I n the span of a few months, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as the aetiological agent of coronavirus disease 2019 (COVID-19). Weeks later, viral diagnostic measures were deployed 1. This served to supplement the common disease signs and symptoms of COVID-19 of cough, fever and dyspnoea. As all are seen during seasonal upper respiratory tract infections 2 , precise diagnostic tests detect viral nucleic acids, viral antigens or serological tests are required to affirm SARS-CoV-2 infection 3. Chest computed tomography (CT) or magnetic resonance imaging (MRI) confirm disease manifestations 2,3. The signature of COVID-19 is the life-threatening acute respiratory distress syndrome (ARDS) 4. While the lung is the primary viral target, the cardiovascular, brain, kidney, liver and immune systems are commonly compromised by infection 5. Thus, due to significant COVID-19 morbidity and mortality, containment of viral transmission through contact tracing, clinical assessment and virus detection was implemented through social distancing, face masks, contact isolation and hand hygiene to limit SARS-CoV-2 transmission 6 .
Degeneration of the nigrostriatal dopaminergic pathway, the hallmark of Parkinson's disease, can be recapitulated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. Herein, we demonstrate that adoptive transfer of copolymer-1 immune cells to MPTP recipient mice leads to T cell accumulation within the substantia nigra pars compacta, suppression of microglial activation, and increased local expression of astrocyte-associated glial cell line-derived neurotrophic factor. This immunization strategy resulted in significant protection of nigrostriatal neurons against MPTPinduced neurodegeneration that was abrogated by depletion of donor T cells. Such vaccine treatment strategies may provide benefit for Parkinson's disease.
We investigate the hypothesis that oxidative damage of the cerebral vascular barrier interface (the blood brain barrier, BBB) causes the development of mild traumatic brain injury (mTBI) during primary blast wave spectrum. The underlying biochemical and cellular mechanisms of this vascular layer-structure injury are examined in a novel animal model of shock tube. We first established that low frequency (123 kPa) single or repeated shock wave causes BBB/brain injury through biochemical activation by acute mechanical force that occurs at 6–24 hrs after the exposure. This biochemical damage of the cerebral vasculature is initiated by the induction of free radical generating enzymes NADPH oxidase (NOX1) and inducible nitric oxide synthase (iNOS). Induction of these enzymes by shock wave exposure correlated well with the signatures of oxidative and nitrosative damage (4HNE/3NT) and reduction of the BBB tight junction (TJ) proteins occludin, claudin-5 and zonula occluden 1 (ZO-1) in the brain microvessel. In parallel with TJ protein disruption, the perivascular unit was significantly diminished by single or repeated shock wave exposure coinciding with the kinetic profile. Loosening of the vasculature and perivascular unit was mediated by oxidative stress-induced activation of matrix metalloproteinases and fluid channel aquaporin-4, promoting vascular fluid cavitation/edema, enhanced leakiness of the BBB and progression of neuroinflammation. The BBB leakiness and neuroinflammation were functionally demonstrated in an in vivo model by enhanced permeability of Na-Fl/EB low molecular weight tracers and the infiltration of immune cells across the BBB. The detection of brain cell matters NSE/S100β in the blood samples validated the neuro-astroglial injury in shock wave TBI. Our hypothesis that cerebral vascular injury occurring prior to the development of neurological disorders in mild TBI was further confirmed by the activation of caspase-3 and cell apoptosis mostly around the perivascular region. Thus, induction of oxidative stress and MMPs activation by shock wave underlies the mechanisms of cerebral vascular BBB leakage and neuroinflammation.
Complex dosing regimens, costs, side effects, biodistribution limitations, and variable drug pharmacokinetic patterns have affected the long-term efficacy of antiretroviral medicines. To address these problems, a nanoparticle indinavir (NP-IDV) formulation packaged into carrier bone marrow-derived macrophages (BMMs) was developed. Drug distribution and disease outcomes were assessed in immune-competent and human immunodeficiency virus type 1 (HIV-1)-infected humanized immune-deficient mice, respectively. In the former, NP-IDV formulation contained within BMMs was adoptively transferred. After a single administration, single-photon emission computed tomography, histology, and reverse-phasehigh-performance liquid chromatography (RP-HPLC) demonstrated robust lung, liver, and spleen BMMs and drug distribution. Tissue and sera IDV levels were greater than or equal to 50 M for 2 weeks. NP-IDV-BMMs administered to HIV-1-challenged humanized mice revealed reduced numbers of virus-infected cells in plasma, lymph nodes, spleen, liver, and lung, as well as, CD4 ؉ T-cell protection. We conclude that a single dose of NP-IDV, using BMMs as a carrier, is effective and warrants consideration for human testing. ( IntroductionDespite the significant impact of antiretroviral therapy (ART), the worldwide human immunodeficiency virus type 1 (HIV-1) pandemic continues to grow. [1][2][3] An estimated 40 million people globally are virus infected, with the majority from the developing world. [4][5][6] Although ART has reduced disease morbidity and increased life expectancy, drug expenses, treatment failures, and dosing complexities limit global access. [7][8][9] Multiple daily dosing regimens and untoward secondary side effects diminish achievement of significant long-term HIV-1 suppression in infected people. [10][11][12] Additionally, continuous viral suppression requires maintenance of therapeutically effective drug concentrations. [13][14][15] Most significantly, elimination of viral reservoirs in the infected human host has not yet been achieved. 16,17 To address these challenges to effective antiretroviral delivery, we designed a novel bone marrow-derived macrophage (BMM) pharmacologic nanoparticle (NP) delivery system. This system could provide a strategy to achieve therapeutic efficacy, improve drug distribution to areas of active viral replication, and extend dosing intervals. Because of the small size of the NPs and their highly stable nature, NPs could be packaged within macrophages for subsequent systemic trafficking and sustained drug distribution. We reasoned that such a cell-based drug delivery system could reflect the patterns of viral replication and improve therapeutic outcomes.To test this idea, we loaded indinavir (IDV) nanosuspension into BMMs and administered intravenously into naive mice. Cell tissue distribution was tracked by single-photon emission computed tomography (SPECT) and T 2 * weighted magnetic resonance imaging (MRI) of radio-and superparamagnetic iron oxide (SPIO; Feridex)-labeled BMMs, and confirme...
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