scholarly journals A gene expression network model of type 2 diabetes links cell cycle regulation in islets with diabetes susceptibility

2008 ◽  
Vol 18 (5) ◽  
pp. 706-716 ◽  
Author(s):  
M. P. Keller ◽  
Y. Choi ◽  
P. Wang ◽  
D. Belt Davis ◽  
M. E. Rabaglia ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Cell Cycle ◽  
Network Model ◽  
Cell Cycle Regulation ◽  
Diabetes Susceptibility ◽  
Gene Expression Network ◽  
Cycle Regulation

Dysregulation of components of the inflammasome machinery after bariatric surgery: novel targets for a chronic disease

2021 ◽  
Author(s):  
Vicente Herrero-Aguayo ◽  
Prudencio Sáez-Martínez ◽  
Juan L López-Cánovas ◽  
Juan J Prados-Carmona ◽  
María D Alcántara-Laguna ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Cell Cycle ◽  
Bariatric Surgery ◽  
Dna Damage ◽  
Chronic Disease ◽  
Lipid Accumulation ◽  
Hepg2 Cells ◽  
Metabolic Comorbidities

Abstract Background Obesity is a metabolic-chronic disease with important associated morbidities and mortality. Bariatric-surgery is the most effective treatment for maintaining long-term weight-loss in severe obesity and consequently for decreasing obesity-related complications, including chronic inflammation. Aim To explore changes in components of the inflammasome-machinery after bariatric-surgery and their relations with clinical/biochemical-parameters at baseline and six-months after bariatric-surgery. Patients and methods 22 patients with morbid-obesity that underwent bariatric-surgery (sleeve-gastrectomy and roux-en-Y gastric bypass) were included. Epidemiological/clinical/anthropometric/biochemical evaluation was performed at baseline and six-months after bariatric-surgery. Inflammasome-components and inflammatory-associated factors [NOD-like-receptors (NLRs); inflammasome-activation-components; cytokines and inflammation/apoptosis-related components; and cell-cycle and DNA-damage regulators) were evaluated in peripheral-blood mononuclear-cells (PBMCs) at baseline and six-months after bariatric-surgery. Clinical-molecular correlations/associations were analyzed. Functional parameters (lipid-accumulation/viability/apoptosis) were analyzed in response to specific inflammasome-components silencing in liver HEPG2-cells-). Results A profound dysregulation of inflammasome-components after bariatric-surgery was found, especially in NOD-like-receptors, cell-cycle and DNA-damage regulators. Several components were associated to baseline metabolic comorbidities including type-2-diabetes (CCL2/CXCR1/SIRT1), hypertension (AIM2/ASC/P2RX7) and dyslipidemia (CXCL3/NLRP7), and displayed changes in their molecular profile six-months after bariatric-surgery. Gene-expression fingerprint of certain factors (NLRC4/NLRP12/CXCL3/CCL8/TLR4) accurately differentiated pre- and post-operative PBMCs. Most changes were independent of the performed surgical technique. Silencing of NLRC4/NLRP12- resulted in altered lipid-accumulation, apoptosis-rate and cell-viability in HEPG2-cells. Conclusion Bariatric-surgery induces a profound alteration in gene-expression pattern of components of the inflammasome-machinery in PBMCs. Expression and changes of certain inflammasome-components are associated to baseline metabolic comorbidities, including type-2-diabetes, and may be related to the improvement and reversion of some obesity-related comorbidities after bariatric-surgery.

Modulation of Gene Expression Profile and In Vivo Anti-Myeloma Activity Induced by Valproic Acid, a Histone Deacytylase Inhibitor.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4790-4790
Author(s):  
Paola Neri ◽  
Teresa Calimeri ◽  
Mariateresa Di Martino ◽  
Marco Rossi ◽  
Orietta Eramo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Valproic Acid ◽  
Dna Replication ◽  
Gene Expression Profile ◽  
Cell Cycle Regulation ◽  
Cycle Regulation ◽  
Anti Tumor Activity

Abstract Valproic acid (VPA) is a well-tolerated anticonvulsant drug that has been recently recognized as powerful histone deacetylase (HDCA) inhibitor. VPA induces hyperacetylation of histone H3 and H4 and inhibits both class I and II HDCACs. Recently it has been shown that VPA exerts in vitro and in vivo anti-tumor activity against solid cancers and its in vitro anti-Multiple Myeloma (MM) activity has been previously reported. However, the molecular mechanisms are still unclear. Here we have investigated molecular changes induced by VPA as well as its in vivo activity in murine models of MM. We first studied the in vitro activity of VPA against IL-6 independent as well as IL-6 dependent MM cells. A time- and dose-dependent decrease in proliferation and survival of MM cell lines was observed (IC50 in the range of 1–3 mM). Gene expression profile following treatment with VPA at 2 and 5 mM showed down-regulation of genes involved in cell cycle regulation, DNA replication and transcription as well as up-regulation of genes implicated in apoptosis and chemokine pathways. The signaling pathway analysis performed by Ingenuity Systems Software identified the cell growth, cell cycle, cell death as well as DNA replication and repair as the most important networks modulated by VPA treatment. We next evaluated the in vivo activity of VPA using two xenograft models of human MM. A cohort of SCID mice bearing subcutaneous MM1s or OPM1 were treated i.p. daily with VPA (200 mg/kg, and 300 mg/kg, n=5 mice, respectively), or vehicle alone (n=5 mice) for 16 consecutive days. Tumors were measured every 2 days, and survival was calculated using the Kaplan Mayer method. Following VPA treatment, we found a significant (p=0.006) inhibition of tumor growth in mice bearing subcutaneous MM-1s cells treated with VPA at 200 mg/kg compared to control group, which translated into a significant (p= 0.002) survival advantage in the VPA treated animals. Similar results were obtained in animals bearing subcutaneous OPM1 cells. Flow cytometry analysis performed on retrieved tumor tissues from animals showed reduction of G2-M and S phase in tumor specimens following VPA treatment, versus untreated tumors, strongly suggesting in vivo effects of VPA on cell cycle regulation. Taken together, our data demonstrate the in vitro and in vivo anti-tumor activity of VPA, delineate potential molecular targets triggered by this agent and provide a preclinical rationale for its clinical evaluation, both as a single agent or in combination, to improve patient outcome in MM.

scholarly journals Type 2 Diabetes Susceptibility Gene Expression in Normal or Diabetic Sorted Human Alpha and Beta Cells: Correlations with Age or BMI of Islet Donors

PLoS ONE ◽  
2010 ◽  
Vol 5 (6) ◽  
pp. e11053 ◽  
Author(s):  
Clare L. Kirkpatrick ◽  
Piero Marchetti ◽  
Francesco Purrello ◽  
Salvatore Piro ◽  
Marco Bugliani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Beta Cells ◽  
Susceptibility Gene ◽  
Diabetes Susceptibility ◽  
Diabetes Susceptibility Gene

77 Nobiletin supplementation affects gene expression profiles of the Akt pathway in bovine embryos invitro

2020 ◽  
Vol 32 (2) ◽  
pp. 164
Author(s):  
Y. N. Cajas ◽  
K. Cañón-Beltrán ◽  
C. L. V. Leal ◽  
M. E. González ◽  
A. Gutierrez-Adán ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Cell Cycle ◽  
Embryonic Development ◽  
Cell Cycle Regulation ◽  
Akt Pathway ◽  
Cleavage Rate ◽  
Cell Stage ◽  
Cycle Regulation ◽  
And Oxidative Stress

Embryonic genome activation (EGA) is a critical event in early embryonic development and occurs in 8-16-cell stage embryos in bovine. Invitro embryo production increases reactive oxygen species (ROS), leading to low yield and cell death. Nobiletin is an antioxidant that inhibits ROS production and affects cell cycle regulation. The aim of this study was to evaluate the effect of nobiletin supplementation in two key periods of early embryo development on blastocyst yield and expression of candidate genes of the Akt pathway. Invitro-produced zygotes were cultured in synthetic oviductal fluid supplemented with 5% FCS (control; C); C with 5 or 10 µM nobiletin (MedChemExpress; N5, N10) or C with 0.03% dimethyl sulfoxide (CD vehicle for nobiletin dilution) during the minor (2-8-cell stage; MNEGA) or major (8-16-cell stage; MJEGA) phase of EGA, considered as two separate experiments. For all groups, the speed of development was considered, and normally developing embryos that reach ≥8 cells at 54h post-insemination and ≥16 cells at 96h post-insemination were selected and cultured in control medium until Day 8, respectively. Embryos at ≥8-cell stage (N5/N10 MNEGA), 16-cell stage (N5/N10MJEGA), and Day 7 blastocysts of both periods were snap-frozen in LN2 for gene expression analysis. Cleavage rate and blastocyst yield (Day 7-8) were evaluated. The mRNA abundance of candidate genes related to the Akt pathway (CDK2, PGC1A, PPARG, RPS6KB1) and oxidative stress (GPX1) was measured by quantitative PCR. The H2AFZ and ACTB genes were used as housekeeping genes. Statistical analysis was assessed by one-way ANOVA. Nobiletin supplementation during MNEGA showed no differences in cleavage rate, whereas the blastocyst yield at Day 8 was higher (P<0.001) for N5 (42.9±1.4%) and N10 (45.3±2.1%) compared with C (32.9±1.1%) and CD (32.6±1.4%) groups. When nobiletin was supplemented during MJEGA, no differences were found in cleavage rate; however, Day 8 blastocyst yield was higher (P<0.001) for N10 (61.8±0.7%) compared with C (45.2±1.7%), CD (43.6±1.4%), and N5 (52.1±2.1%) groups, whereas N5 was higher (P<0.05) compared with both control groups. The mRNA abundance of CDK2 significantly increases in 8-cell stage embryos from N5 and N10 groups during MNEGA, whereas 16-cell stage embryos from N10 group during MJEGA showed a significant increase compared with both controls (P<0.05). The expression of PGC1A was significantly higher in blastocysts from N5, N10 during MNEGA, and N10 during MJEGA groups compared with both controls (P<0.05). No differences were observed for PPARG and RPS6KB1 in any group from both phases. GPX1, an oxidative indicator gene, was up-regulated in all nobiletin-supplemented groups from both phases compared with controls (P<0.05). In conclusion, supplementation of embryo culture during MNEGA or MJEGA with nobiletin improves embryo development and induces changes in the transcriptional genes related to cell cycle regulation and oxidative stress. This suggests that nobiletin acts through the Akt pathway during the first stages of embryonic development. Funding was provided by MINECO-Spain AGL2015-70140-R&RTI2018-093548-B-I00; Y. N. Cajas, SENESCYT-Ecuador; C. L. V. Leal, FAPESP-Brasil 2017/20339-3.

Sign in / Sign up

Export Citation Format

Share Document