Opioid-Use, COVID-19 Infection, and Their Neurological Implications.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an imminent threat to human health and public safety. ACE2 and transmembrane serine protease 2 proteins on host cells provide the viral entry point to SARS-CoV-2. Although SARS-CoV-2 mainly infects the respiratory system, there have been reports of viral neurotropism and central nervous system injury as indicated by plasma biomarkers, including neurofilament light chain protein and glial fibrillary acidic protein. Even with a small proportion of infections leading to neurological manifestation, the overall number remains high. Common neurological manifestations of SARS-CoV-2 infection include anosmia, ageusia, encephalopathy, and stroke, which are not restricted to only the most severe infection cases. Opioids and opioid antagonists bind to the ACE2 receptor and thereby have been hypothesized to have therapeutic potential in treating COVID-19. However, in the case of other neurotropic viral infections such as human immunodeficiency virus (HIV), opioid use has been established to exacerbate HIV-mediated central nervous system pathogenesis. An analysis of electronic health record data from more than 73 million patients shows that people with Substance Use Disorders are at higher risk of contracting COVID-19 and suffer worse consequences then non-users. Our in-vivo and in-vitro unpublished studies show that morphine treatment causes increased expression of ACE2 in murine lung and brain tissue as early as 24 h post treatment. At the same time, we also observed morphine and lipopolysaccharides treatment lead to a synergistic increase in ACE2 expression in the microglial cell line, SIM-A9. This data suggests that opioid treatment may potentially increase neurotropism of SARS-CoV-2 infection. We have previously shown that opioids induce gut microbial dysbiosis. Similarly, gut microbiome alterations have been reported with SARS-CoV-2 infection and may play a role in predicting COVID-19 disease severity. However, there are no studies thus far linking opioid-mediated dysbiosis with the severity of neuron-specific COVID-19 infection.

Opioid Use, Gut Dysbiosis, Inflammation, and the Nervous System.

Opioid use disorder (OUD) is defined as the chronic use or misuse of prescribed or illicitly obtained opioids and is characterized by clinically significant impairment. The etiology of OUD is multifactorial as it is influenced by genetics, environmental factors, stress response and behavior. Given the profound role of the gut microbiome in health and disease states, in recent years there has been a growing interest to explore interactions between the gut microbiome and the central nervous system as a causal link and potential therapeutic source for OUD. This review describes the role of the gut microbiome and opioid-induced immunopathological disturbances at the gut epithelial surface, which collectively contribute to OUD and perpetuate the vicious cycle of addiction and relapse.

The Impact of CRISPR-Cas9 on Age-related Disorders: From Pathology to Therapy.

With advances in medical technology, the number of people over the age of 60 is on the rise, and thus, increasing the prevalence of age-related pathologies within the aging population. Neurodegenerative disorders, cancers, metabolic and inflammatory diseases are some of the most prevalent age-related pathologies affecting the growing population. It is imperative that a new treatment to combat these pathologies be developed. Although, still in its infancy, the CRISPR-Cas9 system has become a potent gene-editing tool capable of correcting gene-mediated age-related pathology, and therefore ameliorating or eliminating disease symptoms. Deleting target genes using the CRISPR-Cas9 system or correcting for gene mutations may ameliorate many different neurodegenerative disorders detected in the aging population. Cancer cells targeted by the CRISPR-Cas9 system may result in an increased sensitivity to chemotherapeutics, lower proliferation, and higher cancer cell death. Finally, reducing gene targeting inflammatory molecules production through microRNA knockout holds promise as a therapeutic strategy for both arthritis and inflammation. Here we present a review based on how the expanding world of genome editing can be applied to disorders and diseases affecting the aging population.

Role of Non-Coding RNAs in Lung Circadian Clock Related Diseases.

Circadian oscillations are regulated at both central and peripheral levels to maintain physiological homeostasis. The central circadian clock consists of a central pacemaker in the suprachiasmatic nucleus that is entrained by light dark cycles and this, in turn, synchronizes the peripheral clock inherent in other organs. Circadian dysregulation has been attributed to dysregulation of peripheral clock and also associated with several diseases. Components of the molecular clock are disrupted in lung diseases like chronic obstructive pulmonary disease (COPD), asthma and IPF. Airway epithelial cells play an important role in temporally organizing magnitude of immune response, DNA damage response and acute airway inflammation. Non-coding RNAs play an important role in regulation of molecular clock and in turn are also regulated by clock components. Dysregulation of these non-coding RNAs have been shown to impact the expression of core clock genes as well as clock output genes in many organs. However, no studies have currently looked at the potential impact of these non-coding RNAs on lung molecular clock. This review focuses on the ways how these non-coding RNAs regulate and in turn are regulated by the lung molecular clock and its potential impact on lung diseases.

Aberrant MicroRNAomics in Pulmonary Complications: Implications in Lung Health and Diseases.

Over the last few decades, evolutionarily conserved molecular networks have emerged as important regulators in the expression and function of eukaryotic genomes. Recently, miRNAs (miRNAs), a large family of small, non-coding regulatory RNAs were identified in these networks as regulators of endogenous genes by exerting post-transcriptional gene regulation activity in a broad range of eukaryotic species. Dysregulation of miRNA expression correlates with aberrant gene expression and can play an essential role in human health and disease. In the context of the lung, miRNAs have been implicated in organogenesis programming, such as proliferation, differentiation, and morphogenesis. Gain- or loss-of-function studies revealed their pivotal roles as regulators of disease development, potential therapeutic candidates/targets, and clinical biomarkers. An altered microRNAome has been attributed to several pulmonary diseases, such as asthma, chronic pulmonary obstructive disease, cystic fibrosis, lung cancer, and idiopathic pulmonary fibrosis. Considering the relevant roles and functions of miRNAs under physiological and pathological conditions, they may lead to the invention of new diagnostic and therapeutic tools. This review will focus on recent advances in understanding the role of miRNAs in lung development, lung health, and diseases, while also exploring the progress and prospects of their application as therapeutic leads or as biomarkers.

A guanylurea-functionalized conjugated polymer enables RNA interference in ex vivo human airway epithelium.

We demonstrate a successful target gene knockdown in ex vivo normal human bronchial epithelium (NHBE) cells covered with mucus layers using the guanylurea functionalization technique modulating the chemical environment at the positive charge of a gene carrier.

Signaling pathways and therapeutic perspectives related to environmental factors associated with multiple sclerosis.

Multiple sclerosis (MS) is an immune-mediated demyelinating disorder of unknown etiology. Both genetic-susceptibility and environment exposures, including vitamin D deficiency, Epstein-Barr viral and Herpesvirus (HHV-6) infections are strongly implicated in the activation of T cells and MS-pathogenesis. Despite precise knowledge of how these factors could be operating alone or in combination to facilitate and aggravate the disease progression, it is clear that prolonged induction of inflammatory molecules and recruitment of other immune cells by the activated T cells results in demyelination and axonal damage. It is imperative to understand the risk factors associated with MS progression and how these factors contribute to disease pathology. Understanding of the underlying mechanisms of what factors triggers activation of T cells to attack myelin antigen are important to strategize therapeutics and therapies against MS. Current review provides a detailed literature to understand the role of both pathogenic and non-pathogenic factors on the impact of MS.

Aptamers in HIV research diagnosis and therapy.

Aptamers are high affinity single-stranded nucleic acid or protein ligands which exhibit specificity and avidity comparable to, or exceeding that of antibodies and can be generated against most targets. The functionality of aptamers is based on their unique tertiary structure, complexity and their ability to attain unique binding pockets by folding. Aptamers are selected in vitro by a process called Systematic Evolution of Ligands by Exponential enrichment (SELEX). The Kd values for the selected aptamer are often in the picomolar to low nanomolar range. Stable and nontoxic aptamers could be selected for a wide range of ligands including small molecules to large proteins. Aptamers have shown tremendous potential and have found multipurpose application in the field of therapeutic, diagnostic, biosensor and bio-imaging. While their mechanism of action can be similar to that of monoclonal antibodies, aptamers provide additional advantages in terms of production cost, simpler regulatory approval and lower immunogenicity as they are synthesized chemically. Human immunodeficiency virus (HIV) is the primary cause of acquired immune deficiency syndrome (AIDS), which causes significant morbidity and mortality with a significant consequent decrease in the quality of patient's lives. While cART has led to good viral control, people living with HIV now suffer from non-HIV comorbidities due to viral protein expression that cannot be controlled by cART. Hence pathophysiological mechanisms that govern these comorbidities with a focus on therapies that neutralize these HIV effects gained increased attention. Recent advances in HIV/AIDS research have identified several molecular targets and for the development of therapeutic and diagnostic using aptamers against HIV/AIDS. This review presents recent advances in aptamers technology for potential application in HIV diagnostics and therapeutics towards improving the quality of life of people living with HIV.

Overview on the Current Status of Zika Virus Pathogenesis and Animal Related Research.

There is growing evidence that Zika virus (ZIKV) infection is linked with activation of Guillan-Barré syndrome (GBS) in adults infected with the virus and microcephaly in infants following maternal infection. With the recent outpour in publications by numerous research labs, the association between microcephaly in newborns and ZIKV has become very apparent in which large numbers of viral particles were found in the central nervous tissue of an electively aborted microcephalic ZIKV-infected fetus. However, the underlying related mechanisms remain poorly understood. Thus, development of ZIKV-infected animal models are urgently required. The need to develop drugs and vaccines of high efficacy along with efficient diagnostic tools for ZIKV treatment and management raised the demand for a very selective animal model for exploring ZIKV pathogenesis and related mechanisms. In this review, we describe recent advances in animal models developed for studying ZIKV pathogenesis and evaluating potential interventions against human infection, including during pregnancy. The current research directions and the scientific challenges ahead in developing effective vaccines and therapeutics are also discussed.