scholarly journals Repeated toxic injuries of murine liver are tolerated through microsteatosis and mild inflammation

2022 ◽  
Author(s):  
Seddik Hammad ◽  
Christoph Ogris ◽  
Amnah Othman ◽  
Pia Erdoesi ◽  
Wolfgang Schmidt-Heck ◽  
...  
Keyword(s):  
Lipid Droplets ◽  
Network Inference ◽  
Critical Time ◽  
Toxic Chemicals ◽  
Time Resolved ◽  
Ecm Remodeling ◽  
Acute Response ◽  
Inflammatory State ◽  
Multi Level ◽  
Liver Response

The liver has a remarkable capacity to regenerate and thus compensates for repeated injuries through toxic chemicals, drugs, alcohol or malnutrition for decades. However, largely unknown is how and when alterations in the liver occur due to tolerable damaging insults. To that end, we induced repeated liver injuries over ten weeks in a mouse model injecting carbon tetrachloride (CCl4) twice a week. We lost 10% of the study animals within the first six weeks, which was accompanied by a steady deposition of extracellular matrix (ECM) regardless of metabolic activity of the liver. From week six onwards, all mice survived, and in these mice ECM deposition was rather reduced, suggesting ECM remodeling as a liver response contributing to better coping with repeated injuries. The data of time-resolved paired transcriptome and proteome profiling of 18 mice was subjected to multi-level network inference, using Knowledge guided Multi-Omics Network inference (KiMONo), identified multi-level key markers exclusively associated with the injury-tolerant liver response. Interestingly, pathways of cancer and inflammation were lighting up and were validated using independent data sets compiled of 1034 samples from publicly available human cohorts. A yet undescribed link to lipid metabolism in this damage-tolerant phase was identified. Immunostaining revealed an unexpected accumulation of small lipid droplets (microvesicular steatosis) in parallel to a recovery of catabolic processes of the liver to pre-injury levels. Further, mild inflammation was experimentally validated. Taken together, we identified week six as a critical time point to switch the liver response program from an acute response that fosters ECM accumulation to a tolerant 'survival' phase with pronounced deposition of small lipid droplets in hepatocytes potentially protecting against the repetitive injury with toxic chemicals. Our data suggest that microsteatosis formation plus a mild inflammatory state represent biomarkers and probably functional liver requirements to resist chronic damage.

Large scale gene regulatory network inference with a multi-level strategy

2016 ◽  
Vol 12 (2) ◽  
pp. 588-597 ◽  
Author(s):  
Jun Wu ◽  
Xiaodong Zhao ◽  
Zongli Lin ◽  
Zhifeng Shao
Keyword(s):  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Large Scale ◽  
Network Inference ◽  
Biological Processes ◽  
Molecular Processes ◽  
Gene Regulatory Network Inference ◽  
Cell Functions ◽  
Multi Level ◽  
Gene Regulatory

Transcriptional regulation is a basis of many crucial molecular processes and an accurate inference of the gene regulatory network is a helpful and essential task to understand cell functions and gain insights into biological processes of interest in systems biology.

scholarly journals Examining the Association between Socioeconomic Status and Exposure to Carcinogenic Emissions in Gyeonggi of South Korea: A Multi-Level Analysis

2019 ◽  
Vol 11 (6) ◽  
pp. 1777 ◽  
Author(s):  
Jeong-Il Park ◽  
Hye-Seon Kwon
Keyword(s):  
Socioeconomic Status ◽  
South Korea ◽  
Negative Binomial ◽  
Toxic Chemicals ◽  
Foreign Born ◽  
Industrial Facilities ◽  
Industrial Land Use ◽  
Gyeonggi Province ◽  
Multi Level ◽  
Justice Studies

Although South Korea introduced the Pollutant Release and Transfer Register system in 1996, there is relatively limited evidence on how socioeconomic status at both individual and municipal levels is associated with exposure to toxic chemicals in Korea because of limited data sources. Using a multi-level negative binomial model, this study examined the socioeconomic status of both individuals and municipalities with a higher level of exposure to carcinogenic emissions from industrial facilities in Gyeonggi province, South Korea. The results reveal that economic minority individuals (national basic livelihood security recipients, unemployed people, and tenants), municipalities with higher percentages of industrial land use, and foreign-born populations had more facilities that produce carcinogenic emissions. While similar findings have been reported by many environmental justice studies conducted in other countries, this is the first Korean case study that reports the relationship between socioeconomic status at both individual and municipal levels and exposure to toxic chemicals.

scholarly journals “They Just Need to Come Down a Little Bit to Your Level”: A Qualitative Study of Parents’ Views and Experiences of Early Life Interventions to Promote Healthy Growth and Associated Behaviours

2020 ◽  
Vol 17 (10) ◽  
pp. 3605
Author(s):  
Marita Hennessy ◽  
Molly Byrne ◽  
Rachel Laws ◽  
Caroline Heary
Keyword(s):  
Health Professionals ◽  
Early Life ◽  
Critical Time ◽  
Evidence Based ◽  
Structured Interviews ◽  
Critical Window ◽  
Time Period ◽  
Multi Level ◽  
To Come ◽  
Healthy Growth

The first 1000 days is a critical window of opportunity to promote healthy growth and associated behaviours. Health professionals can play an important role, in part due to the large number of routine contacts they have with parents. There is an absence of research on the views of parents towards obesity prevention and the range of associated behaviours during this time period. This study aimed to elicit parents’ views on early life interventions to promote healthy growth/prevent childhood obesity, particularly those delivered by health professionals. Semi-structured interviews were conducted with 29 parents (24 mothers, 5 fathers) who were resident in Ireland and had at least one child aged under 30 months. Data were analysed using reflexive thematic analysis. Two central themes were generated: (1) navigating the uncertainty, stress, worries, and challenges of parenting whilst under scrutiny and (2) accessing support in the broader system. Parents would welcome support during this critical time period; particularly around feeding. Such support, however, needs to be practical, realistic, evidence-based, timely, accessible, multi-level, non-judgemental, and from trusted sources, including both health professionals and peers. Interventions to promote healthy growth and related behaviours need to be developed and implemented in a way that supports parents and their views and circumstances.

scholarly journals Retinoids Issued from Hepatic Stellate Cell Lipid Droplet Loss as Potential Signaling Molecules Orchestrating a Multicellular Liver Injury Response

Cells ◽  
2018 ◽  
Vol 7 (9) ◽  
pp. 137 ◽  
Author(s):  
Marie Bobowski-Gerard ◽  
Francesco Zummo ◽  
Bart Staels ◽  
Philippe Lefebvre ◽  
Jérôme Eeckhoute
Keyword(s):  
Liver Injury ◽  
Lipid Droplets ◽  
Stellate Cell ◽  
Matrix Proteins ◽  
Main Body ◽  
Retinoic Acids ◽  
Transcriptional Regulatory ◽  
Elevated Expression ◽  
The One ◽  
Liver Response

Hepatic stellate cells (HSCs) serve as the main body storage compartment for vitamin A through retinyl ester (RE)-filled lipid droplets (LDs). Upon liver injury, HSCs adopt a myofibroblastic phenotype characterized by an elevated expression of extracellular matrix proteins and a concomitant loss of LDs. On the one hand, LD breakdown has been suggested to provide the energy required for HSC activation into myofibroblast-like cells. On the other hand, this process could mitigate HSC activation following the transformation of released REs into retinoic acids (RAs), ligands for nuclear receptors exerting antifibrotic transcriptional regulatory activities in HSCs. Importantly, RAs may also constitute a means for HSCs to orchestrate the liver response to injury by triggering transcriptional effects in multiple additional surrounding liver cell populations. We envision that new approaches, such as single-cell technologies, will allow to better define how RAs are issued from LD loss in HSCs exert a multicellular control of the liver (patho)physiology.

scholarly journals The impact of skeletal muscle contraction on CD146+Lin− pericytes

2019 ◽  
Vol 317 (5) ◽  
pp. C1011-C1024 ◽  
Author(s):  
Svyatoslav Dvoretskiy ◽  
Koyal Garg ◽  
Michael Munroe ◽  
Yair Pincu ◽  
Ziad S. Mahmassani ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Contraction ◽  
Cell Types ◽  
Matrix Remodeling ◽  
Ecm Remodeling ◽  
Acute Response ◽  
Skeletal Muscle Contraction ◽  
Surrounding Connective Tissue ◽  
And Function ◽  
The Impact

Unaccustomed resistance exercise can initiate skeletal muscle remodeling and adaptive mechanisms that can confer protection from damage and enhanced strength with subsequent stimulation. The myofiber may provide the primary origin for adaptation, yet multiple mononuclear cell types within the surrounding connective tissue may also contribute. The purpose of this study was to evaluate the acute response of muscle-resident interstitial cells to contraction initiated by electrical stimulation (e-stim) and subsequently determine the contribution of pericytes to remodeling as a result of training. Mice were subjected to bilateral e-stim or sham treatment. Following a single session of e-stim, NG2+CD45−CD31− (NG2+Lin−) pericyte, CD146+Lin− pericyte, and PDGFRα+ fibroadipogenic progenitor cell quantity and function were evaluated via multiplex flow cytometry and targeted quantitative PCR. Relative quantity was not significantly altered 24 h postcontraction, yet unique gene signatures were observed for each cell population at 3 h postcontraction. CD146+Lin− pericytes appeared to be most responsive to contraction, and upregulation of genes related to immunomodulation and extracellular matrix remodeling was observed via RNA sequencing. Intramuscular injection of CD146+Lin− pericytes did not significantly increase myofiber size yet enhanced ECM remodeling and angiogenesis in response to repeated bouts of e-stim for 4 wk. The results from this study provide the first evidence that CD146+Lin− pericytes are responsive to skeletal muscle contraction and may contribute to the beneficial outcomes associated with exercise.

scholarly journals Knowledge guided multi-level network inference

2020 ◽  
Author(s):  
Christoph Ogris ◽  
Yue Hu ◽  
Janine Arloth ◽  
Nikola S. Müller
Keyword(s):  
Data Analysis ◽  
Quantitative Trait ◽  
Network Inference ◽  
Integrated Analysis ◽  
Full Potential ◽  
Omics Data ◽  
Lasso Regression ◽  
Data Set ◽  
Level Data ◽  
Multi Level

AbstractConstantly decreasing costs of high-throughput profiling on many molecular levels generate vast amounts of so-called multi-omics data. Studying one biomedical question on two or more omic levels provides deeper insights into underlying molecular processes or disease pathophysiology. For the majority of multi-omics data projects, the data analysis is performed level-wise, followed by a combined interpretation of results. Few exceptions exist, for example the pairwise integration for quantitative trait analysis. However, the full potential of integrated data analysis is not leveraged yet, presumably due to the complexity of the data and the lacking toolsets. Here we propose a versatile approach, to perform a multi-level integrated analysis: The Knowledge guIded Multi-Omics Network inference approach, KiMONo. KiMONo performs network inference using statistical modeling on top of a powerful knowledge-guided strategy exploiting prior information from biological sources. Within the resulting network, nodes represent features of all input types and edges refer to associations between them, e.g. underlying a disease. Our method infers the network by combining sparse grouped-LASSO regression with a genomic position-confined Biogrid protein-protein interaction prior. In a comprehensive evaluation, we demonstrate that our method is robust to noise and still performs on low-sample size data. Applied to the five-level data set of the publicly available Pan-cancer collection, KiMONO integrated mutation, epigenetics, transcriptomics, proteomics and clinical information, detecting cancer specific omic features. Moreover, we analysed a four-level data set from a major depressive disorder cohort, including genetic, epigenetic, transcriptional and clinical data. Here we demonstrated KiMONo’s analytical power to identify expression quantitative trait methylation sites and loci and show it’s advantage to state-of-the-art methods. Our results show the general applicability to the full spectrum multi-omics data and demonstrating that KiMONo is a powerful approach towards leveraging the full potential of data sets. The method is freely available as an R package (https://github.com/cellmapslab/kimono).

scholarly journals Lipid Droplets, Phospholipase A2, Arachidonic Acid, and Atherosclerosis

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1891
Author(s):  
Miguel A. Bermúdez ◽  
María A. Balboa ◽  
Jesús Balsinde
Keyword(s):  
Arachidonic Acid ◽  
Phospholipase A2 ◽  
Lipid Droplet ◽  
Lipid Droplets ◽  
Lipid Synthesis ◽  
Lipid Mediator ◽  
Droplet Dynamics ◽  
Potent Inducer ◽  
Inflammatory State ◽  
Dynamic Structures

Lipid droplets, classically regarded as static storage organelles, are currently considered as dynamic structures involved in key processes of lipid metabolism, cellular homeostasis and signaling. Studies on the inflammatory state of atherosclerotic plaques suggest that circulating monocytes interact with products released by endothelial cells and may acquire a foamy phenotype before crossing the endothelial barrier and differentiating into macrophages. One such compound released in significant amounts into the bloodstream is arachidonic acid, the common precursor of eicosanoids, and a potent inducer of neutral lipid synthesis and lipid droplet formation in circulating monocytes. Members of the family of phospholipase A2, which hydrolyze the fatty acid present at the sn-2 position of phospholipids, have recently emerged as key controllers of lipid droplet homeostasis, regulating their formation and the availability of fatty acids for lipid mediator production. In this paper we discuss recent findings related to lipid droplet dynamics in immune cells and the ways these organelles are involved in regulating arachidonic acid availability and metabolism in the context of atherosclerosis.

scholarly journals Intracellular development and impact of a eukaryotic parasite on its zombified microalgal host in the marine plankton

2021 ◽  
Author(s):  
Johan Decelle ◽  
Ehsan Kayal ◽  
Estelle Bigeard ◽  
Benoit Gallet ◽  
Jeremy Bougoure ◽  
...  
Keyword(s):  
Energy Production ◽  
Lipid Droplets ◽  
Fold Increase ◽  
Chemical Imaging ◽  
Cellular Organization ◽  
Time Resolved ◽  
Apicomplexan Parasites ◽  
Open Questions ◽  
Algal Host ◽  
Host Nucleus

Parasites are widespread and diverse in the oceanic plankton, and many of them infect single-celled algae for survival. How these parasites develop and scavenge energy within the host and whether the cellular organization and metabolism of the host is altered remain open questions. Combining quantitative structural and chemical imaging with time-resolved transcriptomics, we unveil dramatic morphological and metabolic changes of the parasite Amoebophrya (Syndiniales) during intracellular infection (e.g. 200-fold increase of mitochondrion volume), particularly following digestion of nutrient-rich host chromosomes. Some of these changes are also found in the apicomplexan parasites (e.g. sequential acristate and cristate mitochondrion, switch from glycolysis to TCA), thus underlining key evolutionary-conserved mechanisms. In the algal host, energy-producing organelles (chloroplast) remain intact during most of the infection, but sugar reserves diminish while lipid droplets increase. Thus, rapid infection of the host nucleus could be a zombifying strategy to digest nutrient-rich chromosomes and escape cytoplasmic defense while benefiting from the maintained C-energy production of the host cell.

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