The vitamin D receptor (VDR) protects pancreatic beta cells against Forkhead box class O1 (FOXO1)-induced mitochondrial dysfunction and cell apoptosis

ABSTRACT Objectives Systemic lupus erythematosus (SLE) is characterised by accumulated cell apoptosis. Vitamin D receptor (VDR) has immunomodulatory effect and potent anti-apoptosis activities. The aim of this study was to examine the correlation between CD4+T cells VDR expression, cell apoptosis, and disease activity in patients with SLE. Methods Forty-five SLE patients were recruited and 50 healthy individuals served as controls. The expression of VDR in CD4+T cells and their subsets were determined by flow cytometry. The correlations between VDR expression and cell apoptosis or disease parameters in SLE patients were analysed. Results VDR expression in CD4+T cells and their subsets were upregulated in SLE patients, especially in help T (Th)1, regulatory T (Treg), and follicular helper T (Tfh) cells. Frequency of VDR-positive CD4+T cells was positively associated with SLE disease activity index (SLEDAI)-2K values and inversely correlated with serum C3 concentration. The frequency of VDR-positive CD4+T cells, Th1 cells, Th2 cells, Th17 cells, Treg cells, and Tfh cells was positively correlated with cells apoptosis. Conclusion VDR expression in CD4+T cells and their subsets were increased in SLE. VDR expression was positively associated with disease activity and cell apoptosis in SLE patients.

Download Full-text

Bergenin protects pancreatic beta cells against cytokine-induced apoptosis in INS-1E cells

PLoS ONE ◽

10.1371/journal.pone.0241349 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0241349

Author(s):

Sajid Ali Rajput ◽

Munazza Raza Mirza ◽

M. Iqbal Choudhary

Keyword(s):

Insulin Secretion ◽

Beta Cell ◽

Beta Cells ◽

Proinflammatory Cytokines ◽

Cell Apoptosis ◽

Pancreatic Beta Cells ◽

Cell Function ◽

Beta Cell Apoptosis ◽

Atp Levels ◽

Induced Apoptosis

Beta cell apoptosis induced by proinflammatory cytokines is one of the hallmarks of diabetes. Small molecules which can inhibit the cytokine-induced apoptosis could lead to new drug candidates that can be used in combination with existing therapeutic interventions against diabetes. The current study evaluated several effects of bergenin, an isocoumarin derivative, in beta cells in the presence of cytokines. These included (i) increase in beta cell viability (by measuring cellular ATP levels) (ii) suppression of beta cell apoptosis (by measuring caspase activity), (iii) improvement in beta cell function (by measuring glucose-stimulated insulin secretion), and (iv) improvement of beta cells mitochondrial physiological functions. The experiments were carried out using rat beta INS-1E cell line in the presence or absence of bergenin and a cocktail of proinflammatory cytokines (interleukin-1beta, tumor necrosis factor-alpha, and interferon- gamma) for 48 hr. Bergenin significantly inhibited beta cell apoptosis, as inferred from the reduction in the caspase-3 activity (IC50 = 7.29 ± 2.45 μM), and concurrently increased cellular ATP Levels (EC50 = 1.97 ± 0.47 μM). Bergenin also significantly enhanced insulin secretion (EC50 = 6.73 ± 2.15 μM) in INS-1E cells, presumably because of the decreased nitric oxide production (IC50 = 6.82 ± 2.83 μM). Bergenin restored mitochondrial membrane potential (EC50 = 2.27 ± 0.83 μM), decreased ROS production (IC50 = 14.63 ± 3.18 μM), and improved mitochondrial dehydrogenase activity (EC50 = 1.39 ± 0.62 μM). This study shows for the first time that bergenin protected beta cells from cytokine-induced apoptosis and restored insulin secretory function by virtue of its anti-inflammatory, antioxidant and anti-apoptotic properties. To sum up, the above mentioned data highlight bergenin as a promising anti-apoptotic agent in the context of diabetes.

Download Full-text

Peroxiredoxin 6 Attenuates Alloxan-Induced Type 1 Diabetes Mellitus in Mice and Cytokine-Induced Cytotoxicity in RIN-m5F Beta Cells

Journal of Diabetes Research ◽

10.1155/2020/7523892 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Elena G. Novoselova ◽

Olga V. Glushkova ◽

Sergey M. Lunin ◽

Maxim O. Khrenov ◽

Svetlana B. Parfenyuk ◽

...

Keyword(s):

Type 1 Diabetes ◽

Beta Cells ◽

Cell Apoptosis ◽

Pancreatic Beta Cells ◽

Apoptotic Cell ◽

Main Idea ◽

Severe Form ◽

Peroxiredoxin 6 ◽

Cells Cultured

Type 1 diabetes is associated with the destruction of pancreatic beta cells, which is mediated via an autoimmune mechanism and consequent inflammatory processes. In this article, we describe a beneficial effect of peroxiredoxin 6 (PRDX6) in a type 1 diabetes mouse model. The main idea of this study was based on the well-known data that oxidative stress plays an important role in pathogenesis of diabetes and its associated complications. We hypothesised that PRDX6, which is well known for its various biological functions, including antioxidant activity, may provide an antidiabetic effect. It was shown that PRDX6 prevented hyperglycemia, lowered the mortality rate, restored the plasma cytokine profile, reversed the splenic cell apoptosis, and reduced the β cell destruction in Langerhans islets in mice with a severe form of alloxan-induced diabetes. In addition, PRDX6 protected rat insulinoma RIN-m5F β cells, cultured with TNF-α and IL-1β, against the cytokine-induced cytotoxicity and reduced the apoptotic cell death and production of ROS. Signal transduction studies showed that PRDX6 prevented the activation of NF-κB and c-Jun N-terminal kinase signaling cascades in RIN-m5F β cells cultured with cytokines. In conclusion, there is a prospect for therapeutic application of PRDX6 to delay or even prevent β cell apoptosis in type 1 diabetes.

Download Full-text

Gut Epithelial Vitamin D Receptor Controls Mucosal Inflammation by Blocking Intestinal Epithelial Cell Apoptosis

Gastroenterology ◽

10.1016/s0016-5085(17)33270-5 ◽

2017 ◽

Vol 152 (5) ◽

pp. S964

Author(s):

Lei He ◽

Tiangjing Liu ◽

Yongyan Shi ◽

Feng Tian ◽

Huiyuan Hu ◽

...

Keyword(s):

Vitamin D ◽

Epithelial Cell ◽

Vitamin D Receptor ◽

Cell Apoptosis ◽

Intestinal Epithelial Cell ◽

Mucosal Inflammation ◽

Intestinal Epithelial ◽

Epithelial Cell Apoptosis

Download Full-text

Sirolimus induces depletion of intracellular calcium stores and mitochondrial dysfunction in pancreatic beta cells

Scientific Reports ◽

10.1038/s41598-017-15283-y ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 15

Author(s):

Angela Lombardi ◽

Jessica Gambardella ◽

Xue-Liang Du ◽

Daniela Sorriento ◽

Maurizio Mauro ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Intracellular Calcium ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Calcium Stores ◽

Intracellular Calcium Stores

Download Full-text

Immunohistochemical Expression of Vitamin D Receptor and Forkhead Box P3 in Classic Hodgkin Lymphoma: Correlation with Clinical and Pathologic Findings

10.21203/rs.2.17527/v2 ◽

2020 ◽

Author(s):

Gaurav Gupta ◽

Tanupriya Agrawal ◽

Monika Pilichowska

Keyword(s):

Vitamin D ◽

T Cells ◽

Hodgkin Lymphoma ◽

Vitamin D Receptor ◽

Clinical Stage ◽

Foxp3 Expression ◽

Immunohistochemical Expression ◽

Forkhead Box P3 ◽

Forkhead Box ◽

Classic Hodgkin Lymphoma

Abstract Background Expression of forkhead box P3 (FOXP3), a key regulator of T-cell function, in the tumor immune microenvironment is related to survival in classic Hodgkin lymphoma (CHL). Vitamin D receptor (VDR), a transcription factor , agonists have been shown to induce FOXP3 expression in T-cells and enhance recruitment of these cells to the inflammatory sites. VDR expression is CHL has beenis described. However, there is no data on expression of VDR in context of quantity of FOXP3 positiveexpressing cells in CHL. Methods We examined and correlated immunohistochemical expression of VDR and FOXP3 along with clinical and pathology findings in 29 cases of CHL. Results VDR was expressed in Hodgkin Reed-Sternberg (HRS) cells and background lymphocytes and FOXP3 was expressed in background lymphocytes. 82% of CHL cases, regardless of the subtype, expressed VDR and in majority of the cases, VDR expression was directly proportional to the quantity of FOXP3 expressing lymphocytes in the tumor microenvironment. In cases with higher clinical stage (III/IV), only 28.5% of cases diffusely expressed VDR and FOXP3 compared to 71.4% showing focal positivity. Whereas in cases with lower clinical stages (I/II), the expression pattern of VDR and FOXP3 was almost similar (41.6% diffuse versus 33.3% focal). Interestingly, focal VDR and FOXP3 expression pattern was significantly higher among males. Mixed cellularity cases showed predilection for focal VDR and FOXP3 expression (80% cases); whereas nodular sclerosis subtype had focal and diffuse VDR and FOXP3 expression patterns in similar proportion. Cases with diffuse VDR and FOXP3 expression were less likely to have bone marrow involvement. Epstein Barr virus- encoded small RNA (EBER) positive cases were predominantly focally positive (80%) for VDR and FOXP3. Conclusions In summary, quantity of FOXP3 positive T-cells in CHL microenvironment seems to correlate with VDR expression. Clinical stage show a trend of inverse correlation with expression of VDR and quantity of FOXP3 positive T-cells. These findings suggest that VDR could be a possible prognostic and therapeutic target in CHL.

Download Full-text