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Background and Aim Vitamin D3 improves portal hypertension (PH) through the activation of vitamin D receptor (VDR) and calcium-sensing receptor (CaSR) in cirrhotic rats. Propranolol is a non-selective β-blocker that is recommended for the treatment of PH. The present study aims to investigate the detail systemic and hepatic mechanisms of vitamin D3 and propranolol, alone or in combination, in cirrhotic rats. Methods Common bile duct-ligated and thioacetamide cirrhotic rats were treated with vehicle, propranolol (30 mg/kg/day), vitamin D3 (0.5 μg/100 g/day, twice weekly), or propranolol + vitamin D3, separately. Results Significantly, propranolol and vitamin D3 produced a similar magnitude of reduction in portal venous pressure (PVP) in cirrhotic rats through different mechanisms: whereas propranolol decreased PVP by reducing splanchnic hyperemia and cardiac index, vitamin D3 decreased PVP by decreasing intrahepatic resistance (IHR). However, propranolol + vitamin D3 did not further decrease PVP in cirrhotic rats. Notably, a marked decrease in hepatic VDR and CaSR expressions was noted in cirrhotic human/rat livers compared with non-cirrhotic human/rat livers. In cirrhotic rats, vitamin D3 administration decreasing IHR by inhibiting the renin–angiotensin system, hepatic oxidative stress, inflammation/fibrosis, angiotensin II (ANGII) production, CaSR-mediated ANGII hyperresponsiveness, ANGII-induced hepatic stellate cells contraction, and correcting hepatic endothelial dysfunction through upregulation of hepatic VDR, CaSR, and endothelial nitric oxide synthase expressions. Conclusion Chronic vitamin D3 treatment alone results in comparative portal hypotensive effects as propranolol alone in cirrhotic rats with PH. Taken together, chronic vitamin D3 administration was an ideal alternative strategy to effectively improve PH without unwanted systemic side-effects.

Background and Aim Vascular endothelial (VEGF) and fibroblast growth factor (FGF)-induced hepatic stellate (HSCs) and liver endothelial cells (LECs) activation accelerates hepatic fibrogenesis and angiogenesis, and hemodynamic dysarrangements in cirrhosis. VEGF targeting agents had been reported as potential drugs for cirrhosis. However, the evaluation of effects of dual VEGF/FGF targeting agent in cirrhosis is still limited. Methods Using hemodynamic parameters, blood chemistry, primary isolated HSCs and LECs, histology, and digital imaging, we assess the effects of 2-week brivanib alaninate, a dual VEGFR/FGFR inhibitor, treatment in the pathophysiology of bile duct-ligated-cirrhotic rats. Results Fibrogenic and angiogenic markers in the serum and liver of bile duct-ligated-cirrhotic rats, including hydroxyproline, transforming growth factor-β1, angiopoietin-1, VEGF, FGF-2, endocan and phosphorylated-VEGFR2/VEGFR2, and phosphorylated-FGFR/FGFR together with hepatic CD31/angiopoietin-1 expressions (immunohistochemistry staining), angiogenesis (micro-computed tomography scan), microcirculatory dysfunction (in vivo miscroscopy and in situ liver perfusion study), portal hypertension, and hyperdynamic circulations (colored microsphere methods) were markedly suppressed and ameliorated by brivanib alaninate treatment. In in vitro study, acute brivanib alaninate incubation inhibited the transforming growth factor-β1-induced HSCs contraction/migration and VEGF-induced LECs angiogenesis. Concomitantly, the overexpression of various fibrogenic and angiogenic markers in HSCs and LECs, and in their culture media, was increased in parallel and these changes were suppressed by acute brivanib alaninate incubation. Conclusions This study demonstrated that brivanib alaninate targeting multiple mechanisms and working in the different pathogenic steps of the complications of cirrhotic rats with portal hypertension.

Mammalian aging of many tissues is associated with a decline in the replicative and functional capacity of somatic stem cells. Understanding the basis of this decline is a major goal of aging research. Human bone marrow-derived multipotent stromal cells (MSCs) have been applied in the treatment of fracture nonunion. Clinical application of MSCs requires abundant cells that can be overcome by ex vivo expansion of cells, but often at the expense of stemness and differentiation potentiality. We first demonstrated that late-passage MSCs exhibited decreased proliferation capacity, reduced expression of stemness markers such as Oct-4 and Nanog, and deterioration of osteogenic potential. Further, late-passage MSCs showed increased expression of p21(Cip1/Waf1) (p21), an inhibitor of the cyclin-dependent kinase. Knockdown of p21 by lentivirus-mediated shRNAs against p21 in late-passage MSCs increased the proliferation capacity, the expression of Oct-4 and Nanog, and osteogenic potential compared with cells transduced with control shRNA. More importantly, reduction in p21 expression in MSCs enhanced the bone repair capacity of MSCs in a rodent calvarial defect model. Knockdown of p21 in MSCs also increased the telomerase activity and telomere length, and did not show chromosomal abnormalities or acquire transformation ability. Therefore, these data successfully demonstrate the involvement of senescence gene in the expression of stemness markers and osteogenic potential of MSCs.