Therapeutic role of inflammasome inhibitors in neurodegenerative disorders.

Neuroinflammation, characterized by the activation of glial cells, is a hallmark in several neurological and neurodegenerative disorders. Inadequate inflammation cannot eliminate the infection of pathogens, while excessive or hyper-reactive inflammation can cause chronic or systemic inflammatory diseases affecting the central nervous system (CNS). In response to a brain injury or pathogen invasion, the pathogen recognition receptors (PRRs) expressed on glial cells are activated via binding to cellular damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs). This subsequently leads to the activation of NOD (nucleotide-binding oligomerization domain)-like receptor proteins (NLRs). In neurodegenerative diseases such as HIV-1-associated neurocognitive disorders (HAND), Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), chronic inflammation is a critical contributing factor for disease manifestation including pathogenesis. Emerging evidence points to the involvement of "inflammasomes", especially the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing (NLRP) complex in the development of these diseases. The activated NLRP3 results in the proteolytic activation of caspase-1 that facilitates the cleavage of pro-IL-1ß and the secretion of IL-1ß and IL-18 proinflammatory cytokines. Accordingly, these and other seminal findings have led to the development of NLRP-targeting small-molecule therapeutics as possible treatment options for neurodegenerative disorders. In this review, we will discuss the new advances and evidence-based literature concerning the role of inflammasomes in neurodegenerative diseases, its role in the neurological repercussions of CNS chronic infection, and the examples of preclinical or clinically tested NLRP inhibitors as potential strategies for the treatment of chronic neurological diseases.

Perspectives of characterization and bioconjugation of gold nanoparticles and their application in lateral flow immunosensing.

Gold nanoparticles (AuNPs) are an important component in the field of biomedical diagnostics. Because of its unique physicochemical properties, AuNPs have been widely used in biomedical applications such as photothermal cancer therapy, drug delivery, optical imaging, labeling, and biosensing. In this review, we have described synthesis and characterization techniques for AuNPs with recent advancements. Characterization of AuNPs has played an important role in directing its application in various fields and elaborated understanding of its functioning. The characterization techniques used for the analysis of AuNPs utilize its intrinsic properties, such as surface plasmon resonance (SPR) and size-dependent shift in absorption. These properties of AuNPs are furthermore used for the characterization of bioconjugated AuNPs. Surface conjugation of the AuNPs with biomolecules is explored widely for its use in numerous biosensing applications. Biosensor-based diagnostic devices use AuNPs conjugated with a sensing probe for the detection of a specific analyte. AuNPs are also commonly used as a colorimetric sensor in various point-of-care diagnostic techniques. Lateral flow immunosensing (LFIS) technique utilizes AuNPs for the rapid and sensitive detection of various analytes. LFIS is a paper-based detection technique, where the sample containing the analyte flows through the membrane, interacts with immobilized counterparts, and produces results using a detection probe. AuNPs are used as color markers in LFIS, and the presence of an analyte is indicated by the appearance of colored lines on the membrane. The color is a result of the accumulation of AuNP complexes containing the analyte and probe. Effect of characterization parameters of AuNPs on the sensitivity of LFIS, advantages, and disadvantages of using AuNPs for LFIS are discussed concerning the recent reports. Recent applications of AuNPs in LFIS development for the detection of various biomarkers are summarized comprehensively in the table. The review may offer significant insight into the utility of AuNPs for application in the LFIS technique for future development. Graphical abstract Schematic representation of the various applications of gold nanoparticles.

Development and Challenges of Nanotherapeutic Formulations for Targeting Mitochondrial Cell Death Pathways in Lung and Brain Degenerative Diseases.

Mitochondria are among the most dynamic organelles regulating a wide array of cellular processes. They are the cellular hub for oxidative phosphorylation, energy production, and cellular metabolism, and they are important determinants of cell fate, as they control cell death/survival pathways. The mitochondrial network plays a critical role in cellular inflammatory responses, and mitochondria are central in many pathologic conditions such as chronic inflammatory and aging-associated degenerative diseases. Recent advancements in our understanding of the pathogenic pathways and the role of mitochondria therein have identified highly specific therapeutic targets in order to develop personalized nanomedicine approaches for treatment. A wide array of nanoparticle-based formulations has been employed for potential usage in both diagnosing and treating chronic and fatal conditions, with gold nanoparticles and liposomal encapsulation being of particular interest. In this review, we highlight and summarize the advantages and challenges of developing these nanoformulations for targeted and spatiotemporally controlled drug delivery. We discuss the potential of nanotherapy in neoplasms to target the mitochondrial regulated cell death pathways and recent seminal developments in liposomal nanotherapy against chronic inflammatory lung diseases. The need for further development of nanoparticle-based treatment options for neuroinflammatory and neurodegenerative conditions, such as Alzheimer's disease (AD), is also discussed.

Biomaterials and cells for neural tissue engineering: Current choices.

The treatment of nerve injuries has taken a new dimension with the development of tissue engineering techniques. Prior to tissue engineering, suturing and surgery were the only options for effective treatment. With the advent of tissue engineering, it is now possible to design a scaffold that matches the exact biological and mechanical properties of the tissue. This has led to substantial reduction in the complications posed by surgeries and suturing to the patients. New synthetic and natural polymers are being applied to test their efficiency in generating an ideal scaffold. Along with these, cells and growth factors are also being incorporated to increase the efficiency of a scaffold. Efforts are being made to devise a scaffold that is biodegradable, biocompatible, conducting and immunologically inert. The ultimate goal is to exactly mimic the extracellular matrix in our body, and to elicit a combination of biochemical, topographical and electrical cues via various polymers, cells and growth factors, using which nerve regeneration can efficiently occur.

Electrochemical Biosensors for Early Stage Zika Diagnostics.

Health agencies have declared the recent Zika virus (ZIKV) infection an epidemic and a public health emergency of global concern due to its association with microcephaly and serious neurological disorders. The unavailability of effective drugs, vaccines, and diagnostic tools increases the demand for efficient analytical devices to detect ZIKV infection. However, high costs, longer diagnostic times, and stringent expertise requirements limit the utility of reverse transcriptase-PCR methods for rapid diagnostics. Therefore, developing portable, sensitive, selective, and cost-effective sensing systems to detect ZIKV at picomolar concentrations in biofluids would be a breakthrough in diagnostics and therapeutics. This paper highlights the advancements in developing smart sensing strategies to monitor ZIKV progression, with rapid point-of-care diagnostics as the ultimate aim.

Magnetically guided central nervous system delivery and toxicity evaluation of magneto-electric nanocarriers.

Least component-based delivery of drug-tagged-nanocarriers across blood-brain-barriers (BBB) will allow site-specific and on-demand release of therapeutics to prevent CNS diseases. We developed a non-invasive magnetically guided delivery of magneto-electric nanocarriers (MENCs), ~20 nm, 10 mg/kg, across BBB in C57Bl/J mice. Delivered MENCs were uniformly distributed inside the brain, and were non-toxic to brain and other major organs, such as kidney, lung, liver, and spleen, and did not affect hepatic, kidney and neurobehavioral functioning.

Therapeutical Neurotargeting via Magnetic Nanocarrier: Implications to Opiate-Induced Neuropathogenesis and NeuroAIDS.

Magnetite (Fe3O4) is the most commonly and extensively explored magnetic nanoparticles (MNPs) for drug-targeting and imaging in the field of biomedicine. Nevertheless, its potential application as safe and effective drug-carrier for CNS (Central Nervous System) anomalies is very limited. Previous studies have shown an entangled epidemic of opioid use and HIV infection and increased neuropathogenesis. Opiate such as morphine, heroine, etc. are used frequently as recreational drugs. Existing treatments to alleviate the action of opioid are less effective at CNS level due to impermeability of therapeutic molecules across brain barriers. Thus, development of an advanced nanomedicine based approach may pave the way for better treatment strategies. We herein report magnetic nanoformulation of a highly selective and potent morphine antagonist, CTOP (D-Pen-Cys-Tyr-DTrp-Orn-Thr-Pen-Thr-NH2), which is impenetrable to the brain. MNPs, synthesized in size range from 25 to 40 nm, were characterized by Transmission electron microscopy and assembly of MNPs-CTOP nanoformulations were confirmed by FTIR spectroscopy and fluorescent detection. Flow-cytometry analysis showed that biological efficacy of this nanoformulation in prevention of morphine induced apoptosis in peripheral blood mononuclear cells remains equivalent to that of free CTOP. Similarly, confocal microscopy reveals comparable efficacy of free and MNPs bound CTOP in protecting modulation of neuronal dendrite and spine morphology during morphine exposure and morphine-treated HIV infection. Further, typical transmigration assay showed increased translocation of MNPs across in vitro blood-brain barrier upon exposure of external magnetic force where barrier integrity remains unaltered. Thus, the developed nanoformulation could be effective in targeting brain by application of external magnetic force to treat morphine addiction in HIV patients.

HIV-1 subtypes B and C Tat differentially impact synaptic plasticity expression and implicates HIV-associated neurocognitive disorders.

Earlier studies have established that infection with HIV-1 subtypes (clades) might differentially influence the neuropathogenesis of HIV-1-associated neurocognitive dysfunction (HAND). HIV-1 Trans activator of transcription protein (Tat) is of considerable significance and plays a major role in the central nervous system (CNS) dysfunction. However, these HIV-1 clades exert diverse cellular effects that leads to neuropathogenic dysfunction has not been well established. We hypothesized that the HIV-1 clade B and clade C Tat proteins effect synaptic plasticity expression in neuroblastoma cells (SK-N-MC) by diverse methods, and accordingly modulates the development of HAND. In the present study, we have analyzed important and highly expressed 84 key human synaptic plasticity genes expression which differentially impact in clade B and clade C Tat treated SK-N-MC cells using RT(2) Profile PCR Array human Synaptic Plasticity kit. Observed results demonstrate that out of 84 key synaptic plasticity genes, 36 and 25 synaptic genes were substantially (≥3 fold) up-regulated and 5 and 5 genes considerably (≥3 fold) down-regulated in clade B and clade C Tat treated cells, respectively, compared to the control SK-N-MC. We have also estimated the levels of glutamine and glutamate in HIV-1 clade B and C Tat exposed SK-N-MC cells compared to untreated cells. Our results indicate that levels of glutamate, glutamine and expression of synaptic plasticity genes were highly dysregulated by HIV-1 clade B Tat compared to clade C Tat in SK-N-MC cells. In summary, this study suggests that clade B Tat substantially potentiates neuronal toxicity and further dysregulated synaptic plasticity genes in SK-N-MC may contribute to the severe neuropathogenesis linked with HAND.