ABSTRACT
Sarcoidosis is a multisystem chronic inflammatory condition of unknown etiology that has the potential to involve every tissue in the body. Sarcoidosis in the gastrointestinal system, and particularly the colon, is very rare. Here, we report the case of a 57-year-old man with no previous diagnosis of sarcoidosis who presented with new onset of abdominal pain and constipation. A colonoscopy revealed that the abdominal pain was caused by an obstructing lesion in the cecum-ascending colon and lacked a clear histologic diagnosis. Radiologic investigation revealed concentric wall thickening of the cecum-ascending colon with multiple satellite lymphadenopathies, highly suggestive of a malignancy. The patient underwent a laparotomy and a right hemicolectomy was performed. A diagnosis of colonic sarcoidosis was made after the resected specimen was examined. Additionally, a chest computed tomography scan revealed lung involvement with atypical radiologic features in the absence of respiratory symptoms. Only histologic examination of the surgical specimen can yield a diagnosis of gastrointestinal sarcoidosis due to the non-specificity of endoscopic and radiologic findings.
Subject(s)
Colonic Diseases , Sarcoidosis , Abdominal Pain/etiology , Biopsy , Colectomy/methods , Colonic Diseases/complications , Colonic Diseases/diagnosis , Colonic Diseases/surgery , Colonoscopy , Constipation/etiology , Humans , Intestinal Obstruction/diagnosis , Intestinal Obstruction/etiology , Intestinal Obstruction/surgery , Male , Middle Aged , Predictive Value of Tests , Sarcoidosis/complications , Sarcoidosis/diagnosis , Sarcoidosis/surgery , Sarcoidosis, Pulmonary/diagnosis , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
Prostate and breast cancer are major causes of death worldwide, mainly due to patient relapse upon disease recurrence through formation of metastases. Chemokines are small proteins with crucial roles in the immune system, and their regulation is finely tuned in early inflammatory responses. They are key molecules during inflammatory processes, and many studies are focusing on their regulatory functions in tumor growth and angiogenesis during metastatic cell seeding and spreading. Bindarit is an anti-inflammatory indazolic derivative that can inhibit the synthesis of MCP-1/CCL2, with a potential inhibitory function in tumor progression and metastasis formation. We show here that in vitro, bindarit can modulate cancer-cell proliferation and migration, mainly through negative regulation of TGF-ß and AKT signaling, and it can impair the NF-κB signaling pathway through enhancing the expression of the NF-κB inhibitor IkB-α. In vivo administration of bindarit results in impaired metastatic disease in prostate cancer xenograft mice (PC-3M-Luc2 cells injected intra-cardially) and impairment of local tumorigenesis in syngeneic Balb/c mice injected under the mammary gland with murine breast cancer cells (4T1-Luc cells). In addition, bindarit treatment significantly decreases the infiltration of tumor-associated macrophages and myeloid-derived suppressor cells in 4T1-Luc primary tumors. Overall, our data indicate that bindarit is a good candidate for new therapies against prostate and breast tumorigenesis, with an action through impairment of inflammatory cell responses during formation of the tumor-stroma niche microenvironment.
Subject(s)
Breast Neoplasms/pathology , Chemokine CCL2/biosynthesis , Indazoles/pharmacology , Propionates/pharmacology , Prostatic Neoplasms/pathology , Animals , Cell Line, Tumor , Cell Movement , Cell Proliferation , Chemokine CCL2/chemistry , Chemokine CCL2/metabolism , Female , Humans , Macrophages/metabolism , Male , Mice , Mice, Inbred BALB C , NF-kappa B/metabolism , Neoplasm Metastasis , Neoplasm Transplantation , Signal TransductionABSTRACT
The activation of nuclear factor (NF)κB pathway and its transducing signaling cascade has been associated with the pathogenesis of many inflammatory diseases. The central role that IκBα and p65 phosphorylation play in regulating NFκB signalling in response to inflammatory stimuli made these proteins attractive targets for therapeutic strategies. Although several chemical classes of NFκB inhibitors have been identified, it is only for a few of those that a safety assessment based on a comprehensive understanding of their pharmacologic mechanism of action has been reported. Here, we describe the specific anti-inflammatory effect of bindarit, an indazolic derivative that has been proven to have anti-inflammatory activity in a variety of models of inflammatory diseases (including lupus nephritis, arthritis and pancreatitis). The therapeutic effects of bindarit have been associated with its ability to selectively interfere with monocyte recruitment and the "early inflammatory response," although its specific molecular mechanisms have remained ill-defined. For this purpose, we investigated the effect of bindarit on the LPS-induced production of inflammatory cytokines (MCP-1 and MCPs, IL-12ß/p40, IL-6 and IL-8/KC) in both a mouse leukaemic monocyte-macrophage cell line and bone marrow derived macrophages (BMDM). Bindarit inhibits the LPS-induced MCP-1 and IL-12ß/p40 expression without affecting other analyzed cytokines. The effect of bindarit is mediated by the downregulation of the classical NFκB pathway, involving a reduction of IκBα and p65 phosphorylation, a reduced activation of NFκB dimers and a subsequently reduced nuclear translocation and DNA binding. Bindarit showed a specific inhibitory effect on the p65 and p65/p50 induced MCP-1 promoter activation, with no effect on other tested activated promoters. We conclude that bindarit acts on a specific subpopulation of NFκB isoforms and selects its targets wihtin the whole NFκB inflammatory pathway. These findings pave the way for future applications of bindarit as modulator of the inflammatory response.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Indazoles/pharmacology , NF-kappa B/metabolism , Propionates/pharmacology , Animals , Base Sequence , Cells, Cultured , Chemokine CCL2/genetics , Chemokine CCL2/metabolism , Down-Regulation/drug effects , I-kappa B Proteins/metabolism , Interleukin-12 Subunit p40/metabolism , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred C57BL , Molecular Sequence Data , NF-kappa B/antagonists & inhibitors , Phosphorylation , Promoter Regions, Genetic , Signal Transduction , Transcription Factor RelA/metabolismABSTRACT
BACKGROUND/AIMS: To test the role of chemokine C-C motif ligand 2 (CCL2) in the pathogenesis of lupus nephritis (LN), we evaluated the effects of CCL2 inhibition by bindarit therapy in patients with systemic lupus and active renal disease. METHODS: In this proof-of-concept, prospective, randomized, double-blind clinical study, 22 subjects with acute LN were assigned on a 1:1 ratio to 24-week treatment with bindarit (1,200 mg/day) or matching placebo. All subjects were on the same standardized steroid background therapy. Urinary CCL2, urinary albumin excretion (UAE), estimated glomerular filtration rate, time to remission and time to relapse of LN were compared between groups. RESULTS: Urinary CCL2 significantly decreased during bindarit therapy (p = 0.008 vs. baseline) with a reduction that approximated 50% at study end. CCL2 reduction was paralleled by a persistent reduction in UAE that averaged 80% vs. baseline and approximated 90% at study end. Renal function recovery was similar and no difference was found in terms of time to remission and time to relapse of LN between treatment arms. Treatment was safe and well tolerated in all patients. CONCLUSION: In lupus subjects with active nephritis, bindarit significantly reduced albuminuria and urinary CCL2 levels. This study provides the background for longer trials to test renoprotective effect of CCL2 inhibition in LN.
Subject(s)
Chemokine CCL2/metabolism , Lupus Nephritis/metabolism , Proteinuria/complications , Acute Disease , Adult , Double-Blind Method , Female , Glomerular Filtration Rate , Humans , Indazoles/therapeutic use , Kidney Diseases/complications , Kidney Diseases/drug therapy , Lupus Nephritis/complications , Male , Middle Aged , Placebos , Propionates/therapeutic use , Prospective Studies , Proteinuria/drug therapy , Remission InductionABSTRACT
OBJECTIVE: We have previously demonstrated that bindarit, a selective inhibitor of monocyte chemotactic proteins (MCPs), is effective in reducing neointimal formation in rodent models of vascular injury by reducing smooth muscle cell proliferation and migration and neointimal macrophage content, effects associated with the inhibition of MCP-1/CCL2 production. The aim of the current study was to evaluate the efficacy of bindarit on in-stent stenosis in the preclinical porcine coronary stent model. METHODS AND RESULTS: One or 2 bare metal stents (Multi-Link Vision, 3.5 mm) were deployed (1:1.2 oversize ratio) in the coronary arteries of 42 pigs (20 bindarit versus 22 controls). Bindarit (50 mg/kg per day) was administered orally from 2 days before stenting until the time of euthanasia at 7 and 28 days. Bindarit caused a significant reduction in neointimal area (39.4%, P<0.001, n=9 group), neointimal thickness (51%, P<0.001), stenosis area (37%, P<0.001), and inflammatory score (40%, P<0.001) compared with control animals, whereas there was no significant difference in the injury score between the 2 groups. Moreover, treatment with bindarit significantly reduced the number of proliferating cells (by 45%, P<0.05; n=6 group) and monocyte/macrophage content (by 55%, P<0.01; n=5-6 group) in stented arteries at day 7 and 28, respectively. These effects were associated with a significant (P<0.05) reduction of MCP-1 plasma levels at day 28. In vitro data showed that bindarit (10-300 µmol/L) reduced tumor necrosis factor-α (50 ng/mL)-induced pig coronary artery smooth muscle cell proliferation and inhibited MCP-1 production. CONCLUSION: Our results show the efficacy of bindarit in the prevention of porcine in-stent stenosis and support further investigation for clinical application of this compound.
Subject(s)
Coronary Stenosis/prevention & control , Coronary Vessels/pathology , Indazoles/administration & dosage , Indazoles/therapeutic use , Propionates/administration & dosage , Propionates/therapeutic use , Stents , Administration, Oral , Animals , Cell Proliferation/drug effects , Coronary Stenosis/pathology , Coronary Vessels/drug effects , Indazoles/pharmacology , Male , Models, Animal , Monocyte Chemoattractant Proteins/antagonists & inhibitors , Monocyte Chemoattractant Proteins/blood , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/pathology , Neointima/pathology , Neointima/prevention & control , Propionates/pharmacology , Swine , Treatment OutcomeABSTRACT
AIMS: Bindarit is an original compound with peculiar anti-inflammatory activity due to a selective inhibition of a subfamily of inflammatory chemokines, including the monocyte chemotactic proteins MCP-1/CCL2, MCP-3/CCL7, and MCP-2/CCL8. In this study, we investigated the effect of bindarit on neointima formation using two animal models of arterial injury: rat carotid artery balloon angioplasty and wire-induced carotid injury in apolipoprotein E-deficient (apoE(-/-)) mice. METHODS AND RESULTS: Treatment of rats with bindarit (200 mg/kg/day) significantly reduced balloon injury-induced neointima formation by 39% at day 14 without affecting re-endothelialization and reduced the number of medial and neointimal proliferating cells at day 7 by 54 and 30%, respectively. These effects were associated with a significant reduction of MCP-1 levels both in sera and in injured carotid arteries of rats treated with bindarit. In addition, in vitro data showed that bindarit (10-300 microM) reduced rat vascular smooth muscle cell (VSMC) proliferation, migration, and invasion, processes contributing to the injury-induced neointima formation in vivo. Similar results were observed in hypercholesterolaemic apoE(-/-) mice in which bindarit administration resulted in a 42% reduction of the number of proliferating cells at day 7 after carotid injury and in a 47% inhibition of neointima formation at day 28. Analysis of the cellular composition in neointimal lesions of apoE(-/-) mice treated with bindarit showed that the relative content of macrophages and the number of VSMCs were reduced by 66 and 30%, respectively, compared with the control group. CONCLUSION: This study demonstrates that bindarit is effective in reducing neointima formation in both non-hyperlipidaemic and hyperlipidaemic animal models of vascular injury by a direct effect on VSMC proliferation and migration and by reducing neointimal macrophage content. All of these data were associated with the inhibition of MCP-1 production.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Cell Movement/drug effects , Cell Proliferation/drug effects , Hyperlipidemias/pathology , Indazoles/pharmacology , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/pathology , Propionates/pharmacology , Animals , Apolipoproteins E/genetics , Apolipoproteins E/metabolism , Carotid Arteries/drug effects , Carotid Arteries/metabolism , Carotid Artery Injuries/metabolism , Carotid Artery Injuries/pathology , Cells, Cultured , Chemokine CCL2/antagonists & inhibitors , Chemokine CCL2/metabolism , Disease Models, Animal , Female , Hyperlipidemias/metabolism , Male , Mice , Mice, Knockout , Muscle, Smooth, Vascular/metabolism , Rats , Rats, WistarABSTRACT
Bindarit is an indazolic derivative that is devoid of any immunosuppressive effects and has no effect on arachidonic acid metabolism. However, it has been proved to have anti-inflammatory activity in a number of experimental diseases, including pancreatitis, arthritis, and lupus nephritis. This therapeutic effect has been associated with its ability to interfere selectively with monocyte recruitment, although the underlying molecular mechanisms are unknown. Here we comprehensively examine the effect of bindarit on the chemokine system, and report that in activated monocytes and endothelial cells, it selectively inhibits the production of the monocyte chemotactic protein subfamily of CC inflammatory chemokines (MCP-1/CCL2, MCP-3/CCL7, MCP-2/CCL8). The capacity of bindarit to inhibit the production of a defined set of related CC chemokines by monocytes and endothelial cells likely underlies the anti-inflammatory activity of this agent in disease. The exploitation of the chemokine system as drug target in inflammatory disease has relied mainly on the development of receptor antagonists and blocking antibodies. Here we report on the use of inhibition of synthesis as a potentially viable and selective approach to modify the chemokine system.