scholarly journals Flavonoids Identification and Pancreatic Beta-Cell Protective Effect of Lotus Seedpod

Antioxidants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 658 ◽  
Author(s):  
Ming-Shih Lee ◽  
Charng-Cherng Chyau ◽  
Chi-Ping Wang ◽  
Ting-Hsuan Wang ◽  
Jing-Hsien Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Cell Injury ◽  
Pancreatic Beta Cell ◽  
B Cell Lymphoma ◽  
Pancreatic Cell ◽  
Traditional Chinese Herbal Medicine ◽  
Lotus Seedpod

Oxidative stress is highly associated with the development of diabetes mellitus (DM), especially pancreatic beta-cell injury. Flavonoids derived from plants have caused important attention in the prevention or treatment of DM. Lotus seedpod belongs to a traditional Chinese herbal medicine and has been indicated to possess antioxidant, anti-age, anti-glycative, and hepatoprotective activities. The purpose of this study was to demonstrate the pancreatic beta-cell protective effects of lotus seedpod aqueous extracts (LSE) against oxidative injury. According to HPLC/ESI-MS-MS method, LSE was confirmed to have flavonoids derivatives, especially quercetin-3-glucuronide (Q3G). In vitro, LSE dose-dependently improved the survival and function of rat pancreatic beta-cells (RIN-m5F) from hydrogen peroxide (H2O2)-mediated loss of cell viability, impairment of insulin secretion, and promotion of oxidative stress. LSE showed potential in decreasing the H2O2-induced occurrence of apoptosis. In addition, H2O2-triggered acidic vesicular organelle formation and microtubule-associated protein light chain 3 (LC3)-II upregulation, markers of autophagy, were increased by LSE. Molecular data explored that antiapoptotic and autophagic effects of LSE, comparable to that of Q3G, might receptively be mediated via phospho-Bcl-2-associated death promoter (p-Bad)/B-cell lymphoma 2 (Bcl-2) and class III phosphatidylinositol-3 kinase (PI3K)/LC3-II signal pathway. In vivo, LSE improved the DM symptoms and pancreatic cell injury better than metformin, a drug that is routinely prescribed to treat DM. These data implied that LSE induces the autophagic signaling, leading to protect beta-cells from oxidative stress-related apoptosis and injury.

scholarly journals LncRNA LEGLTBC Functions as a ceRNA to Antagonize the Effects of miR-34a on the Downregulation of SIRT1 in Glucolipotoxicity-Induced INS-1 Beta Cell Oxidative Stress and Apoptosis

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Xiang Kong ◽  
Chong-xiao Liu ◽  
Guo-dong Wang ◽  
Hui Yang ◽  
Xin-ming Yao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Cell Injury ◽  
Cell Damage ◽  
High Serum ◽  
Cell Dysfunction ◽  
Beta Cell Damage

Type 2 diabetes mellitus is a chronic metabolic disorder characterized by elevated blood glucose and/or high serum free fatty acids. Chronic hyperlipidemia causes the dysfunction of pancreatic beta cells, which is aggravated in the presence of hyperglycemia (glucolipotoxicity). Long noncoding RNAs (lncRNAs) have been suggested to play key roles in type 1 diabetes mellitus development. However, their roles in glucolipotoxicity-induced beta cell dysfunction are not fully understood. In the present study, we identified the differentially expressed lncRNAs in INS-1 cells exposed to high glucose and palmitate (HG/PA). Among the dysregulated lncRNAs, NONRATT003679.2 (low expression in glucolipotoxicity-treated beta cells (LEGLTBC)) was involved in glucolipotoxicity-evoked rat islet beta cell damage. LEGLTBC functioned as a molecular sponge of miR-34a in INS-1 cells. Additionally, SIRT1 was identified as a target of miR-34a and LEGLTBC promoted SIRT1 expression by sponging miR-34a. The upregulation of LEGLTBC attenuated HG/PA-induced INS-1 cell injury through the promotion of SIRT1-mediated suppression of ROS accumulation and apoptosis. This is the first study to comprehensively identify the lncRNA expression profiling of HG/PA-treated INS-1 beta cells and to demonstrate that LEGLTBC functions as a competing endogenous RNA and regulates miR-34a/SIRT1-mediated oxidative stress and apoptosis in INS-1 cells undergoing glucolipotoxicity.

scholarly journals Update on the Protective Molecular Pathways Improving Pancreatic Beta-Cell Dysfunction

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Alessandra Puddu ◽  
Roberta Sanguineti ◽  
François Mach ◽  
Franco Dallegri ◽  
Giorgio Luciano Viviani ◽  
...  
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Pancreatic Beta Cell ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Beta Cell Dysfunction ◽  
Molecular Pathways ◽  
Cell Dysfunction

The primary function of pancreatic beta-cells is to produce and release insulin in response to increment in extracellular glucose concentrations, thus maintaining glucose homeostasis. Deficient beta-cell function can have profound metabolic consequences, leading to the development of hyperglycemia and, ultimately, diabetes mellitus. Therefore, strategies targeting the maintenance of the normal function and protecting pancreatic beta-cells from injury or death might be crucial in the treatment of diabetes. This narrative review will update evidence from the recently identified molecular regulators preserving beta-cell mass and function recovery in order to suggest potential therapeutic targets against diabetes. This review will also highlight the relevance for novel molecular pathways potentially improving beta-cell dysfunction.

scholarly journals High dose of histone deacetylase inhibitors affects insulin secretory mechanism of pancreatic beta cell line

2018 ◽  
Vol 52 (1) ◽  
pp. 21-26 ◽  
Author(s):  
Eiji Yamato
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Cell Line ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Pancreatic Beta Cell ◽  
High Dose ◽  
Min6 Cells ◽  
Beta Cell Line ◽  
High Doses

Abstract Objective. Histone deacytylase inhibitors (HDACis) inhibit the deacetylation of the lysine residue of proteins, including histones, and regulate the transcription of a variety of genes. Recently, HDACis have been used clinically as anti-cancer drugs and possible anti-diabetic drugs. Even though HDACis have been proven to protect the cytokine-induced damage of pancreatic beta cells, evidence also shows that high doses of HDACis are cytotoxic. In the present study, we, therefore, investigated the eff ect of HDACis on insulin secretion in a pancreatic beta cell line. Methods. Pancreatic beta cells MIN6 were treated with selected HDACis (trichostatin A, TSA; valproic acid, VPA; and sodium butyrate, NaB) in medium supplemented with 25 mM glucose and 13% heat-inactivated fetal bovine serum (FBS) for indicated time intervals. Protein expression of Pdx1 and Mafa in MIN6 cells was demonstrated by immunohistochemistry and immunocytochemistry, expression of Pdx1 and Mafa genes was measured by quantitative RT-PCR method. Insulin release from MIN6 cells and insulin cell content were estimated by ELISA kit. Superoxide production in MIN6 cells was measured using a Total ROS/Superoxide Detection System. Results. TSA, VPA, and NaB inhibited the expression of Pdx1 and Mafa genes and their products. TSA treatment led to beta cell malfunction, characterized by enhanced insulin secretion at 3 and 9 mM glucose, but impaired insulin secretion at 15 and 25 mM glucose. Th us, TSA induced dysregulation of the insulin secretion mechanism. TSA also enhanced reactive oxygen species production in pancreatic beta cells. Conclusions. Our results showed that HDACis caused failure to suppress insulin secretion at low glucose concentrations and enhance insulin secretion at high glucose concentrations. In other words, when these HDACis are used clinically, high doses of HDACis may cause hypoglycemia in the fasting state and hyperglycemia in the fed state. When using HDACis, physicians should, therefore, be aware of the capacity of these drugs to modulate the insulin secretory capacity of pancreatic beta cells.

Catecholamine modulation of calcium currents in clonal pancreatic beta-cells

1989 ◽  
Vol 257 (6) ◽  
pp. C1171-C1176 ◽  
Author(s):  
H. H. Keahey ◽  
A. E. Boyd ◽  
D. L. Kunze
Keyword(s):  
Beta Cell ◽  
G Protein ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Calcium Influx ◽  
Pancreatic Beta Cell ◽  
Cytosolic Calcium ◽  
Calcium Currents ◽  
Secretory Process ◽  
Beta Cell Line

The mechanisms by which norepinephrine and epinephrine activate alpha 2-adrenergic receptors and inhibit insulin release from the pancreatic beta-cell (19, 21, 23) are not yet clear but may involve modulation at several sites. Because intracellular calcium has been implicated in the secretory process, it has been suggested that catecholamines may inhibit secretion by blocking calcium influx, thus reducing the free cytosolic calcium concentration (23). The present study examines the effects of epinephrine, norepinephrine, and clonidine on calcium current in an SV40-transformed hamster beta-cell line (HIT cells). Under voltage-clamp conditions, calcium currents were reversibly inhibited by norepinephrine, epinephrine, and clonidine in the low nanomolar range. The effects were blocked by 1) the alpha 2-antagonist yohimbine, 2) preincubation of the cells with pertussis toxin (PTX), and 3) guanosine 5'-O-(2-thiodiphosphate) (GDP beta S), the nonhydrolyzable GDP analogue that competitively inhibits the interaction of GTP with G proteins. In contrast, guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) caused irreversible blockade by catecholamines. These effects could not be overcome by adenosine 3',5'-cyclic monophosphate (cAMP), suggesting that the adenylate cyclase pathway is not involved in the G protein coupling with the channels. These studies show that catecholamines inhibit calcium currents in beta-cells through an alpha 2-adrenoreceptor PTX-sensitive G protein pathway and could inhibit insulin secretion by this mechanism.

scholarly journals Glucagon-Like Peptide-1 Triggers Protective Pathways in Pancreatic Beta-Cells Exposed to Glycated Serum

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Alessandra Puddu ◽  
Roberta Sanguineti ◽  
Arianna Durante ◽  
Alessio Nencioni ◽  
François Mach ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Pancreatic Beta Cell ◽  
Redox Balance ◽  
Insulin Gene ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Pancreatic Beta Cell Function

Advanced glycation end products (AGEs) might play a pathophysiological role in the development of diabetes and its complications. AGEs negatively affect pancreatic beta-cell function and the expression of transcriptional factors regulating insulin gene. Glucagon-like peptide-1 (GLP-1), an incretin hormone that regulates glucose homeostasis, might counteract the harmful effects of AGEs on the beta cells in culture. The aim of this study was to identify the intracellular mechanisms underlying GLP-1-mediated protection from AGE-induced detrimental activities in pancreatic beta cells. HIT-T15 cells were cultured for 5 days with glycated serum (GS, consisting in a pool of AGEs), in the presence or absence of 10 nmol/L GLP-1. After evaluation of oxidative stress, we determined the expression and subcellular localization of proteins involved in maintaining redox balance and insulin gene expression, such as nuclear factor erythroid-derived 2 (Nrf2), glutathione reductase, PDX-1, and MafA. Then, we investigated proinsulin production. The results showed that GS increased oxidative stress, reduced protein expression of all investigated factors through proteasome activation, and decreased proinsulin content. Furthermore, GS reduced ability of PDX-1 and MafA to bind DNA. Coincubation with GLP-1 reversed these GS-mediated detrimental effects. In conclusion, GLP-1, protecting cells against oxidants, triggers protective intercellular pathways in HIT-T15 cells exposed to GS.

scholarly journals PCSK9 affects expression of key surface proteins in human pancreatic beta cells through intra- and extracellular regulatory circuits

2021 ◽  
Author(s):  
kevin Saitoski ◽  
Maria Ryaboshapkina ◽  
Ghaith Hamza ◽  
Andrew F Jarnuczak ◽  
claire berthault ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Beta Cell ◽  
Pancreatic Islets ◽  
Cell Line ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Pancreatic Beta Cell ◽  
Loss Of Function ◽  
Beta Cell Line ◽  
Gain And Loss

Aims/hypothesis: Proprotein convertase subtilisin/kexin 9 (PCSK9) is involved in the degradation of LDLR. However, PCSK9 can target other proteins in a cell-type specific manner. While PCSK9 has been detected in pancreatic islets, its expression in insulin-producing pancreatic beta cells is debated. Herein, we studied PCSK9 expression, regulation and function in the human pancreatic beta cell line EndoC-βH1. Methods: We assessed PCSK9 expression in mouse and human pancreatic islets, and in the pancreatic beta cell line EndoC-βH1. We also studied PCSK9 regulation by cholesterol, lipoproteins, Mevastatin, and by SREBPs transcription factors. To evaluate PCSK9 function in pancreatic beta cells, we performed PCSK9 gain-and loss-of-function experiments in EndoC-βH1 using siPCSK9 or recombinant PCSK9 treatments, respectively. Results: We demonstrate that PCSK9 is expressed and secreted by pancreatic beta cells. In EndoC-βH1 cells, PCSK9 expression is regulated by cholesterol and by SREBPs transcription factors. Importantly, PCSK9 knockdown results in multiple transcriptome, proteome and secretome deregulations and impaired insulin secretion. By gain- and loss-of- function experiments, we observed that PCSK9 regulates the expression levels of LDLR and VLDLR through an extracellular mechanism while CD36, PD-L1 and HLA-ABC are regulated through an intracellular mechanism. Conclusions/interpretation: Collectively, these results highlight PCSK9 as an important regulator of CD36, PD-L1 and HLA-ABC cell surface expression in pancreatic beta cells. Data availability: RNA-seq data have been deposited to GEO database with accession number GSE182016. Mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the following identifiers: PXD027921, PXD027911 and PXD027913.

Regulation of alpha 2-adrenergic receptor expression and signaling in pancreatic beta-cells

1995 ◽  
Vol 269 (1) ◽  
pp. E162-E171 ◽  
Author(s):  
D. Hamamdzic ◽  
E. Duzic ◽  
J. D. Sherlock ◽  
S. M. Lanier
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Cell Lines ◽  
Pancreatic Beta Cells ◽  
Pancreatic Beta Cell ◽  
Receptor Activation ◽  
Tissue Response ◽  
Receptor Expression ◽  
Receptor Density ◽  
Binding Studies

Activation of alpha 2-adrenergic receptors (alpha 2-AR) in pancreatic beta-cells inhibits insulin secretion in response to various stimuli, and acute or long-term regulation of alpha 2-AR receptor-mediated effects may influence the tissue response to glucose dishomeostasis. As an initial approach to this issue, we determined the effect of various metabolic and hormonal treatments on alpha 2-AR expression and coupling in the pancreatic beta-cell lines HIT-T15 and RIN-5AH. Radioligand binding studies ([3H]RX-821002) and RNA blot analysis indicate that both pancreatic beta-cell lines express the alpha 2A/D-AR subtype [for HIT-T15 the maximum binding (Bmax) = 113 +/- 28; for RIN-5AH Bmax = 93 +/- 18 fmol/mg of cellular protein]. Treatment of HIT-T15 or RIN-5AH cells with glucocorticoids [dexamethasone, hydrocortisone, or prednisolone (1 microM)] increased alpha 2-AR mRNA level and receptor protein density three- to fivefold. The glucocorticoid-induced increase in receptor density in HIT-T15 cells was associated with 1) an increase in the amount of receptors coupled to G protein as determined by analysis of high-affinity 5'-guanylyl imidodiphosphate-sensitive binding of [3H]UK-14304, a selective alpha 2-AR agonist, and 2) a greater inhibition of forskolin-induced elevation of cellular adenosine 3',5'-cyclic monophosphate after receptor activation. Receptor density in HIT-T15 cells was not altered by different growth conditions, insulin (1 microM), phorbol 12-myristate 13-acetate (1 microM), or the sex steroids testosterone and progesterone (1 microM). These data indicate that glucocorticoids upregulate alpha 2-AR expression and signaling in pancreatic beta-cells. Such regulation may operate in a cell-specific manner, allowing discrete modulation of tissue responses to glucose dishomeostasis.

scholarly journals Extracellular Vesicles Released by Enterovirus-Infected EndoC-βH1 Cells Mediate Non-Lytic Viral Spread

2020 ◽  
Vol 8 (11) ◽  
pp. 1753
Author(s):  
Eitan Netanyah ◽  
Matteo Calafatti ◽  
Jeanette Arvastsson ◽  
Eduardo Cabrera-Rode ◽  
Corrado M. Cilio ◽  
...  
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Extracellular Vesicles ◽  
Pancreatic Beta Cells ◽  
Neutralizing Antibodies ◽  
Pancreatic Beta Cell ◽  
Virus Production ◽  
Size Exclusion ◽  
Infectious Dose ◽  
Viral Spread

While human enteroviruses are generally regarded as a lytic virus, and persistent non-cytolytic enterovirus infection in pancreatic beta cells has been suspected of playing a role in type 1 diabetes pathogenesis. However, it is still unclear how enteroviruses could exit the pancreatic beta cell in a non-lytic manner. This study aimed to investigate the role of beta cell-derived extracellular vesicles (EVs) in the non-lytic enteroviral spread and infection. Size-exclusion chromatography and antibody-based immunoaffinity purification were used to isolate EVs from echovirus 16-infected human beta EndoC-βH1 cells. EVs were then characterized using transmission electron microscopy and Multiplex Bead-Based Flow Cytometry Assay. Virus production and release were quantified by 50% cell culture infectious dose (CCID50) assay and qRT-PCR. Our results showed that EVs from echovirus 16-infected EndoC-βH1 cells harbor infectious viruses and promote their spread during the pre-lytic phase of infection. Furthermore, the EVs-mediated infection was not inhibited by virus-specific neutralizing antibodies. In summary, this study demonstrated that enteroviruses could exit beta cells non-lytically within infectious EVs, thereby thwarting the access of neutralizing antibodies to viral particles. These data suggest that enterovirus transmission through EVs may contribute to viral dissemination and immune evasion in persistently infected beta cells.

scholarly journals The structure and function of the ATP-sensitive K+ channel in insulin-secreting pancreatic beta-cells

1999 ◽  
Vol 22 (2) ◽  
pp. 113-123 ◽  
Author(s):  
T Miki ◽  
K Nagashima ◽  
S Seino
Keyword(s):  
Molecular Structure ◽  
Insulin Secretion ◽  
Beta Cell ◽  
Beta Cells ◽  
Katp Channel ◽  
Pancreatic Beta Cells ◽  
Pancreatic Beta Cell ◽  
Molecular Genetic ◽  
Katp Channels ◽  
K Channel

ATP-sensitive K+ channels (KATP channels) play important roles in many cellular functions by coupling cell metabolism to electrical activity. The KATP channels in pancreatic beta-cells are thought to be critical in the regulation of glucose-induced and sulfonylurea-induced insulin secretion. Until recently, however, the molecular structure of the KATP channel was not known. Cloning members of the novel inwardly rectifying K+ channel subfamily Kir6.0 (Kir6.1 and Kir6.2) and the sulfonylurea receptors (SUR1 and SUR2) has clarified the molecular structure of KATP channels. The pancreatic beta-cell KATP channel comprises two subunits: a Kir6.2 subunit and an SUR1 subunit. Molecular biological and molecular genetic studies have provided insights into the physiological and pathophysiological roles of the pancreatic beta-cell KATP channel in insulin secretion.

scholarly journals Pancreatic beta-cell-type-specific expression of the rat insulin II gene is controlled by positive and negative cellular transcriptional elements.

1989 ◽  
Vol 9 (8) ◽  
pp. 3253-3259 ◽  
Author(s):  
J Whelan ◽  
D Poon ◽  
P A Weil ◽  
R Stein
Keyword(s):  
Transcription Factors ◽  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Pancreatic Beta Cell ◽  
Cell Type ◽  
Specific Expression ◽  
Cis Acting ◽  
Cell Type Specific Expression ◽  
Cell Type Specific

The insulin gene is expressed almost exclusively in pancreatic beta-cells. The DNA sequences that control cell-specific expression are located upstream of the transcription initiation site. To identify the cis-acting transcriptional control regions within the rat insulin II gene that are responsible for this tissue-specific expression pattern, we constructed a series of 5'-flanking deletion mutants and analyzed their expression in vivo in transfected insulin-producing and -nonproducing cell lines. Pancreatic beta-cell-specific expression was shown to be controlled by enhancer sequences lying between nucleotides -342 and -91 relative to the transcription start site. The rat insulin II enhancer appears to be a chimera, composed of a number of distinct cis-acting DNA elements. Both positive and negative transcriptional regulatory elements appear to be responsible for this cell-type-specific expression. We have shown that expression from one element within the enhancer, which is found between nucleotides -100 and -91, is regulated by both positive- and negative-acting cellular transcription factors. Expression from chimeras containing only the enhancer element sequences from -100 to -91 were active only in insulin-producing cells, indicating that the positive-acting factor(s) required for this activity may be active only in beta-cells. In contrast to the enhancer region, the rat insulin II gene promoter did not appear to require cell-specific transcription factors. Promoter mutants with 5'-flanking sequences extending to nucleotides -90 and -73 were constitutively active in both insulin-producing and -nonproducing cells. These results suggest that rat insulin II gene transcription in pancreatic beta-cells is imparted by a combination of both negative- and positive-acting cellular factors interacting with the gene enhancer.

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