alitretinoin and Inflammation

Fatty acids beyond their role as an endogenous energy source and storage are increasingly considered as signaling molecules regulating various physiological effects in metabolism and inflammation. Accordingly, the molecular targets involved in formation and physiological activities of fatty acids hold significant therapeutic potential. A number of these fatty acid targets are addressed by some of the oldest and most widely used drugs such as cyclooxygenase inhibiting NSAIDs, whereas others remain unexploited. Compounds orthosterically binding to proteins that endogenously bind fatty acids are considered as fatty acid mimetics. On the basis of their structural resemblance, fatty acid mimetics constitute a family of bioactive compounds showing specific binding thermodynamics and following similar pharmacokinetic mechanisms. This perspective systematically evaluates targets for fatty acid mimetics, investigates their common structural characteristics, and highlights demands in their discovery and design. In summary, fatty acid mimetics share particularly favorable characteristics justifying the conclusion that their therapeutic potential vastly outweighs the challenges in their design.

Topics: Animals; Cyclooxygenase Inhibitors; Drug Discovery; Fatty Acids; Humans; Inflammation; Models, Molecular

Compound

Topics: Humans; Inflammation; Ligands; Retinoid X Receptors; Skin Neoplasms; Tetrahydronaphthalenes; Tretinoin; Triglycerides

Alzheimer's disease (AD) is associated with the accumulation and deposition of a beta-amyloid (Αβ) peptide in the brain, resulting in increased neuroinflammation and synaptic dysfunction. Intranasal delivery of targeted drugs to the brain represents a noninvasive pathway that bypasses the blood-brain barrier and minimizes systemic exposure. The aim of this study was to evaluate the therapeutic effect of intranasally delivered 9-cis retinoic acid (RA) on the neuropathology of an AD mouse model. Herein, we observed dramatically decreased Αβ deposition in the brains of amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic mice (APP/PS1) treated intranasally with 9-cis RA for 4 weeks compared to that in the brains of vehicle-treated mice. Importantly, intranasal delivery of 9-cis RA suppressed Αβ-associated astrocyte activation and neuroinflammation and ultimately restored synaptic deficits in APP/PS1 transgenic mice. These results support the critical roles of Αβ-associated neuroinflammation responses to synaptic deficits, particularly during the deposition of Αβ. Our findings provide strong evidence that intranasally delivered 9-cis RA attenuates neuronal dysfunction in an AD mouse model and is a promising therapeutic strategy for the prevention and treatment of AD.

Topics: Administration, Intranasal; Alitretinoin; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Astrocytes; Brain; Disease Models, Animal; Inflammation; Inflammation Mediators; Mice; Mice, Transgenic; Microglia; Presenilin-1

An inflammatory response induced by high glucose is a cause of endothelial dysfunction in diabetes and is an important contributing link to atherosclerosis. Diabetes is an independent risk factor of atherosclerosis and activation of retinoid X receptor (RXR) has been shown to exert anti-atherogenic effects. In the present study, we examined the effects of the RXR ligands 9-cis-retinoic acid (9-cis-RA) and SR11237 on high glucose-induced inflammation in human umbilical endothelial vein endothelial cells (HUVECs) and explored the potential mechanism. Our results showed that the inflammation induced by high-glucose in HUVECs was mainly mediated by the activation of nuclear factor-B (NF- κB). High glucose-induced expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were in comparison, significantly decreased by treatment with RXR. The effect of RXR agonists was mainly due to the inhibition of NF-κB activation. Using pharmacological inhibitors and siRNA, we confirmed that nicotinamide adenine dinucleotide phosphate (NADPH) oxidase was an upstream activator of NF-κB. Furthermore, RXR agonists significantly inhibited high glucose-induced activation of NADPH oxidase and significantly decreased the production of reactive oxygen species (ROS). To explore whether the rapid inhibitory effects of RXR agonists were in fact mediated by RXR, we examined the effect of RXR downregulation by RXR siRNA. Our results showed that RXR siRNA largely abrogated the effects of RXR agonists, suggesting the requirement of RXR expression. Therefore, we have shown that RXR is involved in the regulation of NADPH oxidase- NF-κB signal pathway, as the RXR ligands antagonized the inflammatory response in HUVECs induced by high glucose.

Topics: Alitretinoin; Antineoplastic Agents; Atherosclerosis; Benzoates; Cells, Cultured; Diabetes Mellitus; Endothelium, Vascular; Gene Expression Regulation; Glucose; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Intercellular Adhesion Molecule-1; NADPH Oxidase 4; NADPH Oxidases; Reactive Oxygen Species; Retinoid X Receptors; Retinoids; RNA Interference; RNA, Small Interfering; Transcription Factor RelA; Tretinoin; Up-Regulation; Vascular Cell Adhesion Molecule-1

Palmoplantar pustular psoriasis is often recalcitrant to therapy. Here we evaluated the therapeutic effect of alitretinoin in patients with recalcitrant palmoplantar pustular psoriasis and investigated subsequent immunopathological alterations.. Seven patients with palmoplantar pustular psoriasis were treated with oral alitretinoin 30 mg once daily for 12 weeks. Efficacy was assessed by palmoplantar pustular psoriasis area and severity index (PPPASI), visual analogue scales (VAS) on intensity of pain and pruritus and an overall patient assessment. Immunohistochemical staining for neutrophil elastase, CD3, CD4, CD8, CD1a CD11c, CD303,CD68, CD69, CD208 and HLA-DR was on lesional skin biopsies obtained before and after 12 weeks of treatment.. PPPASI and VAS for pruritus and pain decreased significantly after 12 weeks of treatment with alitretinoin. The overall patient assessment ranged from 60% to 90% clinical improvement. In correlation with clinical improvement a significant reduction, particularly of neutrophils, macrophages and dendritic cells, was also observed in the skin sections. Alitretinoin was well tolerated except for headache during the first month of treatment in two patients. Limitations of the study are a missing control group and the concomitant usage of topical therapy.. Our findings suggest that alitretinoin may represent a new and promising therapy for recalcitrant palmo-plantar psoriasis and warrants further controlled studies to confirm efficacy and safety of alitretinoin in this disease.

Topics: Adult; Aged; Alitretinoin; Antineoplastic Agents; Female; Humans; Inflammation; Male; Middle Aged; Psoriasis; Treatment Outcome; Tretinoin; Young Adult

Surgery, even modern minimal invasive laparoscopic surgery, induces an initial inflammatory and acute phase response which is followed by a period of immunosuppression rendering surgical patients more susceptible to infection. Here, we aimed to study changes in monocyte inflammatory responses and inflammatory modulation mechanisms following laparoscopic colorectal surgery for colon cancer. Blood samples were collected from 19 colon cancer patients before, directly after and daily for 3 days following surgery. Blood cells were exposed ex vivo to bacterial lipopolysaccharide (LPS) or the inflammatory modulator 9-cis retinoic acid (9cisRA). In blood samples taken prior to surgery, we found significant pro-inflammatory responses to LPS, indicating classical monocyte activation. Directly after surgery, LPS induced significantly less early pro-inflammatory cytokines and monocyte/granulocyte-attracting chemokines. The LPS-mediated release of interleukin (IL)-1β was still significantly attenuated 3 days after surgery. In patient monocytes collected after surgery, we found increased levels of suppressors of cytokine signaling (SOCS)1 and SOCS3 mRNA, reported to be associated with polarization towards resolving macrophages. The retinoic acid isomer 9cisRA, reported to attenuate LPS-mediated inflammatory responses and alter chemokine responses in cultured monocytes, had a similar effect in patient blood. Three days after surgery, 9cisRA still attenuated pro-inflammatory responses, but the induction of monocyte chemoattractive protein (MCP)-1/CCL2 mRNA in monocytes was reduced. This study indicates changes in monocyte responses that last for at least 3 days after laparoscopic surgery.

Topics: Adult; Aged; Aged, 80 and over; Alitretinoin; C-Reactive Protein; Colonic Neoplasms; Female; Gene Expression Regulation; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Laparoscopy; Lipopolysaccharides; Male; Middle Aged; Monocytes; RNA, Messenger; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Treatment Outcome; Tretinoin

The epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) has important roles in the initiation of allergic airway inflammation and the activation of dendritic cells. We have shown that the human TSLP gene is regulated in a NF-kappaB-dependent manner; however the factors that negatively regulate TSLP expression are not known. In this study we demonstrate that 9-cis-retinoic acid (9-cis-RA) is a negative regulator of TSLP expression in airway epithelial cells. This inhibition is manifested as a block in the IL-1beta-mediated recruitment of NF-kappaB to the human TSLP promoter. 9-cis-RA-mediated inhibition is not restricted to TSLP gene expression but rather reflects a general inhibition of NF-kappaB activation, as other NF-kappaB-regulated-genes were also inhibited in a similar manner by 9-cis-RA treatment. Taken as a whole, these data demonstrate that inhibition of IL-1beta-dependent genes by active retinoid X receptors involves antagonism of NF-kappaB signaling.

Topics: Alitretinoin; Antineoplastic Agents; Cell Line; Cytokines; Epithelial Cells; Gene Expression Regulation; Humans; Inflammation; Interleukin-1beta; NF-kappa B; Promoter Regions, Genetic; Respiratory Hypersensitivity; Respiratory Mucosa; Retinoid X Receptors; Signal Transduction; Thymic Stromal Lymphopoietin; Tretinoin

We studied the effect of agonists of peroxisome proliferator-activated receptors alpha and gamma and retinoid X receptors on the concentration and synthesis of lipids in macrophages of C57B1/6 mice with inflammation induced by intraperitoneal injection of zymosan. We revealed a significant increase in [1-14C]oleate incorporation into cholesterol esters and triglycerides, increase in the content of free cholesterol, cholesterol esters, and triglycerides, and formation of oil red-stained lipid inclusions in peritoneal macrophages 24 h after administration of zymosan in a dose of 50 mg/kg. Treatment with agonists of retinoid X receptors and peroxisome proliferator-activated receptors alpha and gamma 30 min before and 12 h after zymosan injection decreased the synthesis of triglycerides and cholesterol esters, reduced the content of free cholesterol, cholesterol esters, and triglycerides in macrophages, and prevented the formation of cytoplasmic lipid inclusions in macrophage-derived foam cells during inflammation.

Topics: Alitretinoin; Animals; Bezafibrate; Cholesterol; Cholesterol Esters; Foam Cells; Inflammation; Injections, Intraperitoneal; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C57BL; PPAR alpha; PPAR gamma; Retinoid X Receptors; Rosiglitazone; Thiazolidinediones; Tretinoin; Triglycerides; Tumor Necrosis Factor-alpha; Zymosan

Retinoic acid (RA) regulates a wide range of biologic process, including inflammation. Previously, RA was shown to inhibit the clinical signs of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). The current study investigated the effects of 9-cis-RA on primary mouse microglia and astrocytes, two cell types implicated in the pathology of MS and EAE. The studies demonstrated that 9-cis-RA inhibited the production of nitric oxide (NO) as well as the pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-12 p40 by LPS-stimulated microglia. However, this retinoid had no effect on IL-6 secretion and increased MCP-1 production by LPS-stimulated microglia. In LPS-stimulated astrocytes, 9-cis-RA inhibited NO and TNF-alpha production but had not effect on IL-1beta, IL-6 and MCP-1 secretion. These results suggest that RA modulates EAE, at least in part, by suppressing the production of NO and specific inflammatory cytokines from activated glia and suggests that RA might be effective in the treatment of MS.

Topics: Alitretinoin; Analysis of Variance; Animals; Animals, Newborn; Antineoplastic Agents; Astrocytes; Cell Survival; Cerebral Cortex; Cytokines; Dose-Response Relationship, Drug; Drug Interactions; Enzyme-Linked Immunosorbent Assay; Inflammation; Interferon-alpha; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Microglia; Nitric Oxide; Tretinoin

In most neurodegenerative disorders, including multiple sclerosis, Parkinson disease, and Alzheimer disease, a massive neuronal cell death occurs as a consequence of an uncontrolled inflammatory response, where activated astrocytes and microglia and their cytotoxic agents play a crucial pathological role. Current treatments for these diseases are not effective. In the present study we investigate the effect of thiadiazolidinone derivatives, which have been recently suggested to play a role in neurodegenerative disorders. We have found that thiadiazolidinones are potent neuroprotector compounds. Thiadiazolidinones inhibited inflammatory activation of cultured brain astrocytes and microglia by diminishing lipopolysaccharide-induced interleukin 6, tumor necrosis factor alpha, inducible nitric-oxide synthase, and inducible cyclooxygenase type 2 expression. In addition, thiadiazolidinones inhibited tumor necrosis factor-alpha and nitric oxide production and, concomitantly, protected cortical neurons from cell death induced by the cell-free supernatant from activated microglia. The neuroprotective effects of thiadiazolidinones are completely inhibited by the peroxisome proliferator-activated receptor gamma antagonist GW9662. In contrast the glycogen synthase kinase 3beta inhibitor LiCl did not show any effect. These findings suggest that thiadiazolidinones potently attenuate lipopolysaccharide-induced neuroinflammation and reduces neuronal death by a mechanism dependent of peroxisome proliferator-activated receptor gamma activation.

Topics: Alitretinoin; Anilides; Animals; Anti-Inflammatory Agents; Apoptosis; Astrocytes; Brain; Cell Death; Cell Line; Cell-Free System; Cells, Cultured; Cyclooxygenase 2; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glutamic Acid; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Immunohistochemistry; In Vitro Techniques; Inflammation; Interleukin-6; Lipopolysaccharides; Lithium Chloride; Mice; Microscopy, Confocal; Microscopy, Fluorescence; Models, Chemical; Neurodegenerative Diseases; Neuroglia; Neurons; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitrites; PPAR gamma; Prostaglandin-Endoperoxide Synthases; Rats; Staurosporine; Thiazolidinediones; Time Factors; Transfection; Tretinoin; Tumor Necrosis Factor-alpha

The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) plays a key role in lipid metabolism and inflammation. Recently, we demonstrated that administration of the PPAR-alpha agonists gemfibrozil and fenofibrate, inhibit the clinical signs of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). In the present study we investigated the effects of PPAR-alpha agonists on primary mouse microglia, a cell type implicated in the pathology of MS and EAE. Our studies demonstrated that the PPAR-alpha agonists ciprofibrate, fenofibrate, gemfibrozil, and WY 14,643 each inhibited NO production by cytokine-stimulated microglia in a dose-dependent manner. However, fenofibrate and WY 14,643 were more potent inhibitors than gemfibrozil and ciprofibrate. In LPS-stimulated microglia, only fenofibrate and WY 14,643 significantly suppressed NO production. Additionally, PPAR-alpha agonists inhibited the secretion of the proinflammatory cytokines IL-1beta, TNF-alpha, IL-6, and IL-12 p40 and the chemokine MCP-1 by LPS-stimulated microglia. Retinoid X receptors (RXRs) physically interact with PPAR-alpha receptors, and the resulting heterodimers regulate the expression of PPAR-responsive genes. Interestingly, the RXR agonist 9-cis retinoic acid (9-cis RA) inhibited NO production by LPS-stimulated microglia. Furthermore, a combination of 9-cis RA and the PPAR-alpha agonist fenofibrate cooperatively inhibited NO production by these cells. A combination of these agonists also selectively inhibited the expression of proinflammatory cytokines including IL-1beta, TNF-alpha, and IL-6 by LPS-stimulated microglia. Collectively, these results raise the possibility that PPAR-alpha and RXR agonists might have benefit as a therapy in MS, where activated microglia are believed to contribute to disease pathology.

Topics: Alitretinoin; Analysis of Variance; Animals; Animals, Newborn; Cell Survival; Cells, Cultured; Cerebral Cortex; Chemokines; Cytokines; Dose-Response Relationship, Drug; Drug Interactions; Enzyme-Linked Immunosorbent Assay; Inflammation; Interferon-gamma; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Microglia; Nitric Oxide; Peroxisome Proliferators; PPAR alpha; Retinoid X Receptors; Tetrazolium Salts; Thiazoles; Tretinoin; Tumor Necrosis Factor-alpha

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear-receptor superfamily that binds to DNA with retinoid X receptors (RXRs) as PPAR-RXR heterodimers. In experimental autoimmune encephalomyelitis (EAE), the gene expression of PPAR-gamma was demonstrated in spinal cord during the course of EAE. Administration of 15-deoxy-(12,14)-prostaglandin J2 (15d-PGJ2) or 9-cis-retinoic acid (RA) alone at the onset of clinical signs of EAE reduced the severity of disease, however, their combination resulted in enhanced amelioration of disease. These results suggest that use of RXR specific ligands may be highly effective when combined with PPAR-gamma agonists in the treatment of autoimmune demyelinating diseases such as multiple sclerosis (MS).

Topics: Alitretinoin; Analysis of Variance; Animals; Cells, Cultured; Cytokines; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Encephalomyelitis, Autoimmune, Experimental; Enzyme-Linked Immunosorbent Assay; Immunization; Immunohistochemistry; Inflammation; Ligands; Lymph Nodes; Mice; Mice, Transgenic; Microglia; Myelin Basic Protein; Nitric Oxide; Peptide Fragments; Prostaglandin D2; Receptors, Antigen, T-Cell, alpha-beta; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Retinoid X Receptors; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spleen; Time Factors; Transcription Factors; Tretinoin