Assessment of the protective effects of oral tocotrienols in arginine chronic-like pancreatitis

Abstract

González AM, Garcia T, Samper E, Rickmann M, Vaquero EC, Molero X. Assessment of the protective effects of oral tocotrienols in arginine chronic-like pancreatitis. Am J Physiol Gastrointest Liver Physiol 301: G846 -G855, 2011. First published August 18, 2011 doi:10.1152/ajpgi.00485.2010.-Tocotrienols exhibit anti-inflammatory properties over macrophages and promote cytotoxicity in activated pancreatic stellate cells, suggesting that they may limit chronic pancreatitis progression. We aimed to quantitate the effect of oral tocotrienols on a rat model of chronic pancreatic injury. Chroniclike pancreatitis was induced by repeated arginine pancreatitis. Palm oil tocotrienol-rich fraction (TRF) was given by gavage before and after pancreatitis inductions. Amylase and hydroxyproline were determined in pancreatic homogenates; collagen, fibronectin, ␣-smooth muscle actin (SMA), glial fibrillary acidic protein (GFAP), and phosphorylated Smad3 were assessed by Western blotting. Transforming growth factor (TGF)-␤1 was measured in plasma. Morphological assessment included light microscopy, fibrosis area fraction, and collagen network fractal analysis. Arginine pancreatitis induced pancreatic atrophy and increased hydroxyproline that ameliorated after TRF. Arginine increased TGF-␤1 (185 Ϯ 40 vs. 15 Ϯ 2 ng/ml; P Ͻ0.01) that was blunted by TRF (53 Ϯ 19; P Ͻ 0.01). TRF reduced protease and Smad3 activation, collagen, and fibronectin. ␣-SMA increased and GFAP diminished in arginine pancreatitis, consistent with long-term stellate cell activation, and TRF reverted these changes to basal. Arginine pancreatitis increased fibrosis area fraction (4.5 Ϯ 0.3% vs. 0.2 Ϯ 0.2%), collagen network complexity (fractal dimension 1.52 Ϯ 0.03 vs. 1.42 Ϯ 0.01; P Ͻ 0.001), and inhomogeneity (lacunarity 0.63 Ϯ 0.03 vs. 0.40 Ϯ 0.02; P Ͻ 0.001), which were all reduced by TRF (1.3 Ϯ 0.4%, 1.43 Ϯ 0.02%, and 0.51 Ϯ 0.03%, respectively; P Ͻ 0.01). Best correlation coefficients were obtained when comparing fibrosis area fraction with lacunarity (r ϭ 0.88) and both parameters with pancreatic weight (r ϭ Ϫ0.91 and Ϫ0

Pancreatic Stellate Cells and CX3CR1

“…A number of our results, in both the acute and chronic pancreatitis models, are consistent with the conclusion that CX3CR1 is expressed in activated PSCs in these models and that the CX3CR1 is increased on the cell surface membrane, a finding which is not seen in normal pancreas. First, we observed an increased numbers of activated PSCs in L-arginine induced acute pancreatitis, which is consistent with findings from a previous report 75,76 , which demonstrated increased α-SMA expression (a marker for activated PSCs) coincided with TGF-β1 activation in this model. Second, in the chronic pancreatitis model (WBN/KOB rat), we also demonstrated increased number of PSCs, which is consistent with findings in other studies 77,78 .…”

Tocotrienol alleviates inflammation and oxidative stress in a rat model of spinal cord injury via suppression of transforming growth factor-β

“…The present findings support the protective effects of tocotrienol, which inhibited the serum levels of NF-κB p65 unit, TNF-α, IL-1β and IL-6 in SCI rats. González et al (25) indicated that tocotrienols exhibit anti-inflammatory properties and protect from arginine chronic-like pancreatitis. Yam et al (26) suggested that tocotrienols suppress proinflammatory markers in RAW264.7 macrophages.…”

“…In the present study, tocotrienol treatment significantly reduced the collagen type IV and fibronectin protein expression levels of SCI rats. González et al reported that tocotrienol prevents against lipid-induced nephropathy through suppression of TGF-β and collagen type IV (25).…”

“…Furthermore, pretreatment with tocotrienol treatment significantly reduced the protein expression of fibronectin in SCI rats, in the present study. González et al (25) reported that oral tocotrienols improve quantitative measures of chronic pancreatic damage through fibronectin.…”

Natural forms of vitamin E: metabolism, antioxidant, and anti-inflammatory activities and their role in disease prevention and therapy

“…Tsuduki et al [125] reported that γTE-rich tocotrienols attenuated allergic dermatitis in mice and suppressed degranulation and histamine release in mast cells. In addition, tocotrienol rich fraction from palm oil mitigated chronic pancreatitis [126], showed protection against potassium dichromate-caused acute renal injury [127], and attenuated the increase of plasma liver enzyme and inflammatory cell infiltration to the liver in high carbohydrate plus high fat diet-induced chronic disease model [128]. …”