scholarly journals An Exon-Based Comparative Variant Analysis Pipeline to Study the Scale and Role of Frameshift and Nonsense Mutation in the Human-Chimpanzee Divergence

2009 ◽  
Vol 2009 ◽  
pp. 1-19 ◽  
Author(s):  
GongXin Yu
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Cell Lineage ◽  
Nonsense Mutations ◽  
Less Is More ◽  
Sequencing Errors ◽  
Evolutionary Force ◽  
Variant Analysis ◽  
Species Specific

Chimpanzees and humans are closely related but differ in many deadly human diseases and other characteristics in physiology, anatomy, and pathology. In spite of decades of extensive research, crucial questions about the molecular mechanisms behind the differences are yet to be understood. Here I reportExonVar, a novel computational pipeline forExon-based human-chimpanzee comparativeVariant analysis. The objective is to comparatively analyze mutations specifically those that caused the frameshift and nonsense mutations and to assess their scale and potential impacts on human-chimpanzee divergence. Genomewide analysis of human and chimpanzee exons withExonVaridentified a number of species-specific, exon-disrupting mutations in chimpanzees but much fewer in humans. Many were found on genes involved in important biological processes such as T cell lineage development, the pathogenesis of inflammatory diseases, and antigen induced cell death. A “less-is-more” model was previously established to illustrate the role of the gene inactivation and disruptions during human evolution. Here this analysis suggested a different model where the chimpanzee-specific exon-disrupting mutations may act as additional evolutionary force that drove the human-chimpanzee divergence. Finally, the analysis revealed a number of sequencing errors in the chimpanzee and human genome sequences and further illustrated that they could be corrected without resequencing.

Microvascular Mechanisms of Polyphosphate-Induced Neutrophil-Endothelial Cell Interactions in vivo

2019 ◽  
Vol 60 (1-2) ◽  
pp. 53-62
Author(s):  
Feifei Du ◽  
Yongzhi Wang ◽  
Zhiyi Ding ◽  
Matthias W. Laschke ◽  
Henrik Thorlacius
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Pharmacological Intervention ◽  
Lymphocyte Function ◽  
Microvascular Endothelium ◽  
Recruitment Methods ◽  
Leukocyte Accumulation ◽  
Tnf Α

Background: Polyphosphates (PolyPs) have been reported to exert pro-inflammatory effects. However, the molecular mechanisms regulating PolyP-provoked tissue accumulation of leukocytes are not known. The aim of the present investigation was to determine the role of specific adhesion molecules in PolyP-mediated leukocyte recruitment. Methods: PolyPs and TNF-α were intrascrotally administered, and anti-P-selectin, anti-E-selectin, anti-P-selectin glycoprotein ligand-1 (PSGL-1), anti-membrane-activated complex-1 (Mac-1), anti-lymphocyte function antigen-1 (LFA-1), and neutrophil depletion antibodies were injected intravenously or intraperitoneally. Intravital microscopy of the mouse cremaster microcirculation was used to examine leukocyte-endothelium interactions and recruitment in vivo. Results: Intrascrotal injection of PolyPs increased leukocyte accumulation. Depletion of neutrophils abolished PolyP-induced leukocyte-endothelium interactions, indicating that neutrophils were the main leukocyte subtype responding to PolyP challenge. Immunoneutralization of P-selectin and PSGL-1 abolished PolyP-provoked neutrophil rolling, adhesion, and emigration. Moreover, immunoneutralization of Mac-1 and LFA-1 had no impact on neutrophil rolling but markedly reduced neutrophil adhesion and emigration evoked by PolyPs. Conclusion: These results suggest that P-selectin and PSGL-1 exert important roles in PolyP-induced inflammatory cell recruitment by mediating neutrophil rolling. In addition, our data show that Mac-1 and LFA-1 are necessary for supporting PolyP-triggered firm adhesion of neutrophils to microvascular endothelium. These novel findings define specific molecules as potential targets for pharmacological intervention in PolyP-dependent inflammatory diseases.

Role of macrophage CD44 in the disposal of inflammatory cell corpses*

2002 ◽  
Vol 103 (5) ◽  
pp. 441-449 ◽  
Author(s):  
Sharon VIVERS ◽  
Ian DRANSFIELD ◽  
Simon P. HART
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Surrounding Tissue ◽  
Human Macrophage ◽  
Neutrophil Granulocytes ◽  
Apoptotic Cells ◽  
Tissue Destruction

Understanding the cellular and molecular mechanisms that determine whether inflammation resolves or progresses to scarring and tissue destruction should lead to the development of effective therapeutic strategies for inflammatory diseases. Apoptosis of neutrophil granulocytes is an important determinant of the resolution of inflammation, providing a mechanism for down-regulation of function and triggering clearance by macrophages without inducing a pro-inflammatory response. However, if the rate of cell death by apoptosis is such that the macrophage clearance capacity is exceeded, apoptotic cells may progress to secondary necrosis, resulting in the release of harmful cellular contents and in damage to the surrounding tissue. There are many possible ways in which the rate and capacity of the macrophage-mediated clearance of apoptotic cells may be enhanced or suppressed. Ligation of human macrophage surface CD44 by bivalent monoclonal antibodies rapidly and profoundly augments the capacity of macrophages to phagocytose apoptotic neutrophils in vitro. The molecular mechanism behind this effect and its potential significance in vivo is a current focus of research.

scholarly journals Mechanisms of innate immunity in pathogenesis of psoriasis: approaches to targeted therapy

2020 ◽  
Vol 22 (3) ◽  
pp. 449-458
Author(s):  
E. D. Merkushova ◽  
E. M. Khasanova ◽  
L. V. Gankovskaya
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Targeted Therapy ◽  
Inflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Pathological Process ◽  
Climatic Conditions ◽  
Keratinocyte Differentiation

Psoriasis is a chronic auto-inflammatory, genetically determined dermatosis, being multifactorial by origin, characterized by hyperproliferation of epidermis, affected keratinocyte differentiation and inflammatory reaction in dermis. The disease is characterized by a tendency to spread over the area of lesion, and involvement of articular tissue in the pathological process, which significantly affects the living standards of patients and causes their disability. There are many provoking factors that contribute to occurrence of psoriasis, or progression of existing psoriatic process in individuals with a genetic predisposition. These factors include adverse climatic conditions, skin trauma, exposure to ultraviolet light, burns, infections, etc.This review describes the role of innate immunity in pathogenesis of psoriasis, and describes in detail the mechanisms involved into induction of inflammation of PAMPs and DAMPs. In psoriasis, positively charged catelicidin is considered one of the most important DAMPs, which can form a complex with negatively charged cell polyanions-LL-37/auto-RNA and LL-37/auto-DNA. The interaction of PAMP/DAMP ligands with specific PRR receptors leads to signal activation of effector components of immune system, i.e., assembly of inflammasome complex, caspase activation, synthesis of inflammatory cytokines and processing of their immature forms. The review focuses on the role of TLRs under the conditions of physiological norm, which recognize danger signals and provide protection from pathogens and their timely elimination, and in development of pathological process. Activation of TLRs induces the production of pro-inflammatory cytokines, interferons and antimicrobial peptides, chemokines that support the development of psoriatic inflammation.In addition to TLRs, the mechanisms of involvement of inflammasomes in the development of psoriasis, which provides processing of mature forms of IL-1β and IL-18, are described in detail. Mature forms of these cytokines mediate the development of inflammation in psoriatic focus. In addition, processing of these cytokines by caspases using the positive feedback mechanism provides an additional signal to activate transcriptional activity of their genes and contributes to perpetuated inflammation.The review presents data confirming participation of inflammasomes in the pathogenesis of psoriasis. Much attention is paid to description of pharmacological inhibitors of inflammasomes, which in the future may be the drugs of choice for treatment of inflammatory diseases. The study of molecular mechanisms of the innate immune system will reveal new approaches to prognosis and development of targeted therapy for psoriasis.

Preventive Role of Resveratrol Against Inflammatory Cytokines and Related Diseases

2019 ◽  
Vol 25 (12) ◽  
pp. 1345-1371 ◽  
Author(s):  
Tanzir Rafe ◽  
Parvez Ahmed Shawon ◽  
Liyad Salem ◽  
Nafij Imtiyaj Chowdhury ◽  
Farjana Kabir ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Human Subjects ◽  
Inflammatory Cells ◽  
Host Cells ◽  
Inflammatory Disorder ◽  
Inflammatory Disorders ◽  
Long Run

Background:Immunity is the ultimate barrier between foreign stimuli and a host cell. Unwanted immune responses can threaten the host cells and may eventually damage a vital organ. Overproduction of inflammatory cytokines may also lead to autoimmune diseases. Inflammatory cells and pro-inflammatory cytokines can eventually progress to renal, cardiac, brain, hepatic, pancreatic and ocular inflammation that can result in severe damage in the long run. Evidence also suggests that inflammation may lead to atherosclerosis, Alzheimer’s, hypertension, stroke, cysts and cancers.Methods:This study was designed to correlate the possible molecular mechanisms for inflammatory diseases and prevent biochemical changes owing to inflammatory cytokines by using Resveratrol. Therefore, we searched and accumulated very recent literature on inflammatory disorders and Resveratrol. We scoured PubMed, Scopus, Science Direct, PLoS One and Google Scholar to gather papers and related information.Results:Reports show that inflammatory diseases are very complex, as multiple cascade systems are involved; therefore, they are quite difficult to cure. However, our literature search also correlates some possible molecular interactions by which inflammation can be prevented. We noticed that Resveratrol is a potent lead component and has multiple activities against harmful inflammatory cytokines and related microRNA. Our study also suggests that the anti-inflammatory properties of Resveratrol have been highly studied on animal models, cell lines and human subjects and proven to be very effective in reducing inflammatory cell production and pro-inflammatory cytokine accumulation. Our tables and figures also demonstrate recent findings and possible preventive activities to minimize inflammatory diseases.Conclusion:This study would outline the role of harmful inflammatory cytokines as well as how they accelerate pathophysiology and progress to an inflammatory disorder. Therefore, this study might show a potential therapeutic value of using Resveratrol by health professionals in preventing inflammatory disorders.

Thiol regulation of pro-inflammatory cytokines and innate immunity: protein S-thiolation as a novel molecular mechanism

2011 ◽  
Vol 39 (5) ◽  
pp. 1268-1272 ◽  
Author(s):  
Lucia Coppo ◽  
Pietro Ghezzi
Keyword(s):  
Inflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Protein S ◽  
Protein Thiol ◽  
Cytokine Inhibitors ◽  
Key Enzyme ◽  
And Oxidative Stress ◽  
Pro Inflammatory Cytokines

Inflammation or inflammatory cytokines and oxidative stress have often been associated, and thiol antioxidants, particularly glutathione, have often been seen as possible anti-inflammatory mediators. However, whereas several cytokine inhibitors have been approved for drug use in chronic inflammatory diseases, this has not happened with antioxidant molecules. We outline the complexity of the role of protein thiol–disulfide oxidoreduction in the regulation of immunity and inflammation, the underlying molecular mechanisms (such as protein glutathionylation) and the key enzyme players such as Trx (thioredoxin) or Grx (glutaredoxin).

scholarly journals IL-17A in Human Respiratory Diseases: Innate or Adaptive Immunity? Clinical Implications

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Dominique M. A. Bullens ◽  
Ann Decraene ◽  
Sven Seys ◽  
Lieven J. Dupont
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Respiratory Diseases ◽  
Inflammatory Diseases ◽  
Cell Lineage ◽  
Innate Immune ◽  
Clinical Implications ◽  
Innate Immune Cells ◽  
Innate Immune Responses

Since the discovery of IL-17 in 1995 as a T-cell cytokine, inducing IL-6 and IL-8 production by fibroblasts, and the report of a separate T-cell lineage producing IL-17(A), called Th17 cells, in 2005, the role of IL-17 has been studied in several inflammatory diseases. By inducing IL-8 production and subsequent neutrophil attraction towards the site of inflammation, IL-17A can link adaptive and innate immune responses. More specifically, its role in respiratory diseases has intensively been investigated. We here review its role in human respiratory diseases and try to unravel the question whether IL-17A only provides a link between the adaptive and innate respiratory immunity or whether this cytokine might also be locally produced by innate immune cells. We furthermore briefly discuss the possibility to reduce local IL-17A production as a treatment option for respiratory diseases.

scholarly journals The Kynurenine Pathway—New Linkage between Innate and Adaptive Immunity in Autoimmune Endocrinopathies

2021 ◽  
Vol 22 (18) ◽  
pp. 9879
Author(s):  
Anna Krupa ◽  
Irina Kowalska
Keyword(s):  
Immune System ◽  
Adaptive Immunity ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Kynurenine Pathway ◽  
Wide Range ◽  
Organ Specific ◽  
Autoimmune And Inflammatory Diseases

The kynurenine pathway (KP) is highly regulated in the immune system, where it promotes immunosuppression in response to infection or inflammation. Indoleamine 2,3-dioxygenase 1 (IDO1), the main enzyme of KP, has a broad spectrum of activity on immune cells regulation, controlling the balance between stimulation and suppression of the immune system at sites of local inflammation, relevant to a wide range of autoimmune and inflammatory diseases. Various autoimmune diseases, among them endocrinopathies, have been identified to date, but despite significant progress in their diagnosis and treatment, they are still associated with significant complications, morbidity, and mortality. The precise cellular and molecular mechanisms leading to the onset and development of autoimmune disease remain poorly clarified so far. In breaking of tolerance, the cells of the innate immunity provide a decisive microenvironment that regulates immune cells’ differentiation, leading to activation of adaptive immunity. The current review provided a comprehensive presentation of the known role of IDO1 and KP activation in the regulation of the innate and adaptive arms of the immune system. Significant attention has been paid to the immunoregulatory role of IDO1 in the most prevalent, organ-specific autoimmune endocrinopathies—type 1 diabetes mellitus (T1DM) and autoimmune thyroiditis.

Role of MCP-1 in cardiovascular disease: molecular mechanisms and clinical implications

2009 ◽  
Vol 117 (3) ◽  
pp. 95-109 ◽  
Author(s):  
Jianli Niu ◽  
Pappachan E. Kolattukudy
Keyword(s):  
Cardiovascular Disease ◽  
Cardiovascular Diseases ◽  
Molecular Mechanisms ◽  
Zinc Finger Protein ◽  
Plaque Rupture ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Protective Effects ◽  
Ischaemia Reperfusion Injury

Many of the major diseases, including cardiovascular disease, are widely recognized as inflammatory diseases. MCP-1 (monocyte chemotactic protein-1) plays a critical role in the development of cardiovascular diseases. MCP-1, by its chemotactic activity, causes diapedesis of monocytes from the lumen to the subendothelial space where they become foam cells, initiating fatty streak formation that leads to atherosclerotic plaque formation. Inflammatory macrophages probably play a role in plaque rupture and the resulting ischaemic episode as well as restenosis after angioplasty. There is strong evidence that MCP-1 plays a major role in myocarditis, ischaemia/reperfusion injury in the heart and in transplant rejection. MCP-1 also plays a role in cardiac repair and manifests protective effects under certain conditions. Such protective effects may be due to the induction of protective ER (endoplasmic reticulum) stress chaperones by MCP-1. Under sustained ER stress caused by chronic exposure to MCP-1, the protection would break down resulting in the development of heart failure. MCP-1 is also involved in ischaemic angiogenesis. The recent advances in our understanding of the molecular mechanisms that might be involved in the roles that MCP-1 plays in cardiovascular disease are reviewed. The gene expression changes induced by the signalling events triggered by MCP-1 binding to its receptor include the induction of a novel zinc-finger protein called MCPIP (MCP-1-induced protein), which plays critical roles in the development of the pathophysiology caused by MCP-1 production. The role of the MCP-1/CCR2 (CC chemokine receptor 2) system in diabetes, which is a major risk factor for cardiovascular diseases, is also reviewed briefly. MCP-1/CCR2- and/or MCPIP-targeted therapeutic approaches to intervene in inflammatory diseases, including cardiovascular diseases, may be feasible.

scholarly journals ZBTB Transcription Factors: Key Regulators of the Development, Differentiation and Effector Function of T Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhong-Yan Cheng ◽  
Ting-Ting He ◽  
Xiao-Ming Gao ◽  
Ying Zhao ◽  
Jun Wang
Keyword(s):  
T Cells ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Cell Lineage ◽  
Transcriptional Factors ◽  
Effector Function ◽  
Invariant Nkt Cells ◽  
Development And Differentiation ◽  
And Function

The development and differentiation of T cells represents a long and highly coordinated, yet flexible at some points, pathway, along which the sequential and dynamic expressions of different transcriptional factors play prominent roles at multiple steps. The large ZBTB family comprises a diverse group of transcriptional factors, and many of them have emerged as critical factors that regulate the lineage commitment, differentiation and effector function of hematopoietic-derived cells as well as a variety of other developmental events. Within the T-cell lineage, several ZBTB proteins, including ZBTB1, ZBTB17, ZBTB7B (THPOK) and BCL6 (ZBTB27), mainly regulate the development and/or differentiation of conventional CD4/CD8 αβ+ T cells, whereas ZBTB16 (PLZF) is essential for the development and function of innate-like unconventional γδ+ T & invariant NKT cells. Given the critical role of T cells in host defenses against infections/tumors and in the pathogenesis of many inflammatory disorders, we herein summarize the roles of fourteen ZBTB family members in the development, differentiation and effector function of both conventional and unconventional T cells as well as the underlying molecular mechanisms.

scholarly journals Potential Cytoprotective Activity of Ozone Therapy in SARS-CoV-2/COVID-19

Antioxidants ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 389 ◽  
Author(s):  
Gregorio Martínez-Sánchez ◽  
Adriana Schwartz ◽  
Vincenzo Di Donna
Keyword(s):  
Mechanism Of Action ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Inflammatory Diseases ◽  
Organ Damage ◽  
Experimental Models ◽  
Ozone Therapy ◽  
Cytoprotective Activity ◽  
Target Organs

(1) Background: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) in China at the end of 2019 has caused a large global outbreak. Systemic ozone therapy (OT) could be potentially useful in the clinical management of several complications secondary to SARS-CoV-2. The rationale and mechanism of action has already been proven clinically in other viral infections and has been shown in research studies to be highly effective at decreasing organ damage mediated by inflammation and oxidative stress. This review summarizes the OT studies that illustrate the possible cytoprotective mechanism of action of ozone and its physiological by-products in target organs affected by SARS-CoV-2. (2) Methods: This review encompasses a total of 74 peer-reviewed original articles. It is mainly focused on ozone as a modulator of the NF-κB/Nrf2 pathways and IL-6/IL-1β expression. (3) Results: In experimental models and the few existent clinical studies, homeostasis of the free radical and antioxidant balance by OT was associated with a modulation of NF-κB/Nrf2 balance and IL-6 and IL-1β expression. These molecular mechanisms support the cytoprotective effects of OT against tissue damage present in many inflammatory diseases, including viral infections. (4) Conclusions: The potential cytoprotective role of OT in the management of organ damage induced by COVID-19 merits further research. Controlled clinical trials are needed.

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