scholarly journals Unfulfilled Inflammatory Resolution: A Key Factor in the Pathogenesis of Psoriasis

2020 ◽  
Author(s):  
Zohreh Jadali
Keyword(s):  
Inflammatory Response ◽  
Chronic Inflammation ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Relevant Literature ◽  
Regulatory Mechanisms ◽  
Immune Mediated ◽  
Key Factor ◽  
Inflammation Resolution

Recent literature has highlighted the importance of chronic inflammation in psoriasis pathogenesis. Non-resolving inflammation can trigger progressive tissue damage and inflammatory mediator release which in turn perpetuate the inflammatory cycle. Under normal conditions, inflammatory responses are tightly controlled through several mechanisms that restore normal tissue function and structure. Defects in regulatory mechanisms of the inflammatory response can result in persistent unresolved inflammation and further increases of inflammation. Therefore, this review focuses on defects in regulatory mechanisms of inflammatory responses that lead to uncontrolled chronic inflammation in psoriasis. Databases such as Pubmed Embase, ISI, and Iranian databases including Iranmedex, and SID were researched to identify relevant literature. The results of this review indicate that dysregulation of the inflammatory response may be a likely cause of various immune-mediated inflammatory disorders such as psoriasis. Based on current findings, advances in understanding the cellular and molecular mechanisms involved in inflammation resolution are not only improving our knowledge of the pathogenesis of chronic inflammatory diseases but also supporting the development of new therapeutic strategies.

scholarly journals Modeling Inflammation in Zebrafish for the Development of Anti-inflammatory Drugs

2021 ◽  
Vol 8 ◽  
Author(s):  
Yufei Xie ◽  
Annemarie H. Meijer ◽  
Marcel J. M. Schaaf
Keyword(s):  
Immune System ◽  
Inflammatory Response ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Model Systems ◽  
Trinitrobenzene Sulfonic Acid ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

Dysregulation of the inflammatory response in humans can lead to various inflammatory diseases, like asthma and rheumatoid arthritis. The innate branch of the immune system, including macrophage and neutrophil functions, plays a critical role in all inflammatory diseases. This part of the immune system is well-conserved between humans and the zebrafish, which has emerged as a powerful animal model for inflammation, because it offers the possibility to image and study inflammatory responses in vivo at the early life stages. This review focuses on different inflammation models established in zebrafish, and how they are being used for the development of novel anti-inflammatory drugs. The most commonly used model is the tail fin amputation model, in which part of the tail fin of a zebrafish larva is clipped. This model has been used to study fundamental aspects of the inflammatory response, like the role of specific signaling pathways, the migration of leukocytes, and the interaction between different immune cells, and has also been used to screen libraries of natural compounds, approved drugs, and well-characterized pathway inhibitors. In other models the inflammation is induced by chemical treatment, such as lipopolysaccharide (LPS), leukotriene B4 (LTB4), and copper, and some chemical-induced models, such as treatment with trinitrobenzene sulfonic acid (TNBS), specifically model inflammation in the gastro-intestinal tract. Two mutant zebrafish lines, carrying a mutation in the hepatocyte growth factor activator inhibitor 1a gene (hai1a) and the cdp-diacylglycerolinositol 3-phosphatidyltransferase (cdipt) gene, show an inflammatory phenotype, and they provide interesting model systems for studying inflammation. These zebrafish inflammation models are often used to study the anti-inflammatory effects of glucocorticoids, to increase our understanding of the mechanism of action of this class of drugs and to develop novel glucocorticoid drugs. In this review, an overview is provided of the available inflammation models in zebrafish, and how they are used to unravel molecular mechanisms underlying the inflammatory response and to screen for novel anti-inflammatory drugs.

scholarly journals Role of IL-10-Producing Natural Killer Cells in the Regulatory Mechanisms of Inflammation during Systemic Infection

Biomolecules ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 4
Author(s):  
Israel Martinez-Espinosa ◽  
José A. Serrato ◽  
Blanca Ortiz-Quintero
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Systemic Infection ◽  
Regulatory Mechanisms ◽  
Infection Model ◽  
Immune Mediated ◽  
Model Understanding

Natural killer (NK) cells have the dual ability to produce pro-inflammatory (IFNγ) and anti-inflammatory (IL-10) cytokines during systemic infection, which points to their crucial role both as inflammatory effectors for infection clearance and as regulators to counterbalance inflammation to limit immune-mediated damage to the host. In particular, immunosuppressive IL-10 secretion by NK cells has been described to occur in systemic, but not local, infections as a recent immunoregulatory mechanism of inflammation that may be detrimental or beneficial, depending on the timing of release, type of disease, or the infection model. Understanding the factors that drive the production of IL-10 by NK cells and their impact during dualistic inflammatory states, such as sepsis and other non-controlled inflammatory diseases, is relevant for achieving effective therapeutic advancements. In this review, the evidence regarding the immunoregulatory role of IL-10-producing NK cells in systemic infection is summarized and discussed in detail, and the potential molecular mechanisms that drive IL-10 production by NK cells are considered.

scholarly journals p38/AP-1 Pathway in Lipopolysaccharide-Induced Inflammatory Responses Is Negatively Modulated by Electrical Stimulation

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Deok Jeong ◽  
Jaehwi Lee ◽  
Young-Su Yi ◽  
Yanyan Yang ◽  
Kyoung Won Kim ◽  
...  
Keyword(s):  
Electrical Stimulation ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Physiological Role ◽  
Peritoneal Macrophages ◽  
Cellular Level ◽  
Transcriptional Level ◽  
Weak Current ◽  
Anti Inflammatory

Electrical stimulation with a weak current has been demonstrated to modulate various cellular and physiological responses, including the differentiation of mesenchymal stem cells and acute or chronic physical pain. Thus, a variety of investigations regarding the physiological role of nano- or microlevel currents at the cellular level are actively proceeding in the field of alternative medicine. In this study, we focused on the anti-inflammatory activity of aluminum-copper patches (ACPs) under macrophage-mediated inflammatory conditions. ACPs generated nanolevel currents ranging from 30 to 55 nA in solution conditions. Interestingly, the nanocurrent-generating aluminum-copper patches (NGACPs) were able to suppress both lipopolysaccharide-(LPS-) and pam3CSK-induced inflammatory responses such as NO and PGE2production in both RAW264.7 cells and peritoneal macrophages at the transcriptional level. Through immunoblotting and immunoprecipitation analyses, we found that p38/AP-1 could be the major inhibitory pathway in the NGACP-mediated anti-inflammatory response. Indeed, inhibition of p38 by SB203580 showed similar inhibitory activity of the production of TNF-αand PGE2and the expression of TNF-αand COX-2 mRNA. These results suggest that ACP-induced nanocurrents alter signal transduction pathways that are involved in the inflammatory response and could therefore be utilized in the treatment of various inflammatory diseases such as arthritis and colitis.

scholarly journals DNA damage independent inhibition of NF-κB transcription by anthracyclines

2020 ◽  
Author(s):  
Angelo Chora ◽  
Dora Pedroso ◽  
Nadja Pejanovic ◽  
Eleni Kyriakou ◽  
Henrique Colaço ◽  
...  
Keyword(s):  
Dna Damage ◽  
Transcription Factors ◽  
Binding Sites ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Anticancer Properties ◽  
Dna Binding Sites ◽  
Immune Mediated ◽  
Life Threatening ◽  
Molecular Patterns

AbstractTranscriptional programs leading to induction of a large number of genes can be rapidly initiated by the activation of only few selected transcription factors. Upon stimulation of macrophages with microbial-associated molecular patterns (MAMPs), the activation of the nuclear factor kappa B (NF-κB) family of transcription factors triggers inflammatory responses that, left uncontrolled, can lead to excessive inflammation with life-threatening consequences for the host. Here we identify and characterize a novel effect of Anthracyclines, a class of drugs currently used as potent anticancer drugs, in the regulation of NF-κB transcriptional activity in BMDMs, in addition to the previously reported DNA damage and histone eviction. Anthracyclines, including Doxorubicin, Daunorubicin and Epirubicin, disturb the complexes formed between the NF-κB subunit RelA and its DNA binding sites, to limit NF-κB-dependent gene transcription during inflammatory responses, including of pivotal pro-inflammatory mediators such as TNF. We observed that suppression of inflammation can also be mediated by Aclarubicin, Doxorubicinone and the newly developed Dimethyl-doxorubicin, which share anticancer properties with the other Anthracyclines, but do not induce DNA damage in the tested concentrations. This novel mechanism of action of Anthracyclines, contributing to the reduction of inflammation, is thus independent of the activation of DNA damage responses and may be relevant for the development of novel strategies targeting immune-mediated inflammatory diseases.

scholarly journals The GTEx Consortium atlas of genetic regulatory effects across human tissues

Science ◽  
2020 ◽  
Vol 369 (6509) ◽  
pp. 1318-1330 ◽  
Author(s):  
Keyword(s):  
Complex Traits ◽  
Molecular Mechanisms ◽  
Tissue Expression ◽  
Genetic Effects ◽  
Regulatory Mechanisms ◽  
Human Tissues ◽  
Genetic Associations ◽  
Key Factor ◽  
Regulatory Effects ◽  
Almost All

The Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the version 8 data, examining 15,201 RNA-sequencing samples from 49 tissues of 838 postmortem donors. We comprehensively characterize genetic associations for gene expression and splicing in cis and trans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue specificity of genetic effects and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.

scholarly journals Tackling Chronic Inflammation with Withanolide Phytochemicals—A Withaferin A Perspective

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1107
Author(s):  
Emilie Logie ◽  
Wim Vanden Berghe
Keyword(s):  
Chronic Inflammation ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Withaferin A ◽  
Related Factor ◽  
Nuclear Factor ◽  
Pharmaceutical Drugs ◽  
In Vivo Models ◽  
Chronic Inflammatory Diseases ◽  
Anti Inflammatory

Chronic inflammatory diseases are considered to be one of the biggest threats to human health. Most prescribed pharmaceutical drugs aiming to treat these diseases are characterized by side-effects and negatively affect therapy adherence. Finding alternative treatment strategies to tackle chronic inflammation has therefore been gaining interest over the last few decades. In this context, Withaferin A (WA), a natural bioactive compound isolated from Withania somnifera, has been identified as a promising anti-cancer and anti-inflammatory compound. Although the majority of studies focus on the molecular mechanisms of WA in cancer models, recent evidence demonstrates that WA also holds promise as a new phytotherapeutic agent against chronic inflammatory diseases. By targeting crucial inflammatory pathways, including nuclear factor kappa B (NF-κB) and nuclear factor erythroid 2 related factor 2 (Nrf2) signaling, WA suppresses the inflammatory disease state in several in vitro and preclinical in vivo models of diabetes, obesity, neurodegenerative disorders, cystic fibrosis and osteoarthritis. This review provides a concise overview of the molecular mechanisms by which WA orchestrates its anti-inflammatory effects to restore immune homeostasis.

scholarly journals Resveratrol Inhibits Particulate Matter-Induced Inflammatory Responses in Human Keratinocytes

2020 ◽  
Vol 21 (10) ◽  
pp. 3446 ◽  
Author(s):  
Jung-Won Shin ◽  
Hyun-Sun Lee ◽  
Jung-Im Na ◽  
Chang-Hun Huh ◽  
Kyung-Chan Park ◽  
...  
Keyword(s):  
Particulate Matter ◽  
Inflammatory Response ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Antioxidant Properties ◽  
Complex Mixture ◽  
Human Keratinocytes ◽  
Receptor Activation ◽  
Air Pollutant ◽  
Cellular Inflammatory Response

Particulate matter (PM), a major air pollutant, is a complex mixture of solid and liquid particles of various sizes. PM has been demonstrated to cause intracellular inflammation in human keratinocytes, and is associated with various skin disorders, including atopic dermatitis, eczema, and skin aging. Resveratrol is a natural polyphenol with strong antioxidant properties, and its beneficial effects against skin changes due to PM remain elusive. Therefore, in the present study, we investigated the effect of resveratrol on PM-induced skin inflammation and attempted to deduce the molecular mechanisms underlying resveratrol’s effects. We found that resveratrol inhibited PM-induced aryl hydrocarbon receptor activation and reactive oxygen species formation in keratinocytes. It also suppressed the subsequent cellular inflammatory response by inhibiting mitogen-activated protein kinase activation. Consequentially, resveratrol reduced PM-induced cyclooxygenase-2/prostaglandin E2 and proinflammatory cytokine expression, including that of matrix metalloproteinase (MMP)-1, MMP-9, and interleukin-8, all of which are known to be central mediators of various inflammatory conditions and aging. In conclusion, resveratrol inhibits the PM-induced inflammatory response in human keratinocytes, and we suggest that resveratrol may have potential for preventing air pollution-related skin problems.

Novel control of cAMP-regulated transcription in vascular endothelial cells

2012 ◽  
Vol 40 (1) ◽  
pp. 1-5 ◽  
Author(s):  
Gillian R. Milne ◽  
Timothy M. Palmer ◽  
Stephen J. Yarwood
Keyword(s):  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Vascular Endothelial Cells ◽  
Inflammatory Diseases ◽  
Circulatory System ◽  
Vascular Endothelial ◽  
Protective Mechanisms ◽  
Enhancer Binding Protein ◽  
Developed World

Chronic inflammatory diseases, such as atherosclerosis, are a major cause of death and disability in the developed world. In this respect, although cholesterol obviously plays a predominant role in atherosclerosis, targeting inflammation at lesion sites may be just as important. Indeed, elevated IL-6 (interleukin 6) levels are as strongly associated with coronary heart disease as increased cholesterol. We have been investigating novel cAMP-regulated pathways that combat the action of pro-inflammatory cytokines, such as IL-6 and leptin, in the VECs (vascular endothelial cells) of the circulatory system. In this respect, we have begun to unravel new molecular mechanisms by which the cAMP/Epac1 (exchange protein directly activated by cAMP 1)/Rap1 pathway can initiate a rigorous programme of protective anti-inflammatory responses in VECs. Central to this is the coupling of cAMP elevation to the mobilization of two C/EBP (CCAAT/enhancer-binding protein) family transcription factors, resulting in the induction of the SOCS3 (suppressor of cytokine signalling 3) gene, which attenuates pro-inflammatory cytokine signalling in VECs. These novel ‘protective’ mechanisms of cAMP action will inform the development of the next generation of pharmaceuticals specifically designed to combat endothelial inflammation associated with cardiovascular disease.

scholarly journals Regulation of common neurological disorders by gut microbial metabolites

2021 ◽  
Author(s):  
Jeongho Park ◽  
Chang H. Kim
Keyword(s):  
Neurological Disorders ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Short Chain Fatty Acids ◽  
Autism Spectrum ◽  
Molecular Networks ◽  
Microbial Metabolites ◽  
Cns Diseases ◽  
The Impact

AbstractThe gut is connected to the CNS by immunological mediators, lymphocytes, neurotransmitters, microbes and microbial metabolites. A mounting body of evidence indicates that the microbiome exerts significant effects on immune cells and CNS cells. These effects frequently result in the suppression or exacerbation of inflammatory responses, the latter of which can lead to severe tissue damage, altered synapse formation and disrupted maintenance of the CNS. Herein, we review recent progress in research on the microbial regulation of CNS diseases with a focus on major gut microbial metabolites, such as short-chain fatty acids, tryptophan metabolites, and secondary bile acids. Pathological changes in the CNS are associated with dysbiosis and altered levels of microbial metabolites, which can further exacerbate various neurological disorders. The cellular and molecular mechanisms by which these gut microbial metabolites regulate inflammatory diseases in the CNS are discussed. We highlight the similarities and differences in the impact on four major CNS diseases, i.e., multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, and autism spectrum disorder, to identify common cellular and molecular networks governing the regulation of cellular constituents and pathogenesis in the CNS by microbial metabolites.

scholarly journals The GTEx Consortium atlas of genetic regulatory effects across human tissues

2019 ◽  
Author(s):  
François Aguet ◽  
Alvaro N Barbeira ◽  
Rodrigo Bonazzola ◽  
Andrew Brown ◽  
Stephane E Castel ◽  
...  
Keyword(s):  
Complex Traits ◽  
Molecular Mechanisms ◽  
Tissue Expression ◽  
Genetic Effects ◽  
Regulatory Mechanisms ◽  
Human Tissues ◽  
Genetic Associations ◽  
Key Factor ◽  
Regulatory Effects ◽  
Almost All

AbstractThe Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues, and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the v8 data, based on 17,382 RNA-sequencing samples from 54 tissues of 948 post-mortem donors. We comprehensively characterize genetic associations for gene expression and splicing incisandtrans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue-specificity of genetic effects, and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.

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