Nicotine-mediated effects in neuronal and mouse models of synucleinopathy.

Introduction: Alpha-synuclein (α-Syn) aggregation, transmission, and contribution to neurotoxicity represent central mechanisms underlying Parkinson's disease. The plant alkaloid "nicotine" was reported to attenuate α-Syn aggregation in different models, but its precise mode of action remains unclear.

Methods: In this study, we investigated the effect of 2-week chronic nicotine treatment on α-Syn aggregation, neuroinflammation, neurodegeneration, and motor deficits in D-line α-Syn transgenic mice.

Toxicological Assessment of Flavor Ingredients in E-Vapor Products.

Many flavor ingredients are often used in potentially reduced-risk tobacco products (such as e-vapor products). Although most are "generally recognized as safe (GRAS)" when used in food, there is limited information available on their long-term health effects when delivered by inhalation. While obtaining route-of-exposure-specific toxicological data on flavor ingredients is critical to product evaluation, the large number of individual flavor ingredients available and their potential combinations render classical toxicological assessment approaches impractical, as they may require years of preclinical investigations and thousands of laboratory animals.

Causal biological network models for reactive astrogliosis: a systems approach to neuroinflammation.

Astrocytes play a central role in the neuroimmune response by responding to CNS pathologies with diverse molecular and morphological changes during the process of reactive astrogliosis. Here, we used a computational biological network model and mathematical algorithms that allow the interpretation of high-throughput transcriptomic datasets in the context of known biology to study reactive astrogliosis. We gathered available mechanistic information from the literature into a comprehensive causal biological network (CBN) model of astrocyte reactivity.

Effects of plant alkaloids on mitochondrial bioenergetic parameters.

Mitochondria are among the first responders to various stress factors that challenge cell and tissue homeostasis. Various plant alkaloids have been investigated for their capacity to modulate mitochondrial activities. In this study, we used isolated mitochondria from mouse brain and liver tissues to assess nicotine, anatabine and anabasine, three alkaloids found in tobacco plant, for potential modulatory activity on mitochondrial bioenergetics parameters.

A meta-analysis of microRNAs expressed in human aerodigestive epithelial cultures and their role as potential biomarkers of exposure response to nicotine-containing products.

The expression of some microRNAs (miRNA) is modulated in response to cigarette smoke (CS), which is a leading cause of major preventable diseases. However, whether miRNA expression is also modulated by the aerosol/extract from potentially reduced-risk products is not well studied. The present work is a meta-analysis of 12 studies in human organotypic epithelial cultures of the aerodigestive tract (buccal, gingival, bronchial, nasal, and small airway epithelia).

Systems toxicology assessment of a representative e-liquid formulation using human primary bronchial epithelial cells.

The development of reduced-risk products aims to provide alternatives to cigarettes that present less risk of harm for adult smokers. Responsible use of flavoring substances in these products may fulfill an important role in product acceptance. While most flavoring substances used in such products are also used by the food industry and are considered safe when ingested, their impact when inhaled may require further assessment.

Mitochondria as a possible target for nicotine action.

Mitochondria are multifunctional and dynamic organelles deeply integrated into cellular physiology and metabolism. Disturbances in mitochondrial function are involved in several disorders such as neurodegeneration, cardiovascular diseases, metabolic diseases, and also in the aging process. Nicotine is a natural alkaloid present in the tobacco plant which has been well studied as a constituent of cigarette smoke.

Comparative effects of a candidate modified-risk tobacco product Aerosol and cigarette smoke on human organotypic small airway cultures: a systems toxicology approach.

Using an human small airway epithelium model, we assessed the biological impact of an aerosol from a candidate modified-risk tobacco product, the tobacco heating system (THS) 2.2, to investigate the potential reduced risk of THS2.2 aerosol exposure compared with cigarette smoke.

Comparative biological impacts of an aerosol from carbon-heated tobacco and smoke from cigarettes on human respiratory epithelial cultures: A systems toxicology assessment.

The biological impact of an aerosol of a potential modified-risk tobacco product, carbon heated tobacco product 1.2 (CHTP1.2), was comprehensively assessed for the first time in vitro using human small airway and nasal epithelial models following a systems toxicology approach.

Comparative systems toxicology analysis of cigarette smoke and aerosol from a candidate modified risk tobacco product in organotypic human gingival epithelial cultures: A 3-day repeated exposure study.

Smoking is one of the major lifestyle-related risk factors for periodontal diseases. Modified risk tobacco products (MRTP) offer a promising alternative in the harm reduction strategy for adult smokers unable to quit. Using a systems toxicology approach, we investigated and compared the exposure effects of a reference cigarette (3R4F) and a heat-not-burn technology-based candidate MRTP, the Tobacco Heating System (THS) 2.

A systems toxicology approach for comparative assessment: Biological impact of an aerosol from a candidate modified-risk tobacco product and cigarette smoke on human organotypic bronchial epithelial cultures.

This study reports a comparative assessment of the biological impact of a heated tobacco aerosol from the tobacco heating system (THS) 2.2 and smoke from a combustible 3R4F cigarette. Human organotypic bronchial epithelial cultures were exposed to an aerosol from THS2.

Gastroparesis: Quality of Life and Health Care Utilization.

Background And Aims: Gastroparesis (GP) patients suffer from recurrent symptoms of nausea, vomiting, early satiety, and abdominal pain. The impact of GP on quality of life (QoL), health care utilization and daily activities is not well understood.

Materials And Methods: Part 1: 398 adult patients (≥18 y) with documented GP (symptoms >6 mo) were surveyed to assess QoL and pain using the Short Form 36 and McGill pain questionnaires.

Systems Toxicology Assessment of the Biological Impact of a Candidate Modified Risk Tobacco Product on Human Organotypic Oral Epithelial Cultures.

Cigarette smoke (CS) has been reported to increase predisposition to oral cancer and is also recognized as a risk factor for many conditions including periodontal diseases, gingivitis, and other benign mucosal disorders. Smoking cessation remains the most effective approach for minimizing the risk of smoking-related diseases. However, reduction of harmful constituents by heating rather than combusting tobacco, without modifying the amount of nicotine, is a promising new paradigm in harm reduction.

3-D nasal cultures: Systems toxicological assessment of a candidate modified-risk tobacco product.

In vitro toxicology approaches have evolved from a focus on molecular changes within a cell to understanding of toxicity-related mechanisms in systems that can mimic the in vivo environment. The recent development of three dimensional (3-D) organotypic nasal epithelial culture models offers a physiologically robust system for studying the effects of exposure through inhalation. Exposure to cigarette smoke (CS) is associated with nasal inflammation; thus, the nasal epithelium is relevant for evaluating the pathophysiological impact of CS exposure.

Assessment of in vitro COPD models for tobacco regulatory science: Workshop proceedings, conclusions and paths forward for in vitro model use.

The Family Smoking Prevention and Tobacco Control Act of 2009 established the Food and Drug Administration Center for Tobacco Products (FDA-CTP), and gave it regulatory authority over the marketing, manufacture and distribution of tobacco products, including those termed 'modified risk'. On 8-10 December 2014, IIVS organised a workshop conference, entitled Assessment of In Vitro COPD Models for Tobacco Regulatory Science, to bring together stakeholders representing regulatory agencies, academia, industry and animal protection, to address the research priorities articulated by the FDA-CTP. Specific topics were covered to assess the status of current in vitro technologies as they are applied to understanding the adverse pulmonary events resulting from tobacco product exposure, and in particular, the progression of chronic obstructive pulmonary disease (COPD).

A framework for in vitro systems toxicology assessment of e-liquids.

Various electronic nicotine delivery systems (ENDS), of which electronic cigarettes (e-cigs) are the most recognized prototype, have been quickly gaining ground on conventional cigarettes because they are perceived as less harmful. Research assessing the potential effects of ENDS exposure in humans is currently limited and inconclusive. New products are emerging with numerous variations in designs and performance parameters within and across brands.

In Vitro Systems Toxicology Assessment of a Candidate Modified Risk Tobacco Product Shows Reduced Toxicity Compared to That of a Conventional Cigarette.

Cigarette smoke increases the risk for respiratory and other diseases. Although smoking prevalence has declined over the years, millions of adults choose to continue to smoke. Modified risk tobacco products (MRTPs) are potentially valuable tools for adult smokers that are unwilling to quit their habit.

Impact Assessment of Cigarette Smoke Exposure on Organotypic Bronchial Epithelial Tissue Cultures: A Comparison of Mono-Culture and Coculture Model Containing Fibroblasts.

Organotypic 3D cultures of epithelial cells are grown at the air-liquid interface (ALI) and resemble the in vivo counterparts. Although the complexity of in vivo cellular responses could be better manifested in coculture models in which additional cell types such as fibroblasts were incorporated, the presence of another cell type could mask the response of the other. This study reports the impact of whole cigarette smoke (CS) exposure on organotypic mono- and coculture models to evaluate the relevancy of organotypic models for toxicological assessment of aerosols.

A systems biology approach reveals the dose- and time-dependent effect of primary human airway epithelium tissue culture after exposure to cigarette smoke in vitro.

To establish a relevant in vitro model for systems toxicology-based mechanistic assessment of environmental stressors such as cigarette smoke (CS), we exposed human organotypic bronchial epithelial tissue cultures at the air liquid interface (ALI) to various CS doses. Previously, we compared in vitro gene expression changes with published human airway epithelia in vivo data to assess their similarities. Here, we present a follow-up evaluation of these in vitro transcriptomics data, using complementary computational approaches and an integrated mRNA-microRNA (miRNA) analysis.

Impact assessment of repeated exposure of organotypic 3D bronchial and nasal tissue culture models to whole cigarette smoke.

Cigarette smoke (CS) has a major impact on lung biology and may result in the development of lung diseases such as chronic obstructive pulmonary disease or lung cancer. To understand the underlying mechanisms of disease development, it would be important to examine the impact of CS exposure directly on lung tissues. However, this approach is difficult to implement in epidemiological studies because lung tissue sampling is complex and invasive.

The response of human nasal and bronchial organotypic tissue cultures to repeated whole cigarette smoke exposure.

Exposure to cigarette smoke (CS) is linked to the development of respiratory diseases, and there is a need to understand the mechanisms whereby CS causes damage. Although animal models have provided valuable insights into smoking-related respiratory tract damage, modern toxicity testing calls for reliable in vitro models as alternatives for animal experimentation. We report on a repeated whole mainstream CS exposure of nasal and bronchial organotypic tissue cultures that mimic the morphological, physiological, and molecular attributes of the human respiratory tract.

Understanding the limits of animal models as predictors of human biology: lessons learned from the sbv IMPROVER Species Translation Challenge.

Motivation: Inferring how humans respond to external cues such as drugs, chemicals, viruses or hormones is an essential question in biomedicine. Very often, however, this question cannot be addressed because it is not possible to perform experiments in humans. A reasonable alternative consists of generating responses in animal models and 'translating' those results to humans.

In vitro systems toxicology approach to investigate the effects of repeated cigarette smoke exposure on human buccal and gingival organotypic epithelial tissue cultures.

Smoking has been associated with diseases of the lung, pulmonary airways and oral cavity. Cytologic, genomic and transcriptomic changes in oral mucosa correlate with oral pre-neoplasia, cancer and inflammation (e.g.

A vascular biology network model focused on inflammatory processes to investigate atherogenesis and plaque instability.

Background: Numerous inflammation-related pathways have been shown to play important roles in atherogenesis. Rapid and efficient assessment of the relative influence of each of those pathways is a challenge in the era of "omics" data generation. The aim of the present work was to develop a network model of inflammation-related molecular pathways underlying vascular disease to assess the degree of translatability of preclinical molecular data to the human clinical setting.

Systems biology approach for evaluating the biological impact of environmental toxicants in vitro.

Exposure to cigarette smoke is a leading cause of lung diseases including chronic obstructive pulmonary disease and cancer. Cigarette smoke is a complex aerosol containing over 6000 chemicals and thus it is difficult to determine individual contributions to overall toxicity as well as the molecular mechanisms by which smoke constituents exert their effects. We selected three well-known harmful and potentially harmful constituents (HPHCs) in tobacco smoke, acrolein, formaldehyde and catechol, and established a high-content screening method using normal human bronchial epithelial cells, which are the first bronchial cells in contact with cigarette smoke.