scholarly journals In Vitro Models for Studying Entry, Tissue Tropism, and Therapeutic Approaches of Highly Pathogenic Coronaviruses

2021 ◽  
Vol 2021 ◽  
pp. 1-21
Author(s):  
Saeid Najafi Fard ◽  
Linda Petrone ◽  
Elisa Petruccioli ◽  
Tonino Alonzi ◽  
Giulia Matusali ◽  
...  
Keyword(s):  
Rna Viruses ◽  
Current Knowledge ◽  
In Vitro Models ◽  
Cell Entry ◽  
Therapeutic Approaches ◽  
Highly Pathogenic ◽  
S Protein ◽  
Viral Attachment ◽  
The Family

Coronaviruses (CoVs) are enveloped nonsegmented positive-sense RNA viruses belonging to the family Coronaviridae that contain the largest genome among RNA viruses. Their genome encodes 4 major structural proteins, and among them, the Spike (S) protein plays a crucial role in determining the viral tropism. It mediates viral attachment to the host cell, fusion to the membranes, and cell entry using cellular proteases as activators. Several in vitro models have been developed to study the CoVs entry, pathogenesis, and possible therapeutic approaches. This article is aimed at summarizing the current knowledge about the use of relevant methodologies and cell lines permissive for CoV life cycle studies. The synthesis of this information can be useful for setting up specific experimental procedures. We also discuss different strategies for inhibiting the binding of the S protein to the cell receptors and the fusion process which may offer opportunities for therapeutic intervention.

Modulation of Matrix Metalloproteinases by Plant-Derived Products

2020 ◽  
Vol 20 ◽  
Author(s):  
Nur Najmi Mohamad Anuar ◽  
Nurul Iman Natasya Zulkafali ◽  
Azizah Ugusman
Keyword(s):  
Clinical Trials ◽  
Natural Products ◽  
Matrix Metalloproteinases ◽  
Animal Studies ◽  
Current Knowledge ◽  
In Vitro Models ◽  
In Vivo Studies ◽  
Extracellular Matrix Components

: Matrix metalloproteinases (MMPs) are a group of zinc-dependent metallo-endopeptidase that are responsible towards the degradation, repair and remodelling of extracellular matrix components. MMPs play an important role in maintaining a normal physiological function and preventing diseases such as cancer and cardiovascular diseases. Natural products derived from plants have been used as traditional medicine for centuries. Its active compounds, such as catechin, resveratrol and quercetin, are suggested to play an important role as MMPs inhibitors, thereby opening new insights into their applications in many fields, such as pharmaceutical, cosmetic and food industries. This review summarises the current knowledge on plant-derived natural products with MMP-modulating activities. Most of the reviewed plant-derived products exhibit an inhibitory activity on MMPs. Amongst MMPs, MMP-2 and MMP-9 are the most studied. The expression of MMPs is inhibited through respective signalling pathways, such as MAPK, NF-κB and PI3 kinase pathways, which contribute to the reduction in cancer cell behaviours, such as proliferation and migration. Most studies have employed in vitro models, but a limited number of animal studies and clinical trials have been conducted. Even though plant-derived products show promising results in modulating MMPs, more in vivo studies and clinical trials are needed to support their therapeutic applications in the future.

scholarly journals Rotavirus Replication Factories Are Complex Ribonucleoprotein Condensates

2020 ◽  
Author(s):  
Florian Geiger ◽  
Guido Papa ◽  
William E. Arter ◽  
Julia Acker ◽  
Kadi L. Saar ◽  
...  
Keyword(s):  
Phase Separation ◽  
Unique Feature ◽  
Rna Viruses ◽  
Therapeutic Approaches ◽  
Subcellular Organelles ◽  
Selective Enrichment ◽  
Novel Therapeutic ◽  
Liquid Liquid Phase Separation

AbstractRNA viruses induce formation of subcellular organelles that provide microenvironments conducive to their replication. Here we show that replication factories of rotaviruses represent protein-RNA condensates that are formed via liquid-liquid phase separation. We demonstrate that rotavirus proteins NSP5 and NSP2 undergo phase separation in vitro and form RNA-rich condensates in vivo that can be reversibly dissolved by aliphatic diols. During infection, these RNA-protein condensates became less dynamic and impervious to aliphatic diols, indicating a transition from a liquid to solid state. Some aspects of assembly of rotavirus replication factories mirror the formation of cytoplasmic ribonucleoprotein granules, while the selective enrichment of viral transcripts appears to be a unique feature of these condensates. Such complex RNA-protein condensates that underlie replication of RNA viruses represent an attractive target for developing novel therapeutic approaches.

scholarly journals Bifidobacteria-Host Interactions—An Update on Colonisation Factors

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Verena Grimm ◽  
Christina Westermann ◽  
Christian U. Riedel
Keyword(s):  
Current Knowledge ◽  
Therapeutic Approaches ◽  
Host Interactions ◽  
Beneficial Effects ◽  
Human Intestinal Microbiota ◽  
Substantial Progress ◽  
Health Promoting ◽  
Pharmaceutical Industries ◽  
Bacterial Groups

Bifidobacteria are one of the predominant bacterial groups of the human intestinal microbiota and have important functional properties making them interesting for the food and dairy industries. Numerousin vitroand preclinical studies have shown beneficial effects of particular bifidobacterial strains or strain combinations on various health parameters of their hosts. This indicates the potential of bifidobacteria in alternative or supplementary therapeutic approaches in a number of diseased states. Based on these observations, bifidobacteria have attracted considerable interest by the food, dairy, and pharmaceutical industries and they are widely used as so-called probiotics. As a consequence of the rapidly increasing number of available bifidobacterial genome sequences and their analysis, there has been substantial progress in the identification of bifidobacterial structures involved in colonisation of and interaction with the host. With the present review, we aim to provide an update on the current knowledge on the mechanisms by which bifidobacteria colonise their hosts and exert health promoting effects.

scholarly journals CADASIL from Bench to Bedside: Disease Models and Novel Therapeutic Approaches

2021 ◽  
Author(s):  
Arianna Manini ◽  
Leonardo Pantoni
Keyword(s):  
Therapeutic Option ◽  
In Vitro Models ◽  
Monogenic Disease ◽  
Therapeutic Approaches ◽  
In Vivo Models ◽  
Human Phenotype ◽  
Knock Out ◽  
Novel Therapeutic

AbstractCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic disease caused by NOTCH3 mutations and characterized by typical clinical, neuroradiological, and pathological features. NOTCH3 belongs to a family of highly conserved transmembrane receptors rich of epidermal growth factor repeats, mostly expressed in vascular smooth muscle cells and pericytes, which perform essential developmental functions and are involved in tissues maintenance and renewal. To date, no therapeutic option for CADASIL is available except for few symptomatic treatments. Novel in vitro and in vivo models are continuously explored with the aim to investigate underlying pathogenic mechanisms and to test novel therapeutic approaches. In this scenario, knock-out, knock-in, and transgenic mice studies have generated a large amount of information on molecular and biological aspects of CADASIL, despite that they incompletely reproduce the human phenotype. Moreover, the field of in vitro models has been revolutionized in the last two decades by the introduction of induced pluripotent stem cells (iPSCs) technology. As a consequence, novel therapeutic approaches, including immunotherapy, growth factors administration, and antisense oligonucleotides, are currently under investigation. While waiting that further studies confirm the promising results obtained, the data reviewed suggest that our therapeutic approach to the disease could be transformed, generating new hope for the future.

Folding brains: from development to disease modeling

2021 ◽  
Author(s):  
Lucia Del Valle Anton ◽  
Victor Borrell
Keyword(s):  
Cerebral Cortex ◽  
Disease Modeling ◽  
Current Knowledge ◽  
In Vitro Models ◽  
Human Cortex ◽  
Large Size ◽  
Stem And Progenitor Cells ◽  
Key Events ◽  
Fine Tune

The human brain is characterized by the large size and intricate folding of its cerebral cortex, which are fundamental for our higher cognitive function and frequently altered in pathological dysfunction. Cortex folding is not unique to humans, nor even to primates, but is common across mammals. Cortical growth and folding are the result of complex developmental processes that involve neural stem and progenitor cells and their cellular lineages, the migration and differentiation of neurons, and the genetic programs that regulate and fine-tune these processes. All these factors combined generate mechanical stress and strain on the developing neural tissue, which ultimately drives orderly cortical deformation and folding. In this review we examine and summarize the current knowledge on the molecular, cellular, histogenic and mechanical mechanisms that are involved in and influence folding of the cerebral cortex, and how they emerged and changed during mammalian evolution. We discuss the main types of pathological malformations of human cortex folding, their specific developmental origin, and how investigating their genetic causes has illuminated our understanding of key events involved. We close our review by presenting the state-of-the-art animal and in vitro models of cortex folding that are currently used to study these devastating developmental brain disorders in children, and what are the main challenges that remain ahead of us to fully understand brain folding.

scholarly journals Glioblastoma under Siege: An Overview of Current Therapeutic Strategies

2018 ◽  
Vol 8 (1) ◽  
pp. 15 ◽  
Author(s):  
◽  
◽  
Keyword(s):  
Viral Vectors ◽  
Checkpoint Inhibitors ◽  
Alkylating Agents ◽  
Pharmaceutical Formulations ◽  
Molecular Classification ◽  
In Vitro Models ◽  
Therapeutic Approaches ◽  
New Strategies

Glioblastoma is known to be one of the most lethal and untreatable human tumors. Surgery and radiotherapy in combination with classical alkylating agents such as temozolomide offer little hope to escape a poor prognosis. For these reasons, enormous efforts are currently devoted to refine in vivo and in vitro models with the specific goal of finding new molecular aberrant pathways, suitable to be targeted by a variety of therapeutic approaches, including novel pharmaceutical formulations and immunotherapy strategies. In this review, we will first discuss current molecular classification based on genomic and transcriptomic criteria. Also, the state of the art in current clinical practice for glioblastoma therapy in the light of the recent molecular classification, together with ongoing phases II and III clinical trials, will be described. Finally, new pharmaceutical formulations such as nanoparticles and viral vectors, together with new strategies entailing the use of monoclonal antibodies, vaccines and immunotherapy agents, such as checkpoint inhibitors, will also be discussed.

scholarly journals Necrotizing Enterocolitis: Overview on In Vitro Models

2021 ◽  
Vol 22 (13) ◽  
pp. 6761
Author(s):  
Luigia De Fazio ◽  
Isadora Beghetti ◽  
Salvatore Nicola Bertuccio ◽  
Concetta Marsico ◽  
Silvia Martini ◽  
...  
Keyword(s):  
Necrotizing Enterocolitis ◽  
Current Knowledge ◽  
Experimental Studies ◽  
In Vitro Models ◽  
Intestinal Microbiome ◽  
Inflammatory Disorder ◽  
Intestinal Epithelial ◽  
Complex Interactions ◽  
Disease Mechanisms

Necrotizing enterocolitis (NEC) is a gut inflammatory disorder which constitutes one of the leading causes of morbidity and mortality for preterm infants. The pathophysiology of NEC is yet to be fully understood; several observational studies have led to the identification of multiple factors involved in the pathophysiology of the disease, including gut immaturity and dysbiosis of the intestinal microbiome. Given the complex interactions between microbiota, enterocytes, and immune cells, and the limited access to fetal human tissues for experimental studies, animal models have long been essential to describe NEC mechanisms. However, at present there is no animal model perfectly mimicking human NEC; furthermore, the disease mechanisms appear too complex to be studied in single-cell cultures. Thus, researchers have developed new approaches in which intestinal epithelial cells are exposed to a combination of environmental and microbial factors which can potentially trigger NEC. In addition, organoids have gained increasing attention as promising models for studying NEC development. Currently, several in vitro models have been proposed and have contributed to describe the disease in deeper detail. In this paper, we will provide an updated review of available in vitro models of NEC and an overview of current knowledge regarding its molecular underpinnings.

scholarly journals hiPSC-Derived Epidermal Keratinocytes from Ichthyosis Patients Show Altered Expression of Cornification Markers

2021 ◽  
Vol 22 (4) ◽  
pp. 1785
Author(s):  
Dulce Lima Cunha ◽  
Amanda Oram ◽  
Robert Gruber ◽  
Roswitha Plank ◽  
Arno Lingenhel ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Human Keratinocytes ◽  
In Vitro Models ◽  
Epidermal Keratinocytes ◽  
Altered Expression ◽  
Epidermal Barrier ◽  
Congenital Ichthyosis ◽  
Autosomal Recessive Congenital Ichthyosis ◽  
Induced Pluripotent

Inherited ichthyoses represent a large heterogeneous group of skin disorders characterised by impaired epidermal barrier function and disturbed cornification. Current knowledge about disease mechanisms has been uncovered mainly through the use of mouse models or human skin organotypic models. However, most mouse lines suffer from severe epidermal barrier defects causing neonatal death and human keratinocytes have very limited proliferation ability in vitro. Therefore, the development of disease models based on patient derived human induced pluripotent stem cells (hiPSCs) is highly relevant. For this purpose, we have generated hiPSCs from patients with congenital ichthyosis, either non-syndromic autosomal recessive congenital ichthyosis (ARCI) or the ichthyosis syndrome trichothiodystrophy (TTD). hiPSCs were successfully differentiated into basal keratinocyte-like cells (hiPSC-bKs), with high expression of epidermal keratins. In the presence of higher calcium concentrations, terminal differentiation of hiPSC-bKs was induced and markers KRT1 and IVL expressed. TTD1 hiPSC-bKs showed reduced expression of FLG, SPRR2B and lipoxygenase genes. ARCI hiPSC-bKs showed more severe defects, with downregulation of several cornification genes. The application of hiPSC technology to TTD1 and ARCI demonstrates the successful generation of in vitro models mimicking the disease phenotypes, proving a valuable system both for further molecular investigations and drug development for ichthyosis patients.

scholarly journals Tendon and multiomics: advantages, advances, and opportunities

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Paula Sarmiento ◽  
Dianne Little
Keyword(s):  
Injury Risk ◽  
Current Knowledge ◽  
Human Subjects ◽  
Therapeutic Approaches ◽  
Tendon Regeneration ◽  
Tendon Tissue Engineering ◽  
Cell Sources ◽  
Anatomic Locations ◽  
Tendon Pathology

AbstractTendons heal by fibrosis, which hinders function and increases re-injury risk. Yet the biology that leads to degeneration and regeneration of tendons is not completely understood. Improved understanding of the metabolic nuances that cause diverse outcomes in tendinopathies is required to solve these problems. ‘Omics methods are increasingly used to characterize phenotypes in tissues. Multiomics integrates ‘omic datasets to identify coherent relationships and provide insight into differences in molecular and metabolic pathways between anatomic locations, and disease stages. This work reviews the current literature pertaining to multiomics in tendon and the potential of these platforms to improve tendon regeneration. We assessed the literature and identified areas where ‘omics platforms contribute to the field: (1) Tendon biology where their hierarchical complexity and demographic factors are studied. (2) Tendon degeneration and healing, where comparisons across tendon pathologies are analyzed. (3) The in vitro engineered tendon phenotype, where we compare the engineered phenotype to relevant native tissues. (4) Finally, we review regenerative and therapeutic approaches. We identified gaps in current knowledge and opportunities for future study: (1) The need to increase the diversity of human subjects and cell sources. (2) Opportunities to improve understanding of tendon heterogeneity. (3) The need to use these improvements to inform new engineered and regenerative therapeutic approaches. (4) The need to increase understanding of the development of tendon pathology. Together, the expanding use of various ‘omics platforms and data analysis resulting from these platforms could substantially contribute to major advances in the tendon tissue engineering and regenerative medicine field.

scholarly journals Pharmacological Therapeutics Targeting RNA-Dependent RNA Polymerase, Proteinase and Spike Protein: From Mechanistic Studies to Clinical Trials for COVID-19

2020 ◽  
Vol 9 (4) ◽  
pp. 1131 ◽  
Author(s):  
Jiansheng Huang ◽  
Wenliang Song ◽  
Hui Huang ◽  
Quancai Sun
Keyword(s):  
Rna Polymerase ◽  
The United States ◽  
Spike Protein ◽  
Therapeutic Approaches ◽  
Rna Dependent Rna Polymerase ◽  
S Protein ◽  
Functional Relationships ◽  
Human Lung Cells ◽  
Novel Coronavirus

An outbreak of novel coronavirus-related pneumonia COVID-19, that was identified in December 2019, has expanded rapidly, with cases now confirmed in more than 211 countries or areas. This constant transmission of a novel coronavirus and its ability to spread from human to human have prompted scientists to develop new approaches for treatment of COVID-19. A recent study has shown that remdesivir and chloroquine effectively inhibit the replication and infection of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, 2019-nCov) in vitro. In the United States, one case of COVID-19 was successfully treated with compassionate use of remdesivir in January of 2020. In addition, a clinically proven protease inhibitor, camostat mesylate, has been demonstrated to inhibit Calu-3 infection with SARS-CoV-2 and prevent SARS-2-spike protein (S protein)-mediated entry into primary human lung cells. Here, we systemically discuss the pharmacological therapeutics targeting RNA-dependent RNA polymerase (RdRp), proteinase and S protein for treatment of SARS-CoV-2 infection. This review should shed light on the fundamental rationale behind inhibition of SARS-CoV-2 enzymes RdRp as new therapeutic approaches for management of patients with COVID-19. In addition, we will discuss the viability and challenges in targeting RdRp and proteinase, and application of natural product quinoline and its analog chloroquine for treatment of coronavirus infection. Finally, determining the structural-functional relationships of the S protein of SARS-CoV-2 will provide new insights into inhibition of interactions between S protein and angiotensin-converting enzyme 2 (ACE2) and enable us to develop novel therapeutic approaches for novel coronavirus SARS-CoV-2.

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