The potent immunomodulatory compound VGX-1027 regulates inflammatory mediators in CD4+ T cells, which are concomitant with the prevention of neuroimmune dysregulation in BTBR T+ Itpr3tf/J mice

Ahmad, Sheikh F.; Nadeem, Ahmed; Ansari, Mushtaq Ahmad; Bakheet, Saleh A.; Alasmari, Fawaz; Alasmari, Abdullah F.; Al-Kharashi, Layla A.; Alqahtani, Qamraa Hamad; Attia, Sabry M.

doi:10.1016/j.lfs.2019.116930

Cited by 14 publications

(7 citation statements)

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“…T cells play a key role in secretion of many cytokines and regulation during local immune responses and can influence CNS functions such as cognitive and behavioural functions 32,33 . Promotion of anti‐inflammatory products and inhibition of inflammation could improve immune function of BTBR T Cells and ameliorate autism‐like symptoms 16,34 …”

Section: Discussionmentioning

confidence: 99%

“…32,33 Promotion of antiinflammatory products and inhibition of inflammation could improve immune function of BTBR T Cells and ameliorate autism-like symptoms. 16,34 Activated T cells can cross the blood-CSF barrier and enter the subarachnoid space. There are two major T cell subsets: CD8 + cytotoxic T cells, which detect antigens presented by MHC I molecules, and CD4 + helper T cells, which detect antigens produced by APCs (including dendritic cells, macrophages, and B cells) and processed antigenic fragments are presented to the Th subsets by MHC-II mole-…”

Section: Discussionmentioning

confidence: 99%

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Constitutive activation of Notch signalling and T cell activation characterize a mouse model of autism

Yao

Uddin

Manley

et al. 2022

Cell Biochemistry & Function

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Gene and protein expression of BTBR T+ Itpr3tf/J (BTBR) mice with autistic‐like behaviours were compared with the C57BL/6J strain, which is considered to have normal immunity and behaviour. Notch signalling pathway was constitutively activated in the immune system and liver of BTBR T+ Itpr3tf/J (BTBR) mice. Notch ligand 4 (Dll4), Notch receptors (Notch1 Notch2 and Notch3) and recombination signal binding protein for immunoglobulin κ j region (RBPJ) were increased both at gene and protein levels in BTBR spleens and thymi. Notch downstream transcriptional factors, Tbx21, Gata3, Rorc and FoxP3 were increased in BTBR spleens, Gata3 and FoxP3 were increased in BTBR thymi and BTBR mice have a high blood CD4/CD8 T cell ratio. Reduced nucleotide excision repair ability in BTBR spleens was associated with increased 8‐oxoguanine, Ogg1 inhibition, an enhanced level of apoptotic thymocytes and higher expression of GATA‐3. Ogg1 inhibition and enhanced GATA‐3 expression also were detected in BTBR brain. Notch signal promoted mitochondrial dynamics switching to enhanced fission with an increased number and mass of mitochondria in immune cells of BTBR mice, but not in livers and brains. Constitutive influences on mitochondria exist in this mouse model of autism spectrum disorder; similar outcomes from environmental exposures might occur perinatally in susceptible individuals to affect the development of autism.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Constitutive activation of Notch signalling and T cell activation characterize a mouse model of autism

Yao

Uddin

Manley

et al. 2022

Cell Biochemistry & Function

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“…In summary, proinflammatory factors may be the mediator between immune dysfunction and RRBs. Many pharmacological studies of RRBs were based on immune abnormalities in ASD ( Ahmad et al, 2019 ). For example, Mirza and Sharma (2019b) found that pioglitazone reduced oxidative stress and nerve inflammation in related brain regions and improved propionic acid-induced neurobehavioral and biochemical impairments in rats.…”

Section: Mechanism Of Repetitive Restricted Behaviorsmentioning

confidence: 99%

Repetitive Restricted Behaviors in Autism Spectrum Disorder: From Mechanism to Development of Therapeutics

2022

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Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by deficits in social communication, social interaction, and repetitive restricted behaviors (RRBs). It is usually detected in early childhood. RRBs are behavioral patterns characterized by repetition, inflexibility, invariance, inappropriateness, and frequent lack of obvious function or specific purpose. To date, the classification of RRBs is contentious. Understanding the potential mechanisms of RRBs in children with ASD, such as neural connectivity disorders and abnormal immune functions, will contribute to finding new therapeutic targets. Although behavioral intervention remains the most effective and safe strategy for RRBs treatment, some promising drugs and new treatment options (e.g., supplementary and cell therapy) have shown positive effects on RRBs in recent studies. In this review, we summarize the latest advances of RRBs from mechanistic to therapeutic approaches and propose potential future directions in research on RRBs.

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“…Numerous inflammatory and oxidative mediators are involved in the development of ALI. Increased expression of proinflammatory cytokines released from infiltrated neutrophils and T cells, including interleukin (IL)-1β, IL-6, IL-17A and tumor necrosis factor-α (TNF-α), further exacerbates pulmonary inflammation ( Ahmad et al, 2019 ; Nadeem et al, 2019 ; Ahmad et al, 2020 ). Excessive production of reactive oxygen species (ROS) by nicotinamide adenine dinucleotide phosphate oxidase activation in neutrophils is the other mechanism mediating ALI ( Nadeem et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Protease-Activated Receptor-1 Antagonist Protects Against Lung Ischemia/Reperfusion Injury

et al. 2021

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Protease-activated receptor (PAR)-1 is a thrombin-activated receptor that plays an essential role in ischemia/reperfusion (IR)-induced acute inflammation. PAR-1 antagonists have been shown to alleviate injuries in various IR models. However, the effect of PAR-1 antagonists on IR-induced acute lung injury (ALI) has not yet been elucidated. This study aimed to investigate whether PAR-1 inhibition could attenuate lung IR injury. Lung IR was induced in an isolated perfused rat lung model. Male rats were treated with the specific PAR-1 antagonist SCH530348 (vorapaxar) or vehicle, followed by ischemia for 40 min and reperfusion for 60 min. To examine the role of PAR-1 and the mechanism of SCH530348 in lung IR injury, western blotting and immunohistochemical analysis of lung tissue were performed. In vitro, mouse lung epithelial cells (MLE-12) were treated with SCH530348 or vehicle and subjected to hypoxia-reoxygenation (HR). We found that SCH530348 decreased lung edema and neutrophil infiltration, attenuated thrombin production, reduced inflammatory factors, including cytokine-induced neutrophil chemoattractant-1, interleukin-6 and tumor necrosis factor-α, mitigated lung cell apoptosis, and downregulated the phosphoinositide 3-kinase (PI3K), nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways in IR-injured lungs. In addition, SCH530348 prevented HR-induced NF-κB activation and inflammatory chemokine production in MLE12 cells. Our results demonstrate that SCH530348 exerts protective effects by blocking PAR-1 expression and modulating the downstream PI3K, NF-κB and MAPK pathways. These findings indicate that the PAR-1 antagonist protects against IR-induced ALI and is a potential therapeutic candidate for lung protection following IR injury.

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The potent immunomodulatory compound VGX-1027 regulates inflammatory mediators in CD4+ T cells, which are concomitant with the prevention of neuroimmune dysregulation in BTBR T+ Itpr3tf/J mice

Cited by 14 publications

References 61 publications

Constitutive activation of Notch signalling and T cell activation characterize a mouse model of autism

Constitutive activation of Notch signalling and T cell activation characterize a mouse model of autism

Repetitive Restricted Behaviors in Autism Spectrum Disorder: From Mechanism to Development of Therapeutics

Protease-Activated Receptor-1 Antagonist Protects Against Lung Ischemia/Reperfusion Injury

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