Advancements in nano-enabled therapeutics for neuroHIV management

This viewpoint is a global call to promote fundamental and applied research aiming toward designing smart nanocarriers of desired properties, novel noninvasive strategies to open the blood–brain barrier (BBB), delivery/release of single/multiple therapeutic agents across the BBB to eradicate neurohuman immunodeficiency virus (HIV), strategies for on-demand site-specific release of antiretroviral therapy, developing novel nanoformulations capable to recognize and eradicate latently infected HIV reservoirs, and developing novel smart analytical diagnostic tools to detect and monitor HIV infection. Thus, investigation of novel nanoformulations, methodologies for site-specific delivery/release, analytical methods, and diagnostic tools would be of high significance to eradicate and monitor neuroacquired immu-nodeficiency syndrome. Overall, these developments will certainly help to develop personalized nanomedicines to cure HIV and to develop smart HIV-monitoring analytical systems for disease management

Nanostructured Gas Sensors for Health Care: An Overview

Nanostructured platforms have been utilized for fabrication of small, sensitive and reliable gas sensing devices owing to high functionality, enhanced charge transport and electro-catalytic property. As a result of globalization, rapid, sensitive and selective detection of gases in environment is essential for health care and security. Nonmaterial such as metal, metal oxides, organic polymers, and organic-inorganic hybrid nanocomposites exhibit interesting optical, electrical, magnetic and molecular properties, and hence are found potential gas sensing materials. Morphological, electrical, and optical properties of such nanostructures can be tailored via controlling the precursor concentration and synthesis conditions resulting to achieve desired sensing. This review presents applications of nano-enabling gas sensors to detect gases for environment monitoring. The recent update, challenges, and future vision for commercial applications of such sensor are also described here

Sustained-release nanoAR T formulation for the treatment of neuroAIDS

A novel approach was developed for the coencapsulation of an anti-HIV drug (tenofovir) and a latency-breaking agent (vorinostat), using magnetically guided layer-by-layer (LbL) assembled nanocarriers for the treatment of neuroAIDS. Ultrasmall iron oxide (Fe3O4) nanoparticles (10±3 nm) were synthesized and characterized. The LbL technique was used to achieve a sustained release profile, and application of 2 bilayers ([tenofovir+dextran sulphate]2+vorinostat)to magnetic nanoparticles resulted in a 2.8 times increase in drug (tenofovir) loading and also resulted in an increase in the drug release period by 30-fold, with 100% drug release in sustained manner over a period of 5 days with the simultaneous stimulation of latent HIV expression. Nanoformulation showed a good blood–brain barrier transmigration ability (37.95%±1.5%) with good in vitro antiviral efficacy (~33% reduction of p24 level) over a period of 5 days after HIV infection in primary human astrocytes, with good cell viability (.90%). Hence, LbL arrangements of drugs on magnetic nanoparticles provides sustained release and, therefore, may improve the patient’s adherence to therapy and lead to better compliance

Electrochemical sensing method for point-of-care cortisol detection in human immunodeficiency virus-infected patients

A novel electrochemical sensing method was devised for the first time to detect plasma cortisol, a potential psychological stress biomarker, in human immunodeficiency virus (HIV)-positive subjects. A miniaturized potentiostat (reconfigured LMP91000 chip) interfaced with a microfluidic manifold containing a cortisol immunosensor was employed to demonstrate electrochemical cortisol sensing. This fully integrated and optimized electrochemical sensing device exhibited a wide cortisol-detection range from 10 pg/mL to 500 ng/mL, a low detection limit of 10 pg/mL, and sensitivity of 5.8 μA (pg mL)-1, with a regression coefficient of 0.995. This cortisol-selective sensing system was employed to estimate plasma cortisol in ten samples from HIV patients. The electrochemical cortisol-sensing performance was validated using an enzyme-linked immunosorbent assay technique. The results obtained using both methodologies were comparable within 2%–5% variation. The information related to psychological stress of HIV patients can be correlated with disease-progression parameters to optimize diagnosis, therapeutic, and personalized health monitoring

Development of TIMP1 magnetic nanoformulation for regulation of synaptic plasticity in HIV-1 infection

Although the introduction of antiretroviral therapy has reduced the prevalence of severe forms of neurocognitive disorders, human immunodeficiency virus (HIV)-1-associated neurocognitive disorders were observed in 50% of HIV-infected patients globally. The blood–brain barrier is known to be impermeable to most of antiretroviral drugs. Successful delivery of antiretroviral drugs into the brain may induce an inflammatory response, which may further induce neurotoxicity. Therefore, alternate options to antiretroviral drugs for decreasing the HIV infection and neurotoxicity may help in reducing neurocognitive impairments observed in HIV-infected patients. In this study, we explored the role of magnetic nanoparticle (MNP)-bound tissue inhibitor of metalloproteinase-1 (TIMP1) protein in reducing HIV infection levels, oxidative stress, and recovering spine density in HIV-infected SK-N-MC neuroblastoma cells. We did not observe any neuronal cytotoxicity with either the free TIMP1 or MNP-bound TIMP1 used in our study. We observed significantly reduced HIV infection in both solution phase and in MNP-bound TIMP1-exposed neuronal cells. Furthermore, we also observed significantly reduced reactive oxygen species production in both the test groups compared to the neuronal cells infected with HIV alone. To observe the effect of both soluble-phase TIMP1 and MNP-bound TIMP1 on spine density in HIV-infected neuronal cells, confocal microscopy was used. We observed significant recovery of spine density in both the test groups when compared to the cells infected with HIV alone, indicting the neuroprotective effect of TIMP1. Therefore, our results suggest that the MNP-bound TIMP1 delivery method across the blood–brain barrier can be used for reducing HIV infectivity in brain tissue and neuronal toxicity in HIV-infected patients

Effect of Cocaine on HIV Infection and Inflammasome Gene Expression Profile in HIV Infected Macrophages

We have observed significantly increased HIV infection in HIV infected macrophages in the presence of cocaine that could be due to the downregulation of BST2 restriction factor in these cells. In human inflammasome PCR array, among different involved in inflammasome formation, in HIV infected macrophages in the presence of cocaine, we have observed significant upregulation of NLRP3, AIM2 genes and downstream genes IL-1? and PTGS2. Whereas negative regulatory gene MEFV was upregulated, CD40LG and PYDC1 were significantly downregulated. Among various NOD like receptors, NOD2 was significantly upregulated in both HIV alone and HIV plus cocaine treated cells. In the downstream genes, chemokine (C-C motif) ligand 2 (CCL2), CCL7 and IL-6 were significantly up regulated in HIV plus cocaine treated macrophages. We have also observed significant ROS production (in HIV and/or cocaine treated cells) which is one of the indirect-activators of inflammasomes formation. Further, we have observed early apoptosis in HIV alone and HIV plus cocaine treated macrophages which may be resultant of inflammasome formation and cspase-1 activation. These results indicate that in case of HIV infected macrophages exposed to cocaine, increased ROS production and IL-1? transcription serve as an activators for the formation of NLRP3 and AIM2 mediated inflammasomes that leads to caspase 1 mediated apoptosis

Investigation of ac-magnetic field stimulated nanoelectroporation of magneto-electric nano-drug-carrier inside CNS cells

In this research, we demonstrate cell uptake of magneto-electric nanoparticles (MENPs) through nanoelectroporation (NEP) using alternating current (ac)-magnetic field stimulation. Uptake of MENPs was confirmed using focused-ion-beam assisted transmission electron microscopy (FIB-TEM) and validated by a numerical simulation model. The NEP was performed in microglial (MG) brain cells, which are highly sensitive for neuro-viral infection and were selected as target for nano-neuro-therapeutics. When the ac-magnetic field optimized (60 Oe at 1?kHz), MENPs were taken up by MG cells without affecting cell health (viability?\u3e?92%). FIB-TEM analysis of porated MG cells confirmed the non-agglomerated distribution of MENPs inside the cell and no loss of their elemental and crystalline characteristics. The presented NEP method can be adopted as a part of future nanotherapeutics and nanoneurosurgery strategies where a high uptake of a nanomedicine is required for effective and timely treatment of brain diseases

Withaferin A Suppresses Beta Amyloid in APP Expressing Cells: Studies for Tat and Cocaine Associated Neurological Dysfunctions

Neurological disorders are the biggest concern globally. Out of ~36 million human immunodeficiency virus (HIV) positive people, about 30%–60% exhibit neurological disorders, including dementia and Alzheimer’s disease (AD) like pathology. In AD or AD like neurological disorders, the pathogenesis is mainly due to the abnormal accumulation of extracellular amyloid beta (Aβ). In this era of antiretroviral therapy, the life span of the HIV-infected individuals has increased leading towards increased neurocognitive dysfunction in nearly 30% of HIV-infected individuals, specifically older people. Deposition of the Aβ plaques in the CNS is one the major phenomenon happening in aging HIV patients. ART suppresses the viral replication, but the neurotoxic protein (Tat) is still produced and results in increased levels of Aβ. Furthermore, drugs of abuse like cocaine (coc) is known to induce the HIV associated neurocognitive disorders as well as the Aβ secretion. To target the Tat and coc induced Aβ secretion, we propose a potent bifunctional molecule Withaferin A (WA) which may act as a neuro-protectant against Aβ neurotoxicity. In this study, we show that WA reduces secreted Aβ and induced neurotoxicity in amyloid precursor protein (APP)-plasmid transfected SH-SY5Y cells (SH-APP). In this study, we show that in SH-APP cells, Aβ secretion is induced in the presence of HIV-1 Tat (neurotoxic) and drug of abuse coc. Our fluorescent microscopy studies show the increased concentration of Aβ40 in Tat (50 ng/ml) and coc (0.1 μM) treated SH-APP cells as compared to control. Our dose optimization study show, lower concentrations (0.5–2 μM) of WA significantly reduce the Aβ40 levels, without inducing cytotoxicity in the SH-APP cells. Additionally, WA reduces the Tat and cocaine induced Aβ levels. Therefore, we propose that Aβ aggregation is induced by the presence of Tat and coc and WA is potent in reducing the secreted Aβ and induced neurotoxicity. Our study provides new opportunities for exploring the pathophysiology and targeting the neurological disorders

Effect of human immunodeficiency virus on blood-brain barrier integrity and function: an update

The blood-brain barrier (BBB) is a diffusion barrier that has an important role in maintaining a precisely regulated microenvironment protecting the neural tissue from infectious agents and toxins in the circulating system. Compromised BBB integrity plays a major role in the pathogenesis of retroviral associated neurological diseases. Human Immunodeficiency Virus (HIV) infection in the Central Nervous System (CNS) is an early event even before the serodiagnosis for HIV positivity or the initiation of antiretroviral therapy (ART), resulting in neurological complications in many of the infected patients. Macrophages, microglia and astrocytes (in low levels) are the most productively/latently infected cell types within the CNS. In this brief review, we have discussed about the effect of HIV infection and viral proteins on the integrity and function of BBB, which may contribute to the progression of HIV associated neurocognitive disorders