Biology subjects

Husain, M. A.

Publications and source records attributed to Husain, M. A..

4 recordsLinked to original sources

bioRxiv2026

Targeting the RNA regulator HuR in acute traumatic brain injury mitigates secondary injury and improves functional outcome by suppressing neuroinflammation

Traumatic brain injury (TBI) affects ~2.5 million people annually in the US. Minutes after TBI, microglia and astrocytes initiate a neuroinflammatory cascade which promotes secondary injury via cytotoxicity, blood-brain barrier damage, edema, and immune cell recruitment. HuR, an RNA regulator, plays a critical role in the glial response by promoting the expression of proinflammatory mediators including IL-6, IL-1{beta}, TNF-, COX-2, CCL2, and CXCL1 via adenine and uridine-rich elements in the 3' untranslated region of their mRNAs. Here, we assessed SRI-42127, a small molecule HuR inhibitor developed by our group, on neuroinflammatory responses, secondary injury, and functional outcome after TBI. Male mice underwent controlled cortical impact (CCI) followed by peripheral administration of SRI-42127. Functional outcomes assessed included: motor function (balance beam/rotarod) and memory function (object location/recognition). Edema, lesion volume, and BBB permeability were assessed by MRI, brain water content, and Evans blue dye extravasation. HuR nucleocytoplasmic translocation, neuronal loss/apoptosis, microglial and astrocyte activation, and neutrophil infiltration were quantified by immunohistochemistry. Proinflammatory mediator induction was assessed by RT-qPCR and/or immunoblot. Results showed that SRI-42127 treatment improved spatial memory and fine motor performance in the first week in parallel with a reduction in edema, vascular permeability, lesion size, and neuronal loss/apoptosis. There was attenuated microglial activation and astrogliosis, decreased neutrophil infiltration, and suppression of proinflammatory mediator induction. Mechanistically, SRI-42127 inhibited HuR nucleocytoplasmic translocation in microglia and astrocytes. In summary, SRI-42127 potently suppresses neuroinflammation and secondary injury after TBI, improves functional outcomes, and identifies HuR as a new therapeutic target in TBI.

neuroscience↗

bioRxiv2024

Inhibition of the RNA Regulator HuR mitigates spinal cord injury by potently suppressing post-injury neuroinflammation

BackgroundNeuroinflammation plays a significant role in promoting secondary tissue injury after spinal cord trauma. Within minutes after spinal cord injury (SCI), microglia and astrocytes become activated and produce inflammatory mediators such as TNF-, IL-6, iNOS and COX-2 which induce tissue injury through cytotoxicity, vascular hyperpermeability, and secondary ischemia. The inflammatory cascade is amplified by chemokines such as CCL2 and CXCL1 that promote recruitment of peripheral inflammatory cells into the injured spinal cord. HuR is a key post-transcriptional RNA regulator that controls glial expression of many pro-inflammatory factors by binding to adenylate- and uridylate-rich elements in 3 untranslated regions of the mRNA. SRI-42127 is a small molecule inhibitor that blocks HuR nucleocytoplasmic translocation, a process critical for its regulatory function. The goal of this study was to assess the potential of SRI-42127 for suppressing neuroinflammation after SCI and improving functional outcome. MethodsAdult female mice underwent a contusion injury at the T10 level. SRI-42127 or vehicle was administered intraperitoneally starting 1 h after injury and up to 5 days. Locomotor function was assessed by open field testing, balance beam and rotarod. Immunohistochemistry was used to assess lesion size, neuronal loss, myelin sparing, microglial activation and HuR localization. Molecular analyses of spinal cord and peripheral tissues for expression of inflammatory mediators included qPCR, immunohistochemistry, ELISA, or western blot. Post-SCI pain was assessed by the mouse grimace scale. ResultsSRI-42127 significantly attenuated loss of locomotor function and post-SCI pain. Histologic correlates to these beneficial effects included reduced lesion size, neuronal loss, and an increase in myelin sparing. There was reduced microglial activation at the epicenter with concomitant attenuation of HuR nucleocytoplasmic translocation. Molecular analysis revealed a striking reduction of pro-inflammatory mediators at the epicenter including IL-6, MMP-12, IL-1{beta}, TNF-, iNOS, COX-2, and chemokines CCL2, CXCL1, and CXCL2. Suppression of inflammatory responses extended peripherally including serum, liver, and spleen. ConclusionTargeting HuR after SCI is a viable therapeutic approach for suppressing neuroinflammatory responses after tissue injury and improving functional outcome.

neuroscience↗

bioRxiv2023

Tracking the progression of Alzheimer's disease with peripheral blood monocytes

BackgroundAlzheimers disease (AD) is the most common form of dementia with the symptoms gradually worsening over the years. However, the driving pathological processes occur well before the appearance of symptoms. AD patients display signs of systemic inflammation, suggesting that it could precede the well-established AD hallmarks. We recently showed that the innate immune response in the form of monocyte activation is detectable at the pre-clinical stage. ObjectivesOur goal here is to characterize changes of gene expression in peripheral blood monocytes from patients at different stages of AD progression and validate potential biomarkers for a better prognosis and diagnosis of AD clinical spectrum. ResultsWe performed a whole transcriptome analysis on monocytes purified from healthy subjects, Mild Cognitive Impairment (MCI) and AD patients, and established the list of genes differentially expressed in monocytes during the disease evolution. We observed that, in the top 500 genes differentially expressed, a majority of these genes were upregulated (65%) during AD progression. These genes are mainly involved in chemokine/cytokine-mediated signaling pathways. We further confirmed several biomarkers by quantitative PCR and immunoblotting and showed that they are often deregulated at pre-clinical stages of the disease (MCI stage), supporting the hyperactivation of monocytes in MCI patients. PerspectivesOur findings provide evidence that the pre-clinical stage of AD can be detected in monocytes using a specific set of biomarkers, highlighting the importance to study the early innate immune response in AD. Our results open the possibility to use these biomarkers with different diagnostic methodologies to better predict and efficiently treat AD.

neuroscience↗

bioRxiv2022

Decoupling of mRNA and protein expression in aging brains reveals the age-dependent adaptation of specific gene subsets

During aging, changes in gene expression are associated with decline in physical and cognitive abilities. Here, we investigated the connection between changes of mRNA and protein expression in the brain by comparing the transcriptome and proteome of the mouse cortex during aging. Our transcriptomic analysis revealed that aging mainly triggers gene activation in the cortex. We showed that increase of mRNA expression correlates with protein expression, specifically in the anterior cingulate cortex where we also observed an increase of cortical thickness during aging. Genes exhibiting an aging-dependent increase of mRNA and protein levels are involved in sensory perception and immune functions. Our proteomic analysis also identified changes in protein abundance in the aging cortex and highlighted a subset of proteins that were differentially enriched but exhibited stable mRNA levels during aging, implying the contribution of aging-related post transcriptional and post-translational mechanisms. These specific genes were associated with general biological processes such as translation, ribosome assembly and protein degradation, but also important brain functions related to neuroplasticity. By decoupling mRNA and protein expression, we have thus characterized distinct subsets of genes that differentially adjust to cellular aging in the cerebral cortex.

biochemistry↗