Etoposide-induced protein 2.4 functions as a regulator of the calcium ATPase and protects pancreatic β-cell survival.
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ABSTRACT:
SUBMITTER: Yuan L
PROVIDER: S-EPMC6028951 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Pattern recognition receptors (PRRs) at the plasma membrane promote plant immunity through the detection of conserved microbe-associated molecular patterns (MAMPs). In plants, the PRR for bacterial flagellin (flg22) is encoded by the receptor kinase FLS2. One of the earliest MAMP responses is the rapid and transient increase of cytosolic calcium (Ca2+) ions, which is required for many of the well-described downstream responses, e.g. generation of reactive oxygen species (ROS) and the transcriptional activation of defence-associated genes. Despite its relevance, the molecular components regulating the Ca2+ burst remain largely unknown. Here, we show that the plasma membrane P2B-type Ca2+ ATPase ACA8 forms a dynamic complex with the PRR FLS2. ACA8 and its closest homologue ACA10 are required for immunity against virulent bacteria. Mutant aca8 aca10 plants are reduced in the flg22-induced Ca2+ burst, show reduced ROS production and exhibit altered transcriptional reprogramming. In particular, flg22-induced gene expression is elevated downstream of signalling mitogen-activated protein (MAP) kinases, but reduced downstream of the calcium-dependent protein (CDP) kinase cascade. These results demonstrate that the fine regulation of Ca2+ fluxes in the cytosol is critical for the coordination of the downstream MAMP responses and provide for the first time a link between the FLS2 receptor complex and signalling kinases via the secondary messenger Ca2+. ACA8 also interacted with the BRI1 and CLV1 receptor kinases, which correlated with the developmental phenotypes of aca8 aca10 mutants suggesting a broader role for Ca2+ ATPases in receptor-mediated signalling. We used Affymetrix Arabidopsis Tiling 1.0R Array to compare global transcript levels in 7 days-old sterile grown seedlings. Steady-state mRNA levels in total RNA samples of 7 days old sterile seedlings
2012-04-24 | E-GEOD-31517 | biostudies-arrayexpress
Project description:Pattern recognition receptors (PRRs) at the plasma membrane promote plant immunity through the detection of conserved microbe-associated molecular patterns (MAMPs). In plants, the PRR for bacterial flagellin (flg22) is encoded by the receptor kinase FLS2. One of the earliest MAMP responses is the rapid and transient increase of cytosolic calcium (Ca2+) ions, which is required for many of the well-described downstream responses, e.g. generation of reactive oxygen species (ROS) and the transcriptional activation of defence-associated genes. Despite its relevance, the molecular components regulating the Ca2+ burst remain largely unknown. Here, we show that the plasma membrane P2B-type Ca2+ ATPase ACA8 forms a dynamic complex with the PRR FLS2. ACA8 and its closest homologue ACA10 are required for immunity against virulent bacteria. Mutant aca8 aca10 plants are reduced in the flg22-induced Ca2+ burst, show reduced ROS production and exhibit altered transcriptional reprogramming. In particular, flg22-induced gene expression is elevated downstream of signalling mitogen-activated protein (MAP) kinases, but reduced downstream of the calcium-dependent protein (CDP) kinase cascade. These results demonstrate that the fine regulation of Ca2+ fluxes in the cytosol is critical for the coordination of the downstream MAMP responses and provide for the first time a link between the FLS2 receptor complex and signalling kinases via the secondary messenger Ca2+. ACA8 also interacted with the BRI1 and CLV1 receptor kinases, which correlated with the developmental phenotypes of aca8 aca10 mutants suggesting a broader role for Ca2+ ATPases in receptor-mediated signalling. We used Affymetrix Arabidopsis Tiling 1.0R Array to compare global transcript levels in 7 days-old sterile grown seedlings.
2012-04-25 | GSE31517 | GEO
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Project description:Pancreatic β-cell death or dysfunction mediated by oxidative stress underlies the development and progression of diabetes mellitus (DM). In this study, we evaluated the effect of lentinan (LNT), an active ingredient purified from the bodies of Lentinus edodes, on pancreatic β-cell apoptosis and dysfunction caused by streptozotocin (STZ) and the possible mechanisms implicated. The rat insulinoma cell line INS-1 were pre-treated with the indicated concentration of LNT for 30 min. and then incubated for 24 hrs with or without 0.5 mM STZ. We found that STZ treatment causes apoptosis of INS-1 cells by enhancement of intracellular reactive oxygen species (ROS) accumulation, inducible nitric oxide synthase (iNOS) expression and nitric oxide release and activation of the c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) signalling pathways. However, LNT significantly increased cell viability and effectively attenuated STZ-induced ROS production, iNOS expression and nitric oxide release and the activation of JNK and p38 MAPK in a dose-dependent manner in vitro. Moreover, LNT dose-dependently prevented STZ-induced inhibition of insulin synthesis by blocking the activation of nuclear factor kappa beta and increasing the level of Pdx-1 in INS-1 cells. Together these findings suggest that LNT could protect against pancreatic β-cell apoptosis and dysfunction caused by STZ and therefore may be a potential pharmacological agent for preventing pancreatic β-cell damage caused by oxidative stress associated with diabetes.
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Project description:Pancreatic beta cell dysfunction caused by metabolic and inflammatory stress contributes to the development of type 2 diabetes (T2D). Butyrate, produced by the gut microbiota, has shown beneficial effects on glucose metabolism in animals and humans and may directly affect beta cell function, but the mechanisms are poorly described. The aim of this study was to investigate the effect of butyrate on cytokine-induced beta cell dysfunction in vitro. Mouse islets, rat INS-1E, and human EndoC-βH1 beta cells were exposed long-term to non-cytotoxic concentrations of cytokines and/or butyrate to resemble the slow onset of inflammation in T2D. Beta cell function was assessed by glucose-stimulated insulin secretion (GSIS), gene expression by qPCR and RNA-sequencing, and proliferation by incorporation of EdU into newly synthesized DNA. Butyrate protected beta cells from cytokine-induced impairment of GSIS and insulin content in the three beta cell models. Beta cell proliferation was reduced by both cytokines and butyrate. Expressions of the beta cell specific genes Ins, MafA, and Ucn3 reduced by the cytokine IL-1β were not affected by butyrate. In contrast, butyrate upregulated the expression of secretion/transport-related genes and downregulated inflammatory genes induced by IL-1β in mouse islets. In summary, butyrate prevents pro-inflammatory cytokine-induced beta cell dysfunction.
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Project description:The precise regulation of Ca(2+) dynamics is crucial for proper differentiation and function of osteoclasts. Here we show the involvement of plasma membrane Ca(2+) ATPase (PMCA) isoforms 1 and 4 in osteoclastogenesis. In immature/undifferentiated cells, PMCAs inhibited receptor activator of NF-κB ligand-induced Ca(2+) oscillations and osteoclast differentiation in vitro. Interestingly, nuclear factor of activated T cell c1 (NFATc1) directly stimulated PMCA transcription, whereas the PMCA-mediated Ca(2+) efflux prevented NFATc1 activation, forming a negative regulatory loop. PMCA4 also had an anti-osteoclastogenic effect by reducing NO, which facilitates preosteoclast fusion. In addition to their role in immature cells, increased expression of PMCAs in mature osteoclasts prevented osteoclast apoptosis both in vitro and in vivo. Mice heterozygous for PMCA1 or null for PMCA4 showed an osteopenic phenotype with more osteoclasts on bone surface. Furthermore, PMCA4 expression levels correlated with peak bone mass in premenopausal women. Thus, our results suggest that PMCAs play important roles for the regulation of bone homeostasis in both mice and humans by modulating Ca(2+) signaling in osteoclasts.
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Project description:BackgroundBlueberry is rich in bioactive substances and possesses powerful antioxidant potential, which can protect against oxidant-induced and inflammatory cell damage and cytotoxicity. The aim of this study was to determine how blueberry affects glucose metabolism and pancreatic β-cell proliferation in high fat diet (HFD)-induced obese mice.MethodsWild type male mice at age of 4 weeks received two different kinds of diets: high-fat diet (HFD) containing 60% fat or modified HFD supplemented with 4% (wt:wt) freeze-dried whole blueberry powder (HFD + B) for 14 weeks. A separate experiment was performed in mice fed with low-fat diet (LFD) containing 10% fat or modified LFD + B supplemented with 4% (wt:wt) freeze-dried whole blueberry powder. The metabolic parameters including blood glucose and insulin levels, glucose and insulin tolerances were measured.ResultsBlueberry-supplemented diet significantly increased insulin sensitivity and glucose tolerance in HFD + B mice compared to HFD mice. However, no difference was observed in blood glucose and insulin sensitivity between LFD + B and LFD mice. In addition, blueberry increased β-cell survival and prevented HFD-induced β-cell expansion. The most important finding was the observation of presence of small scattered islets in blueberry treated obese mice, which may reflect a potential role of blueberry in regenerating pancreatic β-cells.ConclusionsBlueberry-supplemented diet can prevent obesity-induced insulin resistance by improving insulin sensitivity and protecting pancreatic β-cells. Blueberry supplementation has the potential to protect and improve health conditions for both type 1 and type 2 diabetes patients.
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Project description:Aims/hypothesisThere is a great need to identify factors that could protect pancreatic beta cells against apoptosis or stimulate their replication and thus prevent or reverse the development of diabetes. One potential candidate is mesencephalic astrocyte-derived neurotrophic factor (MANF), an endoplasmic reticulum (ER) stress inducible protein. Manf knockout mice used as a model of diabetes develop the condition because of increased apoptosis and reduced proliferation of beta cells, apparently related to ER stress. Given this novel association between MANF and beta cell death, we studied the potential of MANF to protect human beta cells against experimentally induced ER stress.MethodsPrimary human islets were challenged with proinflammatory cytokines, with or without MANF. Cell viability was analysed and global transcriptomic analysis performed. Results were further validated using the human beta cell line EndoC-βH1.ResultsThere was increased expression and secretion of MANF in human beta cells in response to cytokines. Addition of recombinant human MANF reduced cytokine-induced cell death by 38% in human islets (p < 0.05). MANF knockdown in EndoC-βH1 cells led to increased ER stress after cytokine challenge. Mechanistic studies showed that the protective effect of MANF was associated with repression of the NF-κB signalling pathway and amelioration of ER stress. MANF also increased the proliferation of primary human beta cells twofold when TGF-β signalling was inhibited (p < 0.01).Conclusions/interpretationOur studies show that exogenous MANF protein can provide protection to human beta cells against death induced by inflammatory stress. The antiapoptotic and mitogenic properties of MANF make it a potential therapeutic agent for beta cell protection.
| S-EPMC6133171 | biostudies-literature
Project description:Development of the endocrine compartment of the pancreas, as represented by the islets of Langerhans, occurs through a series of highly regulated events encompassing branching of the pancreatic epithelium, delamination and differentiation of islet progenitors from ductal domains, followed by expansion and three-dimensional organization into islet clusters. Cellular interactions with the extracellular matrix (ECM) mediated by receptors of the integrin family are postulated to regulate key functions in these processes. Yet, specific events regulated by these receptors in the developing pancreas remain unknown. Here, we show that ablation of the β1 integrin gene in developing pancreatic β-cells reduces their ability to expand during embryonic life, during the first week of postnatal life, and thereafter. Mice lacking β1 integrin in insulin-producing cells exhibit a dramatic reduction of the number of β-cells to only ∼18% of wild-type levels. Despite the significant reduction in β-cell mass, these mutant mice are not diabetic. A thorough phenotypic analysis of β-cells lacking β1 integrin revealed a normal expression repertoire of β-cell markers, normal architectural organization within islet clusters, and a normal ultrastructure. Global gene expression analysis revealed that ablation of this ECM receptor in β-cells inhibits the expression of genes regulating cell cycle progression. Collectively, our results demonstrate that β1 integrin receptors function as crucial positive regulators of β-cell expansion.
| S-EPMC3737718 | biostudies-literature