S-Equol Enantioselectively Activates cAMP-Protein Kinase A Signaling and Reduces Alloxan-Induced Cell Death in INS-1 Pancreatic ^|^beta;-Cells

Horiuchi, Hiroko; Harada, Naoki; Adachi, Tomohiko; Nakano, Yoshihisa; Inui, Hiroshi; Yamaji, Ryoichi

doi:10.3177/jnsv.60.291

Cited by 26 publications

(22 citation statements)

References 35 publications

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“…The sole member of this genus, Adlercreutzia equolifaciens, is an equol-producing bacterial strain. Though little is currently known about this species, previous work has indicated that the production of equol by gut microbiota can have beneficial metabolic impacts, including improved leptin/BMI profiles (35) and antioxidant activity (36), and protection from b-cell death (37). In addition, comparison of BBc and BBdp rats demonstrated an alteration in the composition of microbiota, many of which are taxonomically related, in the BBdp rat.…”

Section: Discussionmentioning

confidence: 99%

Cathelicidin Antimicrobial Peptide: A Novel Regulator of Islet Function, Islet Regeneration, and Selected Gut Bacteria

et al. 2015

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Cathelicidin antimicrobial peptide (CAMP) is a naturally occurring secreted peptide that is expressed in several organs with pleiotropic roles in immunomodulation, wound healing, and cell growth. We previously demonstrated that gut Camp expression is upregulated when type 1 diabetes–prone rats are protected from diabetes development. Unexpectedly, we have also identified novel CAMP expression in the pancreatic β-cells of rats, mice, and humans. CAMP was present even in sterile rat embryo islets, germ-free adult rat islets, and neogenic tubular complexes. Camp gene expression was downregulated in young BBdp rat islets before the onset of insulitis compared with control BBc rats. CAMP treatment of dispersed islets resulted in a significant increase in intracellular calcium mobilization, an effect that was both delayed and blunted in the absence of extracellular calcium. Additionally, CAMP treatment promoted insulin and glucagon secretion from isolated rat islets. Thus, CAMP is a promoter of islet paracrine signaling that enhances islet function and glucoregulation. Finally, daily treatment with the CAMP/LL-37 peptide in vivo in BBdp rats resulted in enhanced β-cell neogenesis and upregulation of potentially beneficial gut microbes. In particular, CAMP/LL-37 treatment shifted the abundance of specific bacterial populations, mitigating the gut dysbiosis observed in the BBdp rat. Taken together, these findings indicate a novel functional role for CAMP/LL-37 in islet biology and modification of gut microbiota.

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Section: Discussionmentioning

confidence: 99%

Cathelicidin Antimicrobial Peptide: A Novel Regulator of Islet Function, Islet Regeneration, and Selected Gut Bacteria

et al. 2015

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“…Medium with mogrol was replaced to fresh medium every 2 days. The cells were then incubated in fresh medium containing 5% AlamarBlue (Trek Diagnostic Systems, Cleveland, OH, USA) for 4 h in the dark prior to the measurement of fluorescence, as described previously [30]. …”

Section: Methodsmentioning

confidence: 99%

“…3T3-L1 cells grown on a 48-well plate to confluence were transfected with 0.2 μg of p4xCRE-TATA-Luc [30] and 0.1 μg of pGL4.74[hRluc/TK] using 0.75 μL of HilyMax reagent (Dojindo, Kumamoto, Japan) for 48 h. On day 0, the medium was exchanged to normal culture medium or fresh differentiation medium and the cells were incubated in the presence of 20 μM mogrol or 1 mM AICAR for 30 min. Then, cells were stimulated with insulin, DEX, and IBMX for 24 h. Luciferase activities were determined as described previously [31].…”

Section: Methodsmentioning

confidence: 99%

Mogrol Derived from Siraitia grosvenorii Mogrosides Suppresses 3T3-L1 Adipocyte Differentiation by Reducing cAMP-Response Element-Binding Protein Phosphorylation and Increasing AMP-Activated Protein Kinase Phosphorylation

Harada¹,

Ishihara²,

Horiuchi³

et al. 2016

PLoS ONE

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This study investigated the effects of mogrol, an aglycone of mogrosides from Siraitia grosvenorii, on adipogenesis in 3T3-L1 preadipocytes. Mogrol, but not mogrosides, suppressed triglyceride accumulation by affecting early (days 0–2) and late (days 4–8), but not middle (days 2–4), differentiation stages. At the late stage, mogrol increased AMP-activated protein kinase (AMPK) phosphorylation and reduced glycerol-3-phosphate dehydrogenase activity. At the early stage, mogrol promoted AMPK phosphorylation, inhibited the induction of CCAAT/enhancer-binding protein β (C/EBPβ; a master regulator of adipogenesis), and reduced 3T3-L1 cell contents (e.g., clonal expansion). In addition, mogrol, but not the AMPK activator AICAR, suppressed the phosphorylation and activity of the cAMP response element-binding protein (CREB), which regulates C/EBPβ expression. These results indicated that mogrol suppressed adipogenesis by reducing CREB activation in the initial stage of cell differentiation and by activating AMPK signaling in both the early and late stages of this process.

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“…The cells were transfected with double‐strand siRNAs for AR (AR#1 sense: 5′‐GACUCAGCUGCCCCAUCCA(dTdT)‐3′ and AR#2 sense 5′‐ ACCAUGCAGAAUACAAAU(dTdT)‐3′) or control double‐strand siRNA (Sigma, SIC001) as described previously [Harada et al, ; Mitani et al, ]. Briefly, the cells were transfected using 10 nM siRNA and 0.5 μl of Lipofectamine RNAiMAX (Life Technologies, Gaithersburg, MD), incubated for 24 h, and then incubated in the presence or absence of AR ligand for 72 h. Cell viability was determined using AlamarBlue Dye (TREK Diagnostics Systems, Cleveland, OH) and survival rate was determined as described previously [Horiuchi et al, ].…”

Section: Methodsmentioning

confidence: 99%

Androgen Receptor Silences Thioredoxin‐interacting Protein and Competitively Inhibits Glucocorticoid Receptor‐Mediated Apoptosis in Pancreatic β‐Cells

Harada

Katsuki

Takahashi

et al. 2015

J of Cellular Biochemistry

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Androgen receptor (AR) is known to bind to the same cis-element that glucocorticoid receptor (GR) binds to. However, the effects of androgen signaling on glucocorticoid signaling have not yet been elucidated. Here, we investigated the effects of testosterone on dexamethasone (DEX, a synthetic glucocorticoid)-induced apoptosis of pancreatic β-cells, which might be involved in the pathogenesis of type 2 diabetes mellitus in males. We used INS-1 #6 cells, which were isolated from the INS-1 pancreatic β-cell line and which express high levels of AR. Testosterone and dihydrotestosterone inhibited apoptosis induced by DEX in INS-1 #6 cells. AR knockdown and the AR antagonist hydroxyflutamide each diminished the anti-apoptotic effects of testosterone. AR was localized in the nucleus of both INS-1 #6 cells and pancreatic β-cells of male rats. Induction of thioredoxin-interacting protein (TXNIP) is known to cause pro-apoptotic effects in β-cells. Testosterone suppressed the DEX-induced increase of TXNIP at the transcriptional level. A Chromatin immunoprecipitation assays showed that both AR and GR competitively bound to the TXNIP promoter in ligand-dependent manners. Recombinant DNA-binding domain of AR bound to the same cis-element of the TXNIP promoter that GR binds to. Our results show that AR and GR competitively bind to the same cis-element of TXNIP promoter as a silencer and enhancer, respectively. These results indicate that androgen signaling functionally competes with glucocorticoid signaling in pancreatic β-cell apoptosis.

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S-Equol Enantioselectively Activates cAMP-Protein Kinase A Signaling and Reduces Alloxan-Induced Cell Death in INS-1 Pancreatic ^|^beta;-Cells

Cited by 26 publications

References 35 publications

Cathelicidin Antimicrobial Peptide: A Novel Regulator of Islet Function, Islet Regeneration, and Selected Gut Bacteria

Cathelicidin Antimicrobial Peptide: A Novel Regulator of Islet Function, Islet Regeneration, and Selected Gut Bacteria

Mogrol Derived from Siraitia grosvenorii Mogrosides Suppresses 3T3-L1 Adipocyte Differentiation by Reducing cAMP-Response Element-Binding Protein Phosphorylation and Increasing AMP-Activated Protein Kinase Phosphorylation

Androgen Receptor Silences Thioredoxin‐interacting Protein and Competitively Inhibits Glucocorticoid Receptor‐Mediated Apoptosis in Pancreatic β‐Cells

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