• Brain-targeting, acid-responsive antioxidant nanoparticles for stroke treatment and drug delivery

      Zhang, Shenqi; Peng, Bin; Chen, Zeming; Yu, Jiang; Deng, Gang; Bao, Youmei; Ma, Chao; Du, Fengyi; Sheu, Wendy C.; Kimberly, W. Taylor; et al. (KeAi Communications Co., 2022-01-01)
      Stroke is the leading cause of death and disability. Currently, there is no effective pharmacological treatment for this disease, which can be partially attributed to the inability to efficiently deliver therapeutics to the brain. Here we report the development of natural compound-derived nanoparticles (NPs), which function both as a potent therapeutic agent for stroke treatment and as an efficient carrier for drug delivery to the ischemic brain. First, we screened a collection of natural nanomaterials and identified betulinic acid (BA) as one of the most potent antioxidants for stroke treatment. Next, we engineered BA NPs for preferential drug release in acidic ischemic tissue through chemically converting BA to betulinic amine (BAM) and for targeted drug delivery through surface conjugation of AMD3100, a CXCR4 antagonist. The resulting AMD3100-conjugated BAM NPs, or A-BAM NPs, were then assessed as a therapeutic agent for stroke treatment and as a carrier for delivery of NA1, a neuroprotective peptide. We show that intravenous administration of A-BAM NPs effectively improved recovery from stroke and its efficacy was further enhanced when NA1 was encapsulated. Due to their multifunctionality and significant efficacy, we anticipate that A-BAM NPs have the potential to be translated both as a therapeutic agent and as a drug carrier to improve the treatment of stroke. © 2022 The Authors
    • Common coding variant in SERPINA1 increases the risk for large artery stroke

      Malik, R.; Dau, T.; Gonik, M. (National Academy of Sciences, 2017)
      Large artery atherosclerotic stroke (LAS) shows substantial heritability not explained by previous genome-wide association studies. Here, we explore the role of coding variation in LAS by analyzing variants on the HumanExome BeadChip in a total of 3,127 cases and 9,778 controls from Europe, Australia, and South Asia. We report on a nonsynonymous single-nucleotide variant in serpin family A member 1 (SERPINA1) encoding alpha-1 antitrypsin [AAT; p.V213A; P = 5.99E-9, odds ratio (OR) = 1.22] and confirm histone deacetylase 9 (HDAC9) as a major risk gene for LAS with an association in the 3?-UTR (rs2023938; P = 7.76E-7, OR = 1.28). Using quantitative microscale thermophoresis, we show that M1 (A213) exhibits an almost twofold lower dissociation constant with its primary target human neutrophil elastase (NE) in lipoprotein-containing plasma, but not in lipid-free plasma. Hydrogen/deuterium exchange combined with mass spectrometry further revealed a significant difference in the global flexibility of the two variants. The observed stronger interaction with lipoproteins in plasma and reduced global flexibility of the Val-213 variant most likely improve its local availability and reduce the extent of proteolytic inactivation by other proteases in atherosclerotic plaques. Our results indicate that the interplay between AAT, NE, and lipoprotein particles is modulated by the gate region around position 213 in AAT, far away from the unaltered reactive center loop (357-360). Collectively, our findings point to a functionally relevant balance between lipoproteins, proteases, and AAT in atherosclerosis.
    • Endovascular thrombectomy in acute-onset ischemic stroke-beyond the standard time windows: A case report and a review of the literature

      So, C.; Chaudhry, N.; Gandhi, D. (S. Karger AG, 2018)
      Endovascular thrombectomy following an acute ischemic stroke can lead to improved functional outcome when performed early. Current guidelines suggest treatment within 6 h after symptom onset. Recent studies including the DEFUSE-3 and DAWN trials demonstrate that some patients may benefit from thrombectomy up to 16 and 24 h after symptom onset, respectively. We present a case of delayed thrombectomy in a 43-year-old man with acute dysarthria, left-sided weakness, and visual neglect. Initial MRI/A demonstrated a small completed stroke and a thrombus in the right middle cerebral artery. Thirty-seven hours after symptom onset, his weakness acutely worsened. A repeat MRI revealed an unchanged core infarct volume and a cerebral angiogram suggested an abrupt occlusion of the right distal M1. Thrombectomy was performed with complete reperfusion and the patient's strength recovered following the procedure. We compared our clinical reasoning with the DEFUSE-3 and DAWN study criteria, and conclude that there is a subset of patients that may safely benefit from thrombectomy in later time windows beyond the trial criteria, especially in the setting of clinical examination of imaging mismatch. Copyright 2018 The Author(s). Published by S. Karger AG, Basel.
    • The interplay between COVID 19 and non-communicable diseases

      Chaturvedi, S.; Gorelick, P. (W.B. Saunders, 2020)
    • Myeloid-specific TAK1 deletion results in reduced brain monocyte infiltration and improved outcomes after stroke

      Chauhan, A.; Hudobenko, J.; Al Mamun, A. (BioMed Central Ltd., 2018)
      Background: Activation of transforming growth factor-β-activated kinase 1 (TAK1) occurs after stroke and leads to an exacerbation of brain injury. TAK1 is involved in innate and adaptive immune responses, but it has divergent inflammatory effects that are dependent on the cell type in which it is activated. There is a robust infiltration of myeloid cells after stroke; however, the contribution of myeloid TAK1 to cerebral ischemia is currently unknown. We hypothesized that myeloid-specific deletion of TAK1 would protect against ischemic brain injury. Methods: Myeloid TAK1ΔM and wild-type (WT) mice were subjected to middle cerebral artery occlusion (MCAo). Brain-infiltrating and splenic immune cells were evaluated at 3 days after stroke. Assessment of infarct size and behavioral deficits were performed on days 3 and 7 post-stroke. Results: Infarcts were significantly smaller in TAK1ΔM mice (p < 0.01), and behavioral deficits were less severe despite equivalent reduction in cerebral blood flow. Flow cytometry demonstrated an increase in the frequency of splenic monocytes and neutrophils (p < 0.05) and a decrease in splenic CD3+ T (p < 0.01) and CD19+ B (p = 0.06) cells in TAK1ΔM mice compared to WT at baseline. Three days after stroke, a significant increase in the number of brain-infiltrating immune cell was observed in both TAK1ΔM (p < 0.05) and WT (p < 0.001) mice compared to their respective shams. However, there was a significant decrease in the infiltrating CD45hi immune cell counts (p < 0.05), with a pronounced reduction in infiltrating monocytes (p < 0.001) in TAK1ΔM after stroke compared to WT stroke mice. Additionally, a significant reduction in CD49d+ monocytes was seen in the brains of TAK1ΔM stroke mice compared to wild-type mice. Importantly, TAK1ΔM MCAo mice had smaller infarcts and improved behavioral outcomes at day 7 post-stroke. Conclusion: Our results showed that deletion of myeloid TAK1 resulted in smaller infarcts and improved functional outcomes at the peak of inflammation (day 3) and a reduction in brain-infiltrating immune cells that were primarily monocytes. Myeloid TAK1 deletion was also protective at 7 days post MCAo, reflecting a detrimental role of myeloid TAK1 in the progression of ischemic injury. Copyright 2018 The Author(s).