Search

Background and Purpose: alpha- and beta-amyrin are pentacyclic triterpenes found in plants and are known to exhibit pronounced anti-inflammatory effects. Here, we evaluated the effects of a 1:1 mixture of alpha- and beta-amyrin (alpha,beta-amyrin) on an experimental model of colitis in mice.Experimental Approach: Colitis was induced in Swiss male mice by trinitrobenzene sulphonic acid (TNBS) and followed up to 72 h; animals were treated systemically with alpha,beta-amyrin, dexamethasone or vehicle. Macro- and microscopic damage, myeloperoxidase activity and cytokine levels were assessed in colons. Histological sections were immunostained for cyclooxygenase-2 (COX-2), vascular endothelial growth factor, phospho-p65 nuclear factor-kappaB (NF-kappaB) and phospho-cyclic AMP response element-binding protein (CREB).Key Results: TNBS-induced colitis was associated with tissue damage, neutrophil infiltration and time-dependent increase of inflammatory mediators. Treatment with alpha,beta-amyrin (3 mg x kg(-1), i.p.) or dexamethasone (1 mg x kg(-1), s.c.) consistently improved tissue damage scores and abolished polymorphonuclear cell infiltration. alpha,beta-Amyrin, like dexamethasone, significantly diminished interleukin (IL)-1beta levels and partially restored IL-10 levels in colon tissues 72 h after colitis induction, but only alpha,beta-amyrin reduced vascular endothelial growth factor expression by immunohistochemistry. The colonic expression of COX-2 at 24 h and that of phospho-NF-kappaB and phospho-CREB (peaking at 6 h) after colitis induction were consistently inhibited by both alpha,beta-amyrin and dexamethasone.Conclusions and Implications: Systemic administration of alpha,beta-amyrin exerted a marked and rapid inhibition of TNBS-induced colitis, related to the local suppression of inflammatory cytokines and COX-2 levels, possibly via inhibition of NF-kappaB and CREB-signalling pathways. Taken together, our data suggest a potential use of alpha,beta-amyrin to control inflammatory responses in bowel disease. [ABSTRACT FROM AUTHOR]

The Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder characterized by the predisposition for multiple tumors caused by germline mutations in the tumor suppressor gene VHL. This disease is associated with a high morbidity and mortality and presents a variable expression, with different phenotypes from family to family, affecting different organs during the lifetime. The main manifestations of VHL are hemangioblastomas of the central nervous system and retina, renal carcinomas and cysts, bilateral pheochromocytomas, cystic and solid tumors of the pancreas, cystadenomas of the epididymis, and endolymphatic sac tumors. The discovery of any of the syndrome components should raise suspicion of this disease and other stigmas must then be investigated. Due to the complexities associated with management of the various VHL manifestation, the diagnosis and the follow-up of this syndrome is a challenge in the clinical practice and a multidisciplinary approach is needed. The particular relevance to endocrinologists is the detection of pheochromocytomas in 35% and islet cell tumors in 17% of VHL patients, which can be associated with hypertension, hypoglycemia, cardiac arrhythmias, and carcinoid syndrome. The purpose of this review is to define the Von Hippel-Lindau syndrome addressing its clinical aspects and classification, the importance of genetic counseling and to propose a protocol for clinical follow-up.

Aberrant expression of G protein-coupled receptors (GPCR) in the adrenal cortex is observed in some cases of ACTH-independent macronodular adrenal hyperplasias and adenomas associated with Cushing syndrome (CS). Although there is clinical evidence for the implication of these receptors in abnormal regulation of cortisol secretion, whether this aberrant expression also directly causes the development of a benign adrenocortical tumor is an open question. Cell transplantation provides a way to study genes that may be important in human tumor development. The system we developed uses genetically modified adrenocortical cells transplanted into adrenalectomized immunodeficient mice, which form a functional tissue structure. We observed that enforcing expression of the gastric inhibitory polypeptide (GIP) receptor or the luteinizing hormone (LH) receptor genes (taken as canonical examples of aberrantly expressed GPCRs) in adrenocortical cells resulted in the formation of hyperplastic tissues and the development of Cushing syndrome features in transplanted mice.

In the guinea pig bronchus with epithelium, pre-contracted with histamine, bradykinin (BK), lysyl-BK, prostaglandin E2 (PGE2), cromakalim and S-nitroso-N-acetylpenicillamine each caused graded relaxation with mean EC50s of 34 nM, 11 nM, 0.1 nM, 0.3 microM and 3.4 microM, respectively. The addition of NO synthase inhibitors N(W)-nitro-L-arginine (L-NOARG), N(G)-monomethyl-L-arginine or 7-nitroindazole reduced BK-induced relaxation by 41+/-6%, 59+/-4% and 51+/-2%, respectively. The inhibition of BK response caused by L-NOARG was completely reversed by L-, but not by D-arginine. Methylene blue and 6-(phenylamino)-5,8-quinolinedione (LY 83583) inhibited the BK response by 88+/-5% and 64+/-4%, while 1H-[1,2,4]oxadiazolo[4,3-a]quinolaxin- -one (ODQ) had no effect. However, ODQ almost abolished SNAP-induced relaxation. Indomethacin and the cyclo-oxygenase 2 (COX-2) inhibitor 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanon e (DFU) caused graded inhibtion of BK responses with mean IC50s of 60 nM and 0.6 nM, respectively. Addition of tetraethylammonium (TEA), charybdotoxin (ChTx), or iberotoxin (IbTx) inhibited BK-induced relaxation by 76+/-4%, 30+/-4% and 99+/-1%, respectively, but the relaxations of PGE2 and cromakalim were unaffected. In contrast, 4-aminopyridine, apamin or glibenclamide did not affect BK-induced relaxation. These results indicate that BK-induced epithelium-dependent relaxation in the guinea pig bronchus is partially mediated by release of NO or by NO-related substances, involving an activation of both cyclo-oxygenase 1 (COX-1) and COX-2 enzymes, through a cyclic guanosine monophosphate (cGMP)-independent mechanism. Furthermore, BK-induced relaxation involves an activation of high-conductance Ca(2+)-activated K+ channels highly sensitive to IbTx, and to a lesser extent to ChTx and TEA.

Dopexamine is a synthetic catecholamine used for the management of low-cardiac-output states. The purpose of this study was to characterize some of the mechanisms underlying dopexamine-mediated relaxation in the guinea pig pulmonary artery (PA) in vitro. Dopexamine (EC50, 1.2 microM; Rmax, 100%), like dobutamine (EC50, 1.4 microM, Rmax, 93.3%), prostacyclin (PGI2; EC50, 37 nM; Rmax, 96.2%), sodium nitroprusside (EC50, 370 pM; Rmax, 96.9%), forskolin (EC50, 47 pM: Rmax, 98.6%), and SKF 38393 (EC50, 120 nM; Rmax, 100%), caused graded relaxation in rings of PA precontracted by phenylephrine. The dopexamine vasorelaxation was antagonized by propranolol (1 microM), SCH 23390 (100 nM, a D1-dopamine antagonist), sulpiride (1 microM), glibenclamide (30 microM), tetraethylammonium (3 mM), apamin (100 nM), charybdotoxin (100 nM), SQ 22536 (10 microM, an adenylyl cyclase inhibitor), KT 5720 (10 microM, a protein kinase A inhibitor) and by calcitonin gene-related peptide (CGRP) or vasoactive intestinal peptide (VIP)-receptor antagonists (both 100 nM), as well as by chymotrypsin (1 U/ml). Neither the prior incubation of N(G)-nitro-L-arginine (100 pM), indomethacin (1 microM), nor removal of the vascular endothelium interfered with dopexamine vasorelaxation response in PA. Thus dopexamine relaxation in PA is mediated by activation of beta-adrenoceptors and dopamine receptors, and by the opening of both low- and high-conductance Ca2+-activated K+ channels, partially through adenosine triphosphate (ATP)-sensitive K+ channels. In addition, dopexamine-induced relaxation in PA seems to involve the release of peptides such as VIP and CGRP, an effect mediated by a cyclic adenosine monophosphate (cAMP)-dependent mechanism.