Epigenetic Regulations of Inflammatory Cyclooxygenase-Derived Prostanoids: Molecular Basis and Pathophysiological Consequences

The potential relevance of prostanoid signaling in immunity and immunological disorders, or disease susceptibility and individual variations in drug responses, is an important area for investigation. The deregulation of Cyclooxygenase- (COX-) derived prostanoids has been reported in several immunoinflammatory disorders such as asthma, rheumatoid arthritis, cancer, and autoimmune diseases. In addition to the environmental factors and the genetic background to diseases, epigenetic mechanisms involved in the fine regulation of prostanoid biosynthesis and/or receptor signaling appeared to be an additional level of complexity in the understanding of prostanoid biology and crucial in controlling the different components of the COX pathways. Epigenetic alterations targeting inflammatory components of prostanoid biosynthesis and signaling pathways may be important in the process of neoplasia, depending on the tissue microenvironment and target genes. Here, we focused on the epigenetic modifications of inflammatory prostanoids in physiological immune response and immunological disorders. We described how major prostanoids and their receptors can be functionally regulated epigenetically and consequently the impact of these processes in the pathogenesis inflammatory diseases and the development of therapeutic approaches that may have important clinical applications.

Download Full-text

MiR-146a is over-expressed and controls IL-6 production in cystic fibrosis macrophages

Scientific Reports ◽

10.1038/s41598-019-52770-w ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 7

Author(s):

Francesco R. Luly ◽

Manuella Lévêque ◽

Valerio Licursi ◽

Giuseppe Cimino ◽

Corinne Martin-Chouly ◽

...

Keyword(s):

Cystic Fibrosis ◽

Lung Inflammation ◽

Bacterial Infections ◽

Target Genes ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Inherited Disease ◽

Bacterial Killing ◽

Significant Enrichment ◽

The Impact

Abstract Cystic fibrosis (CF) is an inherited disease that is characterised by susceptibility to bacterial infections and chronic lung inflammation. Recently, it was suggested that macrophages contribute to impaired host defence and excessive inflammatory responses in CF. Indeed, dysfunction attributed to CF macrophages includes decreased bacterial killing and exaggerated inflammatory responses. However, the mechanisms behind such defects have only been partially defined. MicroRNAs (miRNAs) have emerged as key regulators of several macrophage functions, including their activation, differentiation and polarisation. The goal of this study was to investigate whether miRNA dysregulation underlies the functional abnormalities of CF macrophages. MiRNA profiling of macrophages was performed, with 22 miRNAs identified as differentially expressed between CF and non-CF individuals. Among these, miR-146a was associated with significant enrichment of validated target genes involved in responses to microorganisms and inflammation. As miR-146a dysregulation has been reported in several human inflammatory diseases, we analysed the impact of increased miR-146a expression on inflammatory responses of CF macrophages. These data show that inhibition of miR-146a in lipopolysaccharide-stimulated CF macrophages results in increased interleukin-6 production, which suggests that miR-146a overexpression in CF is functional, to restrict inflammatory responses.

Download Full-text

Alteraciones sistémicas y metabólicas producidas por lesión medular

Latin american journal of clinical sciences and medical technology ◽

10.34141/ljcs6429407 ◽

2019 ◽

Vol 1 (1) ◽

pp. 59-75

Author(s):

Gabriel Guízar Sahagún

Keyword(s):

Spinal Cord ◽

Daily Living ◽

Autonomic Function ◽

Clinical Presentation ◽

Scientific Literature ◽

International Standards ◽

Therapeutic Approaches ◽

Cord Injury ◽

Life Threatening ◽

The Impact

Besides the well-known loss of motor and sensory capabilities, people with spinal cord injury (SCI) experience a broad range of systemic and metabolic abnormalities including, among others, dysfunction of cardiovascular, respiratory, gastrointestinal, urinary, and endocrine systems. These alterations are a significant challenge for patients with SCI because such disorders severely interfere with their daily living and can be potentially life-threatening. Most of these disorders are associated with impairment of regulation of the autonomic nervous system, arising from disruption of connections between higher brain centers and the spinal cord caudal to the injured zone. Thus, the higher and more complete the lesion, the greater the autonomic dysfunction and the severity of complications.This article summarizes the medical scientific literature on key systemic and metabolic alterations derived of SCI. It provides information primarily focused on the pathophysiology and clinical presentation of these disorders, as well as some guides to prevent and alleviate such complications. Due to the impact of these alterations, this topic must be a priority and diffuse to those involved with the care of people with SCI, including the patient himself/herself. We consider that any collaborative effort should be supported, like the development of international standards, to evaluate autonomic function after SCI, as well as the development of novel therapeutic approaches.

Download Full-text

POS1180 TREATMENT COMPLIANCE OF PATIENTS WITH RHEUMATOID ARTHRITIS DURING THE FIRST WAVE OF THE SARS-CoV-2/COVID-19 PANDEMIC IN PORTUGAL: RESULTS FROM THE COVID IN RA (COVIDRA) SURVEY

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.1152 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 871.2-871

Author(s):

F. Araujo ◽

N. Gonçalves ◽

A. F. Mourão

Keyword(s):

Rheumatoid Arthritis ◽

Inflammatory Diseases ◽

Immunosuppressive Treatment ◽

Treatment Compliance ◽

Web Based ◽

Symptoms Of Depression ◽

Immune Mediated ◽

Attending Physician ◽

The Impact ◽

E Mail

Background:The outcomes of the infection by the SARS-CoV-2 in patients with immune-mediated inflammatory diseases were largely unknown during the early days of the COVID-19 pandemic. It was hypothesized that these patients were at higher risk of morbidity and mortality due to their inherent immune dysfunction and immunosuppressive therapy. Several rheumatology societies issued recommendations urging patients not to stop their anti-rheumatic treatments.Objectives:To assess treatment compliance of patients with rheumatoid arthritis (RA) during the first wave of the SARS-CoV-2/COVID-19 pandemic in Portugal.Methods:The web-based survey COVIDRA (COVID in RA) was developed to assess the impact of the first wave mandatory confinement in patients with RA focusing on 5 domains: RA symptoms, attitudes towards medication, employment status, physical exercise and mental health. The questionnaire was sent to RA patients through e-mail and social media of the Portuguese Society of Rheumatology and two patient associations; and it was filled locally at two rheumatology centers in Lisbon. Recruitment took place during June and July 2020. Descriptive statistics were generated by the survey software and were afterwards transported and evaluated using appropriate biostatistics software.Results:We obtained 441 valid questionnaires. Most respondents were female (88.4%), caucasian (93.6%), with a mean age of 58 (+/-13) years. The majority (57.6%) had longstanding disease (>10 years) and were treated with csDMARDs (63.2%) and/or bDMARDs/tsDMARDS (23,7%). Only 14% (N=61) discontinued or reduced the dosage or frequency of their RA treatment. Most of these changes were previously planned by the attending physician (27.9%). Only 11 patients (18%) discontinued their immunosuppressive medication out of fear of becoming infected with SARS-CoV-2 (corresponding to 2.5% of total responders). Another 11 patients did so because they had no prescription, couldn’t go to the community/hospital pharmacy or couldn’t afford the medication. Although these numbers preclude any statistical analysis, when compared to patients who persisted on their treatment, those discontinuing due to fear of contagion were younger (56.4 vs 58.5 years), all female (100 vs 86.8%), with long-lasting disease (≥ 11 years) (90.9% vs 57.5%), more frequently treated with bDMARDs (36.4 vs 23.1%) and presenting more symptoms of depression (54.5 vs 49.7%).Conclusion:Most RA patients complied with their treatment during the first wave of the SARS-CoV-2 pandemic in Portugal. Only a minority changed their immunosuppressive treatment due to fear of SARS-CoV-2 infection. Very similar rates of immunosuppressive discontinuation due to fear of contagion were reported by other authors (such as Schmeiser et al, Pineda-sic et al and Fragoulis et al).Disclosure of Interests:Filipe Araujo Speakers bureau: Pfizer, Biogen, Novartis, Menarini, Consultant of: MSD, Nuno Gonçalves: None declared, Ana Filipa Mourão: None declared.

Download Full-text

LAT1 and ASCT2 Related microRNAs as Potential New Therapeutic Agents against Colorectal Cancer Progression

Biomedicines ◽

10.3390/biomedicines9020195 ◽

2021 ◽

Vol 9 (2) ◽

pp. 195

Author(s):

Francisca Dias ◽

Cristina Almeida ◽

Ana Luísa Teixeira ◽

Mariana Morais ◽

Rui Medeiros

Keyword(s):

Colorectal Cancer ◽

Amino Acid ◽

Cancer Progression ◽

Cell Metabolism ◽

Tumor Development ◽

Amino Acid Transporters ◽

Epigenetic Alterations ◽

Therapeutic Approaches ◽

Colorectal Cancer Progression ◽

Made In

The development and progression of colorectal cancer (CRC) have been associated with genetic and epigenetic alterations and more recently with changes in cell metabolism. Amino acid transporters are key players in tumor development, and it is described that tumor cells upregulate some AA transporters in order to support the increased amino acid (AA) intake to sustain the tumor additional needs for tumor growth and proliferation through the activation of several signaling pathways. LAT1 and ASCT2 are two AA transporters involved in the regulation of the mTOR pathway that has been reported as upregulated in CRC. Some attempts have been made in order to develop therapeutic approaches to target these AA transporters, however none have reached the clinical setting so far. MiRNA-based therapies have been gaining increasing attention from pharmaceutical companies and now several miRNA-based drugs are currently in clinical trials with promising results. In this review we combine a bioinformatic approach with a literature review in order to identify a miRNA profile with the potential to target both LAT1 and ASCT2 with potential to be used as a therapeutic approach against CRC.

Download Full-text

Identification of anticancer drug target genes using an outside competitive dynamics model on cancer signaling networks

Scientific Reports ◽

10.1038/s41598-021-93336-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Tien-Dzung Tran ◽

Duc-Tinh Pham

Keyword(s):

Anticancer Drug ◽

Drug Target ◽

Target Genes ◽

Signaling Network ◽

Competitive Dynamics ◽

Signaling Networks ◽

Molecular Signaling ◽

Dynamics Model ◽

Cancer Signaling ◽

The Impact

AbstractEach cancer type has its own molecular signaling network. Analyzing the dynamics of molecular signaling networks can provide useful information for identifying drug target genes. In the present study, we consider an on-network dynamics model—the outside competitive dynamics model—wherein an inside leader and an opponent competitor outside the system have fixed and different states, and each normal agent adjusts its state according to a distributed consensus protocol. If any normal agent links to the external competitor, the state of each normal agent will converge to a stable value, indicating support to the leader against the impact of the competitor. We determined the total support of normal agents to each leader in various networks and observed that the total support correlates with hierarchical closeness, which identifies biomarker genes in a cancer signaling network. Of note, by experimenting on 17 cancer signaling networks from the KEGG database, we observed that 82% of the genes among the top 3 agents with the highest total support are anticancer drug target genes. This result outperforms those of four previous prediction methods of common cancer drug targets. Our study indicates that driver agents with high support from the other agents against the impact of the external opponent agent are most likely to be anticancer drug target genes.

Download Full-text

The Impact of Chlorambucil and Valproic Acid on Cell Viability, Apoptosis and Expression of p21, HDM2, BCL2 and MCL1 Genes in Chronic Lymphocytic Leukemia

Cells ◽

10.3390/cells10051088 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1088

Author(s):

Katarzyna Lipska ◽

Agata Filip ◽

Anna Gumieniczek

Keyword(s):

Valproic Acid ◽

Chronic Lymphocytic Leukemia ◽

Cell Viability ◽

Antiepileptic Drug ◽

Drug Combination ◽

Target Genes ◽

Histone Deacetylation ◽

Lymphocytic Leukemia ◽

Malignant Cells ◽

The Impact

Malignant cells in chronic lymphocytic leukemia (CLL) show resistance to apoptosis, as well as to chemotherapy, which are related to deletions or mutations of TP53, high expression of MCL1 and BCL2 genes and other abnormalities. Thus, the main goal of the present study was to assess the impact of chlorambucil (CLB) combined with valproic acid (VPA), a known antiepileptic drug and histone deacetylation inhibitor, on apoptosis of the cells isolated from 17 patients with CLL. After incubation with CLB (17.5 µM) and VPA (0.5 mM), percentage of apoptosis, as well as expression of two TP53 target genes (p21 and HDM2) and two genes from Bcl-2 family (BCL2 and MCL1), were tested. As a result, an increased percentage of apoptosis was observed for CLL cells treated with CLB and VPA, and with CLB alone. Under the treatment with the drug combination, the expression of p21 gene was visibly higher than under the treatment with CLB alone. At the same time, the cultures under CLB treatment showed visibly higher expression of BCL2 than the cultures with VPA alone. Thus, the present study strongly suggests further investigations on the CLB and VPA combination in CLL treatment.

Download Full-text

Specialized Pro-Resolving Lipid Mediators in Neonatal Cardiovascular Physiology and Diseases

Antioxidants ◽

10.3390/antiox10060933 ◽

2021 ◽

Vol 10 (6) ◽

pp. 933

Author(s):

Andrea Gila-Diaz ◽

Gloria Herranz Carrillo ◽

Pratibha Singh ◽

David Ramiro-Cortijo

Keyword(s):

Tissue Repair ◽

Cardiovascular Health ◽

Critical Role ◽

Potential Effect ◽

Lipid Mediators ◽

Physiological Effects ◽

Therapeutic Approaches ◽

The Impact ◽

Long Chain

Cardiovascular disease remains a leading cause of mortality worldwide. Unresolved inflammation plays a critical role in cardiovascular diseases development. Specialized Pro-Resolving Mediators (SPMs), derived from long chain polyunsaturated fatty acids (LCPUFAs), enhances the host defense, by resolving the inflammation and tissue repair. In addition, SPMs also have anti-inflammatory properties. These physiological effects depend on the availability of LCPUFAs precursors and cellular metabolic balance. Most of the studies have focused on the impact of SPMs in adult cardiovascular health and diseases. In this review, we discuss LCPUFAs metabolism, SPMs, and their potential effect on cardiovascular health and diseases primarily focusing in neonates. A better understanding of the role of these SPMs in cardiovascular health and diseases in neonates could lead to the development of novel therapeutic approaches in cardiovascular dysfunction.

Download Full-text

Anemia of Inflammation

Hematology ◽

10.1182/asheducation-2010.1.276 ◽

2010 ◽

Vol 2010 (1) ◽

pp. 276-280 ◽

Cited By ~ 74

Author(s):

Cindy N. Roy

Keyword(s):

Inflammatory Diseases ◽

Underlying Disease ◽

Comorbid Condition ◽

Regulatory Pathways ◽

Hepcidin Expression ◽

Disease States ◽

Poor Outcomes ◽

The Impact ◽

Inflammatory Insult ◽

Anemia Of Inflammation

Abstract Inflammation arising from various etiologies, including infection, autoimmune disorders, chronic diseases, and aging, can promote anemia. The anemia of inflammation (AI) is most often normocytic and normochromic and is usually mild. Characteristic changes in systemic iron handling, erythrocyte production, and erythrocyte life span all contribute to AI. The preferred treatment is directed at the underlying disease. However, when the inflammatory insult is intractable, or the cause has not been diagnosed, there are limited options for treatment of AI. Because anemia is a comorbid condition that is associated with poor outcomes in various chronic disease states, understanding its pathogenesis and developing new tools for its treatment should remain a priority. Hepcidin antimicrobial peptide has taken center stage in recent years as a potent modulator of iron availability. As the technology for quantitative hepcidin analysis improves, hepcidin's role in various disease states is also being revealed. Recent insights concerning the regulatory pathways that modify hepcidin expression have identified novel targets for drug development. As the field advances with such therapeutics, the analysis of the impact of normalized hemoglobin on disease outcomes will confirm whether anemia is a reversible independent contributor to the morbidity and mortality associated with inflammatory diseases.

Download Full-text

Roles of XBP1s in Transcriptional Regulation of Target Genes

Biomedicines ◽

10.3390/biomedicines9070791 ◽

2021 ◽

Vol 9 (7) ◽

pp. 791

Author(s):

Sung-Min Park ◽

Tae-Il Kang ◽

Jae-Seon So

Keyword(s):

Transcriptional Regulation ◽

Er Stress ◽

Target Genes ◽

Inflammatory Diseases ◽

Vital Role ◽

Genes Encoding ◽

Autoimmune And Inflammatory Diseases ◽

Active Transcription ◽

Transcriptional Regulatory Mechanisms ◽

The Unfolded Protein Response

The spliced form of X-box binding protein 1 (XBP1s) is an active transcription factor that plays a vital role in the unfolded protein response (UPR). Under endoplasmic reticulum (ER) stress, unspliced Xbp1 mRNA is cleaved by the activated stress sensor IRE1α and converted to the mature form encoding spliced XBP1 (XBP1s). Translated XBP1s migrates to the nucleus and regulates the transcriptional programs of UPR target genes encoding ER molecular chaperones, folding enzymes, and ER-associated protein degradation (ERAD) components to decrease ER stress. Moreover, studies have shown that XBP1s regulates the transcription of diverse genes that are involved in lipid and glucose metabolism and immune responses. Therefore, XBP1s has been considered an important therapeutic target in studying various diseases, including cancer, diabetes, and autoimmune and inflammatory diseases. XBP1s is involved in several unique mechanisms to regulate the transcription of different target genes by interacting with other proteins to modulate their activity. Although recent studies discovered numerous target genes of XBP1s via genome-wide analyses, how XBP1s regulates their transcription remains unclear. This review discusses the roles of XBP1s in target genes transcriptional regulation. More in-depth knowledge of XBP1s target genes and transcriptional regulatory mechanisms in the future will help develop new therapeutic targets for each disease.

Download Full-text

Obstructive nephropathy and renal fibrosis

AJP Renal Physiology ◽

10.1152/ajprenal.00362.2001 ◽

2002 ◽

Vol 283 (5) ◽

pp. F861-F875 ◽

Cited By ~ 367

Author(s):

Saulo Klahr ◽

Jeremiah Morrissey

Keyword(s):

Renal Disease ◽

Renal Fibrosis ◽

Interstitial Fibrosis ◽

Rodent Model ◽

Renal Diseases ◽

Obstructive Nephropathy ◽

Therapeutic Approaches ◽

Cellular Events ◽

The Impact ◽

Made In

Interstitial fibrosis has a major role in the progression of renal diseases. Several animal models are available for the study of renal fibrosis. The models of aminonucleoside-induced nephrotic syndrome, cyclosporin nephrotoxicity, and passive Heyman nephritis are characterized by molecular and cellular events similar to those that occur in obstructive nephropathy. Additionally, inhibition of angiotensin-converting enzyme exerts salutary effects on the progression of renal fibrosis in obstructive nephropathy. Unilateral ureteral obstruction (UUO) has emerged as an important model for the study of the mechanisms of renal fibrosis and also for the evaluation of the impact of potential therapeutic approaches to ameliorate renal disease. Many quantifiable pathophysiological events occur over the span of 1 wk of UUO, making this an attractive model for study. This paper reviews some of the ongoing studies that utilized a rodent model of UUO. Some of the findings of the animal model have been compared with observations made in patients with obstructive nephropathy. Most of the evidence suggests that the rodent model of UUO is reflective of human renal disease processes.

Download Full-text