Animal models of drug-induced pulmonary fibrosis: an overview of molecular mechanisms and characteristics

Abstract Background Due to the diversity of studies in animal models reporting that molecular mechanisms are involved in the teratogenic effect of the Zika virus (ZIKV), the objective of the present study is to evaluate the methodological quality of these studies, as well as to demonstrate which genes and which molecular pathways are affected by ZIKV in different animal models. Methods This search will be performed in four databases: PubMed/MEDLINE, EMBASE, Web of Science, and Scopus, as well as in the grey literature. The studies selection process will be reported through the PRISMA Statement diagram model. All studies describing the molecular mechanisms possibly involved in the development of malformations caused by embryonic/fetal ZIKV exposure in animal models with an appropriate control group and methodology will be included (including, for instance, randomized and non-randomized studies). All animals used as experimental models for ZIKV teratogenesis may be included as long as exposure to the virus occurred during the embryonic/fetal period. From the selected studies, data will be extracted using a previously prepared standard form. Bias risk evaluation will be conducted following the SYRCLE’s Risk of Bias tool. All data obtained will be tabulated and organized by outcomes (morphological and molecular). Discussion With the proposed systematic review, we expect to present results about the methodological quality of the published studies with animal models that investigated the molecular mechanisms involved in the teratogenic effect of ZIKV, as well as to show the studies with greater reliability. Systematic review registration PROSPERO CRD42019157316

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Anti-Fibrosis Effects of Magnesium Lithospermate B in Experimental Pulmonary Fibrosis: By Inhibiting TGF-βRI/Smad Signaling

Molecules ◽

10.3390/molecules26061715 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1715

Author(s):

Xin Luo ◽

Qiangqiang Deng ◽

Yaru Xue ◽

Tianwei Zhang ◽

Zhitao Wu ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Cell Line ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Salvia Miltiorrhiza ◽

A549 Cells ◽

Epithelial Cell Line ◽

Human Lung Fibroblast ◽

Magnesium Lithospermate B

Pulmonary fibrosis is a severe and irreversible interstitial pulmonary disease with high mortality and few treatments. Magnesium lithospermate B (MLB) is a hydrosoluble component of Salvia miltiorrhiza and has been reported to have antifibrotic effects in other forms of tissue fibrosis. In this research, we studied the effects of MLB on pulmonary fibrosis and the underlying mechanisms. Our results indicated that MLB treatment (50 mg/kg) for seven days could attenuate bleomycin (BLM)-induced pulmonary fibrosis by reducing the alveolar structure disruption and collagen deposition in the C57 mouse model. MLB was also found to inhibit transforming growth factor-beta (TGF-β)-stimulated myofibroblastic transdifferentiation of human lung fibroblast cell line (MRC-5) cells and collagen production by human type II alveolar epithelial cell line (A549) cells, mainly by decreasing the expression of TGF-β receptor I (TGF-βRI) and regulating the TGF-β/Smad pathway. Further studies confirmed that the molecular mechanisms of MLB in BLM-induced pulmonary fibrosis mice were similar to those observed in vitro. In summary, our results demonstrated that MLB could alleviate experimental pulmonary fibrosis both in vivo and in vitro, suggesting that MLB has great potential for pulmonary fibrosis treatment.

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Zebrafish Models of Autosomal Recessive Ataxias

Cells ◽

10.3390/cells10040836 ◽

2021 ◽

Vol 10 (4) ◽

pp. 836

Author(s):

Ana Quelle-Regaldie ◽

Daniel Sobrido-Cameán ◽

Antón Barreiro-Iglesias ◽

María Jesús Sobrido ◽

Laura Sánchez

Keyword(s):

Animal Models ◽

Autosomal Recessive ◽

Molecular Mechanisms ◽

System Development ◽

Rapid Development ◽

Nervous System Development ◽

Central Nervous System Development ◽

Cellular Processes ◽

Recessive Disorders

Autosomal recessive ataxias are much less well studied than autosomal dominant ataxias and there are no clearly defined systems to classify them. Autosomal recessive ataxias, which are characterized by neuronal and multisystemic features, have significant overlapping symptoms with other complex multisystemic recessive disorders. The generation of animal models of neurodegenerative disorders increases our knowledge of their cellular and molecular mechanisms and helps in the search for new therapies. Among animal models, the zebrafish, which shares 70% of its genome with humans, offer the advantages of being small in size and demonstrating rapid development, making them optimal for high throughput drug and genetic screening. Furthermore, embryo and larval transparency allows to visualize cellular processes and central nervous system development in vivo. In this review, we discuss the contributions of zebrafish models to the study of autosomal recessive ataxias characteristic phenotypes, behavior, and gene function, in addition to commenting on possible treatments found in these models. Most of the zebrafish models generated to date recapitulate the main features of recessive ataxias.

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Mitochondrial Dynamics in Drug-Induced Liver Injury

Livers ◽

10.3390/livers1030010 ◽

2021 ◽

Vol 1 (3) ◽

pp. 102-115

Author(s):

Anup Ramachandran ◽

David S. Umbaugh ◽

Hartmut Jaeschke

Keyword(s):

Liver Injury ◽

Molecular Mechanisms ◽

Membrane Lipids ◽

Mitochondrial Dynamics ◽

Adaptive Responses ◽

Drug Induced ◽

Biologically Relevant ◽

Drug Induced Liver Injury ◽

Relevant Role ◽

Atp Generation

Mitochondria have been studied for decades from the standpoint of metabolism and ATP generation. However, in recent years mitochondrial dynamics and its influence on bioenergetics and cellular homeostasis is also being appreciated. Mitochondria undergo regular cycles of fusion and fission regulated by various cues including cellular energy requirements and pathophysiological stimuli, and the network of critical proteins and membrane lipids involved in mitochondrial dynamics is being revealed. Hepatocytes are highly metabolic cells which have abundant mitochondria suggesting a biologically relevant role for mitochondrial dynamics in hepatocyte injury and recovery. Here we review information on molecular mediators of mitochondrial dynamics and their alteration in drug-induced liver injury. Based on current information, it is evident that changes in mitochondrial fusion and fission are hallmarks of liver pathophysiology ranging from acetaminophen-induced or cholestatic liver injury to chronic liver diseases. These alterations in mitochondrial dynamics influence multiple related mitochondrial responses such as mitophagy and mitochondrial biogenesis, which are important adaptive responses facilitating liver recovery in several contexts, including drug-induced liver injury. The current focus on characterization of molecular mechanisms of mitochondrial dynamics is of immense relevance to liver pathophysiology and have the potential to provide significant insight into mechanisms of liver recovery and regeneration after injury.

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Deafness-in-a-dish: modeling hereditary deafness with inner ear organoids

Human Genetics ◽

10.1007/s00439-021-02325-9 ◽

2021 ◽

Author(s):

Daniel R. Romano ◽

Eri Hashino ◽

Rick F. Nelson

Keyword(s):

Animal Models ◽

Inner Ear ◽

Auditory System ◽

Hearing Aids ◽

Molecular Mechanisms ◽

Functional Disability ◽

Experimental Studies ◽

Hereditary Deafness ◽

Human Auditory System ◽

Human Inner Ear

AbstractSensorineural hearing loss (SNHL) is a major cause of functional disability in both the developed and developing world. While hearing aids and cochlear implants provide significant benefit to many with SNHL, neither targets the cellular and molecular dysfunction that ultimately underlies SNHL. The successful development of more targeted approaches, such as growth factor, stem cell, and gene therapies, will require a yet deeper understanding of the underlying molecular mechanisms of human hearing and deafness. Unfortunately, the human inner ear cannot be biopsied without causing significant, irreversible damage to the hearing or balance organ. Thus, much of our current understanding of the cellular and molecular biology of human deafness, and of the human auditory system more broadly, has been inferred from observational and experimental studies in animal models, each of which has its own advantages and limitations. In 2013, researchers described a protocol for the generation of inner ear organoids from pluripotent stem cells (PSCs), which could serve as scalable, high-fidelity alternatives to animal models. Here, we discuss the advantages and limitations of conventional models of the human auditory system, describe the generation and characteristics of PSC-derived inner ear organoids, and discuss several strategies and recent attempts to model hereditary deafness in vitro. Finally, we suggest and discuss several focus areas for the further, intensive characterization of inner ear organoids and discuss the translational applications of these novel models of the human inner ear.

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When things go wrong: Exploring possible mechanisms driving the progressive fibrosis phenotype in interstitial lung diseases

European Respiratory Journal ◽

10.1183/13993003.04507-2020 ◽

2021 ◽

pp. 2004507

Author(s):

Moisés Selman ◽

Annie Pardo

Keyword(s):

Pulmonary Fibrosis ◽

Lung Diseases ◽

Molecular Mechanisms ◽

Lung Parenchyma ◽

Interstitial Lung Diseases ◽

Unknown Etiology ◽

Clinical Behavior ◽

The Past ◽

Appropriate Treatment ◽

Different Types

Interstitial lung diseases (ILD) comprise a large and heterogeneous group of disorders of known and unknown etiology characterised by diffuse damage of the lung parenchyma. In the past years, it has become evident that patients with different types of ILD are at risk of developing progressive pulmonary fibrosis known as pulmonary fibrosing ILD (PF-ILD). This is a phenotype behaving similar to idiopathic pulmonary fibrosis, the archetypical example of progressive fibrosis. PF-ILD is not a distinct clinical entity but describes a group of ILD with a similar clinical behavior. This phenotype may occur in diseases displaying distinct etiologies and different biopathology during their initiation and development. Importantly, these entities may have the potential for improvement or stabilisation prior to entering in the progressive fibrosing phase. The crucial questions are (1) why a subset of patients develops a progressive and irreversible fibrotic phenotype even with appropriate treatment, and (2) what the pathogenic mechanisms driving progression possibly are. We here provide a framework highlighting putative mechanisms underlying progression, including genetic susceptibility, aging, epigenetics, the structural fibrotic distortion, the aberrant composition and stiffness of the extracellular matrix, and the emergence of distinct profibrotic cell subsets. Understanding the cellular and molecular mechanisms behind PF-ILD will provide the basis for identifying risk factors and appropriate therapeutical strategies.

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Anti-fibrosis effect for Hirsutella sinensis mycelium based on inhibition of mTOR p70S6K phosphorylation

Innate Immunity ◽

10.1177/1753425917726361 ◽

2017 ◽

Vol 23 (7) ◽

pp. 615-624 ◽

Cited By ~ 5

Author(s):

Huimin Yue ◽

Yarong Zhao ◽

Haining Wang ◽

Feiya Ma ◽

Fei Liu ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Lung Fibrosis ◽

Molecular Mechanisms ◽

Histopathological Examination ◽

Smooth Muscle Actin ◽

A549 Cells ◽

Mtor Pathway ◽

Cordyceps Sinensis ◽

Tgf Β1

Hirsutella sinensis, cultured in vitro, is an attractive substitute for Cordyceps sinensis as health supplement. The aim of this study was to demonstrate whether H. sinensis mycelium (HSM) attenuates murine pulmonary fibrosis induced by bleomycin and to explore the underlying molecular mechanisms. Using lung fibrosis modle induced by intratracheal instillation of bleomycin (BLM; 4 mg/kg), we observed that the administration of HSM reduced HYP, TGF-β1 and the production of several pro-fibrosis cytokines (α-smooth muscle actin, fibronectin and vimentin) in fibrotic mice lung sections. Histopathological examination of lung tissues also demonstrated that HSM improved BLM-induced pathological damage. Concurrently, HSM supplementation markedly reduced the chemotaxis of alveolar macrophages and potently suppressed the expression of inflammatory cytokines. Also, HSM influenced Th1/Th2 and Th17/Treg imbalance and blocked the phosphorylation of mTOR pathway in vivo. Alveolar epithelial A549 cells acquired a mesenchymal phenotype and an increased expression of myofibroblast markers of differentiation (vimentin and fibronectin) after treatment with TGF-β1. HSM suppressed these markers and blocked the phosphorylation of mTOR pathway in vitro. The results provide evidence supporting the use of HSM in the intervention of pulmonary fibrosis and suggest that HSM is a potential therapeutic agent for lung fibrosis.

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Circadian Rhythms, the Mesolimbic Dopaminergic Circuit, and Drug Addiction

The Scientific World JOURNAL ◽

10.1100/tsw.2007.213 ◽

2007 ◽

Vol 7 ◽

pp. 194-202 ◽

Cited By ~ 65

Author(s):

Colleen A. McClung

Keyword(s):

Circadian Rhythms ◽

Drug Addiction ◽

Molecular Mechanisms ◽

Dopaminergic System ◽

Treatment Options ◽

Drug Induced ◽

Circadian Genes ◽

Dopaminergic Transmission ◽

Central Pacemaker

Drug addiction is a devastating disease that affects millions of individuals worldwide. Through better understanding of the genetic variations that create a vulnerability for addiction and the molecular mechanisms that underlie the progression of addiction, better treatment options can be created for those that suffer from this condition. Recent studies point to a link between abnormal or disrupted circadian rhythms and the development of addiction. In addition, studies suggest a role for specific genes that make up the molecular clock in the regulation of drug sensitivity, sensitization, and reward. The influence of circadian genes and rhythms on drug-induced behaviors may be mediated through the mesolimbic dopaminergic system. This system has long been implicated in the development of addiction, and recent evidence supports a regulatory role for the brain's central pacemaker and circadian gene expression in the regulation of dopaminergic transmission. This review highlights the association between circadian genes and drug addiction, and the possible role of the mesolimbic dopaminergic system in this association.

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NNK-Induced Lung Tumors: A Review of Animal Model

Journal of Oncology ◽

10.1155/2011/635379 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 23

Author(s):

Hua-Chuan Zheng ◽

Yasuo Takano

Keyword(s):

Lung Cancer ◽

Animal Model ◽

Animal Models ◽

Molecular Mechanisms ◽

Expression Profiles ◽

Genetic Mutation ◽

Lung Tumors ◽

Chemotherapeutic Agents ◽

Signal Pathways ◽

Lung Carcinogenesis

The incidence of lung adenocarcinoma has been remarkably increasing in recent years due to the introduction of filter cigarettes and secondary-hand smoking because the people are more exposed to higher amounts of nitrogen oxides, especially 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK), which is widely applied in animal model of lung tumors. In NNK-induced lung tumors, genetic mutation, chromosome instability, gene methylation, and activation of oncogenes have been found so as to disrupt the expression profiles of some proteins or enzymes in various cellular signal pathways. Transgenic animal with specific alteration of lung cancer-related molecules have also been introduced to clarify the molecular mechanisms of NNK in the pathogenesis and development of lung tumors. Based on these animal models, many antioxidant ingredients and antitumor chemotherapeutic agents have been proved to suppress the NNK-induced lung carcinogenesis. In the future, it is necessary to delineate the most potent biomarkers of NNK-induced lung tumorigenesis, and to develop efficient methods to fight against NNK-associated lung cancer using animal models.

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Sunscreen protection against drug-induced phototoxicity in animal models

Toxicology and Applied Pharmacology ◽

10.1016/0041-008x(79)90244-8 ◽

1979 ◽

Vol 49 (2) ◽

pp. 219-224 ◽

Cited By ~ 18

Author(s):

Frank J. Akin ◽

Arthur P. Rose ◽

Thomas W. Chamness ◽

Edward Marlowe

Keyword(s):

Animal Models ◽

Drug Induced

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