Adenoviral-bone morphogenetic protein-7 and/or doxazosin therapies promote the reversion of fibrosis/cirrhosis in a cirrhotic hamster model

Cervantes‐García, Daniel; Cuellar-Juarez, Adriana Guadalupe; Borrego‐Soto, Gissela; Rojas-Martínez, Augusto; Aldaba‐Muruato, Liseth Rubí; Salinas, Eva; Ventura-Juárez, Javier; Muñoz‐Ortega, Martín Humberto

doi:10.3892/mmr.2017.7785

Cited by 10 publications

(13 citation statements)

References 52 publications

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“…The aim of this study was to enhance the understanding of the role of BMP6 in skin fibrosis using human and murine in vitro and in vivo model systems. Notably, previous studies of other BMP-subfamily members, especially BMP7, showed that their effects on fibrosis vary in a tissue-and cell-specific manner (Cervantes-Garcia et al, 2017;Higgins et al, 2017;Jin et al, 2018;Murray et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Bone Morphogenetic Protein-6 Inhibits Fibrogenesis in Scleroderma Offering Treatment Options for Fibrotic Skin Disease

Arndt

Karrer

Hellerbrand

et al. 2019

Journal of Investigative Dermatology

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BMP6 is known to be crucial for regulating embryonic skin development. This study assessed the role of BMP6 in dermal fibrosis. We detected that BMP6 is significantly increased in skin-derived fibroblasts of patients with localized scleroderma. Moreover, it was shown that BMP6 significantly impacts proliferation, migration, cytoskeletal organization, and collagen expression, as well as activity of the major pro-fibrogenic transcription factor AP-1 in dermal fibroblasts. The importance of BMP6 in dermal fibrosis was further confirmed in an in vivo model of dermal fibrosis in which BMP6-deficient mice showed significantly enhanced fibrosis compared with wild-type mice. Conversely, application of recombinant BMP6 significantly ameliorated dermal fibrosis in this preclinical bleomycin-induced sclerosis model, and herewith provided proof of concept for the successful treatment of this fibrotic skin disease.

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Section: Discussionmentioning

confidence: 99%

Bone Morphogenetic Protein-6 Inhibits Fibrogenesis in Scleroderma Offering Treatment Options for Fibrotic Skin Disease

Arndt

Karrer

Hellerbrand

et al. 2019

Journal of Investigative Dermatology

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“…The experiment began with two groups: (i) the intact (control) group (n=5) and (ii) the cirrhosis group (n=20). Cirrhosis was induced by the intraperitoneal administration of 50 mg/kg CCl4 in petrolatum, 2 times per week (n=20) for 20 weeks [17, 18]. Each animal was weighed once per week throughout the experiment.…”

Section: Methodsmentioning

confidence: 99%

“…The remaining 15 hamsters with cirrhosis were divided into three groups (n=5 each) with the following 4-week treatments: (1) carvedilol (1.2 mg/Kg/day, (2) doxazosin (1 mg/Kg/day, and (3) placebo (control of endogenous reversal) (Figure 1); the last one is important to check the activity of the adrenoblockers on hepatic cirrhosis and not only the efficiency of the animal model to reverse the damage on its own. The doses and frequency of administration were based on previous studies [17, 18]. Subsequently, the hamsters were sacrificed and the liver samples were fixed in neutral formalin at 4% for histological examination.…”

Section: Methodsmentioning

confidence: 99%

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Doxazosin and Carvedilol Treatment Improves Hepatic Regeneration in a Hamster Model of Cirrhosis

Salas

Navarro‐Gonzalez

Martínez-Hernández

et al. 2018

BioMed Research International

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Regulation of the mechanisms of fibrosis is an important goal in the treatment of liver cirrhosis. One mechanism is the participation of hepatic stellate cells in fibrogenesis when activated by catecholamines. Consequently, α/β adrenoblockers are proposed as an alternative treatment for chronic liver lesions such as fibrosis and/or cirrhosis and for possible liver regeneration. We herein analyzed the effect of doxazosin and carvedilol treatments during the regeneration of tissue in a hamster model of liver cirrhosis. Tissue samples were examined by H&E and PAS to evaluate tissue damage and with Sirius red to assess collagen fiber content. ALT, AST, albumin, and total proteins were examined by spectrophotometry. Determination of the levels of α-SMA and TGF-β in hepatic tissue was examined by Western blot and of the expression of TIMP-2, MMP-13, α-FP, HGF, CK-7, and c-Myc was examined by qPCR. Treatment with doxazosin or carvedilol prompted histological recovery and reduced collagen fibers in the livers of cirrhotic hamsters. The expression of TIMP-2 decreased and that of MMP-13 increases in animals treated with adrenoblockers with respect to the group with cirrhosis. Additionally, the concentration of α-SMA and TGF-β declined with both drugs with respect to placebo p<0.05. On the other hand, each drug treatment led to a distinct scenario for cell proliferation markers. Whereas doxazosin produced no irregularities in α-FP, Ki-67, and c-Myc expression, carvedilol induced an increment in the expression of these markers with respect to the intact. Hence, doxazosin and carvedilol are potential treatments for the regression of hepatic cirrhosis in hamsters in relation to the decrease of collagen in the hepatic parenchyma. However, at regeneration level we observed that doxazosin caused slight morphological changes in hepatocytes, such as its balonization without affecting the hepatic function, and on the other hand, carvedilol elicited a slight irregular expression of cell proliferation markers.

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“…Carvedilol, a nonselective β -AR, and doxazosin, an α 1-AR blocker (antihypertensive drugs), show antifibrotic effects in in vivo studies [15, 16]. Likewise, it was reported that carvedilol increases risks for hepatorenal syndrome and acute kidney injury, reducing transplant-free survival in cirrhotic patients with spontaneous bacterial peritonitis [17], whereas doxazosin shows hepatotoxic effects in the cirrhotic livers of experimental animals [18, 19].…”

Section: Introductionmentioning

confidence: 99%

Curcumin and α/β-Adrenergic Antagonists Cotreatment Reverse Liver Cirrhosis in Hamsters: Participation of Nrf-2 and NF-κB

Macías‐Pérez

Vázquez-López

Muñoz‐Ortega

et al. 2019

Journal of Immunology Research

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Liver cirrhosis is the result of an uncontrolled fibrogenetic process, due to the activation and subsequent differentiation into myofibroblasts of the hepatic stellate cells (HSC). It is known that HSC express adrenoreceptors (AR), and the use of AR antagonists protects experimental animals from cirrhosis. However, several studies suggest that the toxicity generated by metabolism of these antagonists would hinder its use in cirrhotic patients. In addition, liver fibrosis may be associated with a decrease of the antioxidant response of the nuclear factor erythroid 2-related factor 2 (Nrf-2) and the overregulation of the proinflammatory pathway of nuclear factor kappa B (NF-κB). Therefore, in the present work, the capacity of doxazosin (α1 antagonist), carvedilol (nonselective beta-adrenoceptor blocker with alpha 1-blocking properties), and curcumin (antioxidant and anti-inflammatory compound) to reverse liver cirrhosis and studying the possible modulation of Nrf-2 and NF-κB were evaluated. Hamsters received CCl4 for 20 weeks, and then treatments were immediately administered for 4 weeks more. The individual administration of doxazosin or carvedilol showed less ability to reverse cirrhosis in relation to concomitantly curcumin administration. However, the best effect was the combined effect of doxazosin, carvedilol, and curcumin, reversing liver fibrosis and decreasing the amount of collagen I (Sirius red stain) without affecting the morphology of hepatocytes (hematoxylin and eosin stain), showing normal hepatic function (glucose, albumin, AST, ALT, total bilirubin, and total proteins). In addition, carvedilol treatment and the combination of doxazosin with curcumin increased Nrf-2/NF-κB mRNA ratio and its protein expression in the inflammatory cells in the livers, possibly as another mechanism of hepatoprotection. Therefore, these results suggest for the first time that α/β adrenergic blockers with curcumin completely reverse hepatic damage, possibly as a result of adrenergic antagonism on HSC and conceivably by the increase of Nrf-2/NF-κB mRNA ratio.

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Adenoviral-bone morphogenetic protein-7 and/or doxazosin therapies promote the reversion of fibrosis/cirrhosis in a cirrhotic hamster model

Cited by 10 publications

References 52 publications

Bone Morphogenetic Protein-6 Inhibits Fibrogenesis in Scleroderma Offering Treatment Options for Fibrotic Skin Disease

Bone Morphogenetic Protein-6 Inhibits Fibrogenesis in Scleroderma Offering Treatment Options for Fibrotic Skin Disease

Doxazosin and Carvedilol Treatment Improves Hepatic Regeneration in a Hamster Model of Cirrhosis

Curcumin and α/β-Adrenergic Antagonists Cotreatment Reverse Liver Cirrhosis in Hamsters: Participation of Nrf-2 and NF-κB

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