Signalling by lysophosphatidate and its health implications

2020 ◽  
Vol 64 (3) ◽  
pp. 547-563 ◽  
Author(s):  
Denise G. Hemmings ◽  
David N. Brindley
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Diseases ◽  
Chemotherapeutic Agents ◽  
Receptor Expression ◽  
Cancer Treatments ◽  
Lpa1 Receptor ◽  
Radiation Induced ◽  
Lipid Phosphate Phosphatases ◽  
G Protein Coupled ◽  
Cholestasis Of Pregnancy

Abstract Extracellular lysophosphatidate (LPA) signalling is regulated by the balance of LPA formation by autotaxin (ATX) versus LPA degradation by lipid phosphate phosphatases (LPP) and by the relative expressions of six G-protein-coupled LPA receptors. These receptors increase cell proliferation, migration, survival and angiogenesis. Acute inflammation produced by tissue damage stimulates ATX production and LPA signalling as a component of wound healing. If inflammation does not resolve, LPA signalling becomes maladaptive in conditions including arthritis, neurologic pain, obesity and cancers. Furthermore, LPA signalling through LPA1 receptors promotes fibrosis in skin, liver, kidneys and lungs. LPA also promotes the spread of tumours to other organs (metastasis) and the pro-survival properties of LPA explain why LPA counteracts the effects of chemotherapeutic agents and radiotherapy. ATX is secreted in response to radiation-induced DNA damage during cancer treatments and this together with increased LPA1 receptor expression leads to radiation-induced fibrosis. The anti-inflammatory agent, dexamethasone, decreases levels of inflammatory cytokines/chemokines. This is linked to a coordinated decrease in the production of ATX and LPA1/2 receptors and increased LPA degradation through LPP1. These effects explain why dexamethasone attenuates radiation-induced fibrosis. Increased LPA signalling is also associated with cardiovascular disease including atherosclerosis and deranged LPA signalling is associated with pregnancy complications including preeclampsia and intrahepatic cholestasis of pregnancy. LPA contributes to chronic inflammation because it stimulates the secretion of inflammatory cytokines/chemokines, which increase further ATX production and LPA signalling. Attenuating maladaptive LPA signalling provides a novel means of treating inflammatory diseases that underlie so many important medical conditions.

scholarly journals Melatonin as an Adjuvant to Antiangiogenic Cancer Treatments

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3263
Author(s):  
Alicia González ◽  
Carolina Alonso-González ◽  
Alicia González-González ◽  
Javier Menéndez-Menéndez ◽  
Samuel Cos ◽  
...  
Keyword(s):  
Synergistic Effect ◽  
Protective Effect ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Chemotherapeutic Agents ◽  
Inhibitory Effects ◽  
Anticancer Effect ◽  
Cancer Treatments ◽  
Melatonin Administration ◽  
Effects Of Radiation

Melatonin is a hormone with different functions, antitumor actions being one of the most studied. Among its antitumor mechanisms is its ability to inhibit angiogenesis. Melatonin shows antiangiogenic effects in several types of tumors. Combination of melatonin and chemotherapeutic agents have a synergistic effect inhibiting angiogenesis. One of the undesirable effects of chemotherapy is the induction of pro-angiogenic factors, whilst the addition of melatonin is able to overcome these undesirable effects. This protective effect of the pineal hormone against angiogenesis might be one of the mechanisms underlying its anticancer effect, explaining, at least in part, why melatonin administration increases the sensitivity of tumors to the inhibitory effects exerted by ordinary chemotherapeutic agents. Melatonin has the ability to turn cancer totally resistant to chemotherapeutic agents into a more sensitive chemotherapy state. Definitely, melatonin regulates the expression and/or activity of many factors involved in angiogenesis which levels are affected (either positively or negatively) by chemotherapeutic agents. In addition, the pineal hormone has been proposed as a radiosensitizer, increasing the oncostatic effects of radiation on tumor cells. This review serves as a synopsis of the interaction between melatonin and angiogenesis, and we will outline some antiangiogenic mechanisms through which melatonin sensitizes cancer cells to treatments, such as radiotherapy or chemotherapy.

scholarly journals G Protein-Coupled Estrogen Receptor in Cancer and Stromal Cells: Functions and Novel Therapeutic Perspectives

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 672
Author(s):  
Richard A. Pepermans ◽  
Geetanjali Sharma ◽  
Eric R. Prossnitz
Keyword(s):  
Estrogen Receptor ◽  
G Protein ◽  
Inflammatory Diseases ◽  
Therapy Resistance ◽  
Breast Cancers ◽  
Obesity And Diabetes ◽  
Therapeutic Value ◽  
Health And Disease ◽  
Multiple Cells ◽  
G Protein Coupled

Estrogen is involved in numerous physiological and pathophysiological systems. Its role in driving estrogen receptor-expressing breast cancers is well established, but it also has important roles in a number of other cancers, acting both on tumor cells directly as well as in the function of multiple cells of the tumor microenvironment, including fibroblasts, immune cells, and adipocytes, which can greatly impact carcinogenesis. One of its receptors, the G protein-coupled estrogen receptor (GPER), has gained much interest over the last decade in both health and disease. Increasing evidence shows that GPER contributes to clinically observed endocrine therapy resistance in breast cancer while also playing a complex role in a number of other cancers. Recent discoveries regarding the targeting of GPER in combination with immune checkpoint inhibition, particularly in melanoma, have led to the initiation of the first Phase I clinical trial for the GPER-selective agonist G-1. Furthermore, its functions in metabolism and corresponding pathophysiological states, such as obesity and diabetes, are becoming more evident and suggest additional therapeutic value in targeting GPER for both cancer and other diseases. Here, we highlight the roles of GPER in several cancers, as well as in metabolism and immune regulation, and discuss the therapeutic value of targeting this estrogen receptor as a potential treatment for cancer as well as contributing metabolic and inflammatory diseases and conditions.

scholarly journals Reduced High-Dose Radiation-Induced Residual Genotoxic Damage by Induction of Radioadaptive Response and Prophylactic Mild Dietary Restriction in Mice

Dose-Response ◽  
2021 ◽  
Vol 19 (1) ◽  
pp. 155932582098216
Author(s):  
Bing Wang ◽  
Kaoru Tanaka ◽  
Takanori Katsube ◽  
Kouichi Maruyama ◽  
Yasuharu Ninomiya ◽  
...  
Keyword(s):  
Dietary Restriction ◽  
High Dose ◽  
Cancer Treatments ◽  
Hematopoietic Stem ◽  
Beneficial Effects ◽  
Radiation Induced ◽  
Potential Strategy ◽  
Higher Doses

Radioadaptive response (RAR) describes a phenomenon in a variety of in vitro and in vivo systems that a low-dose of priming ionizing radiation (IR) reduces detrimental effects of a subsequent challenge IR at higher doses. Among in vivo investigations, studies using the mouse RAR model (Yonezawa Effect) showed that RAR could significantly extenuate high-dose IR-induced detrimental effects such as decrease of hematopoietic stem cells and progenitor cells, acute radiation hematopoietic syndrome, genotoxicity and genomic instability. Meanwhile, it has been demonstrated that diet intervention has a great impact on health, and dietary restriction shows beneficial effects on numerous diseases in animal models. In this work, by using the mouse RAR model and mild dietary restriction (MDR), we confirmed that combination of RAR and MDR could more efficiently reduce radiogenotoxic damage without significant change of the RAR phenotype. These findings suggested that MDR may share some common pathways with RAR to activate mechanisms consequently resulting in suppression of genotoxicity. As MDR could also increase resistance to chemotherapy and radiotherapy in normal cells, we propose that combination of MDR, RAR, and other cancer treatments (i.e., chemotherapy and radiotherapy) represent a potential strategy to increase the treatment efficacy and prevent IR risk in humans.

scholarly journals The Biology of Vasopressin

Biomedicines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 89
Author(s):  
Samantha Sparapani ◽  
Cassandra Millet-Boureima ◽  
Joshua Oliver ◽  
Kathy Mu ◽  
Pegah Hadavi ◽  
...  
Keyword(s):  
Parental Behavior ◽  
Cell Types ◽  
G Protein Coupled Receptors ◽  
Receptor Expression ◽  
Evolutionarily Conserved ◽  
Terrestrial Environments ◽  
Intracellular Vesicles ◽  
G Protein Coupled ◽  
Neuropsychiatric Conditions ◽  
Vasopressin Synthesis

Vasopressins are evolutionarily conserved peptide hormones. Mammalian vasopressin functions systemically as an antidiuretic and regulator of blood and cardiac flow essential for adapting to terrestrial environments. Moreover, vasopressin acts centrally as a neurohormone involved in social and parental behavior and stress response. Vasopressin synthesis in several cell types, storage in intracellular vesicles, and release in response to physiological stimuli are highly regulated and mediated by three distinct G protein coupled receptors. Other receptors may bind or cross-bind vasopressin. Vasopressin is regulated spatially and temporally through transcriptional and post-transcriptional mechanisms, sex, tissue, and cell-specific receptor expression. Anomalies of vasopressin signaling have been observed in polycystic kidney disease, chronic heart failure, and neuropsychiatric conditions. Growing knowledge of the central biological roles of vasopressin has enabled pharmacological advances to treat these conditions by targeting defective systemic or central pathways utilizing specific agonists and antagonists.

Proctogyneacology – who should treat? A proposed treatment algorithm

Nowa Medycyna ◽  
2020 ◽  
Vol 27 (4) ◽  
Author(s):  
Małgorzata Kołodziejczak ◽  
Przemysław Ciesielski ◽  
Maja Gorajska-Sieńko
Keyword(s):  
Anal Sphincter ◽  
Reproductive Tract ◽  
Inflammatory Diseases ◽  
Uterine Prolapse ◽  
Treatment Algorithm ◽  
Female Reproductive Tract ◽  
Rectovaginal Septum ◽  
Therapeutic Success ◽  
Radiation Induced ◽  
Rectovaginal Fistulas

Proctogyneacology deals with conditions involving the anal canal, anal sphincter muscles, rectum, rectovaginal septum, and the female reproductive tract. They may be due to sagging of the pelvic floor and the rectovaginal septum (rectal, vaginal or uterine prolapse, enterocele and rectocele), perinatal injury, including sphincter damage, rectovaginal fistulas, endometriosis with anal sphincter and rectovaginal septum involvement, proctological inflammatory diseases in pregnancy, as well as radiation-induced rectal damage after gynaecological cancer treatment. There are no set guidelines defining which specialist should operate on these patients. We attempted to systematise this issue in the form of an algorithm. An interdisciplinary dialogue allowing for our professional development and, most of all, therapeutic success and reduced risk of postoperative complications, seems to be crucial.

The asialoglycoprotein receptor: relationships between structure, function, and expression

1995 ◽  
Vol 75 (3) ◽  
pp. 591-609 ◽  
Author(s):  
R. J. Stockert
Keyword(s):  
Translational Regulation ◽  
Chemotherapeutic Agents ◽  
Asialoglycoprotein Receptor ◽  
Receptor Expression ◽  
Coated Pits ◽  
Receptor Mediated Endocytosis ◽  
Intracellular Compartments ◽  
Foreign Genes ◽  
And Function ◽  
A Site

Transport of macromolecules into the cell by receptor-mediated endocytosis follows a complex series of intracellular transfers, passing through distinct environments. The asialoglycoprotein receptor is a prototype of the class of receptors that constitutively enters cells via coated pits and delivers ligand to these intracellular compartments. In addition to being a model of receptor-mediated endocytosis, the presence of the receptor on hepatocytes provides a membrane-bound active site for cell-to-cell interactions, has made possible the selective targeting of chemotherapeutic agents and foreign genes, and has also been implicated as a site mediating hepatitis B virus uptake. Regulated expression of receptor subunits and their intracellular trafficking during biosynthesis and endocytosis has provided insights into the relationship of receptor structure to its overall function. As a marker of hepatocellular differentiation, its study has uncovered a unique response to intracellular guanosine 3',5'-cyclic monophosphate and translational regulation of the receptor. In this review, an overview of these diverse findings is provided in an attempt to relate the various aspects of structure and function as they impact on receptor expression.

scholarly journals Prospects for use of peptides and their derivatives, structurally corresponding to the G protein-coupled receptors, in medicine

2015 ◽  
Vol 61 (1) ◽  
pp. 19-29 ◽  
Author(s):  
A.O. Shpakov ◽  
E.A. Shpakova
Keyword(s):  
G Protein ◽  
Intracellular Signaling ◽  
High Efficiency ◽  
Clinical Medicine ◽  
Inflammatory Diseases ◽  
G Protein Coupled Receptors ◽  
Signaling Cascades ◽  
G Protein Coupled

The regulation of signaling pathways involved in the control of many physiological functions is carried out via the heterotrimeric G protein-coupled receptors (GPCR). The search of effective and selective regulators of GPCR and intracellular signaling cascades coupled with them is one of the important problems of modern fundamental and clinical medicine. Recently data suggest that synthetic peptides and their derivatives, structurally corresponding to the intracellular and transmembrane regions of GPCR, can interact with high efficiency and selectivity with homologous receptors and influence, thus, the functional activity of intracellular signaling cascades and fundamental cellular processes controlled by them. GPCR-peptides are active in both in vitro and in vivo. They regulate hematopoiesis, angiogenesis and cell proliferation, inhibit tumor growth and metastasis, and prevent the inflammatory diseases and septic shock. These data show greatest prospects in the development of the new generations of drugs based on GPCR-derived peptides, capable of regulating the important functions of the organism.

scholarly journals A 3D Agent-Based Model of Lung Fibrosis

Symmetry ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 90
Author(s):  
Nicolò Cogno ◽  
Roman Bauer ◽  
Marco Durante
Keyword(s):  
Lung Fibrosis ◽  
Computational Models ◽  
Multiple Scales ◽  
Inflammatory Diseases ◽  
Cell Damage ◽  
Heterogeneous Systems ◽  
Chronic Obstructive ◽  
Agent Based Model ◽  
Agent Based ◽  
Radiation Induced

Understanding the pathophysiology of lung fibrosis is of paramount importance to elaborate targeted and effective therapies. As it onsets, the randomly accumulating extracellular matrix (ECM) breaks the symmetry of the branching lung structure. Interestingly, similar pathways have been reported for both idiopathic pulmonary fibrosis and radiation-induced lung fibrosis (RILF). Individuals suffering from the disease, the worldwide incidence of which is growing, have poor prognosis and a short mean survival time. In this context, mathematical and computational models have the potential to shed light on key underlying pathological mechanisms, shorten the time needed for clinical trials, parallelize hypotheses testing, and improve personalized drug development. Agent-based modeling (ABM) has proven to be a reliable and versatile simulation tool, whose features make it a good candidate for recapitulating emergent behaviors in heterogeneous systems, such as those found at multiple scales in the human body. In this paper, we detail the implementation of a 3D agent-based model of lung fibrosis using a novel simulation platform, namely, BioDynaMo, and prove that it can qualitatively and quantitatively reproduce published results. Furthermore, we provide additional insights on late-fibrosis patterns through ECM density distribution histograms. The model recapitulates key intercellular mechanisms, while cell numbers and types are embodied by alveolar segments that act as agents and are spatially arranged by a custom algorithm. Finally, our model may hold potential for future applications in the context of lung disorders, ranging from RILF (by implementing radiation-induced cell damage mechanisms) to COVID-19 and inflammatory diseases (such as asthma or chronic obstructive pulmonary disease).

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