scholarly journals Inhibition of nuclear factor (erythroid-derived 2)-like 2 promotes hepatic progenitor cell activation and differentiation

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Francesco Bellanti ◽  
Giorgia di Bello ◽  
Giuseppina Iannelli ◽  
Giuseppe Pannone ◽  
Maria Carmela Pedicillo ◽  
...  
Keyword(s):  
Progenitor Cell ◽  
Cell Activation ◽  
Xenograft Model ◽  
Nuclear Factor ◽  
Hepatic Progenitor Cell ◽  
Complex Signals ◽  
Ductular Reaction ◽  
In Vivo Models ◽  
Heparg Cell Line

AbstractThe stem cell ability to self-renew and lead regeneration relies on the balance of complex signals in their microenvironment. The identification of modulators of hepatic progenitor cell (HPC) activation is determinant for liver regeneration and may improve cell transplantation for end-stage liver disease. This investigation used different models to point out the Nuclear factor (erythroid-derived 2)-like 2 (NRF2) as a key regulator of the HPC fate. We initially proved that in vivo models of biliary epithelial cells (BECs)/HPC activation show hepatic oxidative stress, which activates primary BECs/HPCs in vitro. NRF2 downregulation and silencing were associated with morphological, phenotypic, and functional modifications distinctive of differentiated cells. Furthermore, NRF2 activation in the biliary tract repressed the ductular reaction in injured liver. To definitely assess the importance of NRF2 in HPC biology, we applied a xenograft model by inhibiting NRF2 in the human derived HepaRG cell line and transplanting into SCID/beige mice administered with anti-Fas antibody to induce hepatocellular apoptosis; this resulted in effective human hepatocyte repopulation with reduced liver injury. To conclude, NRF2 inhibition leads to the activation and differentiation of liver progenitors. This redox-dependent transcription factor represents a potential target to regulate the commitment of undifferentiated hepatic progenitors into specific lineages.

Influence of albuterol on erythropoietin production and erythroid progenitor cell activation

1979 ◽  
Vol 236 (3) ◽  
pp. H422-H426 ◽  
Author(s):  
F. Przala ◽  
D. M. Gross ◽  
B. Beckman ◽  
J. W. Fisher
Keyword(s):  
Bone Marrow ◽  
Progenitor Cell ◽  
Cell Activation ◽  
Plasma Clot ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cell ◽  
Adrenergic Blocker ◽  
Rabbit Bone

The effect of albuterol, a potent beta2-adrenergic agonist, on kidney production of erythropoietin (Ep) was studied. Its effects on erythroid colony (CFU-E) formation in vitro in rabbit bone marrow cultures were also assessed. Albuterol produced a significant increase in plasma Ep levels in conscious rabbits following 7 h intravenous infusion (50 (microgram/kg)/min). This effect was blocked by pretreatment of the rabbits with butoxamine (5 mg/kg ip), a potent beta2-adrenergic blocker. Albuterol in doses of 10(-10) to 10(-8) M in combination with Ep was also found to produce a significant increase in the numbers of CFU-E in the plasma clot culture system of rabbit bone marrow. This effect was blocked completely by DL-propranolol (10(-8) M) and by butoxamine (10(-8) M). The data presented suggest that albuterol, a potent activator of beta2-adrenergic receptors, increases kidney production of Ep in vivo and also produces a direct effect in combination with Ep on the proliferation of the erythroid progenitor cell compartment.

scholarly journals Requirement of the Chemokine Receptor CXCR3 for Acute Allograft Rejection

2000 ◽  
Vol 192 (10) ◽  
pp. 1515-1520 ◽  
Author(s):  
Wayne W. Hancock ◽  
Bao Lu ◽  
Wei Gao ◽  
Vilmos Csizmadia ◽  
Kerrie Faia ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Chemokine Receptor ◽  
Allograft Rejection ◽  
Cell Activation ◽  
Acute Allograft Rejection ◽  
Activated T Cells ◽  
In Vivo Models ◽  
Ifn Γ

Chemokines provide signals for activation and recruitment of effector cells into sites of inflammation, acting via specific G protein–coupled receptors. However, in vitro data demonstrating the presence of multiple ligands for a given chemokine receptor, and often multiple receptors for a given chemokine, have led to concerns of biologic redundancy. Here we show that acute cardiac allograft rejection is accompanied by progressive intragraft production of the chemokines interferon (IFN)-γ–inducible protein of 10 kD (IP-10), monokine induced by IFN-γ (Mig), and IFN-inducible T cell α chemoattractant (I-TAC), and by infiltration of activated T cells bearing the corresponding chemokine receptor, CXCR3. We used three in vivo models to demonstrate a role for CXCR3 in the development of transplant rejection. First, CXCR3-deficient (CXCR3−/−) mice showed profound resistance to development of acute allograft rejection. Second, CXCR3−/− allograft recipients treated with a brief, subtherapeutic course of cyclosporin A maintained their allografts permanently and without evidence of chronic rejection. Third, CXCR+/+ mice treated with an anti-CXCR3 monoclonal antibody showed prolongation of allograft survival, even if begun after the onset of rejection. Taken in conjunction with our findings of CXCR3 expression in rejecting human cardiac allografts, we conclude that CXCR3 plays a key role in T cell activation, recruitment, and allograft destruction.

scholarly journals Prohibitin‐1 Is a Dynamically Regulated Blood Protein With Cardioprotective Effects in Sepsis

2021 ◽  
Author(s):  
Taylor A. Mattox ◽  
Christine Psaltis ◽  
Katie Weihbrecht ◽  
Jacques Robidoux ◽  
Brita Kilburg‐Basnyat ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Blood Protein ◽  
Nuclear Factor ◽  
In Vivo Models ◽  
Endotoxin Challenge ◽  
Atp Production ◽  
Anti Inflammatory ◽  
Prohibitin 1

Background In sepsis, circulating cytokines and lipopolysaccharide elicit mitochondrial dysfunction and cardiomyopathy, a major cause of morbidity and mortality with this condition. Emerging research places the PHB1 (lipid raft protein prohibitin‐1) at the nexus of inflammation, metabolism, and oxidative stress. PHB1 has also been reported in circulation, though its function in this compartment is completely unknown. Methods and Results Using a wide‐ranging approach across multiple in vitro and in vivo models, we interrogated the functional role of intracellular and circulating PHB1 in the heart during sepsis, and elucidated some of the mechanisms involved. Upon endotoxin challenge or sepsis induction in rodent models, PHB1 translocates from mitochondria to nucleus in cardiomyocytes and is secreted into the circulation from the liver in a manner dependent on nuclear factor (erythroid‐derived 2)‐like 2, a key transcriptional regulator of the antioxidant response. Overexpression or treatment with recombinant human PHB1 enhances the antioxidant/anti‐inflammatory response and protects HL‐1 cardiomyocytes from mitochondrial dysfunction and toxicity from cytokine stress. Importantly, administration of recombinant human PHB1 blunted inflammation and restored cardiac contractility and ATP production in mice following lipopolysaccharide challenge. This cardioprotective, anti‐inflammatory effect of recombinant human PHB1 was determined to be independent of nuclear factor (erythroid‐derived 2)‐like 2, but partially dependent on PI3K/AKT  signaling in the heart. Conclusions These findings reveal a previously unknown cardioprotective effect of PHB1 during sepsis, and illustrate a pro‐survival, protective role for PHB1 in the circulation. Exploitation of circulating PHB1 as a biomarker and/or therapeutic could have widespread benefit in the clinical management of sepsis and other severe inflammatory disorders.

scholarly journals Successful Interferon Therapy Reverses Enhanced Hepatic Progenitor Cell Activation in Patients with Chronic Hepatitis C

2015 ◽  
Vol 35 (12) ◽  
pp. 956-962 ◽  
Author(s):  
Hidenao Noritake ◽  
Yoshimasa Kobayashi ◽  
Yukimasa Ooba ◽  
Erika Matsunaga ◽  
Kazuyoshi Ohta ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C ◽  
Chronic Hepatitis C ◽  
Progenitor Cell ◽  
Interferon Therapy ◽  
Cell Activation ◽  
Hepatic Progenitor Cell

Precision-cut liver slices as an ex-vivo model for human NAFLD show hepatic progenitor cell activation and fibrogenesis

2017 ◽  
Vol 66 (1) ◽  
pp. S603 ◽  
Author(s):  
O. Govaere ◽  
L.H. Reed ◽  
H. Brown ◽  
S.J. Cockell ◽  
J.J. French ◽  
...  
Keyword(s):  
Progenitor Cell ◽  
Cell Activation ◽  
Ex Vivo ◽  
Hepatic Progenitor Cell ◽  
Ex Vivo Model ◽  
Liver Slices

Portal inflammation during NAFLD is frequent and associated with the early phases of putative hepatic progenitor cell activation

2015 ◽  
Vol 68 (11) ◽  
pp. 883-890 ◽  
Author(s):  
Simone Carotti ◽  
Umberto Vespasiani-Gentilucci ◽  
Giuseppe Perrone ◽  
Antonio Picardi ◽  
Sergio Morini
Keyword(s):  
Progenitor Cell ◽  
Cell Activation ◽  
Hepatic Progenitor Cell ◽  
Early Phases

scholarly journals The Autophagy Inhibitor Chloroquine, Alone or in Combination with mTOR Inhibitors, Displays Anti-Tumor Effects in In Vitro and In Vivo Lung Carcinoid Models

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6327
Author(s):  
Adi Knigin ◽  
Shani Avniel-Polak ◽  
Gil Leibowitz ◽  
Kira Oleinikov ◽  
David J. Gross ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Cell ◽  
Cell Survival ◽  
Western Blotting ◽  
Xenograft Model ◽  
Neuroendocrine Neoplasms ◽  
In Vivo Models ◽  
Murine Xenograft Model

(1) Background: Neuroendocrine neoplasms of the lung (LNENs, lung carcinoids) are often diagnosed at an advanced stage when they are not surgically curable, and treatment options are limited. One of the approved options for treating inoperable tumors is everolimus—an mTOR inhibitor (mTORi). Activation of mTOR, among many other effects, inhibits autophagy, which is a cell survival mechanism in general, and in tumor cells in particular. Everolimus may paradoxically encourage cancer cell survival. In practice, the drug inhibits tumor development. Chloroquine (CQ) is a known antimalarial compound that inhibits autophagy. Our research is focused on the hypothesis that autophagy plays a key role in the development of tumor resistance to mTORi, and that the addition of autophagy inhibitors to mTORi exerts a synergistic effect on suppressing tumor cell proliferation. We have recently demonstrated that the combination of CQ with different mTORi increases their potency compared with mTORi alone in both in vitro and in vivo models of pancreatic NENs. In this study, we examined the effects of CQ and mTORi on in vitro and in vivo LNEN models. Aims: Testing the effects of CQ together with mTORi on cell proliferation, apoptosis, and autophagy in in vitro and in vivo LNEN models. (2) Methods: The NCI-H727 LNEN cells were treated with CQ ± mTORi. Cells’ viability and proliferation were measured using XTT and Ki-67 FACS staining. The effects of the treatments on the mTOR pathway and autophagy were examined using Western blotting. Cytotoxicity was measured using a cytotoxicity kit; apoptosis was measured by PI FACS staining and Western blotting. We further established an LNEN subcutaneous murine xenograft model and evaluated the effects of the drugs on tumor growth. (3) Results: CQ alone suppressed LNEN cells’ viability and proliferation and increased their cytotoxicity and apoptosis; these effects were augmented when CQ was added to an mTORi. We also showed the possible mechanisms for these results: on the one hand we could see a decrease in P62 levels and the absence of LC3-II (both inversely related to autophagy) following treatment with the mTORi, and on the other hand we could demonstrate an increase in their levels when CQ was added. The effect was less apparent in the murine xenograft model. (4) Conclusions: By inhibiting autophagy and inducing apoptosis, CQ suppresses tumor cell growth in LNENs. CQ potentiates mTORi effects, implying that further studies are needed in order to elucidate its possible role in tumor inhibition in patients with LNENs.

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