Cell-cycle progression and division are fundamental biological processes in animal cells, and their biochemical regulation has been extensively studied. An emerging body of work has revealed how ...mechanical interactions of cells with their microenvironment in tissues, including with the extracellular matrix (ECM) and neighboring cells, also plays a crucial role in regulating cell-cycle progression and division. We review recent work on how cells interpret physical cues and alter their mechanics to promote cell-cycle progression and initiate cell division, and then on how dividing cells generate forces on their surrounding microenvironment to successfully divide. Finally, the article ends by discussing how force generation during division potentially contributes to larger tissue-scale processes involved in development and homeostasis.
Tissue-level tension, cytoskeletal tension, and stiff substrates for 2D culture generally promote cell-cycle progression and division, whereas confining environments or compression inhibit cell growth, leading to delayed or halted cell-cycle progression and division.Cells dividing in confining environments generate extracellular forces to drive major morphological changes which are necessary for proper division completion, including mitotic rounding, division elongation, and postdivision spreading.Extracellular forces generated during cell division contribute to cell migration and tissue-scale processes important in development, including tissue growth, invagination, luminogenesis, and epithelial stratification.Cancer cells are able to undergo cell-cycle progression and cell division within the confining tumor microenvironment.
The recent outbreak of Coronavirus disease (COVID-19), first in Eastern Asia and then essentially across the world has been declared a pandemic by the WHO. COVID-19 is caused by a novel virus ...SARS-CoV2 (2019-nCoV), against which there is currently no vaccine available; and current antiviral therapies have failed, causing a very high mortality rate. Drug repurposing i.e. utilizing an approved drug for different indication, offers a time- and cost-efficient alternative for making new therapies available to patients. Although there are several reports presenting novel approaches to treat COVID-19, still an attentive review of previous scientific literature is essential to overcome their failure to exhibit efficacy. There is an urgent need to provide a comprehensive outlook toward utilizing drug repurposing as a tool for discovery of new therapies against COVID-19. In this article, we aim to provide a to-the-point review of current literature regarding efficacy of repurposed drugs against COVID-19 and other respiratory infections caused by coronaviruses. We have briefly discussed COVID-19 epidemiology, and then have discussed drug repurposing approaches and examples, specific to respiratory viruses. Limitations of utilization of repurposed drug molecules such as dosage regimen and associated challenges such as localized delivery in respiratory tract have also been discussed in detail.
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With the advent of antibiotics, bacterial infections were supposed to be a thing of past. However, this instead led to the selection and evolution of bacteria with mechanisms to counter the action of ...antibiotics. Antibiotic efflux is one of the major mechanisms, whereby bacteria pump out the antibiotics from their cellular interior to the external environment using special transporter proteins called efflux pumps. Inhibiting these pumps seems to be an attractive strategy at a time when novel antibiotic supplies are dwindling. Molecules capable of inhibiting these pumps, known as efflux pump inhibitors (EPIs), have been viewed as potential therapeutic agents that can rejuvenate the activity of antibiotics that are no longer effective against bacterial pathogens. EPIs follow some general mechanisms of efflux inhibition and are derived from various natural as well as synthetic sources. This review focuses on EPIs and identifies the challenges that have kept these futuristic therapeutics away from the commercial realm so far.
The monoamine oxidase (MAO) enzyme is responsible for the deamination of monoamine neurotransmitters and regulates their concentration in the central and peripheral nervous systems. Imbalance in the ...concentration of neurotransmitters in the brain and central nervous system is linked with the biochemical pathology of various neurogenic disorders. Irreversible MAO inhibitors were the first line drugs developed for the management of severe depression but most of these were withdrawn from the clinical practice due to their fatal side effects including food-drug interactions. New generations of MAO inhibitors were developed which were reversible and selective for one of the enzyme isoform and showed improved pharmacological profile. The discovery of crystal structure of MAO-A & MAO-B isoforms helped in understanding the drug-receptor interactions at the molecular level and designing of ligands with selectivity for either of the isoforms. The current article provides an overview on the MAO enzyme as potential drug target for different disease states. The article describes catalytic mechanism of MAO enzyme, crystal structures of the two MAO isoforms, traditional MAO inhibitors and various problems associated with their use, new developments in the MAO inhibitors and their potential as therapeutic agents especially in neurological disorders.
The Trk family of receptors play a wide variety of roles in physiological and disease processes in both neuronal and non-neuronal tissues. Amongst these the TrkB receptor in particular has attracted ...major attention due to its critical role in signalling for brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and neurotrophin-4 (NT4). TrkB signalling is indispensable for the survival, development and synaptic plasticity of several subtypes of neurons in the nervous system. Substantial evidence has emerged over the last decade about the involvement of aberrant TrkB signalling and its compromise in various neuropsychiatric and degenerative conditions. Unusual changes in TrkB signalling pathway have also been observed and implicated in a range of cancers. Variations in TrkB pathway have been observed in obesity and hyperphagia related disorders as well. Both BDNF and TrkB have been shown to play critical roles in the survival of retinal ganglion cells in the retina. The ability to specifically modulate TrkB signalling can be critical in various pathological scenarios associated with this pathway. In this review, we discuss the mechanisms underlying TrkB signalling, disease implications and explore plausible ameliorative or preventive approaches.
•There is an emerging need for new therapies for rare diseases in a shorter time frame.•Drug repurposing could arise from serendipitous observations or exploiting side effects.•Today, researchers ...have addressed drug repurposing in a systematic manner but there are challenges to be overcome for successful repurposing in the future.
Traditional drug discovery and development involves several stages for the discovery of a new drug and to obtain marketing approval. It is necessary to discover new strategies for reducing the drug discovery time frame. Today, drug repurposing has gained importance in identifying new therapeutic uses for already-available drugs. Typically, repurposing can be achieved serendipitously (unintentional fortunate observations) or through systematic approaches. Numerous strategies to discover new indications for FDA-approved drugs are discussed in this article. Drug repurposing has therefore become a productive approach for drug discovery because it provides a novel way to explore old drugs for new use but encounters several challenges. Some examples of different approaches are reviewed here.
A consequence of human purine metabolism is uric acid (UA). An abnormal amount of UA in serum and human urine have substantial clinical repercussions in the majority of individuals. Normal readings ...for the human body range from 3.5 to 7.2 mg/dL. In this work, single-mode fiber-multimode fiber-single-mode fiber (SMS) structure-based probe has been developed for sensing UA levels. The fabricated probe is immobilized using synthesized gold nanoparticles (AuNPs) to improve the sensitivity. The surface plasmon (SP) excitation was induced at the surface of the fiber using AuNPs, which eventually produced the localized SP resonance (LSPR) phenomenon. Its sensitivity was further improved by coating with graphene oxide (GO). Thereafter, uricase enzyme functionalization further improved the detection of the sensor probe. A detailed analysis for the developed SMS probes was performed on parameters, such as sensitivity, linearity, response time, selectivity, reproducibility, and reusability.
Two-dimensional materials-based plasmonic sensors are widely used in many sensing applications, particularly in biosensors due to their distinctive qualities such as label-free detection, ...cost-effective, and real-time monitoring. This article summarizes the advances in the 2-D materials-based plasmonic sensors with respect to different materials such as graphene, antimonene, phosphorene, blue phosphorous, molybdenum sulfide, molybdenum selenide, and tungsten selenide. This review also includes the comparison based on the sensitivity, detection range, and detection limit of the 2-D materials-based plasmonic sensors in context to those biosensing applications. These parameters in true sense determine the sensor’s accuracy and applicability in health monitoring systems for desired results.
Vascular endothelium offers a variety of therapeutic targets for the treatment of cancer, cardiovascular diseases, inflammation, and oxidative stress. Significant research has been focused on ...developing agents to target the endothelium in diseased tissues. This includes identification of antibodies against adhesion molecules and neovascular expression markers or peptides discovered using phage display. Such targeting molecules also have been used to deliver nanoparticles to the endothelium of the diseased tissue. Here we report, based on in vitro and in vivo studies, that the specificity of endothelial targeting can be enhanced further by engineering the shape of ligand-displaying nanoparticles. In vitro studies performed using microfluidic systems that mimic the vasculature (synthetic microvascular networks) showed that rod-shaped nanoparticles exhibit higher specific and lower nonspecific accumulation under flow at the target compared with their spherical counterparts. Mathematical modeling of particle–surface interactions suggests that the higher avidity and specificity of nanorods originate from the balance of polyvalent interactions that favor adhesion and entropic losses as well as shear-induced detachment that reduce binding. In vivo experiments in mice confirmed that shape-induced enhancement of vascular targeting is also observed under physiological conditions in lungs and brain for nanoparticles displaying anti–intracellular adhesion molecule 1 and anti-transferrin receptor antibodies.
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