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Journal articles on the topic 'Defense stimulator'
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1
VadeBoncouer, Timothy R., and Francis X. Riegler. "In Defense of the Nerve Stimulator." Regional Anesthesia & Pain Medicine 23, no. 2 (March 1998): 229–30. http://dx.doi.org/10.1136/rapm-00115550-199823020-00021.
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&NA;. "In Defense of the Nerve Stimulator." Regional Anesthesia and Pain Medicine 23, no. 2 (March 1998): 229–30. http://dx.doi.org/10.1097/00115550-199823020-00021.
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Koçi, Rromir, Fabrice Dupuy, Salim Lebbar, Vincent Gloaguen, and Céline Faugeron Faugeron Girard. "A New Promising Plant Defense Stimulator Derived from a By-Product of Agar Extraction from Gelidium sesquipedale." Horticulturae 8, no. 10 (October 16, 2022): 958. http://dx.doi.org/10.3390/horticulturae8100958.
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Stimulation of plant defenses by elicitors is an alternative strategy to reduce pesticide use. In this study, we examined the elicitor properties of a by-product of the industrial extraction of agar from the red alga Gelidium sesquipedale. Agar extraction process leads to the formation of an alkaline residue which is poorly valorized. This by-product has been analyzed for its chemical composition. It contains 44% minerals and, among the organic compounds, sugars are the most represented and encompass 12.5% of the dry matter. When sprayed on tomato plants, this by-product enhanced the levels of defense markers such as peroxidase or phenylalanine ammonia lyase activities. Furthermore, this treatment increased the expression levels of the pathogenesis-related gene, PR9 encoding peroxidase. A field trial conducted on grapevine revealed that spraying treatment with this by-product resulted in a reduction of the macroscopic disease symptoms induced by Plasmospora viticola, with 40 to 60% efficacy. These results indicate that this agar extraction by-product could be used as a plant defense stimulator.
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Ahn, Jeonghyun, and Glen N. Barber. "STING signaling and host defense against microbial infection." Experimental & Molecular Medicine 51, no. 12 (December 2019): 1–10. http://dx.doi.org/10.1038/s12276-019-0333-0.
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AbstractThe first line of host defense against infectious agents involves activation of innate immune signaling pathways that recognize specific pathogen-associated molecular patterns (PAMPs). Key triggers of innate immune signaling are now known to include microbial-specific nucleic acid, which is rapidly detected in the cytosol of the cell. For example, RIG-I-like receptors (RLRs) have evolved to detect viral RNA species and to activate the production of host defense molecules and cytokines that stimulate adaptive immune responses. In addition, host defense countermeasures, including the production of type I interferons (IFNs), can also be triggered by microbial DNA from bacteria, viruses and perhaps parasites and are regulated by the cytosolic sensor, stimulator of interferon genes (STING). STING-dependent signaling is initiated by cyclic dinucleotides (CDNs) generated by intracellular bacteria following infection. CDNs can also be synthesized by a cellular synthase, cGAS, following interaction with invasive cytosolic self-DNA or microbial DNA species. The importance of STING signaling in host defense is evident since numerous pathogens have developed strategies to prevent STING function. Here, we review the relevance of STING-controlled innate immune signaling in host defense against pathogen invasion, including microbial endeavors to subvert this critical process.
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Bodin, Enora, Anthony Bellée, Marie-Cécile Dufour, Olivier André, and Marie-France Corio-Costet. "Grapevine Stimulation: A Multidisciplinary Approach to Investigate the Effects of Biostimulants and a Plant Defense Stimulator." Journal of Agricultural and Food Chemistry 68, no. 51 (December 14, 2020): 15085–96. http://dx.doi.org/10.1021/acs.jafc.0c05849.
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Bouissil, Soukaina, Claire Guérin, Jane Roche, Pascal Dubessay, Zainab El Alaoui-Talibi, Guillaume Pierre, Philippe Michaud, Said Mouzeyar, Cédric Delattre, and Cherkaoui El Modafar. "Induction of Defense Gene Expression and the Resistance of Date Palm to Fusarium oxysporum f. sp. Albedinis in Response to Alginate Extracted from Bifurcaria bifurcata." Marine Drugs 20, no. 2 (January 20, 2022): 88. http://dx.doi.org/10.3390/md20020088.
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In many African countries, the Bayoud is a common disease spread involving the fungus Fusarium oxusporum f. sp. albedinis (Foa). The induction of plant natural defenses through the use of seaweed polysaccharides to help plants against pathogens is currently a biological and ecological approach that is gaining more and more importance. In the present study, we used alginate, a natural polysaccharide extracted from a brown algae Bifurcaria bifurcata, to activate date palm defenses, which involve phenylalanine ammonia-lyase (PAL), a key enzyme of phenylpropanoid metabolism. The results obtained showed that at low concentration (1 g·L−1), alginate stimulated PAL activity in date palm roots 5 times more compared to the negative control (water-treated) after 24 h following treatment and 2.5 times more compared to the laminarin used as a positive stimulator of plant natural defenses (positive control of induction). Using qRT-PCR, the expression of a selection of genes involved in three different levels of defense mechanisms known to be involved in response to biotic stresses were investigated. The results showed that, generally, the PAL gene tested and the genes encoding enzymes involved in early oxidative events (SOD and LOX) were overexpressed in the alginate-treated plants compared to their levels in the positive and negative controls. POD and PR protein genes selected encoding β-(1,3)-glucanases and chitinases in this study did not show any significant difference between treatments; suggesting that other genes encoding POD and PR proteins that were not selected may be involved. After 17 weeks following the inoculation of the plants with the pathogen Foa, treatment with alginate reduced the mortality rate by up to 80% compared to the rate in control plants (non-elicited) and plants pretreated with laminarin, which agrees with the induction of defense gene expression and the stimulation of natural defenses in date palm with alginate after 24 h. These results open promising prospects for the use of alginate in agriculture as an inducer that triggers immunity of plants against telluric pathogens in general and of date palm against Fusarium oxysporum f. sp. albedinis in particular.
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Xia, Tianli, Takayuki Abe, Ai Harashima, Hiroyasu Konno, Keiko Konno, Alejo Morales, Jeonghyun Ahn, Delia Gutman, and Glen Barber. "STING recognition of cytoplasmic DNA instigates cellular defense (P1393)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 57.8. http://dx.doi.org/10.4049/jimmunol.190.supp.57.8.
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Abstract How the cell recognizes cytosolic DNA including DNA based microbes to trigger host defense related gene activation remains to be fully resolved. Here, we demonstrate that STING (for Stimulator of Interferon Genes), an endoplasmic reticulum (ER) translocon associated transmembrane protein, acts to detect cytoplasmic DNA species. STING homodimers were able to complex with self (apoptotic, necrotic) or pathogen related ssDNA and dsDNA and were indispensible for HSV-1-mediated transcriptional activation of a wide array of innate immune and pro-inflammatory genes in addition to type I IFN. Our data indicates that STING instigates cytoplasmic DNA-mediated cellular defense gene transcription and facilitates adoptive responses that are required for protection of the host. In contrast, chronic STING activation may manifest inflammatory responses and possibly autoimmune disease triggered by self-DNA.
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de Mezer, Mateusz, Jan Rogaliński, Stanisław Przewoźny, Michał Chojnicki, Leszek Niepolski, Magdalena Sobieska, and Agnieszka Przystańska. "SERPINA3: Stimulator or Inhibitor of Pathological Changes." Biomedicines 11, no. 1 (January 7, 2023): 156. http://dx.doi.org/10.3390/biomedicines11010156.
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SERPINA3, also called α-1-antichymotrypsin (AACT, ACT), is one of the inhibitors of serine proteases, one of which is cathepsin G. As an acute-phase protein secreted into the plasma by liver cells, it plays an important role in the anti-inflammatory response and antiviral response. Elevated levels of SERPINA3 have been observed in heart failure and neurological diseases such as Alzheimer’s disease or Creutzfeldt–Jakob disease. Many studies have shown increased expression levels of the SERPINA3 gene in various types of cancer, such as glioblastoma, colorectal cancer, endometrial cancer, breast cancer, or melanoma. In this case, the SERPINA3 protein is associated with an antiapoptotic function implemented by adjusting the PI3K/AKT or MAPK/ERK 1/2 signal pathways. However, the functions of the SERPINA3 protein are still only partially understood, mainly in the context of cancerogenesis, so it seems necessary to summarize the available information and describe its mechanism of action. In particular, we sought to amass the existing body of research focusing on the description of the underlying mechanisms of various diseases not related to cancer. Our goal was to present an overview of the correct function of SERPINA3 as part of the defense system, which unfortunately easily becomes the “Fifth Column” and begins to support processes of destruction.
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York, Autumn, Ann-Jay Tong, Joseph Argus, Elizabeth Gray, Nicholas Wu, Anjie Zhen, Scott Kitchen, Stephen Smale, Daniel Stetson, and Steven Bensinger. "Limiting cholesterol biosynthesis acts as a danger signal that engages STING-dependent inflammation (INM2P.349)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 126.2. http://dx.doi.org/10.4049/jimmunol.194.supp.126.2.
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Abstract Pathogen invasion alters host lipid metabolism, however the mechanisms underlying this remain poorly understood. Here, we show that transcriptional repression of cholesterol and fatty acid biosynthesis is driven by TRIF-dependent danger signals. Unexpectedly, decreasing cholesterol biosynthesis induces type I interferon (IFN)-mediated inflammation in the absence of conventional danger signals, resulting in resistance to pathogens. Spontaneous induction of inflammation was traced to a reduction in cellular cholesterol levels, and normalizing cholesterol attenuated IFNb and interferon stimulated gene expression. Epistasis studies indicate that the Stimulator of Interferon Genes (STING) links cellular cholesterol balance to type I IFN-mediated inflammation. These findings reveal that perturbing cholesterol homeostasis acts as an independent “danger” signal sensed by host defense machinery, and provides mechanistic insights as to how lipid metabolism influences inflammation.
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Krawczyk, Eric, Chase Kangas, and Bin He. "HSV Replication: Triggering and Repressing STING Functionality." Viruses 15, no. 1 (January 13, 2023): 226. http://dx.doi.org/10.3390/v15010226.
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Herpes simplex virus (HSV) has persisted within human populations due to its ability to establish both lytic and latent infection. Given this, human hosts have evolved numerous immune responses to protect against HSV infection. Critical in this defense against HSV, the host protein stimulator of interferon genes (STING) functions as a mediator of the antiviral response by inducing interferon (IFN) as well as IFN-stimulated genes. Emerging evidence suggests that during HSV infection, dsDNA derived from either the virus or the host itself ultimately activates STING signaling. While a complex regulatory circuit is in operation, HSV has evolved several mechanisms to neutralize the STING-mediated antiviral response. Within this review, we highlight recent progress involving HSV interactions with the STING pathway, with a focus on how STING influences HSV replication and pathogenesis.
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Kudria, M. Ya, N. V. Melnikivs’ka, N. V. Ustenko, T. O. Pavlenko, O. S. Lalymenko, I. A. Palagina, A. L. Degtyaryova, and A. D. Ivashchenko. "HEPATOPROTECTIVE ACTIVITY OF SPERMATOZOID STIMULATOR — KATIAZYN UNDER CONDITIONS OF EXPERIMENTAL PARACETAMOL-INDUCED LIVER PATHOLOGY." Problems of Endocrine Pathology 54, no. 4 (December 3, 2015): 53–60. http://dx.doi.org/10.21856/j-pep.2015.4.07.
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It was investigated hepatoprotective properties of camphor acid derivative — katiazin under experimental model conditions of paracetamol drug-induced hepatitis. It was proved that katiazin in two doses (10 and 50 mg/kg body weight) stimulates the non-enzymatic antioxidant defense unit, increasing the concentration of the reduced glutathione and sulfhydryl groups. The application of katiazin led to an increase in the prothrombin time, which can be interpreted as a sign of the compound anticoagulant effect. It was found out that the administration of katiazin enhances liver detoxification function, normalizes carbohydrate and lipid metabolism in rats.
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Wang, Peiyan, Siji Li, Yingchi Zhao, Baohuan Zhang, Yunfei Li, Shengde Liu, Hongqiang Du, et al. "The GRA15 protein from Toxoplasma gondii enhances host defense responses by activating the interferon stimulator STING." Journal of Biological Chemistry 294, no. 45 (August 15, 2019): 16494–508. http://dx.doi.org/10.1074/jbc.ra119.009172.
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Imanishi, Takayuki, Midori Unno, Wakana Kobayashi, Natsumi Yoneda, Satoshi Matsuda, Kazutaka Ikeda, Takayuki Hoshii, et al. "Reciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function." Life Science Alliance 2, no. 1 (January 25, 2019): e201800282. http://dx.doi.org/10.26508/lsa.201800282.
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Stimulator of interferon genes (STING) plays a key role in detecting cytosolic DNA and induces type I interferon (IFN-I) responses for host defense against pathogens. Although T cells highly express STING, its physiological role remains unknown. Here, we show that costimulation of T cells with the STING ligand cGAMP and TCR leads to IFN-I production and strongly inhibits T-cell growth. TCR-mediated mTORC1 activation and sustained activation of IRF3 are required for cGAMP-induced IFN-I production, and the mTORC1 activity is partially counteracted by cGAMP, thereby blocking proliferation. This mTORC1 inhibition in response to costimulation depends on IRF3 and IRF7. Effector T cells produce much higher IFN-I levels than innate cells in response to cGAMP. Finally, we demonstrated that STING stimulation in T cells is effective in inducing antitumor responses in vivo. Our studies demonstrate that the outputs of STING and TCR signaling pathways are mutually regulated through mTORC1 to modulate T-cell functions.
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Majtán, Juraj, Pawan Kumar, Ján Koller, Jana Dragúńová, and Ján Gabriž. "Induction of Metalloproteinase 9 Secretion from Human Keratinocytes by Pleuran (β-Glucan from Pleurotus ostreatus)." Zeitschrift für Naturforschung C 64, no. 7-8 (August 1, 2009): 597–600. http://dx.doi.org/10.1515/znc-2009-7-820.
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Glucan preparations, primarily modifi ed water-soluble glucans, are involved in the activation of the body’s natural defense mechanisms and in the acceleration of the skin’s wound-healing processes. Pleuran, an insoluble β-D-glucan in hydrogel form, offers a natural alternative to more common chemically derivated soluble β-D-glucans. Pleuran was applied to human keratinocyte primary cultures, and after 24 h of incubation the release of matrix metalloproteinase 9 (MMP-9) and metalloproteinase 2 (MMP-2) by stimulated keratinocytes was detected using gelatine zymography. There was a concentration-dependent increase in pro-MMP-9 release after treatment with pleuran over the concentration range of 2 to 200 μg/ml, but pro-MMP-2 was detected at a constant level. Moreover, the active forms of both MMPs were not detectable, indicating that in vitro autoactivation of these zymogens did not occur. The results indicate that pleuran is a potent keratinocyte stimulator of pro- MMP-9 release, which implies its application in dermatological therapies
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Bickett, Thomas, Elizabeth Creissen, Fabiola Silva Angulo, Antonio Izzo, Linda Izzo, and Angelo A. Izzo. "Characterizing the BCG induced T cell independent mechanisms for defense against Mycobacterium tuberculosis." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 62.12. http://dx.doi.org/10.4049/jimmunol.202.supp.62.12.
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Abstract Mycobacterium bovis Bacille Calmette Guérin (BCG) is a potent immune stimulator that activates innate and adaptive immunity. In the C57BL/6 mouse model of tuberculosis, BCG stimulated immunity causes a significant reduction of M. tuberculosis burden after pulmonary infection. The majority of work has focused on BCG induced T cell immunity as CD4+ T cells play a significant role in protection against tuberculosis. We hypothesized that BCG also induced a T cell independent mechanism that was sufficient to significantly restrict mycobacterial growth. BCG robustly activates innate immunity and our preliminary experiments showed that BCG induced a significant reduction in colony forming units (CFU) in the lungs of mice vaccinated 7 days before pulmonary infection. Our studies indicated that although BCG was administered through subcutaneous inoculation, increased numbers of Ly6C+ monocytes were observed in the lungs within 7 days. Selective depletion also determined that neutrophils played a role in priming innate immunity. Others have identified a role for innate immunity during BCG vaccination termed trained innate immunity. However, our results suggested that at day 7 post BCG vaccination trained innate immunity did not cause the CFU reduction, as the NOD2 receptor or NK cell activation were not absolute requirements, despite being linked to trained immunity. Furthermore, in vivo killing of mycobacterium was dependent on BCG being viable and was monocyte derived, highlighting a novel mechanism. Taken together our data suggest that an early innate mechanism induced by viable BCG is responsible for reducing the mycobacterial burden and precedes trained innate immunity.
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Habash, Samer S., Philipp P. Könen, Anita Loeschcke, Matthias Wüst, Karl-Erich Jaeger, Thomas Drepper, Florian M. W. Grundler, and A. Sylvia S. Schleker. "The Plant Sesquiterpene Nootkatone Efficiently Reduces Heterodera schachtii Parasitism by Activating Plant Defense." International Journal of Molecular Sciences 21, no. 24 (December 17, 2020): 9627. http://dx.doi.org/10.3390/ijms21249627.
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Plant parasitic nematodes, including the beet cyst nematode Heterodera schachtii, constitute a devastating problem for crops worldwide. The limited availability of sustainable management options illustrates the need for new eco-friendly control means. Plant metabolites represent an invaluable source of active compounds for the discovery of such novel antagonistic agents. Here, we evaluated the impact of eight plant terpenoids on the H. schachtii parasitism of Arabidopsis thaliana. None of the metabolites affected the plant development (5 or 10 ppm). Nootkatone decreased the number of adult nematodes on A. thaliana to 50%, with the female nematodes being smaller compared to the control. In contrast, three other terpenoids increased the parasitism and/or female size. We discovered that nootkatone considerably decreased the number of nematodes that penetrated A. thaliana roots, but neither affected the nematode viability or attraction to plant roots, nor triggered the production of plant reactive oxygen species or changed the plant’s sesquiterpene profile. However, we demonstrated that nootkatone led to a significant upregulation of defense-related genes involved in salicylic and jasmonic acid pathways. Our results indicate that nootkatone is a promising candidate to be developed into a novel plant protection agent acting as a stimulator of plant immunity against parasitic nematodes.
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Sütö, T. S., L. G. Fine, F. Shimizu, and M. Kitamura. "In vivo transfer of engineered macrophages into the glomerulus: endogenous TGF-beta-mediated defense against macrophage-induced glomerular cell activation." Journal of Immunology 159, no. 5 (September 1, 1997): 2476–83. http://dx.doi.org/10.4049/jimmunol.159.5.2476.
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Abstract Communication between resident glomerular cells and infiltrating macrophages plays a crucial role in the pathogenesis of glomerular disease. Using matrix metalloproteinase-9 (MMP-9) as an indicator molecule, we examined the interaction between mesangial cells and macrophages. Mesangial cells cocultured with activated macrophages or exposed to macrophage-conditioned media produced abundant MMP-9. We identified the stimulator secreted by macrophages as IL-1 because mesangial cells overexpressing IL-1 receptor antagonist protein showed a blunted expression of MMP-9 in response to the macrophage-conditioned medium. In contrast, culture supernatants of mesangial cells inhibited MMP-9 production by macrophages in a dose-dependent fashion. This inhibitor was identified to be TGF-beta1, since neutralization of TGF-beta1 abrogated the inhibitory effect of the mesangial cell-conditioned medium. To investigate whether activated macrophages induce glomerular MMP-9 expression, and if so, how endogenous TGF-beta1 modulates the induction, stimulated reporter macrophages were transferred into normal rat glomeruli or glomeruli in the regeneration phase of acute anti-Thy-1 glomerulonephritis. In the normal glomeruli, MMP-9 expression was up-regulated in resident cells after the transfer of activated macrophages. This induction was substantially repressed in the regenerating glomeruli that produced active TGF-beta1. These results point to potential mechanisms involved in glomerular control of MMP-9. Based upon the in vitro evidence, TGF-beta1 was identified as an endogenous "defender" that attenuates certain actions of infiltrating macrophages in the glomerulus.
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Amparyup, Piti, Walaiporn Charoensapsri, Suthinee Soponpong, Miti Jearaphunt, Ratree Wongpanya, and Anchalee Tassanakajon. "Stimulator of interferon gene (STING) and interferon regulatory factor (IRF) are crucial for shrimp antiviral defense against WSSV infection." Fish & Shellfish Immunology 117 (October 2021): 240–47. http://dx.doi.org/10.1016/j.fsi.2021.08.016.
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Ali, Mamdouh, Eman Noaman, Sherien Kamal, Saaed Soliman, and Dina Ismail. "Role of germanium L-cysteine α-tocopherol complex as stimulator of some antioxidant defense systems in gamma-irradiated rats." Acta Pharmaceutica 57, no. 1 (March 1, 2007): 1–12. http://dx.doi.org/10.2478/v10007-007-0001-0.
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Role of germanium L-cysteine α-tocopherol complex as stimulator of some antioxidant defense systems in gamma-irradiated rats This study was conducted to evaluate the potency of the newly prepared germanium L-cysteine α-tocopherol complex [germanium dichloro tetrakis (L-cysteinyl-α-tocopherol amide) dichloride] as a protective agent against γ-irradiation-induced free radicals production and liver toxicity. Male Swiss albino rats were injected intraperitoneally with the germanium complex in a concentration of 75 mg kg-1 body mass per dose, for 6 successive doses, last dose administered twenty minutes pre-exposure to a single dose of whole body γ-irradiation of 6.5 Gy. Lipid peroxidation (LPx), nitric oxide (NO), glutathione (GSH) levels, and activity of the antioxidant enzymes glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) were estimated in blood and liver. Blood total protein, cholesterol, triglyceride and α-tocopherol content were estimated as well. The results revealed that administration of germanium complex pre-irradiation resulted in significant (p < 0.001) improvement compared to the irradiated group in the level of hepatic and blood LPx. Hepatic GSH revealed a significant increase (p < 0.001), while its level showed no significant variation in blood. Also, the level of NO in blood and liver increased significantly (p < 0.001). On the other hand, pretreatment with the germanium complex normalized the activities of SOD, GPx and CAT in blood and liver when compared to the irradiated group. The study also documents a marked decrease in a blood triglyceride and cholesterol (p < 0.001) and a significant increase (p < 0.001) of α-tocopherol and total protein contents in blood. These biochemical changes were associated with marked improvement of histological status. Therefore, the germanium L-cysteine α-tocopherol complex may be a good candidate for ameliorating the changes induced by irradiation, which indicates the beneficial radio-protective role of this antioxidant agent.
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Prantner, Daniel, Darren J. Perkins, and Stefanie N. Vogel. "AMP-activated Kinase (AMPK) Promotes Innate Immunity and Antiviral Defense through Modulation of Stimulator of Interferon Genes (STING) Signaling." Journal of Biological Chemistry 292, no. 1 (November 22, 2016): 292–304. http://dx.doi.org/10.1074/jbc.m116.763268.
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Torres-Odio, Sylvia, Yuanjiu Lei, Suzana Gispert, Antonia Maletzko, Jana Key, Saeed Menissy, Ilka Wittig, Georg Auburger, and A. Phillip West. "Loss of Mitochondrial Protease CLPP Activates Type I IFN Responses through the Mitochondrial DNA–cGAS–STING Signaling Axis." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 50.05. http://dx.doi.org/10.4049/jimmunol.208.supp.50.05.
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Abstract Caseinolytic mitochondrial matrix peptidase proteolytic subunit (CLPP) is a serine protease that degrades damaged or misfolded mitochondrial proteins. CLPP-null mice exhibit growth retardation, deafness, and sterility, resembling human Perrault syndrome (PS). Absence of CLPP also leads to immune system alterations but the molecular mechanisms and underlying signaling pathways remain unclear. In this study, we report the steady-state activation of type I IFN signaling and antiviral gene expression in CLPP-deficient cells and tissues, resulting in marked resistance to RNA and DNA virus infection. Depletion of the cyclic GMP-AMP (cGAS)-stimulator of IFN genes (STING) DNA sensing pathway reduces steady-state IFN-I signaling and abrogates the broad antiviral phenotype of CLPP-null cells. We report that CLPP deficiency leads to mitochondrial DNA (mtDNA) instability and packaging alterations, a phenotype also observed in CLPP mutant fibroblasts from PS patient. Our work places the cGAS-STING-IFN-I innate immune pathway downstream of CLPP and may have implications for understanding PS and other human diseases involving CLPP dysregulation and proteostasis. Office of the Assistant Secretary of Defense for Health Affairs, U.S. Department of Defense (W81XWH-17-1-0052; W81XWH-20-1-0150); National Heart, Lung, and Blood Institute, National Institutes of Health (R01HL148153)
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Dobrochotova, Yu E., and A. Kh Karanasheva. "Vulvovaginal candidiasis in women of reproductive age: immunological aspects of modern algorithms for examination and treatment." Meditsinskiy sovet = Medical Council, no. 16 (October 7, 2022): 57–61. http://dx.doi.org/10.21518/2079-701x-2022-16-16-57-61.
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immunological defense complex is involved: the role of complement, T-lymphocytes, NK-cells is noted. Of particular importance among immune factors is interferon-γ, which is able to limit the reproduction of Candida fungi in the early stages of infection by stimulating the immune response. This is due to the fact that interferon-γ is the strongest stimulator of effector functions of macrophages (microbicidal activity, cytokine production), increases the expression of histocompatibility molecules MHCI and MHCII, as well as adhesion molecules on endothelial cells, increasing endothelial permeability. Thus, the rate of development and severity of the pathological process depend on the state of the body’s defenses. The use of antibiotics, glucocorticoids and cytostatics, as well as radiation therapy can enhance the adhesive properties of yeast fungi. The choice of treatment for VVC should be based on the results of a comprehensive diagnosis, taking into account the form and risk factors of the disease. Local immunity impairment due to the innate quality of the vaginal epitheliocytes is currently one of the most significant risk factors for the development of VVC. This also explains the availability of sufficient drugs for etiotropic therapy, which does not affect its recurrence rate. The use of topical immunomodulators is a very promising method of overcoming the therapeutic failures in the complex treatment of genital candidiasis.
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Paulis, Annalaura, and Enzo Tramontano. "Unlocking STING as a Therapeutic Antiviral Strategy." International Journal of Molecular Sciences 24, no. 8 (April 18, 2023): 7448. http://dx.doi.org/10.3390/ijms24087448.
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Invading pathogens have developed weapons that subvert physiological conditions to weaken the host and permit the spread of infection. Cells, on their side, have thus developed countermeasures to maintain cellular physiology and counteract pathogenesis. The cyclic GMP-AMP (cGAMP) synthase (cGAS) is a pattern recognition receptor that recognizes viral DNA present in the cytosol, activating the stimulator of interferon genes (STING) protein and leading to the production of type I interferons (IFN-I). Given its role in innate immunity activation, STING is considered an interesting and innovative target for the development of broad-spectrum antivirals. In this review, we discuss the function of STING; its modulation by the cellular stimuli; the molecular mechanisms developed by viruses, through which they escape this defense system; and the therapeutical strategies that have been developed to date to inhibit viral replication restoring STING functionality.
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Soh, Sandrine-M., Yeong-Jun Kim, Hong-Hee Kim, and Hye-Ra Lee. "Modulation of Ubiquitin Signaling in Innate Immune Response by Herpesviruses." International Journal of Molecular Sciences 23, no. 1 (January 1, 2022): 492. http://dx.doi.org/10.3390/ijms23010492.
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The ubiquitin proteasome system (UPS) is a protein degradation machinery that is crucial for cellular homeostasis in eukaryotes. Therefore, it is not surprising that the UPS coordinates almost all host cellular processes, including host–pathogen interactions. This protein degradation machinery acts predominantly by tagging substrate proteins designated for degradation with a ubiquitin molecule. These ubiquitin tags have been involved at various steps of the innate immune response. Hence, herpesviruses have evolved ways to antagonize the host defense mechanisms by targeting UPS components such as ubiquitin E3 ligases and deubiquitinases (DUBs) that establish a productive infection. This review delineates how herpesviruses usurp the critical roles of ubiquitin E3 ligases and DUBs in innate immune response to escape host-antiviral immune response, with particular focus on retinoic acid-inducible gene I (RIG-I)-like receptors (RLR), cyclic-GMP-AMP (cGAMP) synthase (cGAS), stimulator of interferon (IFN) genes (STING) pathways, and inflammasome signaling.
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Ran, Jin-Shan, Jie Jin, Xian-Xian Zhang, Ye Wang, Peng Ren, Jing-Jing Li, Ling-Qian Yin, et al. "Molecular Characterization, Expression and Functional Analysis of Chicken STING." International Journal of Molecular Sciences 19, no. 12 (November 22, 2018): 3706. http://dx.doi.org/10.3390/ijms19123706.
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Innate immunity is an essential line of defense against pathogen invasion which is gained at birth, and the mechanism involved is mainly to identify pathogen-associated molecular patterns through pattern recognition receptors. STING (stimulator of interferon genes) is a signal junction molecule that hosts the perception of viral nucleic acids and produces type I interferon response, which plays a crucial role in innate immunity. However, relatively few studies have investigated the molecular characterization, tissue distribution, and potential function of STING in chickens. In this study, we cloned the full-length cDNA of chicken STING that is composed of 1341 bp. Sequence analyses revealed that STING contains a 1140-bp open-reading frame that probably encodes a 379-amino acid protein. Multiple sequence alignments showed that the similarity of the chicken STING gene to other birds is higher than that of mammals. Real-time polymerase chain reaction (PCR) assays revealed that STING is highly expressed in the spleen, thymus and bursa of fabricious in chickens. Furthermore, we observed that STING expression was significantly upregulated both in vitro and in vivo following infection with Newcastle disease virus (NDV). STING expression was also significantly upregulated in chicken embryo fibroblasts upon stimulation with poly(I:C) or poly(dA:dT). Taken together, these findings suggest that STING plays an important role in antiviral signaling pathways in chickens.
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Franz, Kate M., William J. Neidermyer, Yee-Joo Tan, Sean P. J. Whelan, and Jonathan C. Kagan. "STING-dependent translation inhibition restricts RNA virus replication." Proceedings of the National Academy of Sciences 115, no. 9 (February 12, 2018): E2058—E2067. http://dx.doi.org/10.1073/pnas.1716937115.
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In mammalian cells, IFN responses that occur during RNA and DNA virus infections are activated by distinct signaling pathways. The RIG-I–like-receptors (RLRs) bind viral RNA and engage the adaptor MAVS (mitochondrial antiviral signaling) to promote IFN expression, whereas cGAS (cGMP–AMP synthase) binds viral DNA and activates an analogous pathway via the protein STING (stimulator of IFN genes). In this study, we confirm that STING is not necessary to induce IFN expression during RNA virus infection but also find that STING is required to restrict the replication of diverse RNA viruses. The antiviral activities of STING were not linked to its ability to regulate basal expression of IFN-stimulated genes, activate transcription, or autophagy. Using vesicular stomatitis virus as a model, we identified a requirement of STING to inhibit translation during infection and upon transfection of synthetic RLR ligands. This inhibition occurs at the level of translation initiation and restricts the production of viral and host proteins. The inability to restrict translation rendered STING-deficient cells 100 times more likely to support productive viral infections than wild-type counterparts. Genetic analysis linked RNA sensing by RLRs to STING-dependent translation inhibition, independent of MAVS. Thus, STING has dual functions in host defense, regulating protein synthesis to prevent RNA virus infection and regulating IFN expression to restrict DNA viruses.
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Yu, Xiaofei, Paul Fisher, and Xiang-Yang Wang. "Inhibition of tumor growth by targeting the MDA5-IPS-1 pathway requires coordinated induction of cancer cell death and immune activation (TUM2P.891)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 71.15. http://dx.doi.org/10.4049/jimmunol.192.supp.71.15.
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Abstract Melanoma differentiation-associated antigen 5 (MDA5), a cytosolic innate pattern recognition receptor for sensing double-stranded RNA, functions as a first line of defense against viral infection. Here we report that ectopic expression of MDA5, mediated by a replication incompetent adenovirus (Ad.Mda5), results in prostate cancer cell death and concomitant innate immune activation, e.g., production of type I interferons (IFNs). IFN-β promoter stimulator (IPS)-1, a downstream adaptor protein, is critical for MDA5-stimulated cancer cell apoptosis and type I IFN response. While MDA5-regulated IFN regulatory factor 3-IFN-β signaling cascade remains intact in nontransformed normal cells, these cells are less sensitive to MDA5-induced apoptosis compared with cancer cells. Intriguingly, intratumoral delivery of Ad.Mda5 preferentially remodels the tumor environment toward Th1 polarization, indicated by marked elevation of cytokine IFN-β, IL-12, and IFN-gamma. As a result, in situ overexpression of MDA5 leads to strong suppression of established mouse prostate tumors, which is associated with activation of natural killer (NK) cells and cytotoxic CD8+ T lymphocytes. Genetic ablation or antibody neutralization reveals that antitumor effect of MDA5 therapy depends on IPS1, IFN-β, and IL-12. Therefore, the intrinsic capabilities of ‘danger’ sensing MDA-5 in simultaneously promoting cancer cell death and immune augmentation may be exploited to develop novel cancer therapeutics.
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Yum, Seoyun, Minghao Li, Yan Fang, and Zhijian J. Chen. "TBK1 recruitment to STING activates both IRF3 and NF-κB that mediate immune defense against tumors and viral infections." Proceedings of the National Academy of Sciences 118, no. 14 (March 30, 2021): e2100225118. http://dx.doi.org/10.1073/pnas.2100225118.
Full textAbstract:
The induction of type I interferons through the transcription factor interferon regulatory factor 3 (IRF3) is considered a major outcome of stimulator of interferon genes (STING) activation that drives immune responses against DNA viruses and tumors. However, STING activation can also trigger other downstream pathways such as nuclear factor κB (NF-κB) signaling and autophagy, and the roles of interferon (IFN)-independent functions of STING in infectious diseases or cancer are not well understood. Here, we generated a STING mouse strain with a mutation (S365A) that disrupts IRF3 binding and therefore type I interferon induction but not NF-κB activation or autophagy induction. We also generated STING mice with mutations that disrupt the recruitment of TANK-binding kinase 1 (TBK1), which is important for both IRF3 and NF-κB activation but not autophagy induction (L373A or ∆CTT, which lacks the C-terminal tail). The STING-S365A mutant mice, but not L373A or ∆CTT mice, were still resistant to herpes simplex virus 1 (HSV-1) infections and mounted an antitumor response after cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) treatment despite the absence of STING-induced interferons. These results demonstrate that STING can function independently of type I interferons and autophagy, and that TBK1 recruitment to STING is essential for antiviral and antitumor immunity.
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Demaria, Sandra, and Claire Vanpouille-Box. "TREX1 is a checkpoint for innate immune sensing of DNA damage that fosters cancer immune resistance." Emerging Topics in Life Sciences 1, no. 5 (December 12, 2017): 509–15. http://dx.doi.org/10.1042/etls20170063.
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Genomic instability is a hallmark of neoplastic transformation that leads to the accumulation of mutations, and generates a state of replicative stress in neoplastic cells associated with dysregulated DNA damage repair (DDR) responses. The importance of increasing mutations in driving cancer progression is well established, whereas relatively little attention has been devoted to the DNA displaced to the cytosol of cancer cells, a byproduct of genomic instability and of the ensuing DDR response. The presence of DNA in the cytosol promotes the activation of viral defense pathways in all cells, leading to activation of innate and adaptive immune responses. In fact, the improper accumulation of cytosolic DNA in normal cells is known to drive severe autoimmune pathology. Thus, cancer cells must evade cytoplasmic DNA detection pathways to avoid immune-mediated destruction. The main sensor for cytoplasmic DNA is the cyclic GMP–AMP synthase, cGAS. Upon activation by cytosolic DNA, cGAS catalyzes the formation of the second messenger cGAMP, which activates STING (stimulator of IFN genes), leading to the production of type I interferon (IFN-I). IFN-I is a critical effector of cell-mediated antiviral and antitumor immunity, and its production by cancer cells can be subverted by several mechanisms. However, the key upstream regulator of cytosolic DNA-mediated immune stimulation is the DNA exonuclease 3′-repair exonuclease 1 (TREX1). Here, we will discuss evidence in support of a role of TREX1 as an immune checkpoint that, when up-regulated, hinders the development of antitumor immune responses.
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Cicalese, Stephanie M., Josiane Fernandes da Silva, Fernanda Priviero, R. Clinton Webb, Satoru Eguchi, and Rita C. Tostes. "Vascular Stress Signaling in Hypertension." Circulation Research 128, no. 7 (April 2, 2021): 969–92. http://dx.doi.org/10.1161/circresaha.121.318053.
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Cells respond to stress by activating a variety of defense signaling pathways, including cell survival and cell death pathways. Although cell survival signaling helps the cell to recover from acute insults, cell death or senescence pathways induced by chronic insults can lead to unresolved pathologies. Arterial hypertension results from chronic physiological maladaptation against various stressors represented by abnormal circulating or local neurohormonal factors, mechanical stress, intracellular accumulation of toxic molecules, and dysfunctional organelles. Hypertension and aging share common mechanisms that mediate or prolong chronic cell stress, such as endoplasmic reticulum stress and accumulation of protein aggregates, oxidative stress, metabolic mitochondrial stress, DNA damage, stress-induced senescence, and proinflammatory processes. This review discusses common adaptive signaling mechanisms against these stresses including unfolded protein responses, antioxidant response element signaling, autophagy, mitophagy, and mitochondrial fission/fusion, STING (signaling effector stimulator of interferon genes)-mediated responses, and activation of pattern recognition receptors. The main molecular mechanisms by which the vasculature copes with hypertensive and aging stressors are presented and recent advancements in stress-adaptive signaling mechanisms as well as potential therapeutic targets are discussed.
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Santos, Adriana Silva, Juliana Formiga Almeida, Marcio Santos da Silva, Jackson Silva Nóbrega, Thais Batista de Queiroga, Jessica Alves Ribeiro Pereira, Jéssica Aline Linné, and Fernando Antônio Lima Gomes. "The Influence of H2O2 Application Methods on Melon Plants Submitted to Saline Stress." Journal of Agricultural Science 11, no. 11 (July 31, 2019): 245. http://dx.doi.org/10.5539/jas.v11n11p245.
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The salinity in irrigation water is one of the most important causes to decline cultivated plants yield. The H2O2 application has shown efficiency as a stimulator and activator for antioxidative defense system in plants submitted to biotic and abiotic stresses. The objective of this study was to evaluate methods for hydrogen peroxide application as a strategy to minimize the effects of saline stress on melon plants. The experiment was designed in complete randomized blocks and set in 2 × 4 factorial scheme, consisting two levels for irrigation water salinity (S1 = 0.3 and S2 = 2.0 dS m-1) and four methods for hydrogen peroxide application (15 mM), (T1 = no peroxide application, T2= imbibition of seeds, T3 = at sowing, T4 = Foliar spraying), with five repetitions. It was evaluated the following variables at 58 days after transplanting: plant height, stem diameter, number of leaves, number of flowers, shoot dry mass, root dry mass and total dry mass. The results showed that salinity affected the growth, biomass accumulation and plant quality severely, with the highest losses promoted by the electrical conductivity of 2.0 dS m-1.
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Moskalev, Alexander V., Boris Yu Gumilevsky, Vasiliy Ya Apchel, and Vasiliy N. Tcygan. "Protein signaling molecules affecting the development of innate immunity mechanisms." Bulletin of the Russian Military Medical Academy 24, no. 2 (July 13, 2022): 353–62. http://dx.doi.org/10.17816/brmma100441.
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The principle protein molecules (interferon gene stimulator, adapter proteins, B-cell lymphoma 2 proteins, zinc-finger antiviral protein, and others), mechanisms of apoptosis, necroptosis, perforation of plasma membranes with kinase-like proteins of a mixed line, and ribonucleic acid neutralization, which ensure the development of innate immunity, are described. The main defense mechanisms that viruses have developed at the various stages of evolution are considered. The features of the development of the mechanisms of apoptosis and autophagy in a new coronavirus infection, which are associated with increased secretion of pro-inflammatory cytokines and chemokines, leading to severe damage to host cells, are given. It has been found that serum levels of several proteins formed during autophagy caused by SARS-CoV-2 can be used to predict disease severity. These include a protein associated with microtubules 1A/1B, a protein of sequestoma 1, and a protein of the cellular system of autophagy ― beclin-1. The multifaceted role of interferons in the inhibition of viral infection and the features of the violation of the activating functions of interferons in coronavirus infection are described.
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Yu, Yang, Jingyang Liu, Cun Liu, Ruijuan Liu, Lijuan Liu, Zhenhai Yu, Jing Zhuang, and Changgang Sun. "Post-Translational Modifications of cGAS-STING: A Critical Switch for Immune Regulation." Cells 11, no. 19 (September 28, 2022): 3043. http://dx.doi.org/10.3390/cells11193043.
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Innate immune mechanisms initiate immune responses via pattern-recognition receptors (PRRs). Cyclic GMP-AMP synthase (cGAS), a member of the PRRs, senses diverse pathogenic or endogenous DNA and activates innate immune signaling pathways, including the expression of stimulator of interferon genes (STING), type I interferon, and other inflammatory cytokines, which, in turn, instructs the adaptive immune response development. This groundbreaking discovery has rapidly advanced research on host defense, cancer biology, and autoimmune disorders. Since cGAS/STING has enormous potential in eliciting an innate immune response, understanding its functional regulation is critical. As the most widespread and efficient regulatory mode of the cGAS-STING pathway, post-translational modifications (PTMs), such as the covalent linkage of functional groups to amino acid chains, are generally considered a regulatory mechanism for protein destruction or renewal. In this review, we discuss cGAS-STING signaling transduction and its mechanism in related diseases and focus on the current different regulatory modalities of PTMs in the control of the cGAS-STING-triggered innate immune and inflammatory responses.
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Oelke, Mathias, Tonya J. Webb, Robert L. Giuntoli, II, Pablo H. H. Lopez, Xiangming Li, Ronald Schnaar, Moriya Tsuji, and Jonathan Schneck. "Identification of an inhibitory ganglioside responsible for immune suppressive effects associated with ovarian cancer (100.27)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 100.27. http://dx.doi.org/10.4049/jimmunol.184.supp.100.27.
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Abstract Tumors often use mechanisms to prevent or suppress immune recognition. One such mechanism is the shedding of immune-suppressive glycolipids into the local microenvironment. Previously we reported that pretreatment of CD1d expressing stimulator cells with ascites fluid from ovarian cancer patients inhibited the activation of NKT cells, one of the earliest lines of defense in an anti-cancer immune response. Here we identify the inhibitory factor responsible, ganglioside GD3, which we isolated from the polar lipid fraction of ovarian cancer-associated ascites. GD3 inhibited CD1d-mediated NKT cell activation directly, without antigen processing. Purified GD3 binds with high affinity to CD1d, even when compared to the well-established experimental CD1d activator, α-galactosylceramide. Mechanistically we show that factors in ascites fluid as well as purified GD3 bind directly to the CD1 antigenic binding site, and this presumably displaces endogenous NKT cell ligands. These data indicate that shedding of GD3 by ovarian cancer tumors is a mechanism of immune evasion that inhibits the activation of an anti-tumor NKT cell response.
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Meher, Hari C., Vijay T. Gajbhiye, and Ghanendra Singh. "Salicylic acid-induced glutathione status in tomato crop and resistance to root-knot nematode, Meloidogyne incognita (Kofoid & White) Chitwood." Journal of Xenobiotics 1, no. 1 (October 20, 2011): 5. http://dx.doi.org/10.4081/xeno.2011.e5.
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Salicylic acid-(SA) is a plant defense stimulator. Exogenous application of SA might influence the status of glutathione-(GSH). GSH activates and SA alters the expression of defense genes to modulate plant resistance against pathogens. The fate of GSH in a crop following SA treatment is largely unknown. The SA-induced profiles of free reduced-, free oxidized-(GSSG) and protein bound-(PSSG) glutathione in tomato crop following foliar treatment of transplant at 5.0-10.0 μg mL–1 were measured by liquid chromatography. Resistance to root-knot nematode, <em>Meloidogyne incognita</em> damaging tomato and crop performance were also evaluated. SA treatment at 5.0-10.0 μg mL–1 to tomato transplants increased GSH, GSSG and PSSG in plant leaf and root, more so in leaf, during crop growth and development. As the fruits ripened, GSH and PSSG increased and GSSG declined. SA reduced the root infection by <em>M. incognita</em>, nematode reproduction and thus, improved the resistance of tomato var. Pusa Ruby, but reduced crop growth and redox status. SA at 5.0 μg mL–1 improved yield and fruit quality. The study firstly linked SA with activation of glutathione metabolism and provided an additional dimension to the mechanism of induced resistance against obligate nematode pathogen. SA increased glutathione status in tomato crop, imparted resistance against <em>M. incognita</em>, augmented crop yield and functional food quality. SA can be applied at 5.0 μg mL–1 for metabolic engineering of tomato at transplanting to combine host-plant resistance and health benefits in formulating a strategic nematode management decision.
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Wang, Yue-Feng, Xue-Yue Hou, Jun-Jie Deng, Zhi-Hong Yao, Man-Man Lyu, and Rong-Shu Zhang. "AUXIN RESPONSE FACTOR 1 Acts as a Positive Regulator in the Response of Poplar to Trichoderma asperellum Inoculation in Overexpressing Plants." Plants 9, no. 2 (February 19, 2020): 272. http://dx.doi.org/10.3390/plants9020272.
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Numerous Trichoderma strains have been reported to be optimal biofertilizers and biocontrol agents with low production costs and environmentally friendly properties. Trichoderma spp. promote the growth and immunity of plants by multiple means. Interfering with the hormonal homeostasis in plants is the most critical strategy. However, the mechanisms underlying plants’ responses to Trichoderma remain to be further elucidated. Auxin is the most important phytohormone that regulates almost every aspect of a plant’s life, especially the trade-off between growth and defense. The AUXIN RESPONSE FACTOR (ARF) family proteins are key players in auxin signaling. We studied the responses and functions of the PdPapARF1 gene in a hybrid poplar during its interaction with beneficial T. asperellum strains using transformed poplar plants with PdPapARF1 overexpression (on transcription level in this study). We report that PdPapARF1 is a positive regulator for promoting poplar growth and defense responses, as does T. asperellum inoculation. PdPapARF1 also turned out to be a positive stimulator of adventitious root formation. Particularly, the overexpression of PdPapARF1 induced a 32.3% increase in the height of 40-day-old poplar plants and a 258% increase in the amount of adventitious root of 3-week-old subcultured plant clones. Overexpressed PdPapARF1 exerted its beneficial functions through modulating the hormone levels of indole acetic acid (IAA), jasmonic acid (JA), and salicylic acid (SA) in plants and activating their signaling pathways, creating similar results as inoculated with T. asperellum. Particularly, in the overexpressing poplar plants, the IAA level increased by approximately twice of the wild-type plants; and the signaling pathways of IAA, JA, and SA were drastically activated than the wild-type plants under pathogen attacks. Our report presents the potential of ARFs as the crucial and positive responders in plants to Trichoderma inducing.
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Rice, Marion. "Curriculum Artifacts." Practicing Anthropology 8, no. 3-4 (July 1, 1986): 6–19. http://dx.doi.org/10.17730/praa.8.3-4.j233522h2w7173hj.
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A quarter of a century spans the enactment of the National Defense Education Act (NDEA) of 1958 and the publication of A Nation at Risk in 1983. Both grew out of a concern for the condition of learning in our nation's schools. But there the resemblance ends. NDEA presaged a decade of curriculum creativity, focusing on the structure of the disciplines; the 1983 report thus far has produced primarily attempts to reform through school centralization and bureaucratic monitoring. Forgotten in the recent effort are the three most important ingredients of learning: the teacher, the pupil, and the parent. The teacher is the mentor, the coach, the stimulator of formal instruction. The pupil is the learner, the striver without whose effort there is no learning and no. application. And the parent,. representative of the larger society, is the one who must demand performance and support the efforts of both pupil and teacher. Thus, as we look at education from an anthropological perspective, it seems that in the 1980s we are more concerned with the incidentals than the basic structure of schooling, and that much-touted school reform will have trivial rather than significant consequences.
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Tupik, Juselyn D., Justin W. Markov Madanick, Hannah M. Ivester, and Irving C. Allen. "Detecting DNA: An Overview of DNA Recognition by Inflammasomes and Protection against Bacterial Respiratory Infections." Cells 11, no. 10 (May 19, 2022): 1681. http://dx.doi.org/10.3390/cells11101681.
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The innate immune system plays a key role in modulating host immune defense during bacterial disease. Upon sensing pathogen-associated molecular patterns (PAMPs), the multi-protein complex known as the inflammasome serves a protective role against bacteria burden through facilitating pathogen clearance and bacteria lysis. This can occur through two mechanisms: (1) the cleavage of pro-inflammatory cytokines IL-1β/IL-18 and (2) the initiation of inflammatory cell death termed pyroptosis. In recent literature, AIM2-like Receptor (ALR) and Nod-like Receptor (NLR) inflammasome activation has been implicated in host protection following recognition of bacterial DNA. Here, we review current literature synthesizing mechanisms of DNA recognition by inflammasomes during bacterial respiratory disease. This process can occur through direct sensing of DNA or indirectly by sensing pathogen-associated intracellular changes. Additionally, DNA recognition may be assisted through inflammasome–inflammasome interactions, specifically non-canonical inflammasome activation of NLRP3, and crosstalk with the interferon-inducible DNA sensors Stimulator of Interferon Genes (STING) and Z-DNA Binding Protein-1 (ZBP1). Ultimately, bacterial DNA sensing by inflammasomes is highly protective during respiratory disease, emphasizing the importance of inflammasome involvement in the respiratory tract.
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Hu, Shuiqing, Yan Fang, Xiang Chen, Tianlei Cheng, Miaoqing Zhao, Mingjian Du, Tuo Li, et al. "cGAS restricts colon cancer development by protecting intestinal barrier integrity." Proceedings of the National Academy of Sciences 118, no. 23 (June 1, 2021): e2105747118. http://dx.doi.org/10.1073/pnas.2105747118.
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The DNA-sensing enzyme cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) regulates inflammation and immune defense against pathogens and malignant cells. Although cGAS has been shown to exert antitumor effects in several mouse models harboring transplanted tumor cell lines, its role in tumors arising from endogenous tissues remains unknown. Here, we show that deletion of cGAS in mice exacerbated chemical-induced colitis and colitis-associated colon cancer (CAC). Interestingly, mice lacking cGAS were more susceptible to CAC than those lacking stimulator of interferon genes (STING) or type I interferon receptor under the same conditions. cGAS but not STING is highly expressed in intestinal stem cells. cGAS deficiency led to intestinal stem cell loss and compromised intestinal barrier integrity upon dextran sodium sulfate-induced acute injury. Loss of cGAS exacerbated inflammation, led to activation of STAT3, and accelerated proliferation of intestinal epithelial cells during CAC development. Mice lacking cGAS also accumulated myeloid-derived suppressive cells within the tumor, displayed enhanced Th17 differentiation, but reduced interleukin (IL)-10 production. These results indicate that cGAS plays an important role in controlling CAC development by defending the integrity of the intestinal mucosa.
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Sisson, J. H. "Ethanol stimulates apparent nitric oxide-dependent ciliary beat frequency in bovine airway epithelial cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 268, no. 4 (April 1, 1995): L596—L600. http://dx.doi.org/10.1152/ajplung.1995.268.4.l596.
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The mucociliary apparatus of the lung provides an important host-defense function by clearing the upper airway of inhaled particles and infectious microorganisms. Because lung host defenses are impaired in alcoholics, we hypothesized that ethanol would decrease ciliary motility in airway epithelium. Ciliary beat frequency (CBF) was measured by videomicroscopy in primary cultures of ciliated bovine bronchial epithelial cells (BBECs). Ethanol rapidly stimulated ciliary motility in a time-dependent fashion with concentrations as low as 10 mM. No detectable decreases in ciliary motility were noted until ethanol concentrations exceeded 1,000 mM. Because many substances stimulate ciliary motility by releasing nitric oxide (NO) via upregulation of nitric oxide synthase (NOS), we preincubated ciliated BBECs with a stereospecific NOS inhibitor, NG-monomethyl-L-arginine (L-NMMA). L-NMMA completely blocked ethanol-induced stimulation of CBF, which could be subsequently restored by adding either L-arginine or sodium nitroprusside, which is a direct NO donor. These results indicate that ethanol, at clinically relevant concentrations, stimulates the release of NO by airway epithelium that upregulates ciliary motility. The rapidity of this response suggests upregulation of the constitutive NOS, known to be present in airway epithelium, and may explain the increases in mucociliary clearance observed in previous studies of ethanol ingestion in animals and in humans. These data also suggest a novel signal transduction pathway, the NO/NOS system, by which ethanol may exert some of its diverse biologic effects.
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Gewirtz, A. M., W. Y. Xu, and K. F. Mangan. "Role of natural killer cells, in comparison with T lymphocytes and monocytes, in the regulation of normal human megakaryocytopoiesis in vitro." Journal of Immunology 139, no. 9 (November 1, 1987): 2915–24. http://dx.doi.org/10.4049/jimmunol.139.9.2915.
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Abstract Natural killer (NK) cells are thought to play an important role in host defense against virus-infected and neoplastic cells. Recent reports suggest that these cells may also influence developmental events in the course of normal erythropoiesis and granulopoiesis. The role of NK cells in the regulation of normal human megakaryocytopoiesis has not been reported, but clinical observations suggest that NK cell effects on megakaryocyte progenitors might differ from those of other cell lineages. We therefore carried out in vitro studies designed to assess the influence of NK cells on the growth of autologous megakaryocyte colony-forming units (CFU-Meg). To provide a frame of reference for these experiments, the effect of T lymphocytes, and monocyte-macrophages (M luminal diameter) on autologous CFU-Meg cloning efficiency was also studied. Purified immune effector cells were co-cultured in plasma clots with both unseparated, and progenitor cell-enriched marrow mononuclear cells (MNC) at target to effector cell ratios varying from 100:1 to 1:1. Resulting megakaryocyte colonies were enumerated by indirect fluorescence microscopy by using a rabbit anti-human platelet glycoprotein antiserum as probe for cells of the megakaryocyte lineage. The addition of NK cells to both unseparated (n = 12), and progenitor-enriched (n = 3) MNC at target to effector cell ratios of 2:1 and 1:1 resulted in a significant (p less than 0.05) augmentation in CFU-Meg-derived colony formation. Augmentation of colony formation was blocked by incubating the NK cells in Leu-11b monoclonal antibody. Stimulation appeared to be carried out by the production of a soluble growth factor which was detectable in NK cell-conditioned medium. Exposure of NK cells for 18 hr to highly purified or recombinant gamma-interferon (500 U/10(6) cells), a putative NK cell stimulator, neither increased nor abrogated the stimulatory effect. The latter could be accomplished, however, by centrifuging (200 X G for 5 min), and then preincubating the target and effector cells together for 3 hr before plating. At no time was significant inhibition of CFU-Meg demonstrated. In contrast to these results, when tested at the same ratios, and under the same conditions, no consistent effect on CFU-Meg cloning efficiency could be demonstrated by the addition of whole T cells, T cell subsets, or M luminal diameter. These results suggest that NK cells could play a role in the basal regulation of megakaryocytopoiesis.(ABSTRACT TRUNCATED AT 400 WORDS)
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Martin, Gary R., Carolina Salazar Arcila, Laura J. Hallihan, Teresa Scheidl-Yee, and Frank R. Jirik. "Inducible generalized activation of hSTING-N154S expression in mice leads to lethal hypercytokinemia: a model for “cytokine storm”." Journal of Leukocyte Biology 113, no. 3 (March 1, 2023): 326–33. http://dx.doi.org/10.1093/jleuko/qiac019.
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Abstract Excessive levels of circulating proinflammatory mediators, known as “hypercytokinemia,” that are generated by overwhelming immune system activation can lead to death due to critical organ failure and thrombotic events. Hypercytokinemia has been frequently associated with a variety of infectious and autoimmune diseases, with severe acute respiratory syndrome coronavirus 2 infection currently being the commonest cause, of what has been termed the cytokine storm. Among its various functions within the host, STING (stimulator of interferon genes) is critical in the defense against certain viruses and other pathogens. STING activation, particularly within cells of the innate immune system, triggers potent type I interferon and proinflammatory cytokine production. We thus hypothesized that generalized expression of a constitutively active STING mutant in mice would lead to hypercytokinemia. To test this, a Cre-loxP–based system was used to cause the inducible expression of a constitutively active hSTING mutant (hSTING-N154S) in any tissue or cell type. Herein, we employed a tamoxifen-inducible ubiquitin C-CreERT2 transgenic to obtain generalized expression of the hSTING-N154S protein, thereby triggering the production of IFN-β and multiple proinflammatory cytokines. This required euthanizing the mice within 3 to 4 d after tamoxifen administration. This preclinical model will allow for the rapid identification of compounds aimed at either preventing or ameliorating the lethal effects of hypercytokinemia.
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Zhang, Dandan, Chenhe Su, and Chunfu Zheng. "Herpes Simplex Virus 1 Serine Protease VP24 Blocks the DNA-Sensing Signal Pathway by Abrogating Activation of Interferon Regulatory Factor 3." Journal of Virology 90, no. 12 (April 13, 2016): 5824–29. http://dx.doi.org/10.1128/jvi.00186-16.
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ABSTRACTThe interferon (IFN)-mediated antiviral response is a central aspect of host defense; however, viruses have evolved multiple strategies to counteract IFN-mediated responses in order to successfully infect the host. Herpes simplex virus 1 (HSV-1), a typical human-restricted DNA virus, is capable of counteracting host immune responses via several distinct viral proteins, thus establishing a lifelong latent infection. In this study, we demonstrate that the VP24 protein, a serine protease of HSV-1 essential for the formation and maturation of capsids, is a novel antagonist of the beta interferon (IFN-β) pathway. Here, VP24 was shown for the first time to dampen interferon stimulatory DNA (ISD)-triggered IFN-β production and inhibit IFN-β promoter activation induced by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) and by STING, respectively. Further study demonstrated that ectopic expression of VP24 selectively blocked IFN regulatory factor 3 (IRF3) but not NF-κB promoter activation. In addition, VP24 was demonstrated to downregulate ISD-induced phosphorylation and dimerization of IRF3 during HSV-1 infection with a VP24 stable knockdown human foreskin fibroblast cell line. The underlying molecular mechanism is that VP24 abrogates the interaction between TANK-binding kinase 1 (TBK1) and IRF3, hence impairing IRF3 activation. These results illustrate that VP24 is able to block the production of IFN-β by inhibiting IRF3 activation, which may represent a critical adaptation to enable viral effective replication within the host.IMPORTANCEThis study demonstrated that HSV-1 protein VP24 could inhibit IFN-β production and promoter activation triggered by ISD, cGAS and STING and by STING, respectively. VP24 selectively blocked IRF3 promoter activation and ISD-induced phosphorylation and dimerization of IRF3 without affecting the NF-κB promoter activation during viral infection. VP24 also inhibited IRF3 activation by impeding the interaction between TBK1 and IRF3 during viral infection. This study provides new insights into the immune evasion mediated by HSV-1 and identifies VP24 as a crucial effector for HSV-1 to evade the host DNA-sensing signal pathway.
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Yahyapour, Rasoul, Peyman Amini, Hana Saffar, Elahe Motevaseli, Bagher Farhood, Vahid Pooladvand, Dheyauldeen Shabeeb, Ahmed Eleojo Musa, and Masoud Najafi. "Protective Effect of Metformin, Resveratrol and Alpha-lipoic Acid on Radiation- Induced Pneumonitis and Fibrosis: A Histopathological Study." Current Drug Research Reviews 11, no. 2 (December 10, 2019): 111–17. http://dx.doi.org/10.2174/2589977511666191018180758.
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Background: Radiation-induced pneumonitis and fibrosis are the most common side effects of chest radiotherapy. They result from massive and chronic production of Reactive Oxygen Species (ROS), inhibition of antioxidant enzymes as well as the release of several inflammatory mediators. In this study, we aimed to detect the radioprotective effects of metformin (as inhibitor of mitochondrial ROS), resveratrol (as stimulator of antioxidant defense enzymes) and alpha-lipoic acid (as direct antioxidant) for alleviating radiation-induced pneumonitis and fibrosis. Methods: 80 Male Mice were randomly allotted to eight groups which include G1: control; G2: resveratrol; G3: alpha-lipoic acid; G4: metformin; G5: radiation; G6: radiation plus resveratrol; G7: radiation plus alpha-lipoic acid; G8: radiation plus metformin. Drugs’ doses were as follows: 100 mg/kg metformin, 200 mg/kg resveratrol and 200 mg/kg alpha-lipoic acid. Irradiation with a single radiation dose of 18 Gy was performed using a cobalt-60 (60Co) gamma-ray source. After 80 days, all mice were sacrificed and their lung tissues evaluated for morphological changes using histopathological markers. Results: Irradiation led to acute pneumonitis including infiltration of inflammatory cells and damages to alveolar and vascular, as well as mild fibrosis. Metformin, alpha-lipoic acid and resveratrol were able to reduce pneumonitis and overcome radiation-induced fibrosis. Conclusion: All agents could protect against radiation-induced lung injury moderately. It is possible that administering higher doses of these drugs over a long period of time could give better radioprotection of the lung.
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Morimoto, Daishi, Shigeru Matsumura, Itzel Bustos-Villalobos, Patricia Angela Sibal, Toru Ichinose, Yoshinori Naoe, Ibrahim Ragab Eissa, et al. "C-REV Retains High Infectivity Regardless of the Expression Levels of cGAS and STING in Cultured Pancreatic Cancer Cells." Cells 10, no. 6 (June 15, 2021): 1502. http://dx.doi.org/10.3390/cells10061502.
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Oncolytic virus (OV) therapy is widely considered as a major breakthrough in anti-cancer treatments. In our previous study, the efficacy and safety of using C-REV for anti-cancer therapy in patients during stage I clinical trial was reported. The stimulator of interferon genes (STING)–TBK1–IRF3–IFN pathway is known to act as the central cellular host defense against viral infection. Recent reports have linked low expression levels of cGAS and STING in cancer cells to poor prognosis among patients. Moreover, downregulation of cGAS and STING has been linked to higher susceptibility to OV infection among several cancer cell lines. In this paper, we show that there is little correlation between levels of cGAS/STING expression and susceptibility to C-REV among human pancreatic cancer cell lines. Despite having a responsive STING pathway, BxPC-3 cells are highly susceptible to C-REV infection. Upon pre-activation of the STING pathway, BxPc-3 cells exhibited resistance to C-REV infection. However, without pre-activation, C-REV completely suppressed the STING pathway in BxPC-3 cells. Additionally, despite harboring defects in the STING pathway, other high-grade cancer cell lines, such as Capan-2, PANC-1 and MiaPaCa-2, still exhibited low susceptibility to C-REV infection. Furthermore, overexpression of STING in MiaPaCa-2 cells altered susceptibility to a limited extent. Taken together, our data suggest that the cGAS–STING pathway plays a minor role in the susceptibility of pancreatic cancer cell lines to C-REV infection.
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Pei, Dongli, Qingchen Zhang, Xiaoqin Zhu, and Lei Zhang. "Biological Control of Verticillium Wilt and Growth Promotion in Tomato by Rhizospheric Soil-Derived Bacillus amyloliquefaciens Oj-2.16." Pathogens 12, no. 1 (December 26, 2022): 37. http://dx.doi.org/10.3390/pathogens12010037.
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Verticillium wilt disease caused by Verticillium dahliae seriously affects tomato quality and yield. In this work, strain Oj-2.16 was isolated from rhizosphere soil of the medicinal plant Ophiopogon japonicas and identified as Bacillus amyloliquefaciens on the basis of morphological, physiological, and biochemical characteristics and 16S rDNA sequencing. Strain Oj-2.16 exhibited a high inhibition rate against V. dahliae, and the hyphae inhibited by Oj-2.16 were found to be destroyed on scanning electron microscopy. Lipopeptide and dipeptide genes were detected in the Oj-2.16 genome by PCR amplification involved in surfactin, iturin, fengycin, and bacilysin biosynthesis. In pot experiments, the biocontrol efficacy of strain Oj-2.16 against Verticillium wilt in tomato was 89.26%, which was slightly higher than the efficacy of the chemical fungicide carbendazim. Strain Oj-2.16 can produce indole acetic acid, siderophores, assimilate various carbon sources, and significantly promoted the growth of tomato seedlings by increasing plant height, root length, stem width, fresh weight, and dry weight by 44.44%, 122.22%, 80.19%, 57.65%, 64.00%, respectively. Furthermore, defense-related antioxidant CAT, SOD, POD, and PAL enzyme activities significantly increased and MDA contents significantly decreased in tomato seedlings treated with strain Oj-2.16 upon inoculation of V. dahliae compared with the pathogen-inoculated control. In summary, we concluded that B. amyloliquefaciens Oj-2.16 could be used as a promising candidate for the biocontrol of Verticillium wilt and as plant growth stimulator of tomato.
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Mohanlal, Ramon W., and Lan Huang. "Effect of plinabulin, a novel late-clinical stage immunotherapeutic agent on the adaptive and innate immune system." Journal of Clinical Oncology 38, no. 5_suppl (February 10, 2020): 8. http://dx.doi.org/10.1200/jco.2020.38.5_suppl.8.
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8 Background: Plinabulin (Plin) is a small molecule Dendritic Cell modulator, which in the presence of antigen, increases T-cell proliferation in an antigen-dependent manner marrow. The addition of Plin to Docetaxel (Doc) improved mOS with 4.6 months vs Docetaxel monotherapy, and prolonged DoR with more than 1 year (p < 0.05), which is indicative of an immune-mediated mechanism of action (Mohanlal, ASCO-SITC 2017). Neutrophils are our first line of innate immune defense against foreign invaders. We previously reported that Plinabulin prevents chemotherapy (Chemo) Induced Neutropenia (CIN) in patients receiving Doc or TAC throughout the cycle (Doc, Doxorubicin, Cyclophosphamide) (Blayney ASH 2018, St Gallen 2019). Here we analyzed the onset time of neutrophil increase following Plin administration. In addition, we analyzed the impact of Plin on plasma haptoglobin, which is an acute phase protein with anti-inflammatory effects together with immune-enhancing effects and is an integral part of innate immunity (Kristiansen Nature 2001). Methods: Absolute neutrophil count (ANC) and haptoglobin data were analyzed from Phase 2 study BPI-2358-106 (NCT03294577) with 10 (n = 15), 20 (n = 15) and 30 mg/m2 (n = 12) Plin in Breast Cancer patients receiving TAC. Plin was administered on Day 1. ANC and Haptoglobin were analyzed by a Central Laboratory (Covance), from blood draws at predose, and post-dose Plin at Day 2,3,6,7,8,9,10,11,12,13 and 15, and changes relative to predose value were evaluated. Results: Plin dose-dependently increased ANC within 1 day (P < 0.001) and Haptoglobin within 3 days (P < 0.03) of dosing. Mean haptoglobin (P < 0.0005) and ANC (P < 0.001) levels increased with ~two-fold vs baseline levels. ANC levels remained increased for approximately 1 week and haptoglobin levels for > 3 weeks. Conclusions: Based on Plinabulin’s ability to stimulate the innate system, together with its previously reported evidence as a potent activator of the adaptive immune system (Mohanlal, ASCO-SITC 2017), it is concluded that Plinabulin is a potent stimulator of the adaptive and innate immune system. Clinical trial information: NCT03294577.
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van der Graaf, Chantal A. A., Mihai G. Netea, Ineke Verschueren, Jos W. M. van der Meer, and Bart Jan Kullberg. "Differential Cytokine Production and Toll-Like Receptor Signaling Pathways by Candida albicans Blastoconidia and Hyphae." Infection and Immunity 73, no. 11 (November 2005): 7458–64. http://dx.doi.org/10.1128/iai.73.11.7458-7464.2005.
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ABSTRACT Toll-like receptors (TLR) are crucial for an efficient antifungal defense. We investigated the differential recognition of blastoconidia and hyphae of Candida albicans by TLRs. In contrast to Candida blastoconidia, which stimulated large amounts of gamma interferon (IFN-γ), the tissue-invasive Candida hyphae did not stimulate any IFN-γ by human peripheral blood mononuclear cells (PBMC) or murine splenic lymphocytes. After stimulation with blastoconidia, the production of IFN-γ was TLR4 dependent, as shown by the significantly decreased IFN-γ production in anti-TLR4-treated PBMC and in splenic lymphocytes from TLR4-defective ScCr mice. In addition, peritoneal macrophages from ScCr mice produced less tumor necrosis factor α (TNF-α) than macrophages of control mice did when stimulated with Candida blastoconidia, but not with hyphae, indicating that TLR4-mediated signals are lost during hyphal germination. In contrast, macrophages from TLR2 knockout mice had a decreased production of TNF-α in response to both Candida blastoconidia and hyphae. Candida hyphae stimulated production of interleukin-10 through TLR2-dependent mechanisms. In conclusion, TLR4 mediates proinflammatory cytokine induction after Candida stimulation, whereas Candida recognition by TLR2 leads mainly to anti-inflammatory cytokine release. TLR4-mediated proinflammatory signals are lost during germination of Candida blastoconidia into hyphae. Phenotypic switching during germination may be an important escape mechanism of C. albicans, resulting in counteracting host defense.
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Munroe, Melissa E., Rufei Lu, Yan D. Zhao, Dustin A. Fife, Julie M. Robertson, Joel M. Guthridge, Timothy B. Niewold, et al. "Altered type II interferon precedes autoantibody accrual and elevated type I interferon activity prior to systemic lupus erythematosus classification." Annals of the Rheumatic Diseases 75, no. 11 (January 25, 2016): 2014–21. http://dx.doi.org/10.1136/annrheumdis-2015-208140.
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ObjectivesThe relationship of immune dysregulation and autoantibody production that may contribute to systemic lupus erythematosus (SLE) pathogenesis is unknown. This study evaluates the individual and combined contributions of autoantibodies, type I interferon (IFN-α) activity, and IFN-associated soluble mediators to disease development leading to SLE.MethodsSerial serum specimens from 55 individuals collected prior to SLE classification (average timespan=4.3 years) and unaffected healthy controls matched by age (±5 years), gender, race and time of sample procurement were obtained from the Department of Defense Serum Repository. Levels of serum IFN-α activity, IFN-associated mediators and autoantibodies were evaluated and temporal relationships assessed by growth curve modelling, path analysis, analysis of covariance and random forest models.ResultsIn cases, but not matched controls, autoantibody specificities and IFN-associated mediators accumulated over a period of years, plateauing near the time of disease classification (p<0.001). Autoantibody positivity coincided with or followed type II IFN dysregulation, preceding IFN-α activity in growth curve models, with elevated IFN-α activity and B-lymphocyte stimulator levels occurring shortly before SLE classification (p≤0.005). Cases were distinguished by multivariate random forest models incorporating IFN-γ, macrophage chemoattractant protein (MCP)-3, anti-chromatin and anti-spliceosome antibodies (accuracy 93% >4 years pre-classification; 97% within 2 years of SLE classification).ConclusionsYears before SLE classification, enhancement of the type II IFN pathway allows for accumulation of autoantibodies and subsequent elevations in IFN-α activity immediately preceding SLE classification. Perturbations in select immunological processes may help identify at-risk individuals for further clinical evaluation or participation in prospective intervention trials.
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Anderson, Anne J., and Young Cheol Kim. "The Plant-Stress Metabolites, Hexanoic Aacid and Melatonin, Are Potential “Vaccines” for Plant Health Promotion." Plant Pathology Journal 37, no. 5 (October 1, 2021): 415–27. http://dx.doi.org/10.5423/ppj.rw.01.2021.0011.
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A plethora of compounds stimulate protective mechanisms in plants against microbial pathogens and abiotic stresses. Some defense activators are synthetic compounds and trigger responses only in certain protective pathways, such as activation of defenses under regulation by the plant regulator, salicylic acid (SA). This review discusses the potential of naturally occurring plant metabolites as primers for defense responses in the plant. The production of the metabolites, hexanoic acid and melatonin, in plants means they are consumed when plants are eaten as foods. Both metabolites prime stronger and more rapid activation of plant defense upon subsequent stress. Because these metabolites trigger protective measures in the plant they can be considered as “vaccines” to promote plant vigor. Hexanoic acid and melatonin instigate systemic changes in plant metabolism associated with both of the major defense pathways, those regulated by SA- and jasmonic acid (JA). These two pathways are well studied because of their induction by different microbial triggers: necrosis-causing microbial pathogens induce the SA pathway whereas colonization by beneficial microbes stimulates the JA pathway. The plant’s responses to the two metabolites, however, are not identical with a major difference being a characterized growth response with melatonin but not hexanoic acid. As primers for plant defense, hexanoic acid and melatonin have the potential to be successfully integrated into vaccination-like strategies to protect plants against diseases and abiotic stresses that do not involve man-made chemicals.