Molecular mechanisms of opioid tolerance: From opioid receptors to inflammatory mediators (Review)

Silica exposure triggers inflammatory response and pulmonary fibrosis that is a severe occupational or environmental lung disease with no effective therapies. The complicated biological and molecular mechanisms underlying silica-induced lung damages have not yet been fully understood. miR-135a inhibits inflammation, apoptosis, and cancer cell proliferation. But the roles of miRNA135a involved in the silica-induced lung damages remain largely unexplored. We investigated the roles and mechanisms of miR-135a underlying silica-induced pulmonary fibrosis. The present study showed silica exposure caused the decrease in miR-135a level but the increase in inflammatory mediators. Transduction of lentivirus expressing miR-135a reduced the level of inflammatory mediators in lung tissues from silica-treated mice and improved pulmonary fibrosis which was consistent with the downregulated α-SMA but enhanced E-cadherin. Moreover, miR-135a overexpression inhibited p-p65 level in lung tissues. Overexpression of miR-135a inhibitor strengthened TLR4 protein level and NF-κB activation in BEAS-2B cells. Injection of PDTC, an inhibitor of NF-κB, further reinforced miR-135a-mediated amelioration of inflammation and pulmonary fibrosis induced by silica. The collective data indicate miR-135a restrains NF-κB activation probably through targeting TLR4 to alleviate silica-induced inflammatory response and pulmonary fibrosis.

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Opioid Receptors: Cellular and Molecular Mechanisms Underlying Opioid Receptor Function

Encyclopedia of Signaling Molecules ◽

10.1007/978-1-4419-0461-4_596 ◽

2012 ◽

pp. 1304-1312

Author(s):

Lisa Stowers ◽

Sandeepa Dey ◽

Vladana Vukojević ◽

Yu Ming ◽

Lars Terenius

Keyword(s):

Opioid Receptor ◽

Opioid Receptors ◽

Molecular Mechanisms ◽

Receptor Function

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Neuroinflammatory Nexus of Pediatric Epilepsy

Journal of Pediatric Epilepsy ◽

10.1055/s-0038-1668601 ◽

2018 ◽

Vol 07 (02) ◽

pp. 032-039

Author(s):

Shruti Bagla ◽

Alan Dombkowski

Keyword(s):

Inflammatory Mediators ◽

Molecular Mechanisms ◽

Potential Role ◽

Recent Literature ◽

Refractory Epilepsy ◽

Genetic Mutation ◽

Pediatric Epilepsy ◽

Therapeutic Approaches ◽

New Therapeutic Approaches

AbstractA rapidly growing body of evidence supports the premise that neuroinflammation plays an important role in initiating and sustaining seizures in a range of pediatric epilepsies. Clinical and experimental evidence indicates that neuroinflammation is both an outcome and a contributor to seizures. In this manner, seizures that arise from an initial insult (e.g., infection, trauma, and genetic mutation) contribute to an inflammatory response that subsequently promotes recurrent seizures. This cyclic relationship between seizures and neuroinflammation has been described as a “vicious cycle.” Studies of human tissue resected for surgical treatment of refractory epilepsy have reported activated inflammatory and immune signaling pathways, while animal models have been used to demonstrate that key inflammatory mediators lead to increased seizure susceptibility. Further characterization of the molecular mechanisms involved in this cycle may ultimately enable the development of new therapeutic approaches for the treatment of epilepsy. In this brief review, we focus on key inflammatory mediators that have become prominent in recent literature of epilepsy, including newly characterized microRNAs and their potential role in neuroinflammatory signaling.

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Estimation of ellagic acid and/or repaglinide effects on insulin signaling, oxidative stress, and inflammatory mediators of liver, pancreas, adipose tissue, and brain in insulin resistant/type 2 diabetic rats

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2016-0429 ◽

2017 ◽

Vol 42 (2) ◽

pp. 181-192 ◽

Cited By ~ 17

Author(s):

Mohamed M. Amin ◽

Mahmoud S. Arbid

Keyword(s):

Type 2 Diabetes ◽

Body Weight ◽

Adipose Tissue ◽

Insulin Signaling ◽

Inflammatory Mediators ◽

Ellagic Acid ◽

Molecular Mechanisms ◽

Combined Treatment ◽

Albino Rats

Even though ellagic acid has previously been valued in many models of cancer, so far its full mechanistic effect as a natural antiapoptotic agent in the prevention of type 2 diabetes complications has not been completely elucidated, which was the goal of this study. We fed albino rats a high-fat fructose diet (HFFD) for 2 months to induce insulin resistance/type 2 diabetes and then treated the rats with ellagic acid (10 mg/kg body weight, orally) and/or repaglinide (0.5 mg/kg body weight, orally) for 2 weeks. At the serum level, ellagic acid challenged the consequences of HFFD, significantly improving the glucose/insulin balance, liver enzymes, lipid profile, inflammatory cytokines, redox level, adipokines, ammonia, and manganese. At the tissue level (liver, pancreas, adipose tissue, and brain), ellagic acid significantly enhanced insulin signaling, autophosphorylation, adiponectin receptors, glucose transporters, inflammatory mediators, and apoptotic markers. Remarkably, combined treatment with both ellagic acid and repaglinide had a more pronounced effect than treatment with either alone. These outcomes give new insight into the promising molecular mechanisms by which ellagic acid modulates numerous factors induced in the progression of diabetes.

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Molecular Mechanisms of Mast Cell Activation by Cholesterol-Dependent Cytolysins

Frontiers in Immunology ◽

10.3389/fimmu.2021.670205 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lubica Draberova ◽

Magda Tumova ◽

Petr Draber

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Signaling Pathways ◽

Inflammatory Mediators ◽

Pore Formation ◽

Cell Activation ◽

Molecular Mechanisms ◽

Biologically Active ◽

Mast Cell Activation ◽

Concentration Changes

Mast cells are potent immune sensors of the tissue microenvironment. Within seconds of activation, they release various preformed biologically active products and initiate the process of de novo synthesis of cytokines, chemokines, and other inflammatory mediators. This process is regulated at multiple levels. Besides the extensively studied IgE and IgG receptors, toll-like receptors, MRGPR, and other protein receptor signaling pathways, there is a critical activation pathway based on cholesterol-dependent, pore-forming cytolytic exotoxins produced by Gram-positive bacterial pathogens. This pathway is initiated by binding the exotoxins to the cholesterol-rich membrane, followed by their dimerization, multimerization, pre-pore formation, and pore formation. At low sublytic concentrations, the exotoxins induce mast cell activation, including degranulation, intracellular calcium concentration changes, and transcriptional activation, resulting in production of cytokines and other inflammatory mediators. Higher toxin concentrations lead to cell death. Similar activation events are observed when mast cells are exposed to sublytic concentrations of saponins or some other compounds interfering with the membrane integrity. We review the molecular mechanisms of mast cell activation by pore-forming bacterial exotoxins, and other compounds inducing cholesterol-dependent plasma membrane perturbations. We discuss the importance of these signaling pathways in innate and acquired immunity.

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The Guts of the Opioid Crisis

Physiology ◽

10.1152/physiol.00014.2021 ◽

2021 ◽

Vol 36 (5) ◽

pp. 315-323 ◽

Cited By ~ 1

Author(s):

Karan H. Muchhala ◽

Joanna C. Jacob ◽

Minho Kang ◽

William L. Dewey ◽

Hamid I. Akbarali

Keyword(s):

Molecular Mechanisms ◽

Opioid Tolerance ◽

Central Pain ◽

Analgesic Tolerance ◽

Significant Challenge ◽

Opioid Crisis ◽

Gut Epithelium ◽

Pain Pathways ◽

Gut Homeostasis ◽

Bidirectional Interactions

Bidirectional interactions of the gut epithelium with commensal bacteria are critical for maintaining homeostasis within the gut. Chronic opioid exposure perturbs gut homeostasis through a multitude of neuro-immune-epithelial mechanisms, resulting in the development of analgesic tolerance, a major underpinning of the current opioid crisis. Differences in molecular mechanisms of opioid tolerance between the enteric and central pain pathways pose a significant challenge for managing chronic pain without untoward gastrointestinal effects.

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Molecular mechanisms of biogenesis of apoptotic exosome-like vesicles and their roles as damage-associated molecular patterns

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1811432115 ◽

2018 ◽

Vol 115 (50) ◽

pp. E11721-E11730 ◽

Cited By ~ 32

Author(s):

Soo Jeong Park ◽

Jeong Mi Kim ◽

Jihyo Kim ◽

Jaehark Hur ◽

Sun Park ◽

...

Keyword(s):

Inflammatory Mediators ◽

Molecular Mechanisms ◽

Apoptotic Cell ◽

Inflammatory Factors ◽

In Vivo Models ◽

Marker Proteins ◽

Sphingosine 1 Phosphate ◽

Molecular Patterns

Recent research has led to contradictory notions regarding the conventional theory that apoptotic cell death can evoke inflammatory or immunogenic responses orchestrated by released damage-associated patterns (DAMPs). By inducing IL-1β from bone marrow-derived macrophages in an effort to determine the inflammatory mediators released from apoptotic cells, we found that exosomal fractions called “apoptotic exosome-like vesicles” (AEVs) prepared from apoptotic-conditioned medium were the main inflammatory factors. These AEVs showed characteristics of exosomes in their size, density, morphology, and protein expression but had unique marker proteins, sphingosine-1-phosphate receptors 1 and 3 (S1PR1 and 3). Their biogenesis was completely dependent on cellular sphingosine-1-phosphate (S1P)/S1PRs signaling from multiple fine spindles of plasma membrane accompanied by F-actin, S1PR1, S1PR3, and CD63 at the early apoptotic phase and progressing to the maturation of F-actin–guided multivesicular endosomes mediated by Gβγ subunits of S1PRs downstream. S1P-loaded S1PRs on AEVs were critical factors for inducing IL-1β via NF-κB transcriptional factor and p38 MAPK, possibly through the RHOA/NOD2 axis, in differentiating macrophages. The AEVs induced genes of proinflammatory cytokines, chemokines, and mediators in both in vitro and in vivo models. In conclusion, AEVs could be key inflammatory mediators, acting as DAMPs that could explain the pathogeneses of various chronic inflammations, autoimmune diseases, or cancers in the future.

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Molecular Mechanisms of Opioid Receptor-dependent Signaling and Behavior

Anesthesiology ◽

10.1097/aln.0b013e318238bba6 ◽

2011 ◽

Vol 115 (6) ◽

pp. 1363-1381 ◽

Cited By ~ 261

Author(s):

Ream Al-Hasani ◽

Michael R. Bruchas

Keyword(s):

Opioid Receptor ◽

Opioid Receptors ◽

Molecular Mechanisms ◽

Human Genetics ◽

Receptor Subtypes ◽

Receptor Signaling ◽

Molecular Pharmacology ◽

And Behavior ◽

G Protein Coupled

Opioid receptors have been targeted for the treatment of pain and related disorders for thousands of years and remain the most widely used analgesics in the clinic. Mu (μ), kappa (κ), and delta (δ) opioid receptors represent the originally classified receptor subtypes, with opioid receptor like-1 (ORL1) being the least characterized. All four receptors are G-protein coupled and activate inhibitory G proteins. These receptors form homo- and heterodimeric complexes and signal to kinase cascades and scaffold a variety of proteins.The authors discuss classic mechanisms and developments in understanding opioid tolerance and opioid receptor signaling and highlight advances in opioid molecular pharmacology, behavioral pharmacology, and human genetics. The authors put into context how opioid receptor signaling leads to the modulation of behavior with the potential for therapeutic intervention. Finally, the authors conclude there is a continued need for more translational work on opioid receptors in vivo.

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Tabetri™ (Tabebuia avellanedae Ethanol Extract) Ameliorates Osteoarthritis Symptoms Induced by Monoiodoacetate through Its Anti-Inflammatory and Chondroprotective Activities

Mediators of Inflammation ◽

10.1155/2017/3619879 ◽

2017 ◽

Vol 2017 ◽

pp. 1-14 ◽

Cited By ~ 8

Author(s):

Jae Gwang Park ◽

Young-Su Yi ◽

Yo Han Hong ◽

Sulgi Yoo ◽

Sang Yun Han ◽

...

Keyword(s):

Cell Line ◽

Proinflammatory Cytokines ◽

Inflammatory Mediators ◽

Molecular Mechanisms ◽

Ethanol Extract ◽

Degenerative Joint Disease ◽

Joint Disease ◽

Cellular Models ◽

Anti Inflammatory

Although osteoarthritis (OA), a degenerative joint disease characterized by the degradation of joint articular cartilage and subchondral bones, is generally regarded as a degenerative rather than inflammatory disease, recent studies have indicated the involvement of inflammation in OA pathogenesis. Tabebuia avellanedae has long been used to treat various diseases; however, its role in inflammatory response and the underlying molecular mechanisms remain poorly understood. In this study, the pharmacological effects of Tabetri (Tabebuia avellanedae ethanol extract (Ta-EE)) on OA pathogenesis induced by monoiodoacetate (MIA) and the underlying mechanisms were investigated using experiments with a rat model and in vitro cellular models. In the animal model, Ta-EE significantly ameliorated OA symptoms and reduced the serum levels of inflammatory mediators and proinflammatory cytokines without any toxicity. The anti-inflammatory activity of Ta-EE was further confirmed in a macrophage-like cell line (RAW264.7). Ta-EE dramatically suppressed the production and mRNA expressions of inflammatory mediators and proinflammatory cytokines in lipopolysaccharide-stimulated RAW264.7 cells without any cytotoxicity. Finally, the chondroprotective effect of Ta-EE was examined in a chondrosarcoma cell line (SW1353). Ta-EE markedly suppressed the mRNA expression of matrix metalloproteinase genes. The anti-inflammatory and chondroprotective activities of Ta-EE were attributed to the targeting of the nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) signaling pathways in macrophages and chondrocytes.

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