scholarly journals Thrombospondin-1: Multiple Paths to Inflammation

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Zenaida Lopez-Dee ◽  
Kenneth Pidcock ◽  
Linda S. Gutierrez
Keyword(s):  
Molecular Mechanisms ◽  
Recent Literature ◽  
Tissue Injury ◽  
Matricellular Protein ◽  
Thrombospondin 1 ◽  
Multiple Paths ◽  
Protective Strategy ◽  
Inflammatory Processes ◽  
Cancer And Inflammation

Inflammation is a defensive process against tissue injury. Once this self-protective strategy is initiated, an effective resolution of the process is crucial to avoid major and unnecessary tissue damage. If the underlying event inducing inflammation is not addressed and homeostasis is not restored, this process can become chronic and lead to angiogenesis and carcinogenesis. Thrombospondin-1 (TSP-1) is a matricellular protein involved in angiogenesis, cancer, and inflammation. The effects of TSP-1 have been studied in many preclinical tumor models, and mimetic peptides are being tested in cancer clinical trials. However, the molecular mechanisms explaining its role in inflammatory processes are not well understood. This paper will discuss the role of TSP-1 in inflammation and its interaction with key receptors that may explain its functions in that process. Recent literature will be reviewed showing novel mechanisms by which this multifaceted protein could modulate the inflammatory process and impact its resolution.

scholarly journals Thrombospondin 1 in Metabolic Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Linda S. Gutierrez ◽  
Jovita Gutierrez
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Metabolic Diseases ◽  
Cell Metabolism ◽  
Matricellular Protein ◽  
Published Data ◽  
Obesity And Diabetes ◽  
Thrombospondin 1 ◽  
Cancer And Inflammation

The thrombospondin family comprises of five multifunctional glycoproteins, whose best-studied member is thrombospondin 1 (TSP1). This matricellular protein is a potent antiangiogenic agent that inhibits endothelial migration and proliferation, and induces endothelial apoptosis. Studies have demonstrated a regulatory role of TSP1 in cell migration and in activation of the latent transforming growth factor beta 1 (TGFβ1). These functions of TSP1 translate into its broad modulation of immune processes. Further, imbalances in immune regulation have been increasingly linked to pathological conditions such as obesity and diabetes mellitus. While most studies in the past have focused on the role of TSP1 in cancer and inflammation, recently published data have revealed new insights about the role of TSP1 in physiological and metabolic disorders. Here, we highlight recent findings that associate TSP1 and its receptors to obesity, diabetes, and cardiovascular diseases. TSP1 regulates nitric oxide, activates latent TGFβ1, and interacts with receptors CD36 and CD47, to play an important role in cell metabolism. Thus, TSP1 and its major receptors may be considered a potential therapeutic target for metabolic diseases.

Upregulation of thrombospondin-1 expression by leptin in vascular smooth muscle cells via JAK2- and MAPK-dependent pathways

2012 ◽  
Vol 303 (2) ◽  
pp. C179-C191 ◽  
Author(s):  
Ronaldo J. Chavez ◽  
Rebecca M. Haney ◽  
Rene H. Cuadra ◽  
Rituparna Ganguly ◽  
Ravi K. Adapala ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Muscle Cells ◽  
Matricellular Protein ◽  
Vascular Cells ◽  
Increased Risk ◽  
Thrombospondin 1

Hyperleptinemia, characteristic of diabetes and a hallmark feature of human obesity, contributes to the increased risk of atherosclerotic complications. However, molecular mechanisms mediating leptin-induced atherogenesis and gene expression in vascular cells remain incompletely understood. Accumulating evidence documents a critical role of a potent antiangiogenic and proatherogenic matricellular protein, thrombospondin-1 (TSP-1), in atherosclerosis. Although previous studies reported elevated TSP-1 levels in both diabetic and obese patients and rodent models, there is no direct information on TSP-1 expression in vascular cells in response to leptin. In the present study, we show that leptin upregulates TSP-1 expression in cultured human aortic smooth muscle cells (HASMC) in vitro, and this increase occurs at the level of transcription, revealed by mRNA stability and TSP-1 promoter-reporter assays. Utilizing specific pharmacological inhibitors and siRNA approaches, we demonstrate that upregulation of TSP-1 expression by leptin is mediated by JAK2/ERK/JNK-dependent mechanisms. Furthermore, we report that while ERK and JNK are required for both the constitutive and leptin-induced expression of TSP-1, JAK-2 appears to be specifically involved in leptin-mediated TSP-1 upregulation. Finally, we found that increased HASMC migration and proliferation in response to leptin is significantly inhibited by a TSP-1 blocking antibody, thereby revealing the physiological significance of leptin-TSP-1 crosstalk. Taken together, these findings demonstrate, for the first time, that leptin has a direct regulatory effect on TSP-1 expression in HASMCs, underscoring a novel role of TSP-1 in hyperleptinemia-induced atherosclerotic complications.

scholarly journals THIOZOLIDINEDIONES IN THE TREATMENT OF PATIENTS WITH EXTENSIVE PSORIASIS AND CONCOMITANT ALIMENTARY OBESITY

2020 ◽  
Vol 20 (4) ◽  
pp. 30-34
Author(s):  
Ya.O. Yemchenko ◽  
K.Ye. Ishcheikin ◽  
I.P. Kaidashev
Keyword(s):  
Systemic Inflammation ◽  
Molecular Mechanisms ◽  
Current Data ◽  
The Body ◽  
Internal Organs ◽  
Single View ◽  
Multifactorial Diseases ◽  
Alimentary Obesity ◽  
Inflammatory Processes

Psoriasis is one of the most common chronic recurrent systemic autoimmune multifactorial diseases, affected the skin, joints, internal organs and systems of the body. Despite the significant prevalence of psoriasis and a large number of studies devoted this problem there is still no single view on the pathogenesis of this dermatosis. To clear up the pathogenesis of psoriasis, it seems to be reasonable to focus on the common comorbidities or multimorbidities, which may occur in the course of psoriasis, as this issue is still insufficiently studied. Recent reports have proven the evidences of indisputable link between psoriasis and obesity. The scientific literature extensively covers the issues of identical pathogenetic mechanisms of inflammatory processes in psoriasis and obesity. Given the current data on the role of systemic inflammation underlying the development of both psoriasis and obesity, the study of molecular mechanisms of its development and in particularly the role of proinflammatory nuclear transcription factors, thiazolidinediones have been found out as pathogenetically justified medicine of choice for the therapy of these diseases. In this study, we determined the effectiveness of using 30 mg of pioglitazone daily for 6 months in the course of treatment for patients with extensive psoriasis vulgaris of moderate severity, who were also diagnosed as having concomitant grade І-ІІ alimentary obesity that was supported by clinical and immunological findings evidenced of systemic inflammation. Analyzing the results obtained, we have found out the prolonged therapy with pioglitazone leads to a decrease in systemic inflammation and contributes to a milder recurrent course of psoriasis.

scholarly journals Cyclophilin a as a Mediator of Tissue Injure and Nephrotoxicity

2012 ◽  
Vol 4 (2) ◽  
pp. 42-44
Author(s):  
Grace Moscoso-Solorzano ◽  
Gianna Mastroianni-Kirsztajn
Keyword(s):  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Cyclophilin A ◽  
Common Mechanism ◽  
Ppiase Activity ◽  
Expression Of Genes ◽  
Inflammatory Stimuli ◽  
Genes Encoding ◽  
Inflammatory Processes

Cyclophilin A (CypA) belongs to the peptidyl-prolil isomerase (PPlase) family of proteins and it is also known as the cellular receptor for cyclosporine A (CsA). CsA binds to CypA and inhibits the PPIase activity, but the CypA-CsA complex also binds to calcineurin that promotes the expression of genes encoding cytokines and other proteins required for immune response. In addition, the polymorphism variation of CypA promoter seems to have an influence on the expression of CypA in in vitro studies. CypA was also implicated in inflammatory processes (such as, among others, those observed in rheumatoid arthritis, atherosclerotic disease, nephrotoxicity) and it can be secreted by cells in response to inflammatory stimuli. CypA can also have a role in the molecular mechanisms by which CsA induces nephroxicity but these remain poorly understood. Recent studies suggest that CsA inhibition of CypA PPlase activity is a possible mechanism of this drug toxicity. In addition, CypA overexpression could be protective against CsA nephrotoxicity. Finally, the putative common mechanism by which CypA could be involved in CsA nephrotoxicity and tissue injury is related to its proinflammatory effects in cells.

scholarly journals Paraoxonases Activities and Polymorphisms in Elderly and Old-Age Diseases: An Overview

Antioxidants ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 118 ◽  
Author(s):  
Débora Levy ◽  
Cadiele Oliana Reichert ◽  
Sérgio Paulo Bydlowski
Keyword(s):  
Oxidative Stress ◽  
Aging Process ◽  
Tissue Injury ◽  
Density Lipoprotein ◽  
The Elderly ◽  
Chromosome 7 ◽  
Oxygen Species ◽  
Structural Homology ◽  
Inflammatory Processes

Aging is defined as the accumulation of progressive organ dysfunction. There is much evidence linking the involvement of oxidative stress in the pathogenesis of aging. With increasing age, susceptibility to the development of diseases related to lipid peroxidation and tissue injury increases, due to chronic inflammatory processes, and production of reactive oxygen species (ROS) and free radicals. The paraoxonase (PON) gene family is composed of three members (PON1, PON2, PON3) that share considerable structural homology and are located adjacently on chromosome 7 in humans. The most studied member product is PON1, a protein associated with high-density lipoprotein with paraoxonase/esterase activity. Nevertheless, all the three proteins prevent oxidative stress. The major aim of this review is to highlight the importance of the role of PON enzymes in the aging process, and in the development of the main diseases present in the elderly: cardiovascular disease, diabetes mellitus, neurodegenerative diseases, and cancer.

scholarly journals Cellular Responses to Proteasome Inhibition: Molecular Mechanisms and Beyond

2019 ◽  
Vol 20 (14) ◽  
pp. 3379 ◽  
Author(s):  
Nicolas Albornoz ◽  
Hianara Bustamante ◽  
Andrea Soza ◽  
Patricia Burgos
Keyword(s):  
Side Effects ◽  
Inclusion Bodies ◽  
Molecular Mechanisms ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Cellular Responses ◽  
Cell Responses ◽  
Different Types ◽  
Inflammatory Processes

Proteasome inhibitors have been actively tested as potential anticancer drugs and in the treatment of inflammatory and autoimmune diseases. Unfortunately, cells adapt to survive in the presence of proteasome inhibitors activating a variety of cell responses that explain why these therapies have not fulfilled their expected results. In addition, all proteasome inhibitors tested and approved by the FDA have caused a variety of side effects in humans. Here, we describe the different types of proteasome complexes found within cells and the variety of regulators proteins that can modulate their activities, including those that are upregulated in the context of inflammatory processes. We also summarize the adaptive cellular responses activated during proteasome inhibition with special emphasis on the activation of the Autophagic-Lysosomal Pathway (ALP), proteaphagy, p62/SQSTM1 enriched-inclusion bodies, and proteasome biogenesis dependent on Nrf1 and Nrf2 transcription factors. Moreover, we discuss the role of IRE1 and PERK sensors in ALP activation during ER stress and the involvement of two deubiquitinases, Rpn11 and USP14, in these processes. Finally, we discuss the aspects that should be currently considered in the development of novel strategies that use proteasome activity as a therapeutic target for the treatment of human diseases.

scholarly journals Anti-Inflammatory Cytokines: Important Immunoregulatory Factors Contributing to Chemotherapy-Induced Gastrointestinal Mucositis

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Masooma Sultani ◽  
Andrea M. Stringer ◽  
Joanne M. Bowen ◽  
Rachel J. Gibson
Keyword(s):  
Inflammatory Cytokines ◽  
Proinflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Financial Burden ◽  
Interleukin 1 ◽  
Treatment Strategies ◽  
Inflammatory Reactions ◽  
Anti Inflammatory

“Mucositis” is the clinical term used to describe ulceration and damage of the mucous membranes of the entire gastrointestinal tract (GIT) following cytotoxic cancer chemotherapy and radiation therapy common symptoms include abdominal pain, bloating, diarrhoea, vomiting, and constipation resulting in both a significant clinical and financial burden. Chemotherapeutic drugs cause upregulation of stress response genes including NFκB, that in turn upregulate the production of proinflammatory cytokines such as interleukin-1β (IL-1β), Interleukin-6 (IL-6), and tumour necrosis factor-α (TNF-α). These proinflammatory cytokines are responsible for initiating inflammation in response to tissue injury. Anti-inflammatory cytokines and specific cytokine inhibitors are also released to limit the sustained or excessive inflammatory reactions. In the past decade, intensive research has determined the role of proinflammatory cytokines in development of mucositis. However, a large gap remains in the knowledge of the role of anti-inflammatory cytokines in the setting of chemotherapy-induced mucositis. This critical paper will highlight current literature available relating to what is known regarding the development of mucositis, including the molecular mechanisms involved in inducing inflammation particularly with respect to the role of proinflammatory cytokines, as well as provide a detailed discussion of why it is essential to consider extensive research in the role of anti-inflammatory cytokines in chemotherapy-induced mucositis so that effective targeted treatment strategies can be developed.

scholarly journals Academic-industry partnerships in addressing nutrition – [Infection-immunity-inflammation] interactions

2007 ◽  
Vol 98 (S1) ◽  
pp. S17-S23 ◽  
Author(s):  
Ricardo Uauy
Keyword(s):  
Cell Injury ◽  
Tissue Injury ◽  
Infectious Agent ◽  
Nutritional Supplement ◽  
Novel Foods ◽  
Protein Energy ◽  
Toxic Damage ◽  
Inflammatory Processes ◽  
The Impact

The interaction between nutrition and infection is a key determinant of human health. Traditionally the interaction has centered on the role of nutrients in defining host defenses and the impact of infection in defining nutritional needs and status. Over the past decades the interaction has expanded its scope to encompass the role of specific nutrients in defining acquired immune function, in the modulation of inflammatory processes and on the virulence of the infectious agent itself. More recently the role of micronutrients and fatty acids on the response of cells and tissues to hypoxic and toxic damage has been recognized suggesting a fourth dimension to the interaction. The list of nutrients affecting infection, immunity, inflammation and cell injury has expanded from traditional protein-energy supply to several vitamins, multiple minerals and more recently specific lipid components of the diet. The promise of nutrition in the defense against infection, inflammation and tissue injury has spawned a thriving pharma-nutritional supplement industry and the development of novel foods that require appropriate evaluation of efficacy, safety and effectiveness relative to costs. Academics need to aware of the ethics and the pitfalls in the interaction with industry; conversely industry has to define its role in the process of bringing new knowledge to useful products. The process needs to be interactive, transparent and clearly place public interest above all other considerations.

scholarly journals Autophagy in Alcohol-Induced Multiorgan Injury: Mechanisms and Potential Therapeutic Targets

2014 ◽  
Vol 2014 ◽  
pp. 1-20 ◽  
Author(s):  
Yuan Li ◽  
Shaogui Wang ◽  
Hong-Min Ni ◽  
Heqing Huang ◽  
Wen-Xing Ding
Keyword(s):  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Current Knowledge ◽  
Therapeutic Targets ◽  
Degradation Pathway ◽  
Protective Mechanism ◽  
Intracellular Degradation ◽  
Injury Mechanisms ◽  
Evolutionarily Conserved

Autophagy is a genetically programmed, evolutionarily conserved intracellular degradation pathway involved in the trafficking of long-lived proteins and cellular organelles to the lysosome for degradation to maintain cellular homeostasis. Alcohol consumption leads to injury in various tissues and organs including liver, pancreas, heart, brain, and muscle. Emerging evidence suggests that autophagy is involved in alcohol-induced tissue injury. Autophagy serves as a cellular protective mechanism against alcohol-induced tissue injury in most tissues but could be detrimental in heart and muscle. This review summarizes current knowledge about the role of autophagy in alcohol-induced injury in different tissues/organs and its potential molecular mechanisms as well as possible therapeutic targets based on modulation of autophagy.

scholarly journals Peripheral Mechanisms of Dental Pain: The Role of Substance P

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Paola Sacerdote ◽  
Luca Levrini
Keyword(s):  
Substance P ◽  
Molecular Mechanisms ◽  
Dental Pain ◽  
Therapeutic Strategies ◽  
Current Evidence ◽  
Trigeminal Ganglia ◽  
Clinical Observations ◽  
P Concentration ◽  
Inflammatory Processes

Current evidence supports the central role of neuropeptides in the molecular mechanisms underlying dental pain. In particular, substance P, a neuropeptide produced in neuron cell bodies localised in dorsal root and trigeminal ganglia, contributes to the transmission and maintenance of noxious stimuli and inflammatory processes. The major role of substance P in the onset of dental pain and inflammation is increasingly being recognised. Well-grounded experimental and clinical observations have documented an increase in substance P concentration in patients affected by caries, pulpitis, or granulomas and in those undergoing standard orthodontic or orthodontic/dental care procedures. This paper focuses on the role of substance P in the induction and maintenance of inflammation and dental pain, in order to define future lines of research for the evaluation of therapeutic strategies aimed at modulating the complex effects of this mediator in oral tissues.

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