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
Injury to the vertebrate central nervous system (CNS) induces astrocytes to change their morphology, to increase their rate of proliferation, and to display directional m... More
Injury to the vertebrate central nervous system (CNS) induces astrocytes to change their morphology, to increase their rate of proliferation, and to display directional migration to the injury site, all to facilitate repair. These astrocytic responses to injury occur in a clear temporal sequence and, by their intensity and duration, can have both beneficial and detrimental effects on the repair of damaged CNS tissue. Studies on highly regenerative tissues in non-mammalian vertebrates have demonstrated that the intensity of direct-current extracellular electric fields (EFs) at the injury site, which are 50–100 fold greater than in uninjured tissue, represent a potent signal to drive tissue repair. In contrast, a 10-fold EF increase has been measured in many injured mammalian tissues where limited regeneration occurs. As the astrocytic response to CNS injury is crucial to the reparative outcome, we exposed purified rat cortical astrocytes to EF intensities associated with intact and injured mammalian tissues, as well as to those EF intensities measured in regenerating non-mammalian vertebrate tissues, to determine whether EFs may contribute to the astrocytic injury response. Astrocytes exposed to EF intensities associated with uninjured tissue showed little change in their cellular behavior. However, astrocytes exposed to EF intensities associated with injured tissue showed a dramatic increase in migration and proliferation. At EF intensities associated with regenerating non-mammalian vertebrate tissues, these cellular responses were even more robust and included morphological changes consistent with a regenerative phenotype. These findings suggest that endogenous EFs may be a crucial signal for regulating the astrocytic response to injury and that their manipulation may be a novel target for facilitating CNS repair. Less
The tumor microenvironment is known to play a key role in altering the properties and behavior of nearby cancer cells. Its influence on resistance to endocrine therapy an... More
The tumor microenvironment is known to play a key role in altering the properties and behavior of nearby cancer cells. Its influence on resistance to endocrine therapy and cancer relapse, however, is poorly understood. Here we investigate the interaction of mammary fibroblasts and estrogen receptor-positive breast cancer cells in three-dimensional culture models in order to characterize gene expression, cellular changes, and the secreted protein factors involved in the cellular cross-talk. We show that fibroblasts, which are the predominant cell type found in the stroma adjacent to the cancer cells in a tumor, induce an epithelial-to-mesenchymal transition in the cancer cells, leading to hormone-independent growth, a more invasive phenotype, and resistance to endocrine therapy. Here, we applied a label-free chemical imaging modality, Fourier transform infrared (FT-IR) spectroscopic imaging, to identify cells that had transitioned to hormone-independent growth. Both the molecular and chemical profiles identified here were translated from cell culture to patient samples: a secreted protein signature was used to stratify patient populations based on gene expression and FT-IR was used to characterize breast tumor patient biopsies. Our findings underscore the role of mammary fibroblasts in promoting aggressiveness and endocrine therapy resistance in ER-positive breast cancers and highlight the utility of FT-IR for the further characterization of breast cancer samples. Less
The tumor microenvironment is known to play a key role in altering the properties and behavior of nearby cancer cells. Its influence on resistance to endocrine therapy an... More
The tumor microenvironment is known to play a key role in altering the properties and behavior of nearby cancer cells. Its influence on resistance to endocrine therapy and cancer relapse, however, is poorly understood. Here we investigate the interaction of mammary fibroblasts and estrogen receptor-positive breast cancer cells in three-dimensional culture models in order to characterize gene expression, cellular changes, and the secreted protein factors involved in the cellular cross-talk. We show that fibroblasts, which are the predominant cell type found in the stroma adjacent to the cancer cells in a tumor, induce an epithelial-to-mesenchymal transition in the cancer cells, leading to hormone-independent growth, a more invasive phenotype, and resistance to endocrine therapy. Here, we applied a label-free chemical imaging modality, Fourier transform infrared (FT-IR) spectroscopic imaging, to identify cells that had transitioned to hormone-independent growth. Both the molecular and chemical profiles identified here were translated from cell culture to patient samples: a secreted protein signature was used to stratify patient populations based on gene expression and FT-IR was used to characterize breast tumor patient biopsies. Our findings underscore the role of mammary fibroblasts in promoting aggressiveness and endocrine therapy resistance in ER-positive breast cancers and highlight the utility of FT-IR for the further characterization of breast cancer samples. Less
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