Inhibition of Transforming Growth Factor β Signaling by Halofuginone as a Modality for Pancreas Fibrosis Prevention

Zion, Orit; Genin, Olga; Kawada, Norifumi; Yoshizato, Katsutoshi; Roffe, Suzy; Nagler, Arnon; Iovanna, Juan; Halevy, Orna; Pines, Mark

doi:10.1097/mpa.0b013e3181967670

Cited by 64 publications

(58 citation statements)

References 47 publications

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“…Furthermore, the remaining muscle cells showed a high expression level of P4HB, which generally indicates the development of fibrosis. 31 However, as observed by light microscopy, the urothelium did not appear to be seriously damaged, and the kidneys did not have hydronephrosis (data not shown). In contrast, just after final irradiation, the apparent damage to the urinary bladders just described was highly variable (data not shown).…”

Section: Discussionmentioning

confidence: 87%

Bone Marrow-Derived Cells Implanted into Radiation-Injured Urinary Bladders Reconstruct Functional Bladder Tissues in Rats

Imamura

Ishizuka

Zhang

et al. 2012

Tissue Engineering Part A

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The purpose of this study was to determine whether bone marrow-derived cells implanted into radiation-injured urinary bladders could reconstruct functional bladder tissues. The pelvic region of anesthetized female SpragueDawley (SD) rats was irradiated with 2 Gy once a week for 5 weeks. After the last irradiation, the rats were maintained for 2 weeks. Bone marrow cells were harvested from the femurs of donor male green fluorescence protein (GFP)-transfected SD rats and cultured for 7 days. Two weeks after the last radiation exposure, the cultured adherent, proliferating bone marrow-derived cells were implanted into the walls of irradiated urinary bladders. For controls, cell-free solutions were similarly injected. Four weeks after donor cell or control implantations, cystometric, histological, and immunohistochemical investigations were performed. Two weeks after the last irradiation, the smooth muscle layers and nerve fibers of the irradiated urinary bladders were disorganized. The proportions of smooth muscle layer and nerve fiber areas were significantly decreased compared with sham-irradiated urinary bladders. In addition, the remaining smooth muscle cells within the irradiated urinary bladders expressed P4HB, an indicator of collagen synthesis. In the cystometric investigations, the voiding interval of irradiated rats was irregularly prolonged, 7.92 -1.09 min, and the residual volume, 0.13 -0.03 mL, was significantly higher compared with the sham-irradiated rats (5.50 -0.43 mL and 0.05 -0.01 mL). After 4 weeks, the smooth muscle layers and nerve fibers in the cell-free control urinary bladders remained similar to the preimplanted irradiated urinary bladders; however, the cell-implanted urinary bladders contained reconstructed smooth muscle layers and nerve fibers, the proportions of each were significantly higher than those in the cell-free injected controls. The expression of P4HB within the cell-implanted urinary bladders decreased. Some GFPpositive implanted cells differentiated into smooth muscle-and nerve-like cells and became organized into the reconstructed tissues. The voiding interval of the cell-implanted rats, 5.46 -0.33 min, was regular and similar to that of the sham-irradiated rats, and significantly less than that of the cell-free injected controls, 7.39 -0.54 min. The residual volume, 0.04 -0.01 mL, was similar to that of the sham-irradiated rats and significantly decreased compared with that of the cell-free injected controls, 0.15 -0.05 mL. Therefore, the implantation of bone marrowderived cells is a potentially useful treatment for radiotherapy-induced urinary dysfunctions.

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Section: Discussionmentioning

confidence: 87%

Bone Marrow-Derived Cells Implanted into Radiation-Injured Urinary Bladders Reconstruct Functional Bladder Tissues in Rats

Imamura

Ishizuka

Zhang

et al. 2012

Tissue Engineering Part A

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“…It has consequently been proposed that elevated Cygb expression might serve as a biomarker for fibrotic tissue [14]. Fibrosis/myofibroblasts-specific higher levels of Cygb have also been found in other research models in fibrotic liver [31,108,110,111], kidney [73] and pancreas [26,79]. It is of note that Cygb upregulation frequently coincided with collagen upregulation [26,73,79].…”

Section: Cygb In Fibrosismentioning

confidence: 87%

“…Cygb was first identified in hepatic stellate cells in fibrotic liver, and its fibrosis-induced expression correlated with the upregulation of collagen I protein [14]. Upon fibrogenic stimulus, pancreatic stellate cells and renal interstitial cells also expressed higher Cygb level and, simultaneously, synthesised more collagen [73,79]. Moreover, exogenous overexpression of the globin in combination with TGF-b enhanced collagen production in rat fibroblasts in vitro [26].…”

Section: Collagen Synthesismentioning

confidence: 95%

Cytoglobin: biochemical, functional and clinical perspective of the newest member of the globin family

Oleksiewicz

Liloglou

Field

et al. 2011

Cell. Mol. Life Sci.

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Since the discovery of cytoglobin (Cygb) a decade ago, growing amounts of data have been gathered to characterise Cygb biochemistry, functioning and implication in human pathologies. Its molecular roles remain under investigation, but nitric oxide dioxygenase and lipid peroxidase activities have been demonstrated. Cygb expression increases in response to various stress conditions including hypoxia, oxidative stress and fibrotic stimulation. When exogenously overexpressed, Cygb revealed cytoprotection against these factors. Cygb was shown to be upregulated in fibrosis and neurodegenerative disorders and downregulated in multiple cancer types. CYGB was also found within the minimal region of a hereditary tylosis with oesophageal cancer syndrome, and its expression was reduced in tylotic samples. Recently, Cygb has been shown to inhibit cancer cell growth in vitro, thus confirming its suggested tumour suppressor role. This article aims to review the biochemical and functional aspects of Cygb, its involvement in various pathological conditions and potential clinical utility.

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“…Several recent papers postulated that TGF-β1 plays an important role in the accumulation of extracellular matrix components in pancreatic fibrosis by activating pancreatic stellate cells [11,19,20,21,22,23,24,25,26]. …”

Section: Introductionmentioning

confidence: 99%

“…Several in vitro studies postulated that myofibroblasts (transformed pancreatic stellate cells) and profibrotic cytokines such as platelet-derived growth factor-BB (PDGF-BB) and transforming growth factor-β1 (TGF-β1) play an important role in pancreatic fibrosis [1,2,3,4,5,6,7,8,9,10,11]. …”

Section: Introductionmentioning

confidence: 99%

Coordinated Increase in Serum Platelet-Derived Growth Factor-BB and Transforming Growth Factor-β1 in Patients with Chronic Pancreatitis

et al. 2011

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Inhibition of Transforming Growth Factor β Signaling by Halofuginone as a Modality for Pancreas Fibrosis Prevention

Cited by 64 publications

References 47 publications

Bone Marrow-Derived Cells Implanted into Radiation-Injured Urinary Bladders Reconstruct Functional Bladder Tissues in Rats

Bone Marrow-Derived Cells Implanted into Radiation-Injured Urinary Bladders Reconstruct Functional Bladder Tissues in Rats

Cytoglobin: biochemical, functional and clinical perspective of the newest member of the globin family

Coordinated Increase in Serum Platelet-Derived Growth Factor-BB and Transforming Growth Factor-β1 in Patients with Chronic Pancreatitis

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