Rhein, a Natural Anthraquinone Derivative, Attenuates the Activation of Pancreatic Stellate Cells and Ameliorates Pancreatic Fibrosis in Mice with Experimental Chronic Pancreatitis

Abstract

Pancreatic fibrosis, a prominent histopathological feature of chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma, is essentially a dynamic process that leads to irreversible scarring of parenchymal tissues of the pancreas. Though the exact mechanisms of its initiation and development are poorly understood, recent studies suggested that the activation of pancreatic stellate cells (PSCs) plays a critical role in eliciting such active course of fibrogenesis. Anthraquinone compounds possess anti-inflammatory bioactivities whereas its natural derivative rhein has been shown to effectively reduce tissue edema and free-radical production in rat models of inflammatory conditions. Apart from its anti-inflammatory properties, rhein actually exerts strong anti-fibrotic effects in our current in-vivo and in-vitro experiments. In the mouse model of cerulein-induced CP, prolonged administration of rhein at 50 mg/kg/day significantly decreased immunoreactivities of the principal fibrotic activators alpha-smooth muscle actin (α-SMA) and transforming growth factor-beta (TGF-β) on pancreatic sections implicating the activation of PSCs, which is the central tread to fibrogenesis, was attenuated. Consequently, the overwhelmed deposition of extracellular matrix proteins fibronectin 1 (FN1) and type I collagen (COL I-α1) in exocrine parenchyma was found accordingly reduced. In addition, the expression levels of sonic hedgehog (SHH), which plays important roles in molecular modulation of various fibrotic processes, and its immediate effector GLI1 in pancreatic tissues were positively correlated to the degree of cerulein-induced fibrosis. Such up-regulation of SHH signaling was restrained in rhein-treated CP mice. In cultured PSCs, we demonstrated that the expression levels of TGF-β-stimulated fibrogenic markers including α-SMA, FN1 and COL I-α1 as well as SHH were all notably suppressed by the application of rhein at 10 μM. The present study firstly reported that rhein attenuates PSC activation and suppresses SHH/GLI1 signaling in pancreatic fibrosis. With strong anti-fibrotic effects provided, rhein can be a potential remedy for fibrotic and/or PSC-related pathologies in the pancreas.

Anti-fibrotic and Anti-tumorigenic Effects of Rhein, a Natural Anthraquinone Derivative, in Mammalian Stellate and Carcinoma Cells

“…Sonic hedgehog plays critical roles in inflammation, fibrogenesis and tumorigenesis in addition to embryonic developmental processes. Previous work of our research group manifested that the SHH signalling pathway played an important role in sustaining fibrotic processes in cerulein‐induced chronic pancreatitis (Tsang et al , ). In the present study, we demonstrated that SHH/GLI1 signalling was a transcriptional target of NF‐κB during TGF‐β‐dependent fibrogenesis.…”

Sonic hedgehog delivery from self-assembled nanofiber hydrogels reduces the fibrotic response in models of erectile dysfunction

“…In support of this idea, during development, the expression pattern of type XVIII collagen in the ureter bud is responsive to changes in SHH expression in the epithelium [29]. In the adult, hedgehog (Hh) signaling can regulate lung fibrosis [30], and expression of SHH and GLI were correlated with cerulean-induced fibrosis in the pancreas [31], suggesting that SHH may be a regulator of collagen. In this study we will examine if collagen production is responsive to SHH signaling in the penis and in the CN, and to CN regulation, and thus may provide a novel avenue for clinical intervention post prostatectomy and in diabetic patients.…”

Eruberin A, a Natural Flavanol Glycoside, Exerts Anti-Fibrotic Action on Pancreatic Stellate Cells

“…Previous works of our group showed that aberrant activation of NF-κB was observed in fibrotic and inflammatory conditions of the pancreas [17]. Sonic hedgehog (SHH) and its immediate effector glioma-associated oncogene (GLI1), which are the target genes of NF-κB, were accordingly elicited in response to tissue injury and exogenous stimulation of proinflammatory mediators including TGF-β and TNF-α [17,18]. However, the molecular details of the tight control of NF-κB activation and up-regulation of SHH in fibrogenesis have yet clearly elucidated.…”

“…A number of reports demonstrated that TGF-β is a potent inducer for the activation of NF-κB signaling [15,16]. Previous works of our group showed that aberrant activation of NF-κB was observed in fibrotic and inflammatory conditions of the pancreas [17]. Sonic hedgehog (SHH) and its immediate effector glioma-associated oncogene (GLI1), which are the target genes of NF-κB, were accordingly elicited in response to tissue injury and exogenous stimulation of proinflammatory mediators including TGF-β and TNF-α [17,18].…”

“…Small interfering (siRNA) duplex specifically targeting rat Shh (sense: 5'-GCC GAU AUG AAG GGA AGA U-3'; anti-sense: 5'-AUC UUC CCU UCA UAU CGG C-3') and a non-silencing control duplex (sense: 5'-GCC AUG UAA GGA GAG AGA U-3'; antisense: 5'-AUC UCU CUC CUU ACA UGG C-3') were purchased from Invitrogen [17]. Twenty-four hours before transfection, LTC-14 cells were seeded in 24-well plates at a density of 1×10 5 cells/well in 0.5 ml complete culture medium without antibiotics.…”