scholarly journals A Critical Role for Immune System-released Activating Agent (Israa) in the Ontogenetic Development of the Brain

2020 ◽  
Author(s):  
Aminah M. I. Al-Awadi ◽  
Abdulaziz Isa AlJawder ◽  
Alyaa Mousa ◽  
Safa Taha ◽  
Moiz Bakhiet
Keyword(s):  
Immune System ◽  
Mouse Brain ◽  
Nuclear Translocation ◽  
Critical Role ◽  
Age Groups ◽  
Cytokine Network ◽  
Cellular Survival ◽  
Phosphorylated Proteins ◽  
Cell Age ◽  
Activating Agent

Abstract Background: The Immune System-Released Activating Agent (ISRAA) was discovered as a novel molecule that functions as a mediator between the nervous and immune systems in response to a nervous stimulus following an immune challenge. Thisresearch investigated the role ofISRAA)in promoting the ontogeny of the mouse brain. Methods: Astrocyte cultures were prepared from two-month-old BALB/c mice. Recombinant ISRAA protein was used to stimulate astrocyte cultures. Immunohistochemistry and ELISA were utilized to measure ISRAA andIFN-g levels, IFN-gR expression and STAT1 nuclear translocation. MTT-assay was used to evaluate cellular survival and proliferation. To assess astrocyte cell lysates and tyrosine-phosphorylated proteins, SDS-PAGE and western blot were used.Results: ISRAA was highly expressed in mouse embryonic astrocytes,depending on cell age. Astrocytes agedseven days (E7) showed increased proliferation and diminisheddifferentiation, while 21-day-old (E21)astrocytes depictedreversed effects. ISRAAstimulated the tyrosine phosphorylation of numerous cellular proteins and thenuclear translocation of STAT1. IFN-g was vital for ISRAAactionas ISRAA induced IFN-gin both age groups, but only E21 astrocytes expressed IFN-gR. Conclusion: The results suggest that ISRAA is cruciallyinvolved in mouse brain development through the cytokine network involving IFN-g.

scholarly journals A role for the immune system-released activating agent (ISRAA) in the ontogenetic development of brain astrocytes

2021 ◽  
Author(s):  
Aminah M. I. Al-Awadi ◽  
Abdulaziz Isa AlJawder ◽  
Alyaa Mousa ◽  
Safa Taha ◽  
Moiz Bakhiet
Keyword(s):  
Immune System ◽  
Mouse Brain ◽  
Nuclear Translocation ◽  
Age Groups ◽  
Cytokine Network ◽  
Cellular Survival ◽  
Phosphorylated Proteins ◽  
Cell Age ◽  
Activating Agent ◽  
Ifn Γ

AbstractThe Immune System-Released Activating Agent (ISRAA) was discovered as a novel molecule that functions as a mediator between the nervous and immune systems in response to a nervous stimulus following an immune challenge. This research investigated the role of ISRAA) in promoting the ontogeny of the mouse brain astrocytes. Astrocyte cultures were prepared from two-month-old BALB/c mice. Recombinant ISRAA protein was used to stimulate astrocyte cultures. Immunohistochemistry and ELISA were utilized to measure ISRAA and IFN-γ levels, IFN-γR expression and STAT1 nuclear translocation. MTT-assay was used to evaluate cellular survival and proliferation. To assess astrocyte cell lysates and tyrosine-phosphorylated proteins, SDS-PAGE and western blot were used. ISRAA was highly expressed in mouse embryonic astrocytes, depending on cell age. Astrocytes aged seven days (E7) showed increased proliferation and diminished differentiation, while 21-day-old (E21) astrocytes depicted reversed effects. ISRAA stimulated the tyrosine phosphorylation of numerous cellular proteins and the nuclear translocation of STAT1. IFN-γ was involved in the ISRAA action as ISRAA induced IFN-γ in both age groups, but only E21 astrocytes expressed IFN-γR. The results suggest that ISRAA is involved in mouse brain development through the cytokine network involving IFN-γ.

scholarly journals A role for the immune system-released activating agent (ISRAA) in the ontogenetic development of brain astrocytes

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0248455
Author(s):  
Aminah M. I. Al-Awadi ◽  
Abdulaziz Isa AlJawder ◽  
Alyaa Mousa ◽  
Safa Taha ◽  
Moiz Bakhiet
Keyword(s):  
Immune System ◽  
Mouse Brain ◽  
Nuclear Translocation ◽  
Age Groups ◽  
Cytokine Network ◽  
Cellular Survival ◽  
Phosphorylated Proteins ◽  
Cell Age ◽  
Activating Agent ◽  
Ifn Γ

The Immune System-Released Activating Agent (ISRAA) was discovered as a novel molecule that functions as a mediator between the nervous and immune systems in response to a nervous stimulus following an immune challenge. This research investigated the role of ISRAA) in promoting the ontogeny of the mouse brain astrocytes. Astrocyte cultures were prepared from two-month-old BALB/c mice. Recombinant ISRAA protein was used to stimulate astrocyte cultures. Immunohistochemistry and ELISA were utilized to measure ISRAA and IFN-γ levels, IFN-γR expression and STAT1 nuclear translocation. MTT-assay was used to evaluate cellular survival and proliferation. To assess astrocyte cell lysates and tyrosine-phosphorylated proteins, SDS-PAGE and western blot were used. ISRAA was highly expressed in mouse embryonic astrocytes, depending on cell age. Astrocytes aged seven days (E7) showed increased proliferation and diminished differentiation, while 21-day-old (E21) astrocytes depicted reversed effects. IFN-γ was involved in the ISRAA action as ISRAA induced IFN-γ in both age groups, but only E21 astrocytes expressed IFN-γR. ISRAA stimulation of E21 resulted in tyrosine phosphorylation of numerous cellular proteins and the nuclear translocation of STAT1, a signalling pathway utilized by IFN-γ. The results suggest that ISRAA is involved in mouse brain development through the cytokine network involving IFN-γ.

Assessment of Risk Factors for Severe Coronavirus Disease 2019 among Iranian Patients

2020 ◽  
Keyword(s):  
Risk Factors ◽  
Immune System ◽  
Medical Records ◽  
Critical Role ◽  
Diabetic Patients ◽  
Medication History ◽  
Epidemiological Features ◽  
Hookah Smoking ◽  
And Behavior ◽  
Iranian Patients

Background: The outbreak of Coronavirus Disease 2019 (COVID-19) has led to a major concern for those who are more vulnerable to infections. Objectives: This study aimed to evaluate the most important risk factors for severe COVID-19 pneumonia. Methods: This retrospective study included information on clinical and epidemiological features of 105 patients with severe COVID-19 pneumonia hospitalized in Tajrish Hospital, Tehran, Iran. Initially, the medical records of the patients were investigated, and an interview was conducted based on a pre-prepared checklist to seek information about symptoms, past medical history, medication history, and behavior before hospitalization. Results: Out of 105 participants, 76 (72.5%) cases were male, and 54 (51.4%) patients were older than 54 years old. The majority of the patients (n=18; 17.1%) had both hypertension and diabetes (n=12; 11.4%). Metformin (n=36; 34.3%) was the most used medication amongst the studied patient. In addition, 24 (22.9%) patients were recreational hookah smokers, and the majority (75%) of them were under the age of 46 years old. Eventually, 19 patients were excluded from the study, of whom 11 individuals had diabetes, and 10 cases were using metformin. Conclusion: Apparently, hookah smoking played a critical role in the spread of COVID-19 in Iran and has made younger people more susceptible. In addition to older age, the immunosuppressive effects of Metformin seem to make diabetic patients with an impaired immune system more vulnerable to severe COVID-19 pneumonia. More studies on the immune system of vulnerable individuals by identifying their differences can help to protect them.

Efficacy of one-dose intramuscular rabies vaccine as pre-exposure prophylaxis in travellers

2021 ◽  
Author(s):  
Deborah J Mills ◽  
Colleen L Lau ◽  
Christine Mills ◽  
Luis Furuya-Kanamori
Keyword(s):  
Immune System ◽  
Rapid Development ◽  
Age Groups ◽  
Rabies Vaccine ◽  
Post Exposure Prophylaxis ◽  
Post Intervention ◽  
Quasi Experimental ◽  
Alternative Schedule ◽  
Insufficient Time ◽  
Exposure Prophylaxis

Abstract Background Current guidelines for rabies pre-exposure prophylaxis (PrEP) recommend multiple vaccine doses. Travellers sometimes present for pre-travel consultation with insufficient time to complete standard PrEP schedules. We investigated the efficacy of one-dose intramuscular (IM) vaccine in priming the immune system (as PrEP) by measuring antibody response to simulated post-exposure prophylaxis (PEP). Methods A quasi-experimental pre–post intervention clinical trial was conducted at a specialist travel clinic in Australia. Adults (≥18 years) without a history of rabies vaccination were included. At Visit 1, seronegative status was confirmed and one dose of 0.5 ml IM rabies vaccine (Verorab®) administered. At Visit 2 (≥60 days after Visit 1), serology was repeated and a simulated PEP dose (0.5 ml IM) given on this day and again 3 days later (Visit 3). Serology was repeated at Visit 4 (7 days after Visit 2). Results A total of 94 antibody-negative participants were included (<50 years [n = 50]; ≥50 years [n = 44]). At Visit 2, 38.0 and 31.8% of participants aged <50 and ≥50 years were antibody-positive (≥0.5 EU/ml). At Visit 4, all participants were antibody-positive; 82.0 and 47.7% of participants aged <50 and ≥50 years had antibody levels >4 EU/ml, respectively. Conclusions One-dose IM vaccine was effective as PrEP for priming the immune system in both age groups, resulting in rapid development of antibodies 7 days after commencing simulated PEP. If there is insufficient time to complete a standard PrEP schedule, one-dose IM could be considered as an alternative schedule for short trips, rather than not offering travellers any doses at all. Clinical trials registration: ACTRN12619000946112.

scholarly journals Why Does SARS-CoV-2 Infection Induce Autoantibody Production?

Pathogens ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 380
Author(s):  
Ales Macela ◽  
Klara Kubelkova
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Host Cell ◽  
Critical Role ◽  
Cell Interaction ◽  
Immune Recognition ◽  
Autoantibody Production ◽  
Host Cell Interaction ◽  
Primary Virus

SARS-CoV-2 infection induces the production of autoantibodies, which is significantly associated with complications during hospitalization and a more severe prognosis in COVID-19 patients. Such a response of the patient’s immune system may reflect (1) the dysregulation of the immune response or (2) it may be an attempt to regulate itself in situations where the non-infectious self poses a greater threat than the infectious non-self. Of significance may be the primary virus-host cell interaction where the surface-bound ACE2 ectoenzyme plays a critical role. Here, we present a brief analysis of recent findings concerning the immune recognition of SARS-CoV-2, which, we believe, favors the second possibility as the underlying reason for the production of autoantibodies during COVID-19.

scholarly journals Inhibition of RANKL-Induced Osteoclastogenesis by Novel Mutant RANKL

2021 ◽  
Vol 22 (1) ◽  
pp. 434
Author(s):  
Yuria Jang ◽  
Hong Moon Sohn ◽  
Young Jong Ko ◽  
Hoon Hyun ◽  
Wonbong Lim
Keyword(s):  
Nuclear Translocation ◽  
Critical Role ◽  
Osteoclast Differentiation ◽  
Point Mutations ◽  
Tartrate Resistant Acid Phosphatase ◽  
Mice Model ◽  
Gsk 3Β ◽  
Rank Signaling

Background: Recently, it was reported that leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also called GPR48) is another receptor for RANKL and was shown to compete with RANK to bind RANKL and suppress canonical RANK signaling during osteoclast differentiation. The critical role of the protein triad RANK–RANKL in osteoclastogenesis has made their binding an important target for the development of drugs against osteoporosis. In this study, point-mutations were introduced in the RANKL protein based on the crystal structure of the RANKL complex and its counterpart receptor RANK, and we investigated whether LGR4 signaling in the absence of the RANK signal could lead to the inhibition of osteoclastogenesis.; Methods: The effects of point-mutated RANKL (mRANKL-MT) on osteoclastogenesis were assessed by tartrate-resistant acid phosphatase (TRAP), resorption pit formation, quantitative real-time polymerase chain reaction (qPCR), western blot, NFATc1 nuclear translocation, micro-CT and histomorphological assay in wild type RANKL (mRANKL-WT)-induced in vitro and in vivo experimental mice model. Results: As a proof of concept, treatment with the mutant RANKL led to the stimulation of GSK-3β phosphorylation, as well as the inhibition of NFATc1 translocation, mRNA expression of TRAP and OSCAR, TRAP activity, and bone resorption, in RANKL-induced mouse models; and Conclusions: The results of our study demonstrate that the mutant RANKL can be used as a therapeutic agent for osteoporosis by inhibiting RANKL-induced osteoclastogenesis via comparative inhibition of RANKL. Moreover, the mutant RANKL was found to lack the toxic side effects of most osteoporosis treatments.

scholarly journals Immune System Efficiency in Cancer and the Microbiota Influence

Pathobiology ◽  
2021 ◽  
pp. 1-17
Author(s):  
Ana Margarida Barbosa ◽  
Alexandra Gomes-Gonçalves ◽  
António G. Castro ◽  
Egídio Torrado
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Immune Checkpoint Inhibitors ◽  
Therapeutic Response ◽  
Checkpoint Inhibitors ◽  
Critical Role ◽  
Antitumor Immune Response ◽  
System Efficiency ◽  
Novel Targets ◽  
Cancer Immunosurveillance

The immune system plays a critical role in preventing cancer development and progression. However, the complex network of cells and soluble factor that form the tumor microenvironment (TME) can dictate the differentiation of tumor-infiltrating leukocytes and shift the antitumor immune response into promoting tumor growth. With the advent of cancer immunotherapy, there has been a reinvigorated interest in defining how the TME shapes the antitumor immune response. This interest brought to light the microbiome as a novel player in shaping cancer immunosurveillance. Indeed, accumulating evidence now suggests that the microbiome may confer susceptibility or resistance to certain cancers and may influence response to therapeutics, particularly immune checkpoint inhibitors. As we move forward into the age of precision medicine, it is vital that we define the factors that influence the interplay between the triad immune system-microbiota-cancer. This knowledge will contribute to improve the therapeutic response to current approaches and will unravel novel targets for immunotherapy.

scholarly journals EGF receptor–mediated FUS phosphorylation promotes its nuclear translocation and fibrotic signaling

2020 ◽  
Vol 219 (9) ◽  
Author(s):  
Manuel Chiusa ◽  
Wen Hu ◽  
Jozef Zienkiewicz ◽  
Xiwu Chen ◽  
Ming-Zhi Zhang ◽  
...  
Keyword(s):  
Egf Receptor ◽  
Nuclear Translocation ◽  
Collagen Iv ◽  
Phosphorylation Sites ◽  
Kidney Fibrosis ◽  
Antifibrotic Therapy ◽  
Phosphorylated Proteins ◽  
Fused In Sarcoma ◽  
A Cell ◽  
Excessive Accumulation

Excessive accumulation of collagen leads to fibrosis. Integrin α1β1 (Itgα1β1) prevents kidney fibrosis by reducing collagen production through inhibition of the EGF receptor (EGFR) that phosphorylates cytoplasmic and nuclear proteins. To elucidate how the Itgα1β1/EGFR axis controls collagen synthesis, we analyzed the levels of nuclear tyrosine phosphorylated proteins in WT and Itgα1-null kidney cells. We show that the phosphorylation of the RNA-DNA binding protein fused in sarcoma (FUS) is higher in Itgα1-null cells. FUS contains EGFR-targeted phosphorylation sites and, in Itgα1-null cells, activated EGFR promotes FUS phosphorylation and nuclear translocation. Nuclear FUS binds to the collagen IV promoter, commencing gene transcription that is reduced by inhibiting EGFR, down-regulating FUS, or expressing FUS mutated in the EGFR-targeted phosphorylation sites. Finally, a cell-penetrating peptide that inhibits FUS nuclear translocation reduces FUS nuclear content and collagen IV transcription. Thus, EGFR-mediated FUS phosphorylation regulates FUS nuclear translocation and transcription of a major profibrotic collagen gene. Targeting FUS nuclear translocation offers a new antifibrotic therapy.

scholarly journals LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies

2020 ◽  
Vol 12 (565) ◽  
pp. eaay0399
Author(s):  
Changyoun Kim ◽  
Alexandria Beilina ◽  
Nathan Smith ◽  
Yan Li ◽  
Minhyung Kim ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Critical Role ◽  
Lewy Bodies ◽  
Neuronal Loss ◽  
Activated T Cells ◽  
Behavioral Deficits ◽  
Downstream Signaling ◽  
Toll Like Receptor 2 ◽  
Factor Α

Synucleinopathies are neurodegenerative disorders characterized by abnormal α-synuclein deposition that include Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. The pathology of these conditions also includes neuronal loss and neuroinflammation. Neuron-released α-synuclein has been shown to induce neurotoxic, proinflammatory microglial responses through Toll-like receptor 2, but the molecular mechanisms involved are poorly understood. Here, we show that leucine-rich repeat kinase 2 (LRRK2) plays a critical role in the activation of microglia by extracellular α-synuclein. Exposure to α-synuclein was found to enhance LRRK2 phosphorylation and activity in mouse primary microglia. Furthermore, genetic and pharmacological inhibition of LRRK2 markedly diminished α-synuclein–mediated microglial neurotoxicity via lowering of tumor necrosis factor–α and interleukin-6 expression in mouse cultures. We determined that LRRK2 promoted a neuroinflammatory cascade by selectively phosphorylating and inducing nuclear translocation of the immune transcription factor nuclear factor of activated T cells, cytoplasmic 2 (NFATc2). NFATc2 activation was seen in patients with synucleinopathies and in a mouse model of synucleinopathy, where administration of an LRRK2 pharmacological inhibitor restored motor behavioral deficits. Our results suggest that modulation of LRRK2 and its downstream signaling mediator NFATc2 might be therapeutic targets for treating synucleinopathies.

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