana-1 cells and mouse bone marrow-derived macrophages, stimulated with lipopolysaccharides and oxidized low-density lipoprotein.
RESULTS
The vivo and vitro experiments indicated that Corilagin could effectively reduce serum lipid levels, alleviate aortic pathological changes, and decrease intimal lipid deposition. Additionally, as results showed, Corilagin was able to cut down expressions of molecules associated with the Olfr2 signaling pathway.
DISCUSSION
Our findings indicated that Corilagin effectively inhibited NLRP3 inflammasome activation, consequently diminishing inflammation, macrophage polarization, and pyroptosis in the mouse aorta and cellular models via the Olfr2 pathway. This suggests a novel therapeutic mechanism of Corilagin in the treatment of atherosclerosis.
Topics: Animals; Hydrolyzable Tannins; NLR Family, Pyrin Domain-Containing 3 Protein; Atherosclerosis; Mice; Signal Transduction; Inflammasomes; Glucosides; Macrophages; Male; Disease Models, Animal; Mice, Inbred C57BL; Mice, Knockout, ApoE
PubMed: 38803504
DOI: 10.3389/fimmu.2024.1364161 -
European Journal of Medical Research May 2024Joint contracture is one of the common diseases clinically, and joint capsule fibrosis is considered to be one of the most important pathological changes of joint...
Joint contracture is one of the common diseases clinically, and joint capsule fibrosis is considered to be one of the most important pathological changes of joint contracture. However, the underlying mechanism of joint capsule fibrosis is still controversial. The present study aims to establish an animal model of knee extending joint contracture in rats, and to investigate the role of hypoxia-mediated pyroptosis in the progression of joint contracture using this animal model. 36 male SD rats were selected, 6 of which were not immobilized and were used as control group, while 30 rats were divided into I-1 group (immobilized for 1 week following 7 weeks of free movement), I-2 group (immobilized for 2 weeks following 6 weeks of free movement), I-4 group (immobilized for 4 weeks following 4 weeks of free movement), I-6 group (immobilized for 6 weeks following 2 weeks of free movement) and I-8 group (immobilized for 8 weeks) according to different immobilizing time. The progression of joint contracture was assessed by the measurement of knee joint range of motion, collagen deposition in joint capsule was examined with Masson staining, protein expression levels of HIF-1α, NLRP3, Caspase-1, GSDMD-N, TGF-β1, α-SMA and p-Smad3 in joint capsule were assessed using western blotting, and the morphological changes of fibroblasts were observed by transmission electron microscopy. The degree of total and arthrogenic contracture progressed from the first week and lasted until the first eight weeks after immobilization. The degree of total and arthrogenic contracture progressed rapidly in the first four weeks after immobilization and then progressed slowly. Masson staining indicated that collagen deposition in joint capsule gradually increased in the first 8 weeks following immobilization. Western blotting analysis showed that the protein levels of HIF-1α continued to increase during the first 8 weeks of immobilization, and the protein levels of pyroptosis-related proteins NLRP3, Caspase-1, GSDMD-N continued to increase in the first 4 weeks after immobilization and then decreased. The protein levels of fibrosis-related proteins TGF-β1, p-Smad3 and α-SMA continued to increase in the first 8 weeks after immobilization. Transmission electron microscopy showed that 4 weeks of immobilization induced cell membrane rupture and cell contents overflow, which further indicated the activation of pyroptosis. Knee extending joint contracture animal model can be established by external immobilization orthosis in rats, and the activation of hypoxia-mediated pyroptosis may play a stimulating role in the process of joint capsule fibrosis and joint contracture.
Topics: Animals; Contracture; Pyroptosis; Rats; Male; Knee Joint; Rats, Sprague-Dawley; Hypoxia-Inducible Factor 1, alpha Subunit; NLR Family, Pyrin Domain-Containing 3 Protein; Hypoxia; Disease Models, Animal; Transforming Growth Factor beta1; Joint Capsule; Range of Motion, Articular; Smad3 Protein
PubMed: 38802976
DOI: 10.1186/s40001-024-01890-9