Background/Objectives
Chronic pancreatitis (CP) is a pathological syndrome of the pancreas characterized by fibrosis and inflammation. At present, there is no definitive ... More
Background/Objectives
Chronic pancreatitis (CP) is a pathological syndrome of the pancreas characterized by fibrosis and inflammation. At present, there is no definitive cure for CP. Sodium–glucose cotransporter-2 (SGLT2) inhibitors, a class of antidiabetic drugs, have been reported to exert antifibrotic effects in several organs. We evaluated the antifibrotic effect of the SGLT2 inhibitor canagliflozin on the pancreas.
Methods
C57BL/6 mice carrying a Kras mutation were intraperitoneally injected with caerulein to induce CP. Pancreatic tissues were collected after 8 weeks of feeding with or without canagliflozin and subsequently evaluated. The antifibrotic effects were also assessed in human pancreatic stellate cells (HPSCs) and in pancreatic tissue from patients with CP.
Results
Canagliflozin preserved pancreatic acinar cells and insulin–positive cells, and reduced pancreatic fibrosis in vivo. In HPSCs, canagliflozin suppressed proliferation, migration, and the expression of fibrotic markers and connective tissue growth factor (CTGF), unlike other SGLT2 inhibitors. A cytokine array was used to investigate the antifibrotic mechanism. Canagliflozin significantly downregulated osteoprotegerin (OPG), leading to the suppression of fibrotic markers and CTGF. Furthermore, canagliflozin activated AMP-activated protein kinase (AMPK), which contributed to the downregulation of OPG. This effect was also observed in pancreatic tissue in vivo by Western blot analysis. In addition, pancreatic tissue from patients with CP contained significantly more OPG-positive cells than did control pancreatic tissue. These results indicate that canagliflozin suppressed pancreatic fibrosis by downregulating OPG.
Conclusion
Canagliflozin may be an effective therapeutic agent for CP, and our data suggest the AMPK–OPG–CTGF axis is a novel target in CP. Less
Background The induction of apoptosis in hepatic stellate cells (HSCs) is a promising therapeutic strategy against hepatitis B virus (HBV)-related hepatic fibrosis. The u... More
Background The induction of apoptosis in hepatic stellate cells (HSCs) is a promising therapeutic strategy against hepatitis B virus (HBV)-related hepatic fibrosis. The underlying mechanisms of apoptosis in HSCs, however, are unknown under consideration of HBV infection. In this study, the effects of HBV on apoptosis and endoplasmic reticulum (ER) stress signaling in HSCs were examined. Methods The effects of conditioned media (CM) from HepG2.2.15 on apoptosis induced by the proteasome inhibitor MG132 in LX-2 and HHSteC were studied in regard to c-Jun. In combination with c-Fos, c-Jun forms the AP-1 early response transcription factor, leading to AP-1 activation, signal transduction, endoplasmic reticulum (ER) stress and apoptosis. Results In LX-2 cells, MG132 treatment was associated with the phosphorylation of c-Jun, activation of AP-1 and apoptosis. However, in the presence of CM from HepG2.2.15, these phenomena were attenuated. In HHSteC cells, similar results were observed. HBV genomic DNA is not involved in the process of HSC apoptosis. It is possible that HBeAg has an inhibitory effect on MG132-induced apoptosis in LX-2. We also observed the upregulation of several ER stress-associated genes, such as cAMP responsive element binding protein 3-like 3, inhibin-beta A and solute carrier family 17-member 2, in the presence of CM from HepG2.2.15, or CM from PXB cells infected with HBV. Conclusions HBV inhibits the activation of c-Jun/AP-1 in HSCs, contributing to the attenuation of apoptosis and resulting in hepatic fibrosis. HBV also up-regulated several ER stress genes associated with cell growth and fibrosis. These mechanistic insights might shed new light on a treatment strategy for HBV-associated hepatic fibrosis. Less
Autophagy, a type II programmed cell death, is essential for cell survival under stress, e.g. lung injury, and bone marrow-derived mesenchymal stem cells (BM-MSCs) have g... More
Autophagy, a type II programmed cell death, is essential for cell survival under stress, e.g. lung injury, and bone marrow-derived mesenchymal stem cells (BM-MSCs) have great potential for cell therapy. However, the mechanisms underlying the BM-MSC activation of autophagy to provide a therapeutic effect in ischaemia/reperfusion-induced lung injury (IRI) remain unclear. Thus, we investigate the activation of autophagy in IRI following transplantation with BM-MSCs. Seventy mice were pre-treated with BM-MSCs before they underwent lung IRI surgery in vivo. Human pulmonary micro-vascular endothelial cells (HPMVECs) were pre-conditioned with BM-MSCs by oxygen-glucose deprivation/reoxygenation (OGD) in vitro. Expression markers for autophagy and the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signalling pathway were analysed. In IRI-treated mice, administration of BM-MSCs significantly attenuated lung injury and inflammation, and increased the level of autophagy. In OGD-treated HPMVECs, co-culture with BM-MSCs attenuated endothelial permeability by decreasing the level of cell death and enhanced autophagic activation. Moreover, administration of BM-MSCs decreased the level of PI3K class I and p-Akt while the expression of PI3K class III was increased. Finally, BM-MSCs-induced autophagic activity was prevented using the inhibitor LY294002. Administration of BM-MSCs attenuated lung injury by improving the autophagy level via the PI3K/Akt signalling pathway. These findings provide further understanding of the mechanisms related to BM-MSCs and will help to develop new cell-based therapeutic strategies in lung injury. Less
