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Inflammation resolution is an active process via specialized pro-resolving mediators (SPMs) to fight invading microbes and repair tissue injury. RvD1 and RvD2 are SPMs produced from DHA during inflammation responses and show a benefit in treating inflammation disorders, but it is not completely understood how they act on vasculature and immune cells in the lung to promote inflammation resolution programs. Here, we studied how RvD1 and RvD2 regulated the interactions between endothelial cells and neutrophils in vitro and in vivo. In an acute lung inflammation (ALI) mouse model, we found that RvD1 and RvD2 resolved lung inflammation via their receptors (ALX/GPR32 or GPR18) and enhanced the macrophage phagocytosis of apoptotic neutrophils, which may be the molecular mechanism of lung inflammation resolution. Interestingly, we observed the higher potency of RvD1 over RvD2, which may be associated with unique downstream signaling pathways. Together, our studies suggest that the targeted delivery of these SPMs into inflammatory sites may be novel strategies with which to treat a wide range of inflammatory diseases. [ABSTRACT FROM AUTHOR]

Chronic pain burdens patients and healthcare systems worldwide. Pain control remains urgently required. IL-17 (interleukin-17)-mediated neuroinflammation is of unique importance in spinal nociceptive transduction in pathological pain development. Recently, resolvin D2 (RvD2), as a bioactive, specialized pro-resolving mediator derived from docosahexaenoic acid, exhibits potent resolution of inflammation in several neurological disorders. This preclinical study evaluates the therapeutic potential and underlying targets of RvD2 in two mouse models of chronic pain, including sciatic nerve ligation-caused neuropathic pain and sarcoma-caused bone cancer pain. Herein, we report that repetitive injections of RvD2 (intrathecal, 500 ng) reduce the initiation of mechanical allodynia and heat hyperalgesia following sciatic nerve damage and bone cancer. Single exposure to RvD2 (intrathecal, 500 ng) attenuates the established neuropathic pain and bone cancer pain. Furthermore, systemic RvD2 (intravenous, 5 μg) therapy is effective in attenuating chronic pain behaviors. Strikingly, RvD2 treatment suppresses spinal IL-17 overexpression, chemokine CXCL1 release and astrocyte activation in mice undergoing sciatic nerve trauma and bone cancer. Pharmacological neutralization of IL-17 ameliorates chronic neuropathic pain and persistent bone cancer pain, as well as reducing spinal CXCL1 release. Recombinant IL-17-evoked acute pain behaviors and spinal CXCL1 release are mitigated after RvD2 administration. In addition, RvD2 treatment dampens exogenous CXCL1-caused transient pain phenotypes. Overall, these current findings identify that RvD2 therapy is effective against the initiation and persistence of long-lasting neuropathic pain and bone cancer pain, which may be through spinal down-modulation of IL-17 secretion, CXCL1 release and astrocyte activation. [ABSTRACT FROM AUTHOR]

Inflammation resolution is an active process via specialized pro-resolving mediators (SPMs) to fight invading microbes and repair tissue injury. RvD1 and RvD2 are SPMs produced from DHA during inflammation responses and show a benefit in treating inflammation disorders, but it is not completely understood how they act on vasculature and immune cells in the lung to promote inflammation resolution programs. Here, we studied how RvD1 and RvD2 regulated the interactions between endothelial cells and neutrophils in vitro and in vivo. In an acute lung inflammation (ALI) mouse model, we found that RvD1 and RvD2 resolved lung inflammation via their receptors (ALX/GPR32 or GPR18) and enhanced the macrophage phagocytosis of apoptotic neutrophils, which may be the molecular mechanism of lung inflammation resolution. Interestingly, we observed the higher potency of RvD1 over RvD2, which may be associated with unique downstream signaling pathways. Together, our studies suggest that the targeted delivery of these SPMs into inflammatory sites may be novel strategies with which to treat a wide range of inflammatory diseases.

Chronic pain burdens patients and healthcare systems worldwide. Pain control remains urgently required. IL-17 (interleukin-17)-mediated neuroinflammation is of unique importance in spinal nociceptive transduction in pathological pain development. Recently, resolvin D2 (RvD2), as a bioactive, specialized pro-resolving mediator derived from docosahexaenoic acid, exhibits potent resolution of inflammation in several neurological disorders. This preclinical study evaluates the therapeutic potential and underlying targets of RvD2 in two mouse models of chronic pain, including sciatic nerve ligation-caused neuropathic pain and sarcoma-caused bone cancer pain. Herein, we report that repetitive injections of RvD2 (intrathecal, 500 ng) reduce the initiation of mechanical allodynia and heat hyperalgesia following sciatic nerve damage and bone cancer. Single exposure to RvD2 (intrathecal, 500 ng) attenuates the established neuropathic pain and bone cancer pain. Furthermore, systemic RvD2 (intravenous, 5 μg) therapy is effective in attenuating chronic pain behaviors. Strikingly, RvD2 treatment suppresses spinal IL-17 overexpression, chemokine CXCL1 release and astrocyte activation in mice undergoing sciatic nerve trauma and bone cancer. Pharmacological neutralization of IL-17 ameliorates chronic neuropathic pain and persistent bone cancer pain, as well as reducing spinal CXCL1 release. Recombinant IL-17-evoked acute pain behaviors and spinal CXCL1 release are mitigated after RvD2 administration. In addition, RvD2 treatment dampens exogenous CXCL1-caused transient pain phenotypes. Overall, these current findings identify that RvD2 therapy is effective against the initiation and persistence of long-lasting neuropathic pain and bone cancer pain, which may be through spinal down-modulation of IL-17 secretion, CXCL1 release and astrocyte activation.

Resolvin (Rv) D2 and RvD1 are biosynthesized from docosahexaenoic acid (DHA) and promote resolution of inflammation in multiple organs and tissues, including the conjunctiva. Histamine is a mediator produced by mast cells in the conjunctiva during the allergic response. We determined the interaction of RvD2 with histamine and its receptor subtypes in cultured conjunctival goblet cells and compared them with RvD1 by measuring intracellular [Ca2+] and mucous secretion. Treatment with RvD2 significantly blocked the histamine-induced [Ca2+]i increase as well as secretion. RvD2 and RvD1 counter-regulate different histamine receptor subtypes. RvD2 inhibited the increase in [Ca2+]i induced by the activation of H1, H3, or H4 receptors, whereas RvD1 inhibited H1 and H3 receptors. RvD2 and RvD1 also activate distinct receptor-specific protein kinases to counter-regulate the histamine receptors, probably by phosphorylation. Thus, our data suggest that the counter-regulation of H receptor subtypes by RvD2 and RvD1 to inhibit mucin secretion are separately regulated.

Neuroinflammation induced by protruded nucleus pulposus (NP) has been shown to play a significant role in facilitation of radicular pain. Resolvin D2 (RvD2), a novel member of resolvin family, exhibits potent anti-inflammatory, pro-resolving and antinociceptive effects. But the effect of RvD2 in radicular pain remains unknown. The radicular pain rat models were induced by application of NP to L5 dorsal root ganglion. Each animal received intrathecal injections of vehicle or RvD2 (10 ng µl−1 or 100 ng µl−1). Mechanical thresholds were determined by measuring the paw withdrawal threshold for 7 days. The expressions of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and transforming growth factor-β1 (TGF-β1) in ipsilateral lumbar segment of rat spinal dorsal horns were measured by using ELISA and real time-PCR. Western blot was used to measure the expressions of phosphorylated Akt (p-Akt) and phosphorylated glycogen synthase kinase 3 beta (p-GSK-3β). The expressions and distributions of RvD2 receptor, G-protein-coupled receptor 18 (GPR18), were also explored in the spinal cord of rats by using double-label immunofluorescence. RvD2 treatment caused significant reductions in the intensity of mechanical hypersensitivity and spinal expressions of TNF-α and IL-6. Meanwhile, RvD2 increased the expressions of TGF-β1 and regulated Akt/GSK-3β signaling. Furthermore, immunofluorescence showed that GPR18 colocalized with neurons and astrocytes in spinal cord. The results suggested that RvD2 might attenuate mechanical allodynia via regulating the expressions of inflammatory mediators and activation of Akt/GSK-3β signal pathway. RvD2 might offer a hopeful method for radicular pain therapy. [ABSTRACT FROM AUTHOR]

It is increasingly evident that carcinogenesis, in the vast majority of cancers, cannot be explained simply through an accumulation of somatic mutations, or epigenetics, the stem cell theory, or the Warburg effect. Here, decades of thinking based on incorrect assumptions has resulted in an incorrect hypothesis on the origin of cancer. Many papers studying DNA, genetics, RNA, miRNA, proteomics, and epigenetics have increased our understanding of biology. Our paradigm, though more complex, is more reliable and plausible. It states that cancer originates from a disruption of homeostasis. This essential biological phenomenon, homeostasis, maintains the interrelationships of various signaling pathways and induced crosstalk which modify cellular functions together with the interactions of surrounding cells and structures such that the equilibrium lies towards the optimal health of the organism. This Special Issue “Disruption of signaling homeostasis induced crosstalk in the carcinogenesis paradigm Epistemology of the origin of cancer” provides compelling evidence that carcinogenesis is explained by a six-step sequence of events for the vast majority of cancers. These six steps include, (1) a pathogenic stimulus followed by (2) chronic inflammation, from which develops (3) fibrosis with associated remodeling in the cellular microenvironment. From these changes a (4) pre-cancerous niche develops which triggers the deployment of (5) a chronic stress escape strategy, and when this fails to resolve, and (6) the transition of a normal cell to a cancer cell occurs. This paradigm provides opportunities to move away from a symptom-oriented understanding of cancer and is much closer to a cause-based understanding, which opens the door for early preventative strategies to mitigate cancer as a disease, and to interdict metastases. This is underpinned by the fact that an independent recently published proof of this paradigm showed how a stimulus trigger the proposed multi-sequence cascade of events as abrupt involution-induced chronic inflammation, followed by fibrosis with remodeling, which describes the pre-cancerous niche followed by hyperplasia, metaplasia, and cancer.

Introduction: In chronic rhinosinusitis (CRS), a complex pathophysiology results from varied pro-inflammatory stimuli but is consistently characterized by classic cellular, molecular, and microbial alterations. Normally, endogenous specialized pro-resolving mediators (SPM) actively promote resolution of inflammation through numerous pathways, including those involved in host antimicrobial defense. However, these pathways appear to be disrupted in CRS., Areas Covered: This paper describes features of CRS in the context of chronic tissue inflammation, and potential mechanisms by which specialized pro-resolving mediators promote active resolution of tissue inflammation., Expert Opinion: Temporal phases of resolution must be tightly regulated to successfully resolve inflammation in CRS while preserving tissue functions such as barrier maintenance and special sensory function. Dysregulation of SPM enzymatic pathways has been recently shown in CRS and is associated with disease phenotypes and microbial colonization patterns. Current research in animal models and in vitro human cell culture, as well as human dietary studies, demonstrate relevant changes in cell signaling with lipid mediator bioavailability. Further clinical research may provide insight into the therapeutic value of this approach in CRS.

Resolvin (Rv) D2 and RvD1 are biosynthesized from docosahexaenoic acid (DHA) and promote resolution of inflammation in multiple organs and tissues, including the conjunctiva. Histamine is a mediator produced by mast cells in the conjunctiva during the allergic response. We determined the interaction of RvD2 with histamine and its receptor subtypes in cultured conjunctival goblet cells and compared them with RvD1 by measuring intracellular [Ca2+] and mucous secretion. Treatment with RvD2 significantly blocked the histamine-induced [Ca2+]i increase as well as secretion. RvD2 and RvD1 counter-regulate different histamine receptor subtypes. RvD2 inhibited the increase in [Ca2+]i induced by the activation of H1, H3, or H4 receptors, whereas RvD1 inhibited H1 and H3 receptors. RvD2 and RvD1 also activate distinct receptor-specific protein kinases to counter-regulate the histamine receptors, probably by phosphorylation. Thus, our data suggest that the counter-regulation of H receptor subtypes by RvD2 and RvD1 to inhibit mucin secretion are separately regulated. [ABSTRACT FROM AUTHOR]

Resolvin (Rv) D2 and RvD1 are biosynthesized from docosahexaenoic acid (DHA) and promote resolution of inflammation in multiple organs and tissues, including the conjunctiva. Histamine is a mediator produced by mast cells in the conjunctiva during the allergic response. We determined the interaction of RvD2 with histamine and its receptor subtypes in cultured conjunctival goblet cells and compared them with RvD1 by measuring intracellular [Ca 2+ ] and mucous secretion. Treatment with RvD2 significantly blocked the histamine-induced [Ca 2+ ] i increase as well as secretion. RvD2 and RvD1 counter-regulate different histamine receptor subtypes. RvD2 inhibited the increase in [Ca 2+ ] i induced by the activation of H1, H3, or H4 receptors, whereas RvD1 inhibited H1 and H3 receptors. RvD2 and RvD1 also activate distinct receptor-specific protein kinases to counter-regulate the histamine receptors, probably by phosphorylation. Thus, our data suggest that the counter-regulation of H receptor subtypes by RvD2 and RvD1 to inhibit mucin secretion are separately regulated.

Tumor necrosis factor-alfa (TNF-α) is a pro-inflammatory cytokine highly-involved in intestinal inflammation. Omega-3 polyunsaturated fatty acids (n3-PUFAs) show anti-inflammatory actions. We previously demonstrated that the n3-PUFA EPA prevents TNF-α inhibition of sugar uptake in Caco-2 cells. Here, we investigated whether the n3-PUFA DHA and its derived specialized pro-resolving lipid mediators (SPMs) MaR1, RvD1 and RvD2, could block TNF-α inhibition of intestinal sugar and glutamine uptake. DHA blocked TNF-α-induced inhibition of α-methyl-D-glucose (αMG) uptake and SGLT1 expression in the apical membrane of Caco-2 cells, through a pathway independent of GPR120. SPMs showed the same preventive effect but acting at concentrations 1000 times lower. In diet-induced obese (DIO) mice, oral gavage of MaR1 reversed the up-regulation of pro-inflammatory cytokines found in intestinal mucosa of these mice. However, MaR1 treatment was not able to counteract the reduced intestinal transport of αMG and SGLT1 expression in the DIO mice. In Caco-2 cells, TNF-α also inhibited glutamine uptake being this inhibition prevented by EPA, DHA and the DHA-derived SPMs. Interestingly, TNF-α increased the expression in the apical membrane of the glutamine transporter B0AT1. This increase was partially blocked by the n-3 PUFAs. These data reveal DHA and its SPMs as promising biomolecules to restore intestinal nutrients transport during intestinal inflammation. [ABSTRACT FROM AUTHOR]

Background: Three-dimensional (3D) strain analysis may help overcome the limitations of Doppler and two-dimensional strain analysis for the left ventricle and become the method of choice for left ventricular (LV) systolic function. The aims of this study were to evaluate the feasibility and reproducibility of LV global 3D systolic strain by real-time 3D speckle-tracking echocardiography (STE) in children and to establish their maturational growth patterns and normal values., Methods: A prospective study was conducted in 256 consecutive healthy subjects using real-time 3D echocardiography. Full-volume 3D data were acquired using a 3D matrix-array transducer. Three-dimensional LV peak systolic global strain (GS), global longitudinal strain (GLS), global radial strain (GRS), and global circumferential strain (GCS) values were determined using real-time 3D STE., Results: A total of 228 patients (89%) met the criteria for analysis; 28 (11%) were excluded. The correlations between age and strain variables by real-time 3D STE were poor (R(2) = 0.01-0.05, P < .05). The differences in GLS and GCS among the five age groups were statistically significant but clinically irrelevant. There were no statistical differences in GRS and GS values among the age groups, nor were there statistical differences between the genders for all 3D strain parameters. Intraobserver and interobserver variability ranged from 5.0 ± 4.3% to 10.1 ± 8.5% versus 6.9 ± 6.1% to 17.0 ± 16.2% for coefficients of variation, respectively. Interclass correlation coefficients ranged from 0.78 to 0.87 and from 0.75 to 0.79 for intraobserver and interobserver measurements for GS, GLS, GCS, and GRS, respectively., Conclusions: LV global 3D systolic strain analysis using the new 3D STE is feasible and reproducible in the pediatric population. There are small maturational changes in GLS and GCS, but not in GRS and GS, that are statistically significant but probably clinically irrelevant. Further investigation is warranted for potential clinical application of this new technology in a pediatric population., (Copyright © 2013 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.)