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Determination of signaling pathways that regulate beta-cell replication is critical for beta-cell therapy. Here, we show that blocking pancreatic macrophage infiltration after pancreatic duct ligation (PDL) completely inhibits beta-cell proliferation. The TGFβ superfamily signaling inhibitor SMAD7 was significantly up-regulated in beta cells after PDL. Beta cells failed to proliferate in response to PDL in beta-cell–specific SMAD7 mutant mice. Forced expression of SMAD7 in beta cells by itself was sufficient to promote beta-cell proliferation in vivo. M2, rather than M1 macrophages, seem to be the inducers of SMAD7-mediated beta-cell proliferation. M2 macrophages not only release TGFβ1 to directly induce up-regulation of SMAD7 in beta cells but also release EGF to activate EGF receptor signaling that inhibits TGFβ1-activated SMAD2 nuclear translocation, resulting in TGFβ signaling inhibition. SMAD7 promotes beta-cell proliferation by increasing CyclinD1 and CyclinD2, and by inducing nuclear exclusion of p27. Our study thus reveals a molecular pathway to potentially increase beta-cell mass through enhanced SMAD7 activity induced by extracellular stimuli.

Clinical evidence suggests that patients with chronic pancreatitis (CP) are prone to development of diabetes (chronic pancreatitis-related diabetes; CPRD), whereas the underlying mechanisms are not fully determined. Recently, we showed that the gradual loss of functional beta-cells in a mouse model for CPRD, partial pancreatic duct ligation (PDL), results from a transforming growth factor β1 (TGFβ1)-triggered beta-cell epithelial–mesenchymal transition (EMT), rather than from apoptotic beta-cell death. Here, the role of angiogenesis in CPRD-associated beta-cell EMT was addressed. We detected enhanced angiogenesis in the inflamed pancreas from CP patients by bioinformatic analysis and from PDL-mice. Inhibition of angiogenesis by specific antisera for vascular endothelial growth factor receptor 2 (VEGFR2), DC101, did not alter the loss of beta-cells and the fibrotic process in PDL-pancreas. However, DC101-mediated inhibition of angiogenesis abolished pancreatitis-induced beta-cell EMT and rendered it to apoptotic beta-cell death. Thus, our data suggest that angiogenesis promotes beta-cell survival in the inflamed pancreas, while suppression of angiogenesis turns beta-cell EMT into apoptotic beta-cell death. This finding could be informative during development of intervention therapies for CPRD.

[...]disorders are potent risk factors for cardiovascular disease, diabetes, and non-alcoholic fatty liver disease. [...]how to control cardiovascular and metabolic disorders has become a global target for disease prevention and treatment. [...]Huang et al.revealed that histone deacetylase 3 modulates the inflammatory and metabolic properties of macrophages and accelerates the progression of atherosclerosis in diabetes. Taken together, these articles add to knowledge of the roles of immune cells in cardiovascular and metabolic disorders. [...]they highlight avenues for future research and suggest potential future treatment strategies.

Glioblastoma is a highly malignant and incurable brain tumor characterized by intrinsic and adaptive resistance to immunotherapies. However, how glioma cells induce tumor immunosuppression and escape immunosurveillance remains poorly understood. Here, we find upregulation of cancer-intrinsic chitinase-3-like 1 (CHI3L1) signaling modulating an immunosuppressive microenvironment by reprogramming tumor-associated macrophages (TAMs). Mechanistically, CHI3L1 binding with galectin 3 (Gal3) selectively promotes TAM migration and infiltration with a protumor M2-like, but not an antitumor M1-like, phenotype in vitro and in vivo, governed by a transcriptional program of NF-[kappa]B/CEBP[beta] in the CHI3L1/Gal3-PI3K/AKT/mTOR axis. Conversely, galectin 3-binding protein (Gal3BP) negatively regulates this process by competing with Gal3 to bind CHI3L1. Administration of a Gal3BP mimetic peptide in syngeneic glioblastoma mouse models reverses immune suppression and attenuates tumor progression. These results shed light on the role of CHI3L1 protein complexes in immune evasion by glioblastoma and as a potential immunotherapeutic target for this devastating disease.

Protection and restoration of a functional β-cell mass are fundamental strategies for prevention and treatment of diabetes. Consequently, knowledge of signals that determine the functional β-cell mass is of immense clinical relevance. Transforming growth factor β (TGFβ) superfamily signaling pathways play a critical role in development and tissue specification. Nevertheless, the role of these pathways in adult β-cell homeostasis is not well defined. Here, we ablated TGFβ receptor I and II genes in mice undergoing two surgical β-cell replication models (partial pancreatectomy or partial duct ligation), representing two triggers for β-cell proliferation, increased β-cell workload and local inflammation, respectively. Our data suggest that TGFβ receptor signaling is necessary for baseline β-cell proliferation. By either provision of excess glucose or treatment with exogenous insulin, we further demonstrated that inflammation and increased β-cell workload are both stimulants for β-cell proliferation but are TGFβ receptor signaling dependent and independent, respectively. Collectively, by using a pancreas-specific TGFβ receptor–deleted mouse model, we have identified two distinct pathways that regulate adult β-cell proliferation. Our study thus provides important information for understanding β-cell proliferation during normal growth and in pancreatic diseases.

Aims/hypothesis Vascular endothelial growth factor (VEGF) is essential for proper pancreatic development, islet vascularisation and insulin secretion. In the adult pancreas, VEGF is thought to be predominantly secreted by beta cells. Although human duct cells have previously been shown to secrete VEGF at angiogenic levels in culture, an analysis of the kinetics of VEGF synthesis and secretion, as well as elucidation of an in vivo role for this ductal VEGF in affecting islet function and physiology, has been lacking. Methods We analysed purified duct cells independently prepared by flow cytometry, surgical isolation or laser-capture microdissection. We infected duct cells in vivo with Vegf (also known as Vegfa ) short hairpin RNA (shRNA) in an intrapancreatic ductal infusion system and examined the effect of VEGF knockdown in duct cells in vitro and in vivo. Results Pancreatic duct cells express high levels of Vegf mRNA. Compared with beta cells, duct cells had a much higher ratio of secreted to intracellular VEGF. As a bioassay, formation of tubular structures by human umbilical vein endothelial cells was essentially undetectable when cultured alone and was substantially increased when co-cultured with pancreatic duct cells but significantly reduced when co-cultured with duct cells pretreated with Vegf shRNA. Compared with islets transplanted alone, improved vascularisation and function was detected in the islets co-transplanted with duct cells but not in islets co-transplanted with duct cells pretreated with Vegf shRNA. Conclusions/interpretation Human islet preparations for transplantation typically contain some contaminating duct cells and our findings suggest that the presence of duct cells in the islet preparation may improve transplantation outcomes.

A potential role for macrophage polarization in promoting β‐cell proliferation has only recently been appreciated. Several independent studies, using different regeneration models and demonstrating a substantial inductive role for macrophages in β‐cell proliferation, are discussed. Additional dissection of the involved cell‐cell crosstalk through specific signal transduction pathways should improve our understanding of β‐cell proliferation and might facilitate current β‐cell replacement therapy. Diabetes mellitus can potentially be treated with islet transplantation, but additional sources of β cells are necessary to overcome the short supply of donor pancreases. Although controversy still exists, it is generally believed that the postnatal expansion of the β‐cell mass is mainly through pre‐existing β‐cell replication. Thus, understanding the molecular mechanisms underlying the regulation of β‐cell proliferation might lead to clinical strategies for increasing β‐cell numbers, both in vitro and in vivo. Macrophages have a well‐recognized role in the development of insulitis as part of the pathogenesis of type 1 diabetes. However, a potential role for macrophage polarization, triggered by specific environmental stimuli, in promoting β‐cell proliferation has only recently been appreciated. In the present review, we discuss several independent studies, using different regeneration models, that demonstrate a substantial inductive role for macrophages in β‐cell proliferation. Additional dissection of the involved cell‐cell crosstalk through specific signal transduction pathways is expected to improve our understanding of β‐cell proliferation and might facilitate the current β‐cell replacement therapy. Significance New independent findings from different β‐cell regeneration models, contributed by different research groups, have provided compelling evidence to highlight a previously unappreciated role for macrophages in β‐cell proliferation. Additional dissection of the underlying mechanisms and cell‐cell crosstalk might shed new light on strategies to increase the functional β‐cell mass in vivo and on β‐cell replacement therapies.

Diabetic foot disease (DFD) is a common and serious complication for diabetes and is characterized with impaired angiogenesis. In addition to the well-defined role of vascular endothelial growth factor (VEGF) -A and its defect in the pathogenesis of DFD, another VEGF family member, placental growth factor (PlGF), was also recently found to alter expression pattern in the DFD patients with undetermined mechanisms. This question was thus addressed in the current study. We detected attenuated PlGF upregulation in a mouse DFD model. In addition, the major cell types at the wound to express the unique PlGF receptor, VEGF receptor 1 (VEGFR1), were macrophages and endothelial cells. To assess how PlGF regulates DFD-associated angiogenesis, we injected recombinant PlGF and depleted VEGF1R specifically in macrophages by local injection of an adeno-associated virus (AAV) carrying siRNA for VEGFR1 under a macrophage-specific CD68 promoter. We found that the angiogenesis and recovery of the DFD were both improved by PlGF injection. The PlGF-induced improvement in angiogenesis and the recovery of skin injury were largely attenuated by macrophage-specific depletion of VEGF1R, likely resulting from reduced macrophage number and reduced M2 polarization. Together, our data suggest that reduced PlGF compromises angiogenesis in DFD at least partially through macrophages.

Exendin-4 is a long acting glucagon-like peptide 1 (GLP-1) analogue that is an agonist for the GLP-1 receptor, a G-protein coupled receptor (GPCR). Exendin-4 is used to clinically improve glucose tolerance in diabetic patients due to its ability to enhance insulin secretion. In rodents, and possibly in humans, exendin-4 can stimulate β-cell proliferation. The exact mechanism of action to induce β-cell proliferation is not well understood. Here, using a β-cell specific epidermal growth factor receptor (EGFR) null mouse, we show that exendin-4 induced an increase in proliferation and β-cell mass through EGFR. Thus, our study sheds light on the role of EGFR signaling in the effects of exendin-4 on the control of blood glucose metabolism and β-cell mass.

The antioxidant activities of lycopene (LY), lutein (LU), chlorogenic acid (CA), and delphinidin (DP) were tested in vitro on H9c2 cell-based models. Some indicators, such as the generation of reactive oxygen (ROS), the quantification of cell antioxidant activity (CAA), and the expressions of SOD, GSH-Px, and CAT, were calculated to examine their antioxidant interactions. From our results, the phytochemical mixtures (M1: CA-LU: F3/10, M2: DP-CA: F7/10, M3: DP-LY: F5/10) displayed strong synergistic effects based on the generation of ROS and the quantification of CAA. However, great antagonistic bioactivities were seen in the combinations of LY-LU: F5/10 (M4), CA-LU: F9/10 (M5), and DP-LY: F7/10 (M6). Western blotting analysis indicated that the possible mechanism underlying the synergistic antioxidant interactions among phytochemical combinations was to enhance the accumulation of Nrf2 in the nucleus and the expression of its downstream antioxidant enzymes, HO-1 and GCLC. The combinations (M1–M3 groups) showed significant protection against the loss of mitochondrial membrane potential than individual groups to avoid excessive ROS production. The M4–M6 groups exerted antagonistic protective effects compared with the individual groups. In addition, lutein and lycopene absorption was improved more because of the presence of chlorogenic acid and delphinidin in the M1 and M3 groups, respectively. However, delphinidin significantly reduced the cellular uptake of lycopene in the M6 group. It appeared that antioxidant interactions of phytochemical combinations may contribute to the restoration of cellular redox homeostasis and lead to an improvement in diet quality and collocation.