scholarly journals Empowering Melatonin Therapeutics with Drosophila Models

Diseases ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 67
Author(s):  
Cassandra Millet-Boureima ◽  
Caroline C. Ennis ◽  
Jurnee Jamison ◽  
Shana McSweeney ◽  
Anna Park ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Model Organism ◽  
New Drugs ◽  
Renal Diseases ◽  
Disease Pathogenesis ◽  
Multiple Functions ◽  
Functional Conservation ◽  
Oxidative Response ◽  
Pharmacological Potential ◽  
Drosophila Models

Melatonin functions as a central regulator of cell and organismal function as well as a neurohormone involved in several processes, e.g., the regulation of the circadian rhythm, sleep, aging, oxidative response, and more. As such, it holds immense pharmacological potential. Receptor-mediated melatonin function mainly occurs through MT1 and MT2, conserved amongst mammals. Other melatonin-binding proteins exist. Non-receptor-mediated activities involve regulating the mitochondrial function and antioxidant cascade, which are frequently affected by normal aging as well as disease. Several pathologies display diseased or dysfunctional mitochondria, suggesting melatonin may be used therapeutically. Drosophila models have extensively been employed to study disease pathogenesis and discover new drugs. Here, we review the multiple functions of melatonin through the lens of functional conservation and model organism research to empower potential melatonin therapeutics to treat neurodegenerative and renal diseases.

Pharmacological Targeting of Neuronal Kv7.2/3 Channels: A Focus on Chemotypes and Receptor Sites

2018 ◽  
Vol 25 (23) ◽  
pp. 2637-2660 ◽  
Author(s):  
Francesco Miceli ◽  
Maria V. Soldovieri ◽  
Paolo Ambrosino ◽  
Laura Manocchio ◽  
Ilaria Mosca ◽  
...  
Keyword(s):  
Metabolic Diseases ◽  
Scientific Literature ◽  
New Drugs ◽  
Current Status ◽  
Functional Heterogeneity ◽  
Molecular Scaffolds ◽  
Kv7 Channels ◽  
Receptor Sites ◽  
Pharmacological Targets ◽  
Pharmacological Potential

Background: The Kv7 (KCNQ) subfamily of voltage-gated potassium channels consists of 5 members (Kv7.1-5) each showing characteristic tissue distribution and physiological roles. Given their functional heterogeneity, Kv7 channels represent important pharmacological targets for the development of new drugs for neuronal, cardiovascular and metabolic diseases. <p> Objective: In the present manuscript, we focus on describing the pharmacological relevance and potential therapeutic applications of drugs acting on neuronally-expressed Kv7.2/3 channels, placing particular emphasis on the different chemotypes, and highlighting their pharmacodynamic and, whenever possible, pharmacokinetic peculiarities. <p> Methods: The present work is based on an in-depth search of the currently available scientific literature, and on our own experience and knowledge in the field of neuronal Kv7 channel pharmacology. Space limitations impeded to describe the full pharmacological potential of Kv7 channels; thus, we have chosen to focus on neuronal channels composed of Kv7.2 and Kv7.3 subunits, and to mainly concentrate on their involvement in epilepsy. <p> Results: An astonishing heterogeneity in the molecular scaffolds exploitable to develop Kv7.2/3 modulators is evident, with important structural/functional peculiarities of distinct compound classes. <p> Conclusion: In the present work we have attempted to show the current status and growing potential of the Kv7 pharmacology field. We anticipate a bright future for the field, and express our hopes that the efforts herein reviewed will result in an improved treatment of hyperexcitability (or any other) diseases.

scholarly journals Aureolic Acid Group of Agents as Potential Antituberculosis Drugs

Antibiotics ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 715
Author(s):  
Julia Bespyatykh ◽  
Dmitry Bespiatykh ◽  
Maja Malakhova ◽  
Ksenia Klimina ◽  
Andrey Bespyatykh ◽  
...  
Keyword(s):  
Cell Division ◽  
Bacterial Resistance ◽  
Morphological Changes ◽  
Cell Structure ◽  
Model Organism ◽  
Good Alternative ◽  
Acid Group ◽  
New Drugs ◽  
Antituberculosis Drugs ◽  
Aureolic Acid

Mycobacterium tuberculosis is one of the most dangerous pathogens. Bacterial resistance to antituberculosis drugs grows each year, but searching for new drugs is a long process. Testing for available drugs to find active against mycobacteria may be a good alternative. In this work, antibiotics of the aureolic acid group were tested on a model organism Mycobacterium smegmatis. We presumed that antibiotics of this group may be potential G4 ligands. However, this was not confirmed in our analyses. We determined the antimicrobial activity of these drugs and revealed morphological changes in the cell structure upon treatment. Transcriptomic analysis documented increased expression of MSMEG_3743/soj and MSMEG_4228/ftsW, involved in cell division. Therefore, drugs may affect cell division, possibly disrupting the function of the Z-ring and the formation of a septum. Additionally, a decrease in the transcription level of several indispensable genes, such as nitrate reductase subunits (MSMEG_5137/narI and MSMEG_5139/narX) and MSMEG_3205/hisD was shown. We concluded that the mechanism of action of aureolic acid and its related compounds may be similar to that bedaquiline and disturb the NAD+/NADH balance in the cell. All of this allowed us to conclude that aureolic acid derivatives can be considered as potential antituberculosis drugs.

Molecular, functional, and gene expression analysis of zebrafish hypoxia-inducible factor-3α

2012 ◽  
Vol 303 (11) ◽  
pp. R1165-R1174 ◽  
Author(s):  
Peng Zhang ◽  
Ling Lu ◽  
Qing Yao ◽  
Yun Li ◽  
Jianfeng Zhou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fluorescent Protein ◽  
Cultured Cells ◽  
Hypoxia Inducible Factor ◽  
Model Organism ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Specific Expression ◽  
Physiological Regulation ◽  
Functional Conservation

Hypoxia-inducible factors 1–3 (HIF1–3) are transcription factors that regulate gene expression in response to hypoxia. Compared with our extensive understanding of HIF-1 and HIF-2, our knowledge of HIF-3 is limited. In this study, we characterized the zebrafish hif-3α gene and determined its temporal and spatial expression, physiological regulation, and biological activity. We show that the chromosomal location, gene structure, and protein structure of zebrafish hif-3α are similar to its mammalian orthologs. When tagged with enhanced green fluorescent protein and transfected into cultured cells, zebrafish Hif-3α was localized in the nucleus and stimulated reporter gene expression in a hypoxia response element-dependent manner. During early development, hif-3α mRNA was detected in all tissues with higher levels in the head. This expression pattern became more apparent in larvae at the 72, 96, and 120 hours post fertilization stages. In the adult stage, hif-3α mRNA was detected in all examined tissues with the highest levels in the ovary. Hypoxia treatment increased Hif-3α protein levels in both embryos and adults. Hypoxia also increased hif-3α mRNA expression levels, and this regulation was tissue-specific. Expression of a stabilized form of Hif-1α in zebrafish embryos increased the expression of igfbp-1a, a Hif-1 target gene, whereas it did not change hif-3α mRNA levels, suggesting that hif-3α is not a Hif-1α target. These results provide new information about the structural and functional conservation, spatial and temporal expression, and physiological regulation of hif-3α in a teleost model organism.

scholarly journals Bioluminescent:fluorescent Trypanosoma cruzi Reporter Strains as Tools for Exploring Chagas Disease Pathogenesis and Drug Activity

2020 ◽  
Vol 26 ◽  
Author(s):  
Martin C. Taylor ◽  
Alexander I. Ward ◽  
Francisco Olmo ◽  
Amanda F. Francisco ◽  
Shiromani Jayawardhana ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Parasite Burden ◽  
New Drugs ◽  
Host Cells ◽  
Complex Nature ◽  
Disease Pathogenesis ◽  
Drug Activity ◽  
Cellular Environment

: Chagas disease results from infection with the trypanosomatid parasite Trypanosoma cruzi. Progress in developing new drugs has been hampered by the long term and complex nature of the condition and by our limited understanding of parasite biology. Technical difficulties in assessing the parasite burden during the chronic stage of infection have also proved to be a particular challenge. In this context, the development of non-invasive, highly sensitive bioluminescence imaging procedures, based on parasites that express a red-shifted luciferase, has greatly enhanced our ability to monitor infections in experimental models. Applications of this methodology have led to new insights into tissue tropism and infection dynamics, and have been a major driver in drug development. The system has been further modified by the generation of parasite reporter lines that express bioluminescent:fluorescent fusion proteins, an advance that has allowed chronic infections in mice to be examined at a cellular level. By exploiting bioluminescence to identify the rare sites of tissue infection, and fluorescence to detect T. cruzi at the level of individual host cells in histological sections, it has been possible to investigate the replication and differentiation status of parasites in vivo and to examine the cellular environment of infection foci. In combination, these data are providing a framework for the detailed dissection of disease pathogenesis and drug activity.

Snake Venom Disintegrins: An Overview of their Interaction with Integrins

2019 ◽  
Vol 20 (4) ◽  
pp. 465-477 ◽  
Author(s):  
Pedro Henrique Souza Cesar ◽  
Mariana Aparecida Braga ◽  
Marcus Vinicius Cardoso Trento ◽  
Danilo Luccas Menaldo ◽  
Silvana Marcussi
Keyword(s):  
Signal Transduction ◽  
Cell Surface ◽  
Essential Role ◽  
Antitumor Agents ◽  
Structural Models ◽  
New Drugs ◽  
Snake Venoms ◽  
Cellular Processes ◽  
Pharmacological Potential ◽  
Direct Use

Disintegrins are non-enzymatic proteins that interfere on cell–cell interactions and signal transduction, contributing to the toxicity of snake venoms and play an essential role in envenomations. Most of their pharmacological and toxic effects are the result of the interaction of these molecules with cell surface ligands, which has been widely described and studied. These proteins may act on platelets, leading to hemorrhage, and may also induce apoptosis and cytotoxicity, which highlights a high pharmacological potential for the development of thrombolytic and antitumor agents. Additionally, these molecules interfere with the functions of integrins by altering various cellular processes such as migration, adhesion and proliferation. This review gathers information on functional characteristics of disintegrins isolated from snake venoms, emphasizing a comprehensive view of the possibility of direct use of these molecules in the development of new drugs, or even indirectly as structural models.

scholarly journals Clinical Manifestations, Pathogenesis and Treatment of Hepatitis E Virus Infections

2020 ◽  
Vol 9 (2) ◽  
pp. 331 ◽  
Author(s):  
Sébastien Lhomme ◽  
Olivier Marion ◽  
Florence Abravanel ◽  
Jacques Izopet ◽  
Nassim Kamar
Keyword(s):  
Hepatitis E Virus ◽  
Hematologic Malignancy ◽  
Antiviral Treatment ◽  
Clinical Manifestations ◽  
Hepatitis E ◽  
Immunosuppressive Drugs ◽  
New Drugs ◽  
Renal Diseases ◽  
Solid Organ ◽  
Immunocompromised Patients

Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis throughout the world. Most infections are acute but they can become chronic in immunocompromised patients, such as solid organ transplant patients, patients with hematologic malignancy undergoing chemotherapy and those with a human immunodeficiency virus (HIV) infection. Extra-hepatic manifestations, especially neurological and renal diseases, have also been described. To date, four main genotypes of HEV (HEV1-4) were described. HEV1 and HEV2 only infect humans, while HEV3 and HEV4 can infect both humans and animals, like pigs, wild boar, deer and rabbits. The real epidemiology of HEV has been underestimated because most infections are asymptomatic. This review focuses on the recent advances in our understanding of the pathophysiology of acute HEV infections, including severe hepatitis in patients with pre-existing liver disease and pregnant women. It also examines the mechanisms leading to chronic infection in immunocompromised patients and extra-hepatic manifestations. Acute infections are usually self-limiting and do not require antiviral treatment. Conversely, a chronic HEV infection can be cleared by decreasing the dose of immunosuppressive drugs or by treating with ribavirin for 3 months. Nevertheless, new drugs are needed for those cases in which ribavirin treatment fails.

scholarly journals Small Molecules Targeting Biological Clock; A Novel Prospective for Anti-Cancer Drugs

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 4937
Author(s):  
Sadia Rahman ◽  
Karlo Wittine ◽  
Mirela Sedić ◽  
Elitza P. Markova-Car
Keyword(s):  
Circadian Rhythm ◽  
Small Molecules ◽  
Small Molecule ◽  
Environmental Conditions ◽  
Recent Progress ◽  
Biological Clock ◽  
New Drugs ◽  
Anti Cancer ◽  
Growing Body ◽  
Potential Use

The circadian rhythms are an intrinsic timekeeping system that regulates numerous physiological, biochemical, and behavioral processes at intervals of approximately 24 h. By regulating such processes, the circadian rhythm allows organisms to anticipate and adapt to continuously changing environmental conditions. A growing body of evidence shows that disruptions to the circadian rhythm can lead to various disorders, including cancer. Recently, crucial knowledge has arisen regarding the essential features that underlie the overt circadian rhythm and its influence on physiological outputs. This knowledge suggests that specific small molecules can be utilized to control the circadian rhythm. It has been discovered that these small molecules can regulate circadian-clock-related disorders such as metabolic, cardiovascular, inflammatory, as well as cancer. This review examines the potential use of small molecules for developing new drugs, with emphasis placed on recent progress that has been made regarding the identification of small-molecule clock modulators and their potential use in treating cancer.

scholarly journals New Horizons: Circadian Control of Metabolism Offers Novel Insight Into the Cause and Treatment of Metabolic Diseases

2020 ◽  
Author(s):  
Shaunak Deota ◽  
Satchidananda Panda
Keyword(s):  
Circadian Rhythm ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Caloric Intake ◽  
Regulatory System ◽  
New Drugs ◽  
New Horizons ◽  
Circadian Control ◽  
Sense And Respond ◽  
Preclinical Animal Models

Abstract Metabolic homeostasis is achieved by endocrine factors, signaling cascades, and metabolic pathways that sense and respond to metabolic demands in different organs. However, the recent discovery that almost every component of this regulatory system is also modulated by circadian rhythm highlights novel etiology and prognosis of metabolic diseases. First, chronic circadian rhythm disruption, as in shiftwork or shiftwork-like lifestyle, can increase the risk for metabolic diseases. Second, by understanding factors that affect circadian rhythm, we can implement new behavioral or pharmacological interventions for the prevention and management of metabolic disorders. One of these novel circadian-based interventions is time-restricted eating (TRE) in which all daily caloric intake is restricted to a consistent window of 8 to 12 hours. In preclinical animal models, TRE can prevent or reverse many metabolic diseases. Circadian research has also catalyzed attempts to optimally time the dosing of existing drugs to treat metabolic diseases or develop new drugs that target the circadian clock to treat metabolic disorders.

scholarly journals Drosophila Models of Parkinson's Disease: Discovering Relevant Pathways and Novel Therapeutic Strategies

2011 ◽  
Vol 2011 ◽  
pp. 1-14 ◽  
Author(s):  
Verónica Muñoz-Soriano ◽  
Nuria Paricio
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Model Organism ◽  
Disease Process ◽  
Therapeutic Strategies ◽  
Progressive Loss ◽  
Novel Therapeutic Strategies ◽  
Drosophila Models

Parkinson's disease (PD) is the second most common neurodegenerative disorder and is mainly characterized by the selective and progressive loss of dopaminergic neurons, accompanied by locomotor defects. Although most PD cases are sporadic, several genes are associated with rare familial forms of the disease. Analyses of their function have provided important insights into the disease process, demonstrating that three types of cellular defects are mainly involved in the formation and/or progression of PD: abnormal protein aggregation, oxidative damage, and mitochondrial dysfunction. These studies have been mainly performed in PD models created in mice, fruit flies, and worms. Among them, Drosophila has emerged as a very valuable model organism in the study of either toxin-induced or genetically linked PD. Indeed, many of the existing fly PD models exhibit key features of the disease and have been instrumental to discover pathways relevant for PD pathogenesis, which could facilitate the development of therapeutic strategies.

scholarly journals Towards a global initiative for fibrosis treatment (GIFT)

2017 ◽  
Vol 3 (4) ◽  
pp. 00106-2017 ◽  
Author(s):  
Maria Molina-Molina ◽  
Alvar Agusti ◽  
Bruno Crestani ◽  
David A. Schwartz ◽  
Melanie Königshoff ◽  
...  
Keyword(s):  
Systems Biology ◽  
Research Strategy ◽  
New Drugs ◽  
Emergent Properties ◽  
Slow Disease Progression ◽  
European Respiratory Society ◽  
Disease Pathogenesis ◽  
Novel Drugs ◽  
Global Initiative ◽  
Society Research

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterised by increased scarring of lung tissue. Despite the recent introduction of novel drugs that slow disease progression, IPF remains a deadly disease, and the benefits of these new drugs differ markedly between patients.Human diseases arise due to alterations in an almost limitless network of interconnected genes, proteins, metabolites, cells and tissues, in direct relationship with a continuously changing macro- or microenvironment. Systems biology is a novel research strategy that seeks to understand the structure and behaviour of the so-called “emergent properties” of complex systems, such as those involved in disease pathogenesis, which are most often overlooked when just one element of disease pathogenesis is observed in isolation.This article summarises the debate that took place during a European Respiratory Society research seminar in Barcelona, Spain on December 15–16, 2016, which focused on how systems biology could generate new data by integrating the different IPF pathogenic levels of complexity. The main conclusion of the seminar was to create a global initiative to improve IPF outcomes by integrating cutting-edge international research that leverages systems biology to develop a precision medicine approach to tackle this devastating disease.

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