76,705 results on '"innate immune system"'
Search Results
2. Molecular Bases and Specificity behind the Activation of the Immune System OAS/RNAse L Pathway by Viral RNA.
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Jung-Rodriguez, Emma, Barbault, Florent, Bignon, Emmanuelle, and Monari, Antonio
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GIBBS' energy diagram , *ALLOSTERIC regulation , *MOLECULAR dynamics , *NUCLEIC acids , *RNA viruses - Abstract
The first line of defense against invading pathogens usually relies on innate immune systems. In this context, the recognition of exogenous RNA structures is primordial to fight, notably, against RNA viruses. One of the most efficient immune response pathways is based on the sensing of RNA double helical motifs by the oligoadenylate synthase (OAS) proteins, which in turn triggers the activity of RNase L and, thus, cleaves cellular and viral RNA. In this contribution, by using long-range molecular dynamics simulations, complemented with enhanced sampling techniques, we elucidate the structural features leading to the activation of OAS by interaction with a model double-strand RNA oligomer mimicking a viral RNA. We characterize the allosteric regulation induced by the nucleic acid leading to the population of the active form of the protein. Furthermore, we also identify the free energy profile connected to the active vs. inactive conformational transitions in the presence and absence of RNA. Finally, the role of two RNA mutations, identified as able to downregulate OAS activation, in shaping the protein/nucleic acid interface and the conformational landscape of OAS is also analyzed. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Microbiome-host interactions in the pathogenesis of acute exacerbation of chronic obstructive pulmonary disease.
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Yao Li, Xiaoyan Mao, Pengfei Shi, Zongren Wan, Dan Yang, Ting Ma, Baolan Wang, Jipeng Wang, Jingjing Wang, and Rong Zhu
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CHRONIC obstructive pulmonary disease ,GENE expression ,HAEMOPHILUS influenzae ,TOLL-like receptors ,CELLULAR signal transduction - Abstract
Objective: To explore the underlying mechanisms the airway microbiome contributes to Acute Exacerbation of Chronic Obstructive Pulmonary Disease(AECOPD). Methods: We enrolled 31 AECOPD patients and 26 stable COPD patients, their sputum samples were collected for metagenomic and RNA sequencing, and then subjected to bioinformatic analyses. The expression of host genes was validated by Quantitative Real-time PCR(qPCR) using the same batch of specimens. Results: Our results indicated a higher expression of Rothia mucilaginosa (p=0.015) in the AECOPD group and Haemophilus influenzae(p=0.005) in the COPD group. The Different expressed genes(DEGs) detected were significantly enriched in "type I interferon signaling pathway"(p<0.001, q=0.001) in gene function annotation, and "Cytosolic DNA-sensing pathway"(p=0.002, q=0.024), "Toll-like receptor signaling pathway"(p=0.006, q=0.045), and "TNF signaling pathway"(p=0.006, q=0.045) in KEGG enrichment analysis. qPCR amplification experiment verified that the expression of OASL and IL6 increased significantly in the AECOPD group. Conclusion: Pulmonary bacteria dysbiosis may regulate the pathogenesis of AECOPD through innate immune system pathways like type I interferon signaling pathway and Toll-like receptor signaling pathway. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Increasing plasma calprotectin (S100A8/A9) is associated with 12-month mortality and unfavourable functional outcome in critically ill COVID-19 patients.
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Didriksson, Ingrid, Lengquist, Maria, Spångfors, Martin, Leffler, Märta, Sievert, Theodor, Lilja, Gisela, Frigyesi, Attila, Friberg, Hans, and Schiopu, Alexandru
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COVID-19 , *CALPROTECTIN , *CRITICALLY ill , *INTENSIVE care units , *MORTALITY - Abstract
Background: Calprotectin (S100A8/A9) is a pro-inflammatory mediator primarily released from neutrophils. Previous studies have revealed associations between plasma calprotectin, disease severity and in-hospital mortality in unselected COVID-19 patients. Objective: We aimed to assess whether plasma calprotectin dynamics during the first week of intensive care are associated with mortality and functional outcome in critically ill COVID-19 patients. Methods: This prospective study included 498 COVID-19 patients admitted to six intensive care units (ICUs) in Sweden between May 2020 and May 2021. Blood samples were collected on ICU admission and on day 7. The primary outcome was 12-month mortality. Secondary outcomes were functional outcome of survivors at 3 and 12 months, and the need for invasive mechanical ventilation (IMV) or continuous renal replacement therapy (CRRT) during the ICU stay. Functional outcome was assessed by the Glasgow Outcome Scale Extended (GOSE, range 1–8, with < 5 representing an unfavourable outcome). Associations between plasma calprotectin and outcomes were examined in binary logistic regression analyses adjusted for age, sex, BMI, hypertension, smoking, and creatinine. Results: High plasma calprotectin on admission and day 7 was independently associated with increased 12-month mortality. Increasing calprotectin from admission to day 7 was independently associated with higher mortality at 12 months [OR 2.10 (95% CI 1.18–3.74), p = 0.012], unfavourable functional outcome at 3 months [OR 2.53 (95% CI 1.07–6.10), p = 0.036], and the use of IMV [OR 2.23 (95% CI 1.10–4.53), p = 0.027)] and CRRT [OR 2.07 (95% CI 1.07–4.00), p = 0.031)]. A receiver operator characteristic (ROC) model including day 7 calprotectin and age was a good predictor of 12-month mortality [AUC 0.79 (95% CI 0.74–0.84), p < 0.001]. Day 7 calprotectin alone predicted an unfavourable functional outcome at 3 months [AUC 0.67 (95% CI 0.58–0.76), p < 0.001]. Conclusion: In critically ill COVID-19 patients, increasing calprotectin levels after admission to the ICU are associated with 12-month mortality and unfavourable functional outcome in survivors. Monitoring plasma calprotectin dynamics in the ICU may be considered to evaluate prognosis in critical COVID-19. Study registration: ClinicalTrials.gov Identifier: NCT04974775, registered April 28, 2020. [ABSTRACT FROM AUTHOR]
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- 2024
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5. The landscape of innate and adaptive immune cell subsets in patients with adult-onset Still's disease.
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Chi, Huihui, Hong, Xinyue, Dai, Ningqi, Chen, Longfang, Zhang, Hao, Liu, Honglei, Cheng, Xiaobing, Ye, Junna, Shi, Hui, Hu, Qiongyi, Meng, Jianfen, Zhou, Zhuochao, Jia, Jinchao, Liu, Tingting, Wang, Fan, Wang, Mengyan, Ma, Yuning, Chen, Xia, You, Yijun, and Zhu, Dehao
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PROTEIN analysis , *FLOW cytometry , *MITOGEN-activated protein kinases , *RESEARCH funding , *MONOCYTES , *MONONUCLEAR leukocytes , *KILLER cells , *T cells , *DATA analysis , *RHEUMATOID arthritis , *IMMUNOGLOBULINS , *IMMUNE system , *MANN Whitney U Test , *DESCRIPTIVE statistics , *GENE expression , *STATISTICS , *NATURAL immunity , *INFLAMMATION , *CYTOKINES , *DATA analysis software , *CELLS - Abstract
Objective Adult-onset Still's disease (AOSD) is a systemic autoinflammatory disorder. The understanding of the changes in adaptive immune cells and the crosstalk between innate and adaptive immune systems in AOSD is limited. This study aimed to examine the peripheral immune cell composition and inflammatory protein levels in AOSD patients. Methods Twenty-nine active AOSD patients were enrolled. Flow cytometry was used to analyse the cell populations in peripheral blood. Antibody chips were utilized to detect the protein expression profile in serum. Results In active AOSD patients, there was an increase in the percentage of classical and non-classical monocytes among peripheral blood mononuclear cells. The proportion of natural killer (NK) cells decreased, with an increase in CD56dim NK1 cells and a decrease in CD56bright NK2 cells compared with healthy controls (HCs). The percentage of naïve central memory T cells was decreased, while the percentage of effector and effector memory T cells was increased among adaptive lymphocytes. The proportion of naïve B and memory B cells was decreased, while plasma cells were increased in AOSD patients, indicating activation of the adaptive immune system. Additionally, the serum levels of 40 proteins were elevated in AOSD patients, primarily involved in cytokine–cytokine receptor interaction, inflammatory response and regulation of mitogen-activated protein kinase cascade. Conclusion Our findings showed the activation of the innate and adaptive immune system in AOSD. The protein–protein interaction analysis suggested potential communication between innate and adaptive cell subsets. These findings provide new insights into the pathogenesis of the disease and the development of targeted therapies. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Inflammatory and Immune Mechanisms for Atherosclerotic Cardiovascular Disease in HIV.
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Hmiel, Laura, Zhang, Suyu, Obare, Laventa M., Santana, Marcela Araujo de Oliveira, Wanjalla, Celestine N., Titanji, Boghuma K., Hileman, Corrilynn O., and Bagchi, Shashwatee
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CARDIOVASCULAR diseases , *HIV , *HIV infections , *VASCULAR diseases , *IMMUNE response - Abstract
Atherosclerotic vascular disease disproportionately affects persons living with HIV (PLWH) compared to those without. The reasons for the excess risk include dysregulated immune response and inflammation related to HIV infection itself, comorbid conditions, and co-infections. Here, we review an updated understanding of immune and inflammatory pathways underlying atherosclerosis in PLWH, including effects of viral products, soluble mediators and chemokines, innate and adaptive immune cells, and important co-infections. We also present potential therapeutic targets which may reduce cardiovascular risk in PLWH. [ABSTRACT FROM AUTHOR]
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- 2024
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7. Implications of innate immune sexual dimorphism for MASLD pathogenesis and treatment.
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Booijink, Richell, Ramachandran, Prakash, and Bansal, Ruchi
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GUT microbiome , *SEXUAL dimorphism , *DRUG discovery - Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects men more than women, with severity increasing post menopause, indicating sex-based disparities in MASLD prevalence and progression. Estrogen protects women from MASLD, while the effects of testosterone vary among men and women. This indicates that different sex-dimorphic mechanisms are involved in sex-hormone signaling. Innate immune cells display significant sexual dimorphism in their response to MASLD, wherein male immune cells evidence a more migratory and proinflammatory phenotype. Sex-specific genetic variants and gut microbiota influence MASLD risk, highlighting the opportunity for developing personalized treatments based on individual genetic or microbiome profiles. Current preclinical MASLD models are male biased, indicating the challenges in translating research findings into clinical therapies for developing gender-specific MASLD treatment. Growing evidence suggests that metabolic dysfunction-associated steatotic liver disease (MASLD) is significantly higher in men versus women. Increased prevalence is observed in postmenopausal women, suggesting that age and sex (hormones) influence MASLD development and progression. Molecular data further reveal that sex regulates the innate immune responses with an essential role in MASLD progression. To date, there has been limited focus on the role of innate immune sexual dimorphism in MASLD, and differences between men and women are not considered in the current drug discovery landscape. In this review, we summarize the sex disparities and innate immune sexual dimorphism in MASLD pathogenesis. We further highlight the importance of harnessing sexual dimorphism in identifying therapeutic targets, developing pharmacological therapies, and designing (pre-) clinical studies for the personalized treatment for MASLD. [ABSTRACT FROM AUTHOR]
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- 2024
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8. Increasing plasma calprotectin (S100A8/A9) is associated with 12-month mortality and unfavourable functional outcome in critically ill COVID-19 patients
- Author
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Ingrid Didriksson, Maria Lengquist, Martin Spångfors, Märta Leffler, Theodor Sievert, Gisela Lilja, Attila Frigyesi, Hans Friberg, and Alexandru Schiopu
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COVID-19 ,ICU ,Calprotectin ,Innate immune system ,Mortality ,Medical emergencies. Critical care. Intensive care. First aid ,RC86-88.9 - Abstract
Abstract Background Calprotectin (S100A8/A9) is a pro-inflammatory mediator primarily released from neutrophils. Previous studies have revealed associations between plasma calprotectin, disease severity and in-hospital mortality in unselected COVID-19 patients. Objective We aimed to assess whether plasma calprotectin dynamics during the first week of intensive care are associated with mortality and functional outcome in critically ill COVID-19 patients. Methods This prospective study included 498 COVID-19 patients admitted to six intensive care units (ICUs) in Sweden between May 2020 and May 2021. Blood samples were collected on ICU admission and on day 7. The primary outcome was 12-month mortality. Secondary outcomes were functional outcome of survivors at 3 and 12 months, and the need for invasive mechanical ventilation (IMV) or continuous renal replacement therapy (CRRT) during the ICU stay. Functional outcome was assessed by the Glasgow Outcome Scale Extended (GOSE, range 1–8, with
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- 2024
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9. Immune Cell Ion Channels as Therapeutic Targets
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Selezneva, Anna, Gibb, Alasdair J., Willis, Dean, Stephens, Gary, editor, and Stevens, Edward, editor
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- 2024
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10. Vaccines
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Jiskoot, Wim, Kersten, Gideon F. A., Mastrobattista, Enrico, Slütter, Bram, Crommelin, Daan J. A., editor, Sindelar, Robert D., editor, and Meibohm, Bernd, editor
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- 2024
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11. Diffusion magnetic resonance spectroscopy captures microglial reactivity related to gut-derived systemic lipopolysaccharide: A preliminary study.
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Birg, Aleksandr, van der Horn, Harm J., Ryman, Sephira G., Branzoli, Francesca, Deelchand, Dinesh K., Quinn, Davin K., Mayer, Andrew R., Lin, Henry C., Erhardt, Erik B., Caprihan, Arvind, Zotev, Vadim, Parada, Alisha N., Wick, Tracey V., Matos, Yvette L., Barnhart, Kimberly A., Nitschke, Stephanie R., Shaff, Nicholas A., Julio, Kayla R., Prather, Haley E., and Vakhtin, Andrei A.
- Abstract
• dMRS is a noninvasive, cost-effective sequence for assessing microglial activation. • The sequence has detected neuroinflammation in LPS challenges and serious diseases. • It is unclear if dMRS can detect subtle neuroinflammation without LPS injections. • Here, dMRS reflected intrinsic LPS via neurometabolite diffusivity properties. • The sequence is sensitive to intrinsic plasma levels of LPS without LPS injections. Neuroinflammation is a key component underlying multiple neurological disorders, yet non-invasive and cost-effective assessment of in vivo neuroinflammatory processes in the central nervous system remains challenging. Diffusion weighted magnetic resonance spectroscopy (dMRS) has shown promise in addressing these challenges by measuring diffusivity properties of different neurometabolites, which can reflect cell-specific morphologies. Prior work has demonstrated dMRS utility in capturing microglial reactivity in the context of lipopolysaccharide (LPS) challenges and serious neurological disorders, detected as changes of microglial metabolite diffusivity properties. However, the extent to which such dMRS metrics are capable of detecting subtler and more nuanced levels of neuroinflammation in populations without overt neuropathology is unknown. Here we examined the relationship between intrinsic, gut-derived levels of systemic LPS and dMRS-based apparent diffusion coefficients (ADC) of choline, creatine, and N-acetylaspartate (NAA) in two brain regions: the thalamus and the corona radiata. Higher plasma LPS concentrations were significantly associated with increased ADC of choline and NAA in the thalamic region, with no such relationships observed in the corona radiata for any of the metabolites examined. As such, dMRS may have the sensitivity to measure microglial reactivity across populations with highly variable levels of neuroinflammation, and holds promising potential for widespread applications in both research and clinical settings. [ABSTRACT FROM AUTHOR]
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- 2024
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12. Ginsenoside modified lipid-coated perfluorocarbon nanodroplets: A novel approach to reduce complement protein adsorption and prolong in vivo circulation
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Jie Zhou, Binyang Gao, Huan Zhang, Rui Yang, Jianbo Huang, Xin Li, Yi Zhong, Yan Wang, Xiaoxia Zhu, Yan Luo, and Feng Yan
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Lipid-coated perfluorocarbon nanodroplets ,Protein corona ,Complement C3 ,Phagocytosis ,Ginsenoside lipid-coated perfluorocarbon nanodroplets ,Innate immune system ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Lipid-coated perfluorocarbon nanodroplets (lp-NDs) hold great promise in bio-medicine as vehicles for drug delivery, molecular imaging and vaccine agents. However, their clinical utility is restricted by limited targeted accumulation, attributed to the innate immune system (IIS), which acts as the initial defense mechanism in humans. This study aimed to optimize lp-ND formulations to minimize non-specific clearance by the IIS. Ginsenosides (Gs), the principal components of Panax ginseng, possessing complement inhibition ability, structural similarity to cholesterol, and comparable fat solubility to phospholipids, were used as promising candidate IIS inhibitors. Two different types of ginsenoside-based lp-NDs (Gs lp-NDs) were created, and their efficacy in reducing IIS recognition was examined. The Gs lp-NDs were observed to inhibit the adsorption of C3 in the protein corona (PC) and the generation of SC5b-9. Adding Gs to lp-NDs reduced complement adsorption and phagocytosis, resulting in a longer blood circulation time in vivo compared to lp-NDs that did not contain Gs. These results suggest that Gs can act as anti-complement and anti-phagocytosis adjuvants, potentially reducing non-specific clearance by the IIS and improving lifespan.
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- 2024
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13. Nano-formulated delivery of active ingredients from traditional Chinese herbal medicines for cancer immunotherapy
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Qi Shang, Wandong Liu, Faith Leslie, Jiapei Yang, Mingmei Guo, Mingjiao Sun, Guangji Zhang, Qiang Zhang, and Feihu Wang
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Chinese herbal medicines ,Nano-formulation ,Active ingredients ,Drug delivery ,Cancer immunotherapy ,Innate immune system ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Cancer immunotherapy has garnered promise in tumor progression, invasion, and metastasis through establishing durable and memorable immunological activity. However, low response rates, adverse side effects, and high costs compromise the additional benefits for patients treated with current chemical and biological agents. Chinese herbal medicines (CHMs) are a potential treasure trove of natural medicines and are gaining momentum in cancer immunomodulation with multi-component, multi-target, and multi-pathway characteristics. The active ingredient extracted from CHMs benefit generalized patients through modulating immune response mechanisms. Additionally, the introduction of nanotechnology has greatly improved the pharmacological qualities of active ingredients through increasing the hydrophilicity, stability, permeability, and targeting characteristics, further enhancing anti-cancer immunity. In this review, we summarize the mechanism of active ingredients for cancer immunomodulation, highlight nano-formulated deliveries of active ingredients for cancer immunotherapy, and provide insights into the future applications in the emerging field of nano-formulated active ingredients of CHMs.
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- 2024
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14. Antimicrobial Peptides (AMPs) and the Microbiome in Preterm Infants: Consequences and Opportunities for Future Therapeutics.
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Marissen, Janina, Reichert, Lilith, Härtel, Christoph, Fortmann, Mats Ingmar, Faust, Kirstin, Msanga, Delfina, Harder, Jürgen, Zemlin, Michael, Gomez de Agüero, Mercedes, Masjosthusmann, Katja, and Humberg, Alexander
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PREMATURE infants , *ANTIMICROBIAL peptides , *NEONATAL infections , *THERAPEUTICS , *RESPIRATORY infections , *LUNG diseases - Abstract
Antimicrobial peptides (AMPs) are crucial components of the innate immune system in various organisms, including humans. Beyond their direct antimicrobial effects, AMPs play essential roles in various physiological processes. They induce angiogenesis, promote wound healing, modulate immune responses, and serve as chemoattractants for immune cells. AMPs regulate the microbiome and combat microbial infections on the skin, lungs, and gastrointestinal tract. Produced in response to microbial signals, AMPs help maintain a balanced microbial community and provide a first line of defense against infection. In preterm infants, alterations in microbiome composition have been linked to various health outcomes, including sepsis, necrotizing enterocolitis, atopic dermatitis, and respiratory infections. Dysbiosis, or an imbalance in the microbiome, can alter AMP profiles and potentially lead to inflammation-mediated diseases such as chronic lung disease and obesity. In the following review, we summarize what is known about the vital role of AMPs as multifunctional peptides in protecting newborn infants against infections and modulating the microbiome and immune response. Understanding their roles in preterm infants and high-risk populations offers the potential for innovative approaches to disease prevention and treatment. [ABSTRACT FROM AUTHOR]
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- 2024
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15. Analysis of Selected Toll-like Receptors in the Pathogenesis and Advancement of Non-Small-Cell Lung Cancer.
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Smok-Kalwat, Jolanta, Mertowska, Paulina, Mertowski, Sebastian, Góźdź, Stanisław, Korona-Głowniak, Izabela, Kwaśniewski, Wojciech, and Grywalska, Ewelina
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NON-small-cell lung carcinoma , *TOLL-like receptors , *B cells , *T cells , *NATURAL immunity - Abstract
(1) Background: Non-small-cell lung cancer (NSCLC) represents a significant global health challenge, contributing to numerous cancer deaths. Despite advances in diagnostics and therapy, identifying reliable biomarkers for prognosis and therapeutic stratification remains difficult. Toll-like receptors (TLRs), crucial for innate immunity, now show potential as contributors to cancer development and progression. This study aims to investigate the role of TLR expression as potential biomarkers in the development and progression of NSCLC. (2) Materials and Methods: The study was conducted on 89 patients diagnosed with NSCLC and 40 healthy volunteers, for whom the prevalence of TLR2, TLR3, TLR4, TLR7, TLR8, and TLR9 was assessed on selected subpopulations of T and B lymphocytes in the peripheral blood of recruited patients along with the assessment of their serum concentration. (3) Result: Our study showed several significant changes in NSCLC patients at the beginning of the study. This resulted in a 5-year follow-up of changes in selected TLRs in recruited patients. Due to the high mortality rate of NSCLC patients, only 16 patients survived the 5 years. (4) Conclusions: The results suggest that TLRs may constitute real biomarker molecules that may be used for future prognostic purposes in NSCLC. However, further validation through prospective clinical and functional studies is necessary to confirm their clinical utility. These conclusions may lead to better risk stratification and tailored interventions, benefiting NSCLC patients and bringing medicine closer to precision. [ABSTRACT FROM AUTHOR]
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- 2024
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16. Gene Association Study of the Urokinase Plasminogen Activator and Its Receptor Gene in Alzheimer's Disease.
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Cetinsoy, Ozde, Anyanwu, Ijeoma, Krishnanand, Harikrishnan, Natarajan, Gokulakrishnan, Ramachandran, Naveen, Thomas, Alan, and Brookes, Keeley J.
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PLASMINOGEN activators , *ALZHEIMER'S disease , *UROKINASE , *ALTERNATIVE RNA splicing , *GENES - Abstract
Background: The role of the innate immune system has long been associated with Alzheimer's disease (AD). There is now accumulating evidence that the soluble Urokinase Plasminogen Activator Receptor pathway, and its genes, PLAU and PLAUR may be important in AD, and yet there have been few genetic association studies to explore this. Objective: This study utilizes the DNA bank of the Brains for Dementia Research cohort to investigate the genetic association of common polymorphisms across the PLAU and PLAUR genes with AD. Methods: TaqMan genotyping assays were used with standard procedures followed by association analysis in PLINK. Results: No association was observed between the PLAU gene and AD; however, two SNPs located in the PLAUR gene were indicative of a trend towards association but did not surpass multiple testing significance thresholds. Conclusions: Further genotyping studies and exploration of the consequences of these SNPs on gene expression and alternative splicing are warranted to fully uncover the role this system may have in AD. [ABSTRACT FROM AUTHOR]
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- 2024
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17. Nano-formulated delivery of active ingredients from traditional Chinese herbal medicines for cancer immunotherapy.
- Author
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Shang, Qi, Liu, Wandong, Leslie, Faith, Yang, Jiapei, Guo, Mingmei, Sun, Mingjiao, Zhang, Guangji, Zhang, Qiang, and Wang, Feihu
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CHINESE medicine ,HERBAL medicine ,IMMUNOTHERAPY ,IMMUNE system ,IMMUNE response - Abstract
Cancer immunotherapy has garnered promise in tumor progression, invasion, and metastasis through establishing durable and memorable immunological activity. However, low response rates, adverse side effects, and high costs compromise the additional benefits for patients treated with current chemical and biological agents. Chinese herbal medicines (CHMs) are a potential treasure trove of natural medicines and are gaining momentum in cancer immunomodulation with multi-component, multi-target, and multi-pathway characteristics. The active ingredient extracted from CHMs benefit generalized patients through modulating immune response mechanisms. Additionally, the introduction of nanotechnology has greatly improved the pharmacological qualities of active ingredients through increasing the hydrophilicity, stability, permeability, and targeting characteristics, further enhancing anti-cancer immunity. In this review, we summarize the mechanism of active ingredients for cancer immunomodulation, highlight nano-formulated deliveries of active ingredients for cancer immunotherapy, and provide insights into the future applications in the emerging field of nano-formulated active ingredients of CHMs. Nano-formulated active ingredients from Chinese herbal medicines demonstrate cancer immunomodulation through interacting with the innate and adaptive immune systems and modulating the microenvironment signal molecules. [Display omitted] [ABSTRACT FROM AUTHOR]
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- 2024
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18. Ginsenoside modified lipid-coated perfluorocarbon nanodroplets: A novel approach to reduce complement protein adsorption and prolong in vivo circulation.
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Zhou, Jie, Gao, Binyang, Zhang, Huan, Yang, Rui, Huang, Jianbo, Li, Xin, Zhong, Yi, Wang, Yan, Zhu, Xiaoxia, Luo, Yan, and Yan, Feng
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GINSENOSIDES ,COMPLEMENT (Immunology) ,BLOOD circulation ,COMPLEMENT activation ,COMPLEMENT inhibition ,ECULIZUMAB - Abstract
Lipid-coated perfluorocarbon nanodroplets (lp-NDs) hold great promise in bio-medicine as vehicles for drug delivery, molecular imaging and vaccine agents. However, their clinical utility is restricted by limited targeted accumulation, attributed to the innate immune system (IIS), which acts as the initial defense mechanism in humans. This study aimed to optimize lp-ND formulations to minimize non-specific clearance by the IIS. Ginsenosides (Gs), the principal components of Panax ginseng , possessing complement inhibition ability, structural similarity to cholesterol, and comparable fat solubility to phospholipids, were used as promising candidate IIS inhibitors. Two different types of ginsenoside-based lp-NDs (Gs lp-NDs) were created, and their efficacy in reducing IIS recognition was examined. The Gs lp-NDs were observed to inhibit the adsorption of C3 in the protein corona (PC) and the generation of SC5b-9. Adding Gs to lp-NDs reduced complement adsorption and phagocytosis, resulting in a longer blood circulation time in vivo compared to lp-NDs that did not contain Gs. These results suggest that Gs can act as anti-complement and anti-phagocytosis adjuvants, potentially reducing non-specific clearance by the IIS and improving lifespan. Complement C3, the corona's dominant protein, stimulates the complement cascade and promotes engulfment. Ginsenoside (Gs)-modified lp-NDs hold potential in reducing complement activation, non-specific recognition, phagocytosis, and extending circulation time. [Display omitted] [ABSTRACT FROM AUTHOR]
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- 2024
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19. Epigenetic regulation of innate immune dynamics during inflammation.
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Caldwell, Blake A and Li, Liwu
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EPIGENETICS ,IMMUNOLOGIC memory ,INFLAMMATORY mediators ,PSYCHONEUROIMMUNOLOGY ,INFLAMMATION ,NUCLEOTIDE sequence - Abstract
Innate immune cells play essential roles in modulating both immune defense and inflammation by expressing a diverse array of cytokines and inflammatory mediators, phagocytizing pathogens to promote immune clearance, and assisting with the adaptive immune processes through antigen presentation. Rudimentary innate immune "memory" states such as training, tolerance, and exhaustion develop based on the nature, strength, and duration of immune challenge, thereby enabling dynamic transcriptional reprogramming to alter present and future cell behavior. Underlying transcriptional reprogramming are broad changes to the epigenome, or chromatin alterations above the level of DNA sequence. These changes include direct modification of DNA through cytosine methylation as well as indirect modifications through alterations to histones that comprise the protein core of nucleosomes. In this review, we will discuss recent advances in our understanding of how these epigenetic changes influence the dynamic behavior of the innate immune system during both acute and chronic inflammation, as well as how stable changes to the epigenome result in long-term alterations of innate cell behavior related to pathophysiology. Review of the epigenetic pathways controlling innate immune memory and their impact on acute and chronic inflammation. [ABSTRACT FROM AUTHOR]
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- 2024
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20. Enhanced Immune Activation Following Acute Social Stress Among Adolescents With Early-Life Adversity
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Kuhlman, Kate R, Cole, Steve W, Craske, Michelle G, Fuligni, Andrew J, Irwin, Michael R, and Bower, Julienne E
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Mental Health ,Behavioral and Social Science ,Depression ,Genetics ,Basic Behavioral and Social Science ,Pediatric Research Initiative ,Neurosciences ,Pediatric ,Prevention ,2.1 Biological and endogenous factors ,Aetiology ,2.3 Psychological ,social and economic factors ,Good Health and Well Being ,Adolescence ,Early-life adversity ,Inflammation ,Innate immune system ,Social stress - Abstract
BackgroundEarly-life adversity (ELA) has been linked to higher depression risk across the life span and chronic inflammatory conditions that contribute to earlier mortality. In this study, we characterized innate immune responses to acute social stress in a community sample of adolescents (mean age = 13.9 ± 1.6 years; 46.4% female) as a potential pathway linking ELA and depression pathogenesis.MethodsParents reported their child's exposure to 9 ELAs, and adolescents participated in the Trier Social Stress Test for Children, with blood collected immediately before and then at 60 and 90 minutes thereafter. Overall, 65 adolescents had complete data for analysis of stress-induced changes in gene expression and 84 adolescents had complete data for circulating inflammatory markers.ResultsRelative to adolescents exposed to no ELA (11.9%) or low ELA (ELA = 1-3; 67.9%), those exposed to high ELA (ELA = 4+; 20.2%) showed larger stress-associated increases in expression of both proinflammatory and innate antiviral gene transcripts in circulating blood. Consistent with a potential mediating role of sympathetic nervous system activity, promoter-based bioinformatics analyses implicated CREB transcription factor activity in structuring observed gene expression differences. These effects were accompanied by a smaller initial but protracted increase in circulating interleukin 6 in adolescents with high ELA.ConclusionsResults are consistent with the hypothesis that ELA may enhance cellular and gene regulatory reactivity to stress, which may, in turn, increase vulnerability to depression and other inflammation-related disease processes.
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- 2023
21. Potential acetylcholine-based communication in honeybee haemocytes and its modulation by a neonicotinoid insecticide
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Tobias Pamminger, Kate Basley, Dave Goulson, and William O. H. Hughes
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Haemocytes ,Pesticide ,Innate immune system ,Immune regulation ,Clothianidin ,Neonicotinoid ,Medicine ,Biology (General) ,QH301-705.5 - Abstract
There is growing concern that some managed and wild insect pollinator populations are in decline, potentially threatening biodiversity and sustainable food production on a global scale. In recent years, there has been increasing evidence that sub-lethal exposure to neurotoxic, neonicotinoid pesticides can negatively affect pollinator immunocompetence and could amplify the effects of diseases, likely contributing to pollinator declines. However, a direct pathway connecting neonicotinoids and immune functions remains elusive. In this study we show that haemocytes and non-neural tissues of the honeybee Apis mellifera express the building blocks of the nicotinic acetylcholine receptors that are the target of neonicotinoids. In addition, we demonstrate that the haemocytes, which form the cellular arm of the innate immune system, actively express choline acetyltransferase, a key enzyme necessary to synthesize acetylcholine. In a last step, we show that the expression of this key enzyme is affected by field-realistic doses of clothianidin, a widely used neonicotinoid. These results support a potential mechanistic framework to explain the effects of sub-lethal doses of neonicotinoids on the immune function of pollinators.
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- 2024
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22. Human fasting modulates macrophage function and upregulates multiple bioactive metabolites that extend lifespan in Caenorhabditis elegans: a pilot clinical study
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Rhodes, Christopher H, Zhu, Chenghao, Agus, Joanne, Tang, Xinyu, Li, Qianyan, Engebrecht, JoAnne, and Zivkovic, Angela M
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Medical Biochemistry and Metabolomics ,Biomedical and Clinical Sciences ,Prevention ,Aging ,Clinical Research ,Nutrition ,Inflammatory and immune system ,Good Health and Well Being ,Animals ,Humans ,Caenorhabditis elegans ,Longevity ,Caenorhabditis elegans Proteins ,Pilot Projects ,Fasting ,Macrophages ,prolonged fasting ,fasting ,intermittent fasting ,innate immune system ,anti-inflammatory ,immunology ,lifespan ,longevity ,fasting mimetic ,macrophage ,Engineering ,Medical and Health Sciences ,Nutrition & Dietetics ,Clinical sciences ,Nutrition and dietetics - Abstract
BackgroundPeriodic prolonged fasting (PF) extends lifespan in model organisms and ameliorates multiple disease states both clinically and experimentally owing, in part, to its ability to modulate the immune system. However, the relationship between metabolic factors, immunity, and longevity during PF remains poorly characterized especially in humans.ObjectiveThis study aimed to observe the effects of PF in human subjects on the clinical and experimental markers of metabolic and immune health and uncover underlying plasma-borne factors that may be responsible for these effects.MethodsIn this rigorously controlled pilot study (ClinicalTrial.gov identifier, NCT03487679), 20 young males and females participated in a 3-d study protocol including assessments of 4 distinct metabolic states: 1) overnight fasted baseline state, 2) 2-h postprandial fed state, 3) 36-h fasted state, and 4) final 2-h postprandial re-fed state 12 h after the 36-h fasting period. Clinical and experimental markers of immune and metabolic health were assessed for each state along with comprehensive metabolomic profiling of participant plasma. Bioactive metabolites identified to be upregulated in circulation after 36 h of fasting were then assessed for their ability to mimic the effects of fasting in isolated human macrophage as well as the ability to extend lifespan in Caenorhabditis elegans.ResultsWe showed that PF robustly altered the plasma metabolome and conferred beneficial immunomodulatory effects on human macrophages. We also identified 4 bioactive metabolites that were upregulated during PF (spermidine, 1-methylnicotinamide, palmitoylethanolamide, and oleoylethanolamide) that could replicate these immunomodulatory effects. Furthermore, we found that these metabolites and their combination significantly extended the median lifespan of C. elegans by as much as 96%.ConclusionsThe results of this study reveal multiple functionalities and immunological pathways affected by PF in humans, identify candidates for the development of fasting mimetic compounds, and uncover targets for investigation in longevity research.
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- 2023
23. Changes in Neuroimmunological Synapses During Cerebral Ischemia
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Bitar, Lynn, Puig, Berta, Oertner, Thomas G., Dénes , Ádám, and Magnus, Tim
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- 2024
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24. Immunologische Grundlagen neurologischer Erkrankungen
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Schild, Hansjörg and Bopp, Tobias
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- 2024
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25. Response of the mosquito immune system and symbiotic bacteria to pathogen infection
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Manjin Li, Yang Zhou, Jin Cheng, Yiqing Wang, Cejie Lan, and Yuan Shen
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Mosquito ,Pathogen infection ,Innate immune system ,Immune priming ,Symbiotic bacteria ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Mosquitoes are the deadliest animal in the word, transmitting a variety of insect-borne infectious diseases, such as malaria, dengue fever, yellow fever, and Zika, causing more deaths than any other vector-borne pathogen. Moreover, in the absence of effective drugs and vaccines to prevent and treat insect-borne diseases, mosquito control is particularly important as the primary measure. In recent decades, due to the gradual increase in mosquito resistance, increasing attention has fallen on the mechanisms and effects associated with pathogen infection. This review provides an overview of mosquito innate immune mechanisms in terms of physical and physiological barriers, pattern recognition receptors, signalling pathways, and cellular and humoral immunity, as well as the antipathogenic effects of mosquito symbiotic bacteria. This review contributes to an in-depth understanding of the interaction process between mosquitoes and pathogens and provides a theoretical basis for biological defence strategies against mosquito-borne infectious diseases. Graphical Abstract
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- 2024
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26. An Exploratory Study of Early Immune Response Markers for Pembrolizumab in Urothelial Tract Cancer
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Dag Rune Stormoen, Lise Høj Omland, Kent William Mouw, Zoltan Szallasi, Sisse Rye Ostrowski, Susanne Dam Nielsen, and Helle Pappot
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urinary tract carcinoma ,bladder cancer ,immunotherapy ,response markers ,innate immune system ,trueculture ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Background: This prospective pilot study explored the potential of the innate immune system’s response to cancer-related immuno-stimulants as a predictive biomarker for Immune Checkpoint Inhibitor (ICI) effectiveness, using pembrolizumab-treated metastatic urothelial tract cancer (mUTC) patients as the study population. Methods: We included ten mUTC patients and assessed their innate immune responses before the first and second pembrolizumab cycles with the TruCulture® immunoassay. We also executed survival analysis and compared cytokine release. Results: R848-induced IFNα and HKCA-induced IL-10 values decreased in patients with disease progression (n = 7), while these values increased in non-progressing patients (n = 3), denoting a significant difference (p = 0.00192 and p = 0.00343, respectively). Further, an increased R848-induced IFNα response correlated with extended survival (log-rank p-value of 0.048). Conclusion: Our small study identified distinct immune response patterns following pembrolizumab’s first cycle in mUTC patients, hypothesizing the potential of an increased R848-induced IFNα response for improved survival outcomes. Further confirmatory studies are in progress.
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- 2024
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27. Molecular Profiling of Axial Spondyloarthritis Patients Reveals an Association between Innate and Adaptive Cell Populations and Therapeutic Response to Tumor Necrosis Factor Inhibitors.
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Sobral, Daniel, Fernandes, Ana Filipa, Bernardes, Miguel, Pinto, Patrícia, Santos, Helena, Lagoas-Gomes, João, Tavares-Costa, José, Silva, José A. P., Dias, João Madruga, Bernardo, Alexandra, Gaillard, Jean-Charles, Armengaud, Jean, Benes, Vladimir, Domingues, Lúcia, Maia, Sara, Branco, Jaime C., Coelho, Ana Varela, and Pimentel-Santos, Fernando M.
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- *
TUMOR necrosis factors , *SPONDYLOARTHROPATHIES , *CELL populations , *HAPTOGLOBINS , *BLOOD proteins , *GENE expression - Abstract
This study aims at identifying molecular biomarkers differentiating responders and non-responders to treatment with Tumor Necrosis Factor inhibitors (TNFi) among patients with axial spondyloarthritis (axSpA). Whole blood mRNA and plasma proteins were measured in a cohort of biologic-naïve axSpA patients (n = 35), pre and post (14 weeks) TNFi treatment with adalimumab. Differential expression analysis was used to identify the most enriched pathways and in predictive models to distinguish responses to TNFi. A treatment-associated signature suggests a reduction in inflammatory activity. We found transcripts and proteins robustly differentially expressed between baseline and week 14 in responders. C-reactive protein (CRP) and Haptoglobin (HP) proteins showed strong and early decrease in the plasma of axSpA patients, while a cluster of apolipoproteins (APOD, APOA2, APOA1) showed increased expression at week 14. Responders to TNFi treatment present higher levels of markers of innate immunity at baseline, and lower levels of adaptive immunity markers, particularly B-cells. A logistic regression model incorporating ASDAS-CRP, gender, and AFF3, the top differentially expressed gene at baseline, enabled an accurate prediction of response to adalimumab in our cohort (AUC = 0.97). In conclusion, innate and adaptive immune cell type composition at baseline may be a major contributor to response to adalimumab in axSpA patients. A model including clinical and gene expression variables should also be considered. [ABSTRACT FROM AUTHOR]
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- 2024
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28. Metagenomic insights into the differences in gastrointestinal microbe-mediated metabolism and immunity between wild and captive spotted seals (Phoca largha).
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Wang, Zhen, Lu, Zhichuang, Li, Duohui, Gao, Xianggang, Liu, Baozhan, Xing, Yankuo, Guan, Xiaoyan, Sanganyado, Edmond, and Tian, Jiashen
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- *
MAMMAL conservation , *METAGENOMICS , *ESCHERICHIA coli , *GUT microbiome , *MARINE mammals , *VITAMIN B1 , *METABOLISM - Abstract
Understanding metabolic and immune functional genes in the gut microbiota of sentinel species, such as spotted seals (Phoca largha), is essential for assessing the health of marine mammals and improving conservation strategies. Information on the gut microbiome is essential for improving conditions in captive species thus aiding in pinniped population restoration, however, it remains poorly understood. In this study, the microbiota in feces from wild and captive P. largha obtained from Liaodong Bay and an aquarium in China were analyzed using metagenomic sequencing. The results showed significant differences in the diversity, composition, and function of gut microbiota between wild and captive P. largha. The bacteria responsible for rapid absorption of energy to product body fat, Firmicutes, were more abundant in the gut microbiota of wild P. largha than in captives. Stronger biosynthesis abilities of nutrients and innate immune factors were observed in the gut microbiota of wild P. largha compared to captive samples. Regarding biomolecules (volatile fatty acids, amino acids vitamins, and several innate immune factors), only the biosynthesis of vitamin B1, secondary bile acids, and a few amino acids were significantly higher in the gut microbiota of the captive P. largha. E. coli, and genera of Bradyrhizobium, Bacteroides, and Rhodanobacter were the dominant biosynthesis functional bacteria in wild P. largha. Overall, these findings showed that wild P. largha had better health status compared to captive species; more importantly, they provide critical data for the development of effective strategies to enhance the growth and health of pinnipeds in captive environments. [ABSTRACT FROM AUTHOR]
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- 2024
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29. An Exploratory Study of Early Immune Response Markers for Pembrolizumab in Urothelial Tract Cancer.
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Stormoen, Dag Rune, Omland, Lise Høj, Mouw, Kent William, Szallasi, Zoltan, Ostrowski, Sisse Rye, Nielsen, Susanne Dam, and Pappot, Helle
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- *
TRANSITIONAL cell carcinoma , *BIOMARKERS , *IMMUNE response , *IMMUNE checkpoint inhibitors , *PEMBROLIZUMAB - Abstract
Background: This prospective pilot study explored the potential of the innate immune system's response to cancer-related immuno-stimulants as a predictive biomarker for Immune Checkpoint Inhibitor (ICI) effectiveness, using pembrolizumab-treated metastatic urothelial tract cancer (mUTC) patients as the study population. Methods: We included ten mUTC patients and assessed their innate immune responses before the first and second pembrolizumab cycles with the TruCulture® immunoassay. We also executed survival analysis and compared cytokine release. Results: R848-induced IFNα and HKCA-induced IL-10 values decreased in patients with disease progression (n = 7), while these values increased in non-progressing patients (n = 3), denoting a significant difference (p = 0.00192 and p = 0.00343, respectively). Further, an increased R848-induced IFNα response correlated with extended survival (log-rank p-value of 0.048). Conclusion: Our small study identified distinct immune response patterns following pembrolizumab's first cycle in mUTC patients, hypothesizing the potential of an increased R848-induced IFNα response for improved survival outcomes. Further confirmatory studies are in progress. [ABSTRACT FROM AUTHOR]
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- 2024
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30. Response of the mosquito immune system and symbiotic bacteria to pathogen infection.
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Li, Manjin, Zhou, Yang, Cheng, Jin, Wang, Yiqing, Lan, Cejie, and Shen, Yuan
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MOSQUITO control , *IMMUNE system , *PATTERN perception receptors , *IMMUNE response , *YELLOW fever , *PATHOGENIC microorganisms - Abstract
Mosquitoes are the deadliest animal in the word, transmitting a variety of insect-borne infectious diseases, such as malaria, dengue fever, yellow fever, and Zika, causing more deaths than any other vector-borne pathogen. Moreover, in the absence of effective drugs and vaccines to prevent and treat insect-borne diseases, mosquito control is particularly important as the primary measure. In recent decades, due to the gradual increase in mosquito resistance, increasing attention has fallen on the mechanisms and effects associated with pathogen infection. This review provides an overview of mosquito innate immune mechanisms in terms of physical and physiological barriers, pattern recognition receptors, signalling pathways, and cellular and humoral immunity, as well as the antipathogenic effects of mosquito symbiotic bacteria. This review contributes to an in-depth understanding of the interaction process between mosquitoes and pathogens and provides a theoretical basis for biological defence strategies against mosquito-borne infectious diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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31. The Differential Effect of a Shortage of Thyroid Hormone Compared with Knockout of Thyroid Hormone Transporters Mct8 and Mct10 on Murine Macrophage Polarization.
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Hoen, Esmée, Goossens, Franka M., Falize, Kim, Mayerl, Steffen, van der Spek, Anne H., and Boelen, Anita
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THYROID hormones , *MACROPHAGES , *THYROID hormone receptors , *IMMUNE system , *ENDOCRINE system , *TRIIODOTHYRONINE , *SCARCITY - Abstract
Innate immune cells, including macrophages, are functionally affected by thyroid hormone (TH). Macrophages can undergo phenotypical alterations, shifting between proinflammatory (M1) and immunomodulatory (M2) profiles. Cellular TH concentrations are, among others, determined by TH transporters. To study the effect of TH and TH transporters on macrophage polarization, specific proinflammatory and immunomodulatory markers were analyzed in bone marrow-derived macrophages (BMDMs) depleted of triiodothyronine (T3) and BMDMs with a knockout (KO) of Mct8 and Mct10 and a double KO (dKO) of Mct10/Mct8. Our findings show that T3 is important for M1 polarization, while a lack of T3 stimulates M2 polarization. Mct8 KO BMDMs are unaffected in their T3 responsiveness, but exhibit slight alterations in M2 polarization, while Mct10 KO BMDMs show reduced T3 responsiveness, but unaltered polarization markers. KO of both the Mct8 and Mct10 transporters decreased T3 availability and, contrary to the T3-depleted BMDMs, showed partially increased M1 markers and unaltered M2 markers. These data suggest a role for TH transporters besides transport of TH in BMDMs. This study highlights the complex role of TH transporters in macrophages and provides a new angle on the interaction between the endocrine and immune systems. [ABSTRACT FROM AUTHOR]
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- 2024
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32. Effects of immune exhaustion and senescence of innate immunity in autoimmune disorders
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A.L.S. Cunha and S.F. Perazzio
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Immune exhaustion ,Immune senescence ,Innate immune system ,Autoimmunity and immunology ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Innate immune system activation is crucial in the inflammatory response, but uncontrolled activation can lead to autoimmune diseases. Cellular exhaustion and senescence are two processes that contribute to innate immune tolerance breakdown. Exhausted immune cells are unable to respond adequately to specific antigens or stimuli, while senescent cells have impaired DNA replication and metabolic changes. These processes can impair immune system function and disrupt homeostasis, leading to the emergence of autoimmunity. However, the influence of innate immune exhaustion and senescence on autoimmune disorders is not well understood. This review aims to describe the current findings on the role of innate immune exhaustion and senescence in autoimmunity, focusing on the cellular and molecular changes involved in each process. Specifically, the article explores the markers and pathways associated with immune exhaustion, such as PD-1 and TIM-3, and senescence, including Β-galactosidase (β-GAL), lamin B1, and p16ink4a, and their impact on autoimmune diseases, namely type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, and immune-mediated myopathies. Understanding the mechanisms underlying innate immune exhaustion and senescence in autoimmunity may provide insights for the development of novel therapeutic strategies.
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- 2024
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33. Bacterial metallothionein, PmtA, a novel stress protein found on the bacterial surface of Pseudomonas aeruginosa and involved in management of oxidative stress and phagocytosis
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Michele Maltz-Matyschsyk, Clare K. Melchiorre, David A. Knecht, and Michael A. Lynes
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Pseudomonas aeruginosa ,bacterial metallothionein ,innate immune system ,phagocytosis ,oxidative stress ,Microbiology ,QR1-502 - Abstract
ABSTRACT Metallothioneins (MTs) are small cysteine-rich proteins that play important roles in homeostasis and protection against heavy metal toxicity and oxidative stress. The opportunistic pathogen, Pseudomonas aeruginosa, expresses a bacterial MT known as PmtA. Utilizing genetically modified P. aeruginosa PAO1 strains (a human clinical wound isolate), we show that inducing pmtA increases levels of pyocyanin and biofilm compared to other PAO1 isogenic strains, supporting previous results that pmtA is important for pyocyanin and biofilm production. We also show that overexpression of pmtA in vitro provides protection for cells exposed to oxidants, which is a characteristic of inflammation, indicating a role for PmtA as an antioxidant in inflammation. We found that a pmtA clean deletion mutant is phagocytized faster than other PAO1 isogenic strains in THP-1 human macrophage cells, indicating that PmtA provides protection from the phagocytic attack. Interestingly, we observed that monoclonal anti-PmtA antibody binds to PmtA, which is accessible on the surface of PAO1 strains using both flow cytometry and enzyme-linked immunosorbent assay techniques. Finally, we investigated intracellular persistence of these PAO1 strains within THP-1 macrophages cells and found that the phagocytic endurance of PAO1 strains is affected by pmtA expression. These data show for the first time that a bacterial MT (pmtA) can play a role in the phagocytic process and can be found on the outer surface of PAO1. Our results suggest that PmtA plays a role both in protection from oxidative stress and in the resistance to the host’s innate immune response, identifying PmtA as a potential therapeutic target in P. aeruginosa infection.IMPORTANCEThe pathogen Pseudomonas aeruginosa is a highly problematic multidrug-resistant (MDR) pathogen with complex virulence networks. MDR P. aeruginosa infections have been associated with increased clinical visits, very poor healthcare outcomes, and these infections are ranked as critical on priority lists of both the Centers for Disease Control and Prevention and the World Health Organization. Known P. aeruginosa virulence factors have been extensively studied and are implicated in counteracting host defenses, causing direct damage to the host tissues, and increased microbial competitiveness. Targeting virulence factors has emerged as a new line of defense in the battle against MDR P. aeruginosa strains. Bacterial metallothionein is a newly recognized virulence factor that enables evasion of the host immune response. The studies described here identify mechanisms in which bacterial metallothionein (PmtA) plays a part in P. aeruginosa pathogenicity and identifies PmtA as a potential therapeutic target.
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- 2024
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34. Fish oil supplementation in obese rats ameliorates metabolic syndrome response
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D.M.B. Freitas, B.A.C. Oliveira, L.D.V. Henschel, M.H.A.P.C. Oliveira, M. Zazula, E. Horlem, D.F.S. Rodriguez, S.R.S. Carvalhal, F. Iagher, R. Fernandez, K. Naliwaiko, and L.C. Fernandes
- Subjects
Obesity ,Metabolic syndrome ,Innate immune system ,Adiposity ,Metabolism ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Accumulation of visceral adipose tissue is associated with metabolic syndrome (MS), insulin resistance, and dyslipidemia. Here we examined several morphometric and biochemical parameters linked to MS in a rodent litter size reduction model, and how a 30-day fish oil (FO) supplementation affected these parameters. On day 3 post-birth, pups were divided into groups of ten or three. On day 22, rats were split into control (C) and small litter (SL) until 60 days old. Then, after metabolic disturbance and obesity were confirmed, FO supplementation started for 30 days and the new groups were named control (C), FO supplemented (FO), obese (Ob), and obese FO supplemented (ObFO). Comparison was performed by Student t-test or 2-way ANOVA followed by Tukey post hoc test. At the end of the 60-day period, SL rats were hyperphagic, obese, hypoinsulinemic, normoglycemic, and had high visceral fat depot and high interleukin (IL)-6 plasma concentration. Obese rats at 90 days of age were fatter, hyperphagic, hyperglycemic, hypertriacylgliceromic, hipoinsulinemic, with low innate immune response. IL-6 production ex vivo was higher, but in plasma it was not different from the control group. FO supplementation brought all biochemical changes to normal values, normalized food intake, and reduced body weight and fat mass in obese rats. The innate immune response was improved but still not as efficient as in lean animals. Our results suggested that as soon MS appears, FO supplementation must be used to ameliorate the morpho- and biochemical effects caused by MS and improve the innate immune response.
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- 2024
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35. A potential immunotherapy target for breast cancer: parenchymal and immune-stromal expression of the NLRP3 inflammasome pathway
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Qian-mei Zhu, Hui-xian Li, Pei-qing Ma, Lin-xin Wu, Tai-hang Wang, Wen-bin Li, Lin Zhang, Xue Yang, Xiangyi Kong, Yu-lin Sun, and Tao Yan
- Subjects
NLRP3 inflammasome ,Innate immune system ,Caspase-1 ,ASC ,Breast cancer ,Prognosis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background The NOD-, LRR- and pyrin domain‑containing 3 (NLRP3) inflammasome is a critical component of the innate immune system. It has been known to play an important role in the carcinogenesis and prognosis of breast cancer patients. While the clinical evidence of the relationship between NLRP3 inflammasome activation and long-term survival is still limited, the possible roles of parenchymal or immune-stromal cells of breast cancer tissues in contributing to such carcinogenesis and progression still need to be clarified. This study is an analysis of patients receiving breast cancer surgery in a previous clinical trial. Methods Immunohistochemistry (IHC) was used to detect the expression levels of NLRP3 inflammasome pathway-related proteins, including NLRP3, caspase-1, apoptosis-associated speck-like protein (ASC), IL-1β, and IL-18, in parenchymal and immune-stromal cells of breast cancer tissues compared to those of adjacent normal tissues, respectively. The relationship between NLRP3 inflammasome expression and clinicopathological characteristics, as well as 5-year survivals were analyzed using the Chi-square test, Kaplan–Meier survival curves, and Cox regression analysis. Results In the parenchymal cells, ASC and IL-18 protein levels were significantly up-regulated in breast cancer tissues compared with adjacent normal tissues (P
- Published
- 2023
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36. Molecular Bases and Specificity behind the Activation of the Immune System OAS/RNAse L Pathway by Viral RNA
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Emma Jung-Rodriguez, Florent Barbault, Emmanuelle Bignon, and Antonio Monari
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innate immune system ,oligoadenylate synthase ,RNA viruses ,molecular dynamics ,free energy profiles ,Microbiology ,QR1-502 - Abstract
The first line of defense against invading pathogens usually relies on innate immune systems. In this context, the recognition of exogenous RNA structures is primordial to fight, notably, against RNA viruses. One of the most efficient immune response pathways is based on the sensing of RNA double helical motifs by the oligoadenylate synthase (OAS) proteins, which in turn triggers the activity of RNase L and, thus, cleaves cellular and viral RNA. In this contribution, by using long-range molecular dynamics simulations, complemented with enhanced sampling techniques, we elucidate the structural features leading to the activation of OAS by interaction with a model double-strand RNA oligomer mimicking a viral RNA. We characterize the allosteric regulation induced by the nucleic acid leading to the population of the active form of the protein. Furthermore, we also identify the free energy profile connected to the active vs. inactive conformational transitions in the presence and absence of RNA. Finally, the role of two RNA mutations, identified as able to downregulate OAS activation, in shaping the protein/nucleic acid interface and the conformational landscape of OAS is also analyzed.
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- 2024
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37. Inflammatory and Immune Mechanisms for Atherosclerotic Cardiovascular Disease in HIV
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Laura Hmiel, Suyu Zhang, Laventa M. Obare, Marcela Araujo de Oliveira Santana, Celestine N. Wanjalla, Boghuma K. Titanji, Corrilynn O. Hileman, and Shashwatee Bagchi
- Subjects
atherosclerosis ,HIV ,inflammation ,immune system ,innate immune system ,adaptive immune system ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Atherosclerotic vascular disease disproportionately affects persons living with HIV (PLWH) compared to those without. The reasons for the excess risk include dysregulated immune response and inflammation related to HIV infection itself, comorbid conditions, and co-infections. Here, we review an updated understanding of immune and inflammatory pathways underlying atherosclerosis in PLWH, including effects of viral products, soluble mediators and chemokines, innate and adaptive immune cells, and important co-infections. We also present potential therapeutic targets which may reduce cardiovascular risk in PLWH.
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- 2024
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38. Myocarditis following COVID-19 vaccination: incidence, mechanisms, and clinical considerations
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Power, John R, Keyt, Lucas K, and Adler, Eric D
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Biotechnology ,Vaccine Related ,Clinical Research ,Prevention ,Immunization ,Prevention of disease and conditions ,and promotion of well-being ,3.4 Vaccines ,Infection ,Good Health and Well Being ,COVID-19 ,COVID-19 Vaccines ,Humans ,Incidence ,Male ,Myocarditis ,SARS-CoV-2 ,Vaccination ,vaccine ,incidence ,molecular mimicry ,innate immune system ,in vitro transcribed mRNA ,clinical ,Cardiorespiratory Medicine and Haematology ,Public Health and Health Services ,Cardiovascular System & Hematology - Abstract
IntroductionVaccines have demonstrated protection against the morbidity and mortality of COVID-19, but concerns regarding the rare side effect of acute myocarditis have stymied immunization efforts. This review aims to describe the incidence and theorized mechanisms of COVID vaccine-associated myocarditis and review relevant principles for management of vaccine-associated myocarditis.Areas coveredEpidemiologic studies of myocarditis after COVID vaccination are reviewed, which show an incidence of approximately 20-30 per million patients. The vast majority of these cases are seen with mRNA vaccines especially in male patients under 30 years of age. Mechanisms are largely theoretical, but molecular mimicry and dysregulated innate immune reactions have been proposed. While studies suggest that this subtype of myocarditis is mild and self-limited, long-term evidence is lacking. Principles of myocarditis treatment and surveillance are outlined as they apply to COVID vaccine-associated myocarditis.Expert opinionCOVID vaccine-associated myocarditis is rare but well described in certain at-risk groups. Better understanding of its pathogenesis is key to mitigating this complication and advancing vaccination efforts. Risk-benefit analyses demonstrate that individual- and population-level benefits of vaccination exceed the risks of this rare and mild form of myocarditis.
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- 2022
39. Assembly and activation of the C1 complex of complement
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Jones, Laura C.
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Complement ,Innate immune system ,C1 Complex ,Hexameric protein ,Polypeptide chains ,Antigen-antibody complexes ,Intramolecular model ,Intermolecular model ,Molecular and Cellular Biology ,Homodimers ,Collagen triple helix ,Thesis - Abstract
Complement is an essential component of the innate immune system. The classical pathway of complement activation is initiated by the 774 kDa C1 complex. The C1 complex comprises two C1r and two C1s serine proteases, synthesised as zymogens and arranged as a C1s-C1r-C1r-C1s, Ca2+ dependent, heterotetramer bound to the centre of one C1q molecule. C1q is a hexameric protein formed from six copies of three different polypeptide chains, designated A, B and C, with a bouquet-like architecture. The C1 complex is activated upon interaction with an activating surface such as antigen-antibody complexes, leading to auto-activation of C1r followed by activation of C1s. Two contrasting models have been proposed to explain how the C1 complex assembles and activates; the intramolecular model in which activation is driven by separation and subsequent activation of C1r polypeptides when C1 binds to an activating surface, and the intermolecular model whereby C1r polypeptides separate upon binding to C1q, and neighbouring C1 complexes activate each other. In this project, I investigated how C1 assembles, and initiates complement activation at the molecular level. I created stable C1r homodimers by incorporating a disulphide bond at the C1r-C1r interface that prevents the separation of the polypeptides. I showed that these modified C1r molecules could be incorporated into the C1r2C1s2 tetramer and the C1 complex, determining that C1r polypeptides do not need to separate upon binding to C1q and hence providing evidence to support the intramolecular activation mechanism of C1. Alongside these findings, I have solved several crystal structures of a fragment of C1s in complex with collagen-like peptides derived from the A, B and C polypeptide chains of C1q. The chains of the collagen triple helix of C1q are staggered, creating a leading, middle, and lagging strand, but the order of these chains was unknown until now. From these structures, I propose that C1qB forms the leading strand, C1qA forms the middle strand, and C1qC forms the lagging strand of C1q.
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- 2022
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40. Trafficking and effect of released DNA on cGAS-STING signaling pathway and cardiovascular disease.
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Zimo Zhou, Changhan Ou-yang, Qingjie Chen, Zhanhong Ren, Xiying Guo, Min Lei, Chao Liu, and Xiaosong Yang
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CELLULAR signal transduction ,DNA ,CARDIOVASCULAR diseases ,INFLAMMATION ,TYPE I interferons ,NUCLEIC acids ,PATTERN perception receptors ,EXONUCLEASES - Abstract
Evidence from clinical research and animal studies indicates that inflammation is an important factor in the occurrence and development of cardiovascular disease (CVD). Emerging evidence shows that nucleic acids serve as crucial pathogen-associated molecular patterns (PAMPs) or noninfectious damage-associated molecular patterns (DAMPs), are released and then recognized by pattern recognition receptors (PRRs), which activates immunological signaling pathways for host defense. Mechanistically, the released nucleic acids activate cyclic GMP-AMP synthase (cGAS) and its downstream receptor stimulator of interferon genes (STING) to promote type I interferons (IFNs) production, which play an important regulatory function during the initiation of an innate immune response to various diseases, including CVD. This pathway represents an essential defense regulatory mechanism in an organism’s innate immune system. In this review, we outline the overall profile of cGAS-STING signaling, summarize the latest findings on nucleic acid release and trafficking, and discuss their potential role in CVD. This review also sheds light on potential directions for future investigations on CVD. [ABSTRACT FROM AUTHOR]
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- 2023
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41. Roles of inflammatory cell infiltrate in periprosthetic osteolysis.
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Panez-Toro, Isidora, Heymann, Dominique, Gouin, François, Amiaud, Jérôme, Heymann, Marie-Françoise, and Córdova, Luis A.
- Subjects
MULTINUCLEATED giant cells ,BONE resorption ,ARTHROPLASTY ,OSTEOCLASTS ,ORTHOPEDIC implants ,ARTIFICIAL joints ,JOINT infections ,PERIPROSTHETIC fractures ,INTERLEUKIN-21 - Abstract
Classically, particle-induced periprosthetic osteolysis at the implant-bone interface has explained the aseptic loosening of joint replacement. This response is preceded by triggering both the innate and acquired immune response with subsequent activation of osteoclasts, the bone-resorbing cells. Although particle-induced periprosthetic osteolysis has been considered a foreign body chronic inflammation mediated by myelomonocytic-derived cells, current reports describe wide heterogeneous inflammatory cells infiltrating the periprosthetic tissues. This review aims to discuss the role of those non-myelomonocytic cells in periprosthetic tissues exposed to wear particles by showing original data. Specifically, we discuss the role of T cells (CD3
+ , CD4+ , and CD8+ ) and B cells (CD20+ ) coexisting with CD68+ /TRAP- multinucleated giant cells associated with both polyethylene and metallic particles infiltrating retrieved periprosthetic membranes. This review contributes valuable insight to support the complex cell and molecular mechanisms behind the aseptic loosening theories of orthopedic implants. [ABSTRACT FROM AUTHOR]- Published
- 2023
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42. Immunology of amyotrophic lateral sclerosis - role of the innate and adaptive immunity.
- Author
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Mimic, Stefan, Aru, Başak, Pehlivanoğlu, Cemil, Sleiman, Hadi, Andjus, Pavle R., and Demirel, Gülderen Yanıkkaya
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AMYOTROPHIC lateral sclerosis ,NATURAL immunity ,KILLER cells ,IMMUNOLOGY ,IMMUNE system - Abstract
This review aims to summarize the latest evidence about the role of innate and adaptive immunity in Amyotrophic Lateral Sclerosis (ALS). ALS is a devastating neurodegenerative disease affecting upper and lower motor neurons, which involves essential cells of the immune system that play a basic role in innate or adaptive immunity, that can be neurotoxic or neuroprotective for neurons. However, distinguishing between the sole neurotoxic or neuroprotective function of certain cells such as astrocytes can be challenging due to intricate nature of these cells, the complexity of the microenvironment and the contextual factors. In this review, in regard to innate immunity we focus on the involvement of monocytes/macrophages, microglia, the complement, NK cells, neutrophils, mast cells, and astrocytes, while regarding adaptive immunity, in addition to humoral immunity the most important features and roles of T and B cells are highlighted, specifically different subsets of CD4
+ as well as CD8+ T cells. The role of autoantibodies and cytokines is also discussed in distinct sections of this review. [ABSTRACT FROM AUTHOR]- Published
- 2023
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43. Immunotherapies inducing immunogenic cell death in cancer: insight of the innate immune system.
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Calvillo-Rodríguez, Kenny Misael, Lorenzo-Anota, Helen Yarimet, Rodríguez-Padilla, Cristina, Martínez-Torres, Ana Carolina, and Scott-Algara, Daniel
- Subjects
IMMUNE system ,CELL death ,IMMUNOLOGIC memory ,CANCER cells ,PATTERN perception receptors - Abstract
Cancer immunotherapies include monoclonal antibodies, cytokines, oncolytic viruses, cellular therapies, and other biological and synthetic immunomodulators. These are traditionally studied for their effect on the immune system’s role in eliminating cancer cells. However, some of these therapies have the unique ability to directly induce cytotoxicity in cancer cells by inducing immunogenic cell death (ICD). Unlike general immune stimulation, ICD triggers specific therapy-induced cell death pathways, based on the release of damage-associated molecular patterns (DAMPs) from dying tumour cells. These activate innate pattern recognition receptors (PRRs) and subsequent adaptive immune responses, offering the promise of sustained anticancer drug efficacy and durable antitumour immune memory. Exploring how onco-immunotherapies can trigger ICD, enhances our understanding of their mechanisms and potential for combination strategies. This review explores the complexities of these immunotherapeutic approaches that induce ICD, highlighting their implications for the innate immune system, addressing challenges in cancer treatment, and emphasising the pivotal role of ICD in contemporary cancer research. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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44. Innate Immunity and CKD: Is There a Significant Association?
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Plonsky-Toder, Moran, Magen, Daniella, and Pollack, Shirley
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- *
NATURAL immunity , *CHRONIC kidney failure , *THERAPEUTICS , *RENAL replacement therapy , *CARDIOVASCULAR diseases - Abstract
Chronic kidney disease (CKD) constitutes a worldwide epidemic, affecting approximately 10% of the global population, and imposes significant medical, psychological, and financial burdens on society. Individuals with CKD often face elevated morbidity and mortality rates, mainly due to premature cardiovascular events. Chronic inflammation has been shown to play a significant role in the progression of CKD, as well as in the acceleration of CKD-related complications, including atherosclerosis, cardiovascular disease (CVD), protein–energy wasting, and the aging process. Over the past two decades, a substantial body of evidence has emerged, identifying chronic inflammation as a central element of the uremic phenotype. Chronic inflammation has been shown to play a significant role in the progression of CKD, as well as in the acceleration of CKD-related complications in dialysis patients, including atherosclerosis, CVD, protein–energy wasting, and the aging process. Remarkably, chronic inflammation also impacts patients with CKD who have not yet required renal replacement therapy. While extensive research has been conducted on the involvement of both the adaptive and innate immune systems in the pathogenesis of CKD-related complications, this wealth of data has not yet yielded well-established, effective treatments to counteract this ongoing pathological process. In the following review, we will examine the established components of the innate immune system known to be activated in CKD and provide an overview of the current therapeutic approaches designed to mitigate CKD-related chronic inflammation. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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45. A potential immunotherapy target for breast cancer: parenchymal and immune-stromal expression of the NLRP3 inflammasome pathway.
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Zhu, Qian-mei, Li, Hui-xian, Ma, Pei-qing, Wu, Lin-xin, Wang, Tai-hang, Li, Wen-bin, Zhang, Lin, Yang, Xue, Kong, Xiangyi, Sun, Yu-lin, and Yan, Tao
- Subjects
- *
IMMUNOTHERAPY , *HUMAN carcinogenesis , *NLRP3 protein , *CANCER cell growth , *INFLAMMASOMES , *BREAST cancer , *BREAST cancer surgery , *PROPORTIONAL hazards models - Abstract
Background: The NOD-, LRR- and pyrin domain‑containing 3 (NLRP3) inflammasome is a critical component of the innate immune system. It has been known to play an important role in the carcinogenesis and prognosis of breast cancer patients. While the clinical evidence of the relationship between NLRP3 inflammasome activation and long-term survival is still limited, the possible roles of parenchymal or immune-stromal cells of breast cancer tissues in contributing to such carcinogenesis and progression still need to be clarified. This study is an analysis of patients receiving breast cancer surgery in a previous clinical trial. Methods: Immunohistochemistry (IHC) was used to detect the expression levels of NLRP3 inflammasome pathway-related proteins, including NLRP3, caspase-1, apoptosis-associated speck-like protein (ASC), IL-1β, and IL-18, in parenchymal and immune-stromal cells of breast cancer tissues compared to those of adjacent normal tissues, respectively. The relationship between NLRP3 inflammasome expression and clinicopathological characteristics, as well as 5-year survivals were analyzed using the Chi-square test, Kaplan–Meier survival curves, and Cox regression analysis. Results: In the parenchymal cells, ASC and IL-18 protein levels were significantly up-regulated in breast cancer tissues compared with adjacent normal tissues (P<0.05). In the immune-stromal cells, all the five NLRP3 inflammasome pathway-related proteins were significantly elevated in breast cancer tissues compared with adjacent normal tissues (P < 0.05). Carcinoma cell embolus was found to significantly correlate with high NLRP3 expression in parenchymal cells of the tumor (x2=4.592, P=0.032), while the expression of caspase-1 was negatively correlated with tumor progression. Histological grades were found to have a positive correlation with IL-18 expression in immune-stromal cells of the tumor (x2=14.808, P=0.001). Kaplan–Meier survival analysis revealed that high IL-18 expression in the immune-stromal cells and the positive carcinoma cell embolus were both associated with poor survival (P < 0.05). The multivariable Cox proportional hazards regression model implied that the high IL-18 expression and positive carcinoma cell embolus were both independent risk factors for unfavorable prognosis. Conclusions: The activation of NLRP3 inflammasome pathways in immune-stromal and tumor parenchymal cells in the innate immune system was not isotropic and the main functions are somewhat different in breast cancer patients. Caspase-1 in parenchymal cells of the tumor was negatively correlated with tumor progression, and upregulation of IL-18 in immune-stromal cells of breast cancer tissues is a promising prognostic biomarker and a potential immunotherapy target. Trial registration: This clinical trial has been registered at the Chictr.org.cn registry system on 21/08/2018 (ChiCTR1800017910) [ABSTRACT FROM AUTHOR]
- Published
- 2023
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46. Host Defense Proteins and Peptides with Lipopolysaccharide-Binding Activity from Marine Invertebrates and Their Therapeutic Potential in Gram-Negative Sepsis.
- Author
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Solov'eva, Tamara Fedorovna, Bakholdina, Svetlana Ivanovna, and Naberezhnykh, Gennadii Alexandrovich
- Abstract
Sepsis is a life-threatening complication of an infectious process that results from the excessive and uncontrolled activation of the host's pro-inflammatory immune response to a pathogen. Lipopolysaccharide (LPS), also known as endotoxin, which is a major component of Gram-negative bacteria's outer membrane, plays a key role in the development of Gram-negative sepsis and septic shock in humans. To date, no specific and effective drug against sepsis has been developed. This review summarizes data on LPS-binding proteins from marine invertebrates (ILBPs) that inhibit LPS toxic effects and are of interest as potential drugs for sepsis treatment. The structure, physicochemical properties, antimicrobial, and LPS-binding/neutralizing activity of these proteins and their synthetic analogs are considered in detail. Problems that arise during clinical trials of potential anti-endotoxic drugs are discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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47. Targeting the Heterogeneous Tumour-Associated Macrophages in Hepatocellular Carcinoma.
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Agirre-Lizaso, Aloña, Huici-Izagirre, Maider, Urretabizkaia-Garmendia, Josu, Rodrigues, Pedro M., Banales, Jesus M., and Perugorria, Maria J.
- Subjects
- *
CANCER cell culture , *NATURAL immunity , *DISEASE progression , *MACROPHAGES , *HEPATOCELLULAR carcinoma , *IMMUNOTHERAPY - Abstract
Simple Summary: Hepatocellular carcinoma (HCC) is a highly lethal disease with an increasing incidence. Despite the advancements in diagnosis and recent therapeutic options, improving the prognosis of HCC patients remains challenging. One of the reasons of the unsatisfactory outcome of patients with HCC is the complex tumour microenvironment (TME), which is composed of immune and stromal cells, limiting effective treatments. Recent research has highlighted the importance of macrophages in the development and progression of HCC, opening new possibilities for therapy. This review focuses on the heterogeneity of tumour-associated macrophages (TAMs) in HCC, the mechanisms through which HCC tumour cells polarize macrophages, and the therapeutic targets that are currently being tested to explore novel therapies that can improve the prognosis and quality of life of HCC patients. Hepatocellular carcinoma (HCC) is a prevalent and aggressive cancer that comprises a complex tumour microenvironment (TME). Tumour-associated macrophages (TAMs) are one of the most abundant immune cells present in the TME, and play a key role both in the development and in the progression of HCC. Thus, TAM-based immunotherapy has been presented as a promising strategy to complement the currently available therapies for HCC treatment. Among the novel approaches focusing on TAMs, reprogramming their functional state has emerged as a promising option for targeting TAMs as an immunotherapy in combination with the currently available treatment options. Nevertheless, a further understanding of the immunobiology of TAMs is still required. This review synthesizes current insights into the heterogeneous nature of TAMs in HCC and describes the mechanisms behind their pro-tumoural polarization focusing the attention on their interaction with HCC cells. Furthermore, this review underscores the potential involvement of TAMs' reprogramming in HCC therapy and highlights the urgency of advancing our understanding of these cells within the dynamic landscape of HCC. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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48. Pyroptosis: the potential eye of the storm in adult-onset Still's disease.
- Author
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He, Xinglan, You, Ruixuan, Shi, Yaqian, Zeng, Zhuotong, Tang, Bingsi, Yu, Jiangfan, Xiao, Yangfan, and Xiao, Rong
- Subjects
- *
STILL'S disease , *INTERLEUKIN-1 , *PYROPTOSIS , *APOPTOSIS , *INTERLEUKIN-1 receptors , *MACROPHAGE activation syndrome , *LYSIS - Abstract
Pyroptosis, a form of programmed cell death with a high pro-inflammatory effect, causes cell lysis and leads to the secretion of countless interleukin-1β (IL-1β) and IL-18 cytokines, resulting in a subsequent extreme inflammatory response through the caspase-1-dependent pathway or caspase-1-independent pathway. Adult-onset Still's disease (AOSD) is a systemic inflammatory disease with extensive disease manifestations and severe complications such as macrophage activation syndrome, which is characterized by high-grade inflammation and cytokine storms regulated by IL-1β and IL-18. To date, the pathogenesis of AOSD is unclear, and the available therapy is unsatisfactory. As such, AOSD is still a challenging disease. In addition, the high inflammatory states and the increased expression of multiple pyroptosis markers in AOSD indicate that pyroptosis plays an important role in the pathogenesis of AOSD. Accordingly, this review summarizes the molecular mechanisms of pyroptosis and describes the potential role of pyroptosis in AOSD, the therapeutic practicalities of pyroptosis target drugs in AOSD, and the therapeutic blueprint of other pyroptosis target drugs. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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49. The Mineralocorticoid Receptor Plays a Crucial Role in Macrophage Development and Function.
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Faught, Erin and Schaaf, Marcel J M
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MINERALOCORTICOID receptors ,MACROPHAGES ,IMMUNOREGULATION - Abstract
Stress and the attendant rise in glucocorticoids (GCs) results in a potent suppression of the immune system. To date, the anti-inflammatory role of GCs, via activation of the glucocorticoid receptor, has been well-characterized. However, cortisol, the primary GC in both fish and humans, also signals through the high-affinity mineralocorticoid receptor (MR), of which the immunomodulatory role is poorly understood. Here, we tested the hypothesis that MR is a key modulator of leukocyte function during inflammation. Using transgenic MR knockout zebrafish with fluorescently labelled leukocytes, we show that a loss of MR results in a global reduction in macrophage number during key development stages. This reduction was associated with impaired macrophage proliferation and responsivity to developmental distribution signals, as well as increased susceptibility to cell death. Using a tail fin amputation in zebrafish larvae as a model for localized inflammation, we further showed that MR knockout larvae display a reduced ability to produce more macrophages under periods of inflammation (emergency myelopoiesis). Finally, we treated wild-type larvae with an MR antagonist (eplerenone) during definitive hematopoiesis, when the macrophages had differentiated normally throughout the larvae. This pharmacological blockade of MR reduced the migration of macrophages toward a wound, which was associated with reduced macrophage Ccr2 signalling. Eplerenone treatment also abolished the cortisol-induced inhibition of macrophage migration, suggesting a role for MR in cortisol-mediated anti-inflammatory action. Taken together, our work reveals that MR is a key modulator of the innate immune response to inflammation under both basal and stressed conditions. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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- View/download PDF
50. The association of blood biomarkers with cerebral white matter and myelin content in bipolar disorder: a systematic review
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Mohammad Ali, Renata Husnudinov, Bianca Wollenhaupt-Aguiar, and Benicio N. Frey
- Subjects
Cytokines ,innate immune system ,kynurenine ,myelin ,genetics ,Psychiatry ,RC435-571 - Abstract
Objectives: Evidence from diffusion tensor imaging (DTI) and postmortem studies has demonstrated white-matter (WM) deficits in bipolar disorder (BD). Changes in peripheral blood biomarkers have also been observed; however, studies evaluating the potential relationship between brain alterations and the periphery are scarce. The objective of this systematic review is to investigate the relationship between blood-based biomarkers and WM in BD. Methods: PubMed, Embase, and PsycINFO were used to conduct literature searches. Cross-sectional or longitudinal studies reporting original data which investigated both a blood-based biomarker and WM (by neuroimaging) in BD were included. Results: Of 3,750 studies retrieved, 23 were included. Several classes of biomarkers were found to have a significant relationship with WM in BD. These included cytokines and growth factors (interleukin-8 [IL-8], tumor necrosis factor alpha [TNF-α], and insulin-like growth factor binding protein 3 [IGFBP-3]), innate immune system (natural killer cells [NK]), metabolic markers (lipid hydroperoxidase, cholesterol, triglycerides), the kynurenine (Kyn) pathway (5-hydroxyindoleacetic acid, kynurenic acid [Kyna]), and various gene polymorphisms (serotonin-transporter-linked promoter region). Conclusion: This systematic review revealed that blood-based biomarkers are associated with markers of WM deficits observed in BD. Longitudinal studies investigating the potential clinical utility of these specific biomarkers are encouraged. Systematic review registration: PROSPERO CRD42021279246.
- Published
- 2024
- Full Text
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