scholarly journals Complexity of TNF-α Signaling in Heart Disease

2020 ◽  
Vol 9 (10) ◽  
pp. 3267
Author(s):  
Filip Rolski ◽  
Przemysław Błyszczuk
Keyword(s):  
Heart Disease ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Cell Types ◽  
Published Data ◽  
Necrosis Factor Alpha ◽  
Failing Heart ◽  
Therapeutic Benefits ◽  
Tnf Α

Heart disease is a leading cause of death with unmet clinical needs for targeted treatment options. Tumor necrosis factor alpha (TNF-α) represents a master pro-inflammatory cytokine that plays an important role in many immunopathogenic processes. Anti-TNF-α therapy is widely used in treating autoimmune inflammatory disorders, but in case of patients with heart disease, this treatment was unsuccessful or even harmful. The underlying reasons remain elusive until today. This review summarizes the effects of anti-TNF-α treatment in patients with and without heart disease and describes the involvement of TNF-α signaling in a number of animal models of cardiovascular diseases. We specifically focused on the role of TNF-α in specific cardiovascular conditions and in defined cardiac cell types. Although some mechanisms, mainly in disease development, are quite well known, a comprehensive understanding of TNF-α signaling in the failing heart is still incomplete. Published data identify pathogenic and cardioprotective mechanisms of TNF-α in the affected heart and highlight the differential role of two TNF-α receptors pointing to the complexity of the TNF-α signaling. In the light of these findings, it seems that targeting the TNF-α pathway in heart disease may show therapeutic benefits, but this approach must be more specific and selectively block pathogenic mechanisms. To this aim, more research is needed to better understand the molecular mechanisms of TNF-α signaling in the failing heart.

Regulation of microRNAs in Inflammation-Associated Colorectal Cancer: A Mechanistic Approach

2020 ◽  
Vol 20 ◽  
Author(s):  
Sridhar Muthusami ◽  
Ilangovan Ramachandran ◽  
Sneha Krishnamoorthy ◽  
Yuvaraj Sambandam ◽  
Satish Ramalingam ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Colorectal Carcinogenesis ◽  
Model Systems ◽  
Necrosis Factor Alpha ◽  
Multi Stage ◽  
Mechanistic Approach ◽  
Tnf Α ◽  
Factor Alpha

: The development of colorectal cancer (CRC) is a multi-stage process. The inflammation of the colon as in inflammatory bowel disease (IBD) such as ulcerative colitis (UC) or Crohn’s disease (CD) is often regarded as the initial trigger for the development of CRC. Many cytokines such as tumor necrosis factor alpha (TNF-α) and several interleukins (ILs) are known to exert proinflammatory actions, and inflammation initiates or promotes tumorigenesis of various cancers, including CRC through differential regulation of microRNAs (miRNAs/miRs). miRNAs can be oncogenic miRNAs (oncomiRs) or anti-oncomiRs/tumor suppressor miRNAs, and they play key roles during colorectal carcinogenesis. However, the functions and molecular mechanisms of regulation of miRNAs involved in inflammation-associated CRC are still anecdotal and largely unknown. Consolidating the published results and offering perspective solutions to circumvent CRC, the current review is focused on the role of miRNAs and their regulation in the development of CRC. We have also discussed the model systems adapted by researchers to delineate the role of miRNAs in inflammation-associated CRC.

Role of inflammation in the development of colorectal cancer

2020 ◽  
Vol 20 ◽  
Author(s):  
Sridhar Muthusami ◽  
R. Ileng Kumaran ◽  
Kokelavani Nampalli Babu ◽  
Sneha Krishnamoorthy ◽  
Akash Guruswamy ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Chronic Inflammation ◽  
Interleukin 1 ◽  
Cell Types ◽  
Model Systems ◽  
Cytokine Gene Expression ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Proinflammatory Molecules

: Chronic inflammation can lead to the development of many diseases including cancer. Inflammatory bowel disease (IBD) that includes both ulcerative colitis (UC) and Crohn's disease (CD) are risk factors for the development of colorectal cancer (CRC). Many cytokines produced primarily by the gut immune cells either during or in response to localized inflammation in the colon and rectum are known to stimulate the complex interactions between the different cell types in the gut environment resulting in acute inflammation. Subsequently, chronic inflammation together with genetic and epigenetic changes has been shown to lead to the development and progression of CRC. Various cell types present in the colon such as enterocytes, Paneth cells, goblet cells and macrophages express receptors for inflammatory cytokines and respond to tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6 and other cytokines. Among the several cytokines produced, TNF-α and IL-1β are the key proinflammatory molecules that play critical roles in the development of CRC. The current review is intended to consolidate the published findings to focus on the role of proinflammatory cytokines, namely TNF-α and IL-1β, on inflammation (and the altered immune response) in the gut, to better understand the development of CRC in IBD, using various experimental model systems, preclinical and clinical studies. Moreover, this review also highlights the current therapeutic strategies available (monotherapy and combination therapy), to alleviate the symptoms or treat inflammationassociated CRC by using monoclonal antibodies or aptamers to block proinflammatory molecules, inhibitors of tyrosine kinases in inflammatory signaling cascade, competitive inhibitors of proinflammatory molecules, and the nucleic acid drugs like small activating RNAs (saRNAs) or microRNA (miRNA) mimics to activate tumor suppressor or repress oncogene/proinflammatory cytokine gene expression.

The role of interleukins in the ovary

1996 ◽  
Vol 5 (1) ◽  
pp. 51-63 ◽  
Author(s):  
C Simón ◽  
A Tsafriri ◽  
A Pellicer ◽  
ML Polan
Keyword(s):  
Cell Types ◽  
Necrosis Factor Alpha ◽  
Communication Signals ◽  
Ability To Act ◽  
Tnf Α ◽  
History Of ◽  
Specific Antigens ◽  
Factor Alpha ◽  
Different Populations

A brief look at the history of cytokine research shows that the term ‘lymphokine’ was first described in 1969 as the product of sensitized lymphocytes exposed to specific antigens. To eliminate the incorrect notion that such proteins can be produced only by lymphocytes, Cohenet al.(1974) proposed the term ‘cytokines’ to indicate their production also by nonlymphoid cells.2After a long-persisting reluctance, it seems that ‘cytokine’ is becoming the prevalent term for these proteins. Meanwhile, a group of participants at the Second International Lymphokine Workshop held in 1979 proposed the term ‘interleukin’ in order to develop, ‘a system of nomenclature based on the protein's ability to act as communication signals between different populations of leukocytes’.3They introduced the names IL-I and IL-2 for two important cytokines. Since then the number of described interleukins reached 16 and this number may increase. Furthermore, notwithstanding this previous notion, interleukins are now known to be produced in a variety of tissues other than leucocytes and affect the functions of many and diverse somatic cell types (e.g. IL-1 or IL-6). Therefore, while many cytokines are now termed as interleukins, others continue to be known by their old names [e.g. tumour necrosis factor-alpha (TNF-α)], suggesting that they had been recognized earlier, but all of them are included under the generic name of cytokines.

Inflammatory Related Cardiovascular Diseases: From Molecular Mechanisms to Therapeutic Targets

2020 ◽  
Vol 26 (22) ◽  
pp. 2565-2573 ◽  
Author(s):  
Celestino Sardu ◽  
Giuseppe Paolisso ◽  
Raffaele Marfella
Keyword(s):  
Heart Disease ◽  
Molecular Mechanisms ◽  
Inflammatory Biomarkers ◽  
Target Tissue ◽  
Necrosis Factor Alpha ◽  
Inflammatory Stress ◽  
Factor Alpha ◽  
New Biomarkers ◽  
Rheumatic Heart

Inflammation is a pathogenic response to multiple factors, that causes over-activation of different molecules and pro-inflammatory cellular lines. Different behavioral factors and risk factors might enhance the inflammatory stress, and this might cause cardiovascular disease (CVD). CVD is the world’s leading cause of morbidity and mortality, and it is represented by hypertension, coronary heart disease, cerebrovascular disease, peripheral vascular disease, heart failure, rheumatic heart disease, congenital heart disease and cardiomyopathies. In this context, inflammation is both a cause and an aggravating factor in CVD, as well as a mediator of its worst prognostic. The mechanisms that link inflammation to CVD are multiple, complex and multi-factorial. To date, the role of inflammation in the genesis and progression of CVD has been extensively analyzed in recent studies. However, in the last decades, new biomarkers are joining the already known inflammatory biomarkers, such as Creactive protein, interleukins, tumor necrosis factor alpha and nitrotyrosine. Among these new biomarkers, we have to report sirtuins, microRNAs, ST2 protein, apolipoprotein E protein, adiponectin, and others. These biomarkers are preferentially expressed locally in the target tissue of inflammation, but also released in peripheral blood and then used as diagnostic and prognostic biomarkers. Indeed, these biomarkers might also predict future adverse cardiovascular events and worse prognosis in patients with CVD. Furthermore, these new inflammatory biomarkers can also be analyzed to evaluate therapeutic efficacy in patients with CVD. Furthermore, this might open up new fields and interesting research concerning the link between inflammation and CVD.

scholarly journals Role of Long Non-Coding RNAs and the Molecular Mechanisms Involved in Insulin Resistance

2021 ◽  
Vol 22 (14) ◽  
pp. 7256
Author(s):  
Vianet Argelia Tello-Flores ◽  
Fredy Omar Beltrán-Anaya ◽  
Marco Antonio Ramírez-Vargas ◽  
Brenda Ely Esteban-Casales ◽  
Napoleón Navarro-Tito ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Biological Species ◽  
Necrosis Factor Alpha ◽  
Polypyrimidine Tract Binding Protein ◽  
Non Coding Rnas

Long non-coding RNAs (lncRNAs) are single-stranded RNA biomolecules with a length of >200 nt, and they are currently considered to be master regulators of many pathological processes. Recent publications have shown that lncRNAs play important roles in the pathogenesis and progression of insulin resistance (IR) and glucose homeostasis by regulating inflammatory and lipogenic processes. lncRNAs regulate gene expression by binding to other non-coding RNAs, mRNAs, proteins, and DNA. In recent years, several mechanisms have been reported to explain the key roles of lncRNAs in the development of IR, including metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), imprinted maternal-ly expressed transcript (H19), maternally expressed gene 3 (MEG3), myocardial infarction-associated transcript (MIAT), and steroid receptor RNA activator (SRA), HOX transcript antisense RNA (HOTAIR), and downregulated Expression-Related Hexose/Glucose Transport Enhancer (DREH). LncRNAs participate in the regulation of lipid and carbohydrate metabolism, the inflammatory process, and oxidative stress through different pathways, such as cyclic adenosine monophosphate/protein kinase A (cAMP/PKA), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), polypyrimidine tract-binding protein 1/element-binding transcription factor 1c (PTBP1/SREBP-1c), AKT/nitric oxide synthase (eNOS), AKT/forkhead box O1 (FoxO1), and tumor necrosis factor-alpha (TNF-α)/c-Jun-N-terminal kinases (JNK). On the other hand, the mechanisms linked to the molecular, cellular, and biochemical actions of lncRNAs vary according to the tissue, biological species, and the severity of IR. Therefore, it is essential to elucidate the role of lncRNAs in the insulin signaling pathway and glucose and lipid metabolism. This review analyzes the function and molecular mechanisms of lncRNAs involved in the development of IR.

scholarly journals Cellular and mitochondrial mechanisms of atrial fibrillation

2020 ◽  
Vol 115 (6) ◽  
Author(s):  
Fleur E. Mason ◽  
Julius Ryan D. Pronto ◽  
Khaled Alhussini ◽  
Christoph Maack ◽  
Niels Voigt
Keyword(s):  
Atrial Fibrillation ◽  
Nicotinamide Adenine Dinucleotide ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Specific Treatment ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Nicotinamide Adenine ◽  
Mitochondrial Activity ◽  
Atp Production

AbstractThe molecular mechanisms underlying atrial fibrillation (AF), the most common form of arrhythmia, are poorly understood and therefore target-specific treatment options remain an unmet clinical need. Excitation–contraction coupling in cardiac myocytes requires high amounts of adenosine triphosphate (ATP), which is replenished by oxidative phosphorylation in mitochondria. Calcium (Ca2+) is a key regulator of mitochondrial function by stimulating the Krebs cycle, which produces nicotinamide adenine dinucleotide for ATP production at the electron transport chain and nicotinamide adenine dinucleotide phosphate for the elimination of reactive oxygen species (ROS). While it is now well established that mitochondrial dysfunction plays an important role in the pathophysiology of heart failure, this has been less investigated in atrial myocytes in AF. Considering the high prevalence of AF, investigating the role of mitochondria in this disease may guide the path towards new therapeutic targets. In this review, we discuss the importance of mitochondrial Ca2+ handling in regulating ATP production and mitochondrial ROS emission and how alterations, particularly in these aspects of mitochondrial activity, may play a role in AF. In addition to describing research advances, we highlight areas in which further studies are required to elucidate the role of mitochondria in AF.

scholarly journals N-Acetylcysteine (NAC): Impacts on Human Health

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 967
Author(s):  
Micaely Cristina dos Santos Tenório ◽  
Nayara Gomes Graciliano ◽  
Fabiana Andréa Moura ◽  
Alane Cabral Menezes de Oliveira ◽  
Marília Oliveira Fonseca Goulart
Keyword(s):  
Human Health ◽  
Therapeutic Potential ◽  
Experimental Studies ◽  
Primary Role ◽  
Necrosis Factor Alpha ◽  
Biochemical Basis ◽  
Tnf Α ◽  
Factor Alpha ◽  
Anti Inflammatory

N-acetylcysteine (NAC) is a medicine widely used to treat paracetamol overdose and as a mucolytic compound. It has a well-established safety profile, and its toxicity is uncommon and dependent on the route of administration and high dosages. Its remarkable antioxidant and anti-inflammatory capacity is the biochemical basis used to treat several diseases related to oxidative stress and inflammation. The primary role of NAC as an antioxidant stems from its ability to increase the intracellular concentration of glutathione (GSH), which is the most crucial biothiol responsible for cellular redox imbalance. As an anti-inflammatory compound, NAC can reduce levels of tumor necrosis factor-alpha (TNF-α) and interleukins (IL-6 and IL-1β) by suppressing the activity of nuclear factor kappa B (NF-κB). Despite NAC’s relevant therapeutic potential, in several experimental studies, its effectiveness in clinical trials, addressing different pathological conditions, is still limited. Thus, the purpose of this chapter is to provide an overview of the medicinal effects and applications of NAC to human health based on current therapeutic evidence.

scholarly journals Role of NF-κB and Myc Proteins in Apoptosis Induced by Hepatitis B Virus HBx Protein

2001 ◽  
Vol 75 (1) ◽  
pp. 215-225 ◽  
Author(s):  
Fei Su ◽  
Christian N. Theodosis ◽  
Robert J. Schneider
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Apoptotic Cell ◽  
Regulatory Protein ◽  
Family Members ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
B Virus ◽  
High Level

ABSTRACT Chronic infection with hepatitis B virus (HBV) promotes a high level of liver disease and cancer in humans. The HBV HBx gene encodes a small regulatory protein that is essential for viral replication and is suspected to play a role in viral pathogenesis. HBx stimulates cytoplasmic signal transduction pathways, moderately stimulates a number of transcription factors, including several nuclear factors, and in certain settings sensitizes cells to apoptosis by proapoptotic stimuli, including tumor necrosis factor alpha (TNF-α) and etopocide. Paradoxically, HBx activates members of the NF-κB transcription factor family, some of which are antiapoptotic in function. HBx induces expression of Myc protein family members in certain settings, and Myc can sensitize cells to killing by TNF-α. We therefore examined the roles of NF-κB, c-Myc, and TNF-α in apoptotic killing of cells by HBx. RelA/NF-κB is shown to be induced by HBx and to suppress HBx-mediated apoptosis. HBx also induces c-Rel/NF-κB, which can promote apoptotic cell death in some contexts or block it in others. Induction of c-Rel by HBx was found to inhibit its ability to directly mediate apoptotic killing of cells. Thus, HBx induction of NF-κB family members masks its ability to directly mediate apoptosis, whereas ablation of NF-κB reveals it. Investigation of the role of Myc protein demonstrates that overexpression of Myc is essential for acute sensitization of cells to killing by HBx plus TNF-α. This study therefore defines a specific set of parameters which must be met for HBx to possibly contribute to HBV pathogenesis.

scholarly journals Circadian Rhythms, the Mesolimbic Dopaminergic Circuit, and Drug Addiction

2007 ◽  
Vol 7 ◽  
pp. 194-202 ◽  
Author(s):  
Colleen A. McClung
Keyword(s):  
Circadian Rhythms ◽  
Drug Addiction ◽  
Molecular Mechanisms ◽  
Dopaminergic System ◽  
Treatment Options ◽  
Drug Induced ◽  
Circadian Genes ◽  
Dopaminergic Transmission ◽  
Central Pacemaker

Drug addiction is a devastating disease that affects millions of individuals worldwide. Through better understanding of the genetic variations that create a vulnerability for addiction and the molecular mechanisms that underlie the progression of addiction, better treatment options can be created for those that suffer from this condition. Recent studies point to a link between abnormal or disrupted circadian rhythms and the development of addiction. In addition, studies suggest a role for specific genes that make up the molecular clock in the regulation of drug sensitivity, sensitization, and reward. The influence of circadian genes and rhythms on drug-induced behaviors may be mediated through the mesolimbic dopaminergic system. This system has long been implicated in the development of addiction, and recent evidence supports a regulatory role for the brain's central pacemaker and circadian gene expression in the regulation of dopaminergic transmission. This review highlights the association between circadian genes and drug addiction, and the possible role of the mesolimbic dopaminergic system in this association.

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