scholarly journals Acute Strenuous Exercise Induces an Imbalance on Histone H4 Acetylation/Histone Deacetylase 2 and Increases the Proinflammatory Profile of PBMC of Obese Individuals

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Gilson P. Dorneles ◽  
Maria Carolina R. Boeira ◽  
Lucas L. Schipper ◽  
Ivy R. V. Silva ◽  
Viviane R. Elsner ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Mononuclear Cells ◽  
Strenuous Exercise ◽  
Low Grade ◽  
Histone H4 ◽  
Peripheral Blood Mononuclear ◽  
Histone Deacetylase 2 ◽  
Histone H4 Acetylation ◽  
Low Grade Inflammation

This study evaluated the response of global histone H4 acetylation (H4ac), histone deacetylase 2 (HDAC2) activity, as well as the production of proinflammatory cytokines and monocyte phenotypes of lean and obese males after exercise. Ten lean and ten obese sedentary men were submitted to one session of strenuous exercise, and peripheral blood mononuclear cells (PBMC) were stimulated in vitro with lipopolysaccharide (LPS). Global H4ac levels, HDAC2 activity in PBMC, and IL-6, IL-8, and TNF-α production were analyzed. Monocyte phenotype was determined in accordance with the expression of CD14 and CD16. At rest, obese individuals presented higher frequency of proinflammatory CD14+CD16+ monocytes. LPS induced a significant augment in global H4ac and in the production of IL-6, IL-8, and TNF-α mainly in obese individuals. After exercise, the increased production of IL-8 and TNF-α and peripheral frequency of CD14+CD16+ were observed in both groups. In addition, exercise also induced a significant hyperacetylation of histone H4 and decreased HDAC2 activity in both nonstimulated and LPS-stimulated PBMC of obese individuals. Our data indicate that the obesity impacts on H4ac levels and that strenuous exercise leads to an enhanced chronic low-grade inflammation profile in obesity via an imbalance on H4ac/HDAC2.

scholarly journals CBIO-19. LOW GLOBAL HISTONE H4 ACETYLATION LEVELS REVEAL CANDIDATE QUIESCENT CELL POPULATIONS IN GLIOMA AND DISTINGUISH TUMORS BY GRADE

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii19-ii19
Author(s):  
Anca Mihalas ◽  
Heather Feldman ◽  
Anoop Patel ◽  
Patrick Paddison
Keyword(s):  
Cell Types ◽  
Strand Break ◽  
Cell Cycle Gene ◽  
Low Grade ◽  
Histone H4 ◽  
Current Standard ◽  
A Genome ◽  
Histone H4 Acetylation

Abstract Current standard of care therapy for glioblastoma (GBM) includes cytoreduction followed by ablative therapies that target rapidly dividing cell types. However, the presence of quiescent-like/G0 states, therefore, represents a natural reservoir of tumor cells that are resistant to current treatments. Quiescence or G0 phase is a reversible state of “stasis” cells enter in response to developmental or environmental cues. To gain insight into how glioblastoma cells might regulate G0-like states, we performed a genome-wide CRISPR-Cas9 screen in patient-derived GBM stem-like cells (GSCs) harboring a G0-reporter to identify genes that when inhibited trap GSCs in G0-like states. Among the top screen hits were members of the Tip60/KAT5 histone acetyltransferase complex, which targets both histones (e.g., H4) and non-histone proteins for acetylation. NuA4 functions as a transcriptional activator, whose activities are coordinated with MYC in certain contexts, and also participates in DNA double-strand break repair by facilitating chromatin opening. However, currently little is known about the roles for NuA4 complex in GBM biology. Through modeling KAT5 function in GSC in vitro cultures and in vivo tumors, we find that KAT5 inhibition causes cells to arrest in a G0-like state with high p27 levels, G1-phase DNA content, low protein synthesis rates, low rRNA rates, lower metabolic rate, suppression of cell cycle gene expression, and low histone H4 acetylation. Interestingly, partial inhibition of KAT5 activity slows highly aggressive tumor growth, while increasing p27hi H4-aclow populations. Remarkably, we that low grade gliomas have significantly higher H4-aclow subpopulations and generally lower H4-ac levels than aggressive grade IV tumors. Taken together, our results suggest that NuA4/KAT5 activity may play a key role in quiescence ingress/egress in glioma and that targeting its activity in high grade tumors may effectively “down grade” them, thus, increase patient survival.

Phase I trial of the oral histone deacetylase inhibitor MS-275 administered with food

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13036-13036 ◽  
Author(s):  
E. A. Donovan ◽  
A. Sparreboom ◽  
W. Figg ◽  
J. Trepel ◽  
K. Maynard ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Mononuclear Cells ◽  
Interindividual Variability ◽  
Protein Acetylation ◽  
Hdac Inhibition ◽  
Peripheral Blood Mononuclear ◽  
Advanced Malignancy ◽  
Grade 3

13036 Background: The histone deacetylase (HDAC) inhibitor MS-275, a synthetic benzamide derivative, has demonstrated antitumor activity in vitro & in vivo. After determining maximum tolerable dose (MTD = 2 mg/m2) & dose limiting toxicity (DLT) for MS-275 given to fasting patients (pts) weekly ×4 q6 weeks, we explored toxicity profile, MTD, & pharmacokinetics (PK) of MS-275 when given po on the same schedule with food. Methods: MS-275 at 2, 4, or 6 mg/m2 was administered to pts with advanced malignancy & PS ≤2, LFTs ≤2.5 × normal, adequate hematopoietic & renal function, & normal resting MUGA. PK samples were analyzed by LC-MS. Data for pts in the fed state were compared to data obtained in previous cohorts of pts treated in the fasting state. Protein acetylation assessed by a novel flow cytometric assay & HDAC enzymatic activity were measured in peripheral blood mononuclear cells (PBMC). Results: 16 pts received a median of 2 cycles (1–5) of MS-275 2–6 mg/m2 with food. No DLT occurred on 2 or 6 mg/m2 (n = 3 each), while 1 pt on 4 mg/m2 (n = 10) had a DLT: grade 3 hypophosphatemia. For 2–6 mg/m2 other grade 3 toxicities were neutropenia & lymphopenia. Grade 1–2 toxicities in >1 pt were leucopenia, anemia, thrombocytopenia, fatigue, nausea, vomiting, headache, hypoalbuminemia, hypophosphatemia, hyponatremia, & hypocalcemia. MTD has not been reached; current dose level is 8 mg/m2. Comparing PK for fasting & fed pts on 2–4 mg/m2, there was no difference in Tmax (0.5h); average Cmax & AUC were 35% & 25% lower, respectively, in fed pts; this difference is not statistically significant. Interindividual variability in exposure to MS-275 increased from 52% in fasting pts to 100% in fed pts. PBMC protein acetylation & HDAC inhibition were seen at all dose levels (2–6 mg/m2) in fed pts. Of 9 pts evaluable for response (2–4 mg/m2), 2 of 6 pts on 4 mg/m2 had stable disease. Conclusions: MTD has not yet been established for MS-275 given with food on this schedule but is ≥4 mg/m2 weekly x4 q6 weeks. Interindividual variability in exposure increases with food. Whether intestinal absorption is decreased when MS-275 is given with food requires further evaluation with additional patients. Drug-related protein hyperacetylation & HDAC inhibition were observed. [Table: see text]

scholarly journals The Influence of Methylsulfonylmethane on Inflammation-Associated Cytokine Release before and following Strenuous Exercise

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Mariè van der Merwe ◽  
Richard J. Bloomer
Keyword(s):  
Whole Blood ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Knee Extension ◽  
Strenuous Exercise ◽  
Peripheral Blood Mononuclear ◽  
Physically Active ◽  
Inflammatory Molecules

Background. Inflammation is associated with strenuous exercise and methylsulfonylmethane (MSM) has been shown to have anti-inflammatory properties.Methods. Physically active men were supplemented with either placebo or MSM (3 grams per day) for 28 days before performing 100 repetitions of eccentric knee extension exercise.Ex vivoandin vitrotesting consisted of evaluating cytokine production in blood (whole blood and isolated peripheral blood mononuclear cells (PBMCs)) exposed to lipopolysaccharide (LPS), before and through 72 hours after exercise, whilein vivotesting included the evaluation of cytokines before and through 72 hours after exercise.Results. LPS stimulation of whole blood after MSM supplementation resulted in decreased induction of IL-1β, with no effect on IL-6, TNF-α, or IL-8. After exercise, there was a reduced response to LPS in the placebo, but MSM resulted in robust release of IL-6 and TNF-α. A small decrease in resting levels of proinflammatory cytokines was noted with MSM, while an acute postexercise increase in IL-10 was observed with MSM.Conclusion. Strenuous exercise causes a robust inflammatory reaction that precludes the cells from efficiently responding to additional stimuli. MSM appears to dampen the release of inflammatory molecules in response to exercise, resulting in a less incendiary environment, allowing cells to still have the capacity to mount an appropriate response to an additional stimulus after exercise.

scholarly journals Kinetics of Replication of a Partially Attenuated Virus and of the Challenge Virus during a Three-Year Intersubtype Feline Immunodeficiency Virus Superinfection Experiment in Cats

1999 ◽  
Vol 73 (2) ◽  
pp. 1518-1527 ◽  
Author(s):  
Mauro Pistello ◽  
Donatella Matteucci ◽  
Giancarlo Cammarota ◽  
Paola Mazzetti ◽  
Simone Giannecchini ◽  
...  
Keyword(s):  
Feline Immunodeficiency Virus ◽  
Mononuclear Cells ◽  
Acute Infection ◽  
Low Grade ◽  
Peripheral Blood Mononuclear ◽  
Subtype B ◽  
Immunodeficiency Virus ◽  
Attenuated Virus

ABSTRACT The effects of preinfecting cats with a partially attenuated feline immunodeficiency virus (FIV) on subsequent infection with a fully virulent FIV belonging to a different subtype were investigated. Eight specific-pathogen-free cats were preinfected with graded doses of a long-term in vitro-cultured cell-free preparation of FIV Petaluma (FIV-P, subtype A). FIV-P established a low-grade or a silent infection in the inoculated animals. Seven months later, the eight preinfected cats and two uninfected cats were challenged with in vivo-grown FIV-M2 (subtype B) and periodically monitored for immunological and virological status. FIV-P-preinfected cats were not protected from acute infection by FIV-M2, and the sustained replication of this virus was accompanied by a reduction of FIV-P viral loads in the peripheral blood mononuclear cells and plasma. However, from 2 years postchallenge (p.c.) until 3 years p.c., when the experiment was terminated, preinfected cats exhibited reduced total viral burdens, and some also exhibited a diminished decline of circulating CD4+ T lymphocytes relative to control cats infected with FIV-M2 alone. Interestingly, most of the virus detected in challenged cats at late times p.c. was of FIV-P origin, indicating that the preinfecting, attenuated virus had become largely predominant. By the end of follow-up, two challenged cats had no FIV-M2 detectable in the tissues examined. The possible mechanisms underlying the interplay between the two viral populations are discussed.

scholarly journals LTB4-Driven Inflammation and Increased Expression of ALOX5/ACE2 During Severe COVID-19 in Individuals with Diabetes

2021 ◽  
Author(s):  
Icaro Bonyek-Silva ◽  
Antônio Fernando Araújo Machado ◽  
Thiago Cerqueira-Silva ◽  
Sara Nunes ◽  
Márcio Rivison Silva Cruz ◽  
...  
Keyword(s):  
Intensive Care ◽  
Mononuclear Cells ◽  
Serum Levels ◽  
Low Grade ◽  
Receptor System ◽  
Peripheral Blood Mononuclear ◽  
Early Markers ◽  
Patients With Diabetes ◽  
Care Assistance ◽  
Low Grade Inflammation

Diabetes is a known risk factor for severe COVID-19, the disease caused by the new coronavirus SARS-CoV-2. However, there is a lack of knowledge about the mechanisms involved in the evolution of COVID-19 in individuals with diabetes. Therefore, we aimed to evaluate whether the chronic low-grade inflammation of diabetes could play a role in the development of severe COVID-19. We collected clinical data and blood samples of hospitalized patients for COVID-19, with diabetes and without diabetes. Plasma samples were used to measure inflammatory mediators and peripheral blood mononuclear cells, for gene expression analysis of SARS-CoV-2 main receptor system (<i>ACE2/TMPRSS2</i>) and main molecule of LTB<sub>4</sub> pathway (<i>ALOX5</i>). We found that diabetes activates LTB<sub>4</sub> pathway, and during COVID-19, it increases <i>ACE2/TMPRSS2</i> as well as <i>ALOX5</i> expression. Diabetes was also associated with COVID-19-related disorders, such as reduced SpO2/FiO2 and PaO2/FiO2 levels, and increased disease duration. In addition, the expression of <i>ACE2</i> and <i>ALOX5</i> are positively correlated, with increased expression in COVID-19 patients with diabetes requiring intensive care assistance. We confirmed these molecular results at the protein level, where plasma LTB<sub>4</sub> is significantly increased in individuals with diabetes. Besides, IL-6 serum levels are increased only in individuals with diabetes requiring intensive care assistance. Together, these results indicate that LTB<sub>4</sub> and IL-6 systemic levels, as well as, <i>ACE2</i><i>/ALOX5</i> blood expression could be early markers of severe COVID-19 in individuals with diabetes.

Phase I clinical, pharmacokinetic, and pharmacodynamic study of CG200745, a histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13560-e13560
Author(s):  
Kyu-Pyo Kim ◽  
Yong Sang Hong ◽  
Jin-Hee Ahn ◽  
Jae-Lyun Lee ◽  
Kyun-Seop Bae ◽  
...  
Keyword(s):  
Single Dose ◽  
Histone Deacetylase ◽  
Hdac Inhibitor ◽  
Mononuclear Cells ◽  
Maximum Tolerated Dose ◽  
Histone H4 ◽  
Peripheral Blood Mononuclear ◽  
Elimination Half ◽  
Solid Malignancies ◽  
Acetylated Histone H4

e13560 Background: The aim of this study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of single dose of intravenous CG200745, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies. Methods: Two to six patients received Intravenous CG200745 every 3 weeks according to the single dose-escalating 2+4 method. Acetylated histone H4 (Acetyl-H4) was measured in peripheral blood mononuclear cells (PBMCs). Results: Ten patients were treated at one of five doses (1.8-24.0 mg/m2) and received 3 (1-7) cycles of CG200745 (median, range). No dose-limiting toxic effects or QTc prolongations were noted. Dose proportionality was observed for both Cmax and AUC. The elimination half-life and mean residual time was 5.43±0.37(mean±SD) and 4.15±0.50 hrs. An increase in Acetyl-H4 was observed at hour 1 and correlated with dose and Cmax. Acetyl-H4 persisted for 8 hrs in 3 pts and 24 hrs in another 3 pts. Stable disease was seen in 2 pts with colorectal cancer at levels 7.2 and 24 mg/m2. Conclusions: CG200745 can be safely administered at the effective dose levels that inhibit HDAC in PBMCs. As MTD was not reached, this agent is under further investigation for multiple ascending doses.

A phase I trial of the histone deacetylase inhibitor panobinostat (LBH589) and epirubicin in patients with solid tumor malignancies.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3058-3058
Author(s):  
Amy Patricia Moore ◽  
Thach-Giao Truong ◽  
Kenneth Ted Thurn ◽  
Scott Thomas ◽  
Charles J. Ryan ◽  
...  
Keyword(s):  
Phase I ◽  
Histone Acetylation ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Phase I Trial ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Deacetylase Inhibitor ◽  
Grade 3

3058 Background: Preclinical and clinical data suggest pre-exposure of cancer cells to a histone deacetylase inhibitor (HDACi) potentiates topoisomerase inhibitors. HDACi-induced histone acetylation and chromatin modulation facilitates DNA access and target recruitment for topo II inhibitors. In vitro data further suggest effective inhibition of HDAC2 is necessary for enhanced epirubicin-induced apoptosis. Methods: This phase I trial explores the safety, tolerability, and maximum tolerated dose (MTD) of escalating doses of panobinostat given orally on days 1, 3, and 5 followed by epirubicin administered intravenously at 75 mg/m2 on day 5 in 21-day cycles. Histone acetylation and HDAC2 expression are evaluated in pre- and post-treatment peripheral blood mononuclear cells (PBMCs) in all patients and in tumor cells of 16 patients treated at the MTD. Results: 36 patients have enrolled [10M/26F, median age 47 years (22-80)] in 5 panobinostat cohorts: 20, 30, 40, 50, 60 mg. Tumor types include melanoma (n=6), breast (n=6), sarcoma (n=16), ovarian (n=2), lung (n=2), and one each of neuroblastoma, pancreatic, testicular, and colon cancer. Prior to enrollment, patients received a median of 3 (0-8) prior chemotherapy regimens and 40% had anthracyclines. Dose-limiting toxicities (DLTs) included 1/3 grade 3 fatigue and 1/3 grade 4 thrombocytopenia at 60 mg of panobinostat, 1/6 patient experienced grade 3 atrial fibrillation at 50 mg, defining 50 mg panobinostat as the MTD. Non-dose–limiting grade 3/4 hematological toxicities include neutropenia (n=19, 53%), febrile neutropenia (n=6, 17%), thrombocytopenia (n=6, 17%), and anemia (n=4, 11%). Of 34 evaluable patients, 5 had partial responses and 14 had stable disease in anthracycline-refractory sarcomas (4) and Her2neu positive breast cancer (2), and small cell lung cancer. Correlative studies demonstrate increased H4 acetylation in PBMCs on day 3 and 5 suggesting sufficient histone deacetylase inhibition. Conclusions: Sequence-specific combination of panobinostat and epirubicin shows early activity without potentiating epirubicin toxicity. Dose expansion in anthracycline-pretreated sarcoma patients is ongoing.

scholarly journals LTB4-Driven Inflammation and Increased Expression of ALOX5/ACE2 During Severe COVID-19 in Individuals with Diabetes

2021 ◽  
Author(s):  
Icaro Bonyek-Silva ◽  
Antônio Fernando Araújo Machado ◽  
Thiago Cerqueira-Silva ◽  
Sara Nunes ◽  
Márcio Rivison Silva Cruz ◽  
...  
Keyword(s):  
Intensive Care ◽  
Mononuclear Cells ◽  
Serum Levels ◽  
Low Grade ◽  
Receptor System ◽  
Peripheral Blood Mononuclear ◽  
Early Markers ◽  
Patients With Diabetes ◽  
Care Assistance ◽  
Low Grade Inflammation

Diabetes is a known risk factor for severe COVID-19, the disease caused by the new coronavirus SARS-CoV-2. However, there is a lack of knowledge about the mechanisms involved in the evolution of COVID-19 in individuals with diabetes. Therefore, we aimed to evaluate whether the chronic low-grade inflammation of diabetes could play a role in the development of severe COVID-19. We collected clinical data and blood samples of hospitalized patients for COVID-19, with diabetes and without diabetes. Plasma samples were used to measure inflammatory mediators and peripheral blood mononuclear cells, for gene expression analysis of SARS-CoV-2 main receptor system (<i>ACE2/TMPRSS2</i>) and main molecule of LTB<sub>4</sub> pathway (<i>ALOX5</i>). We found that diabetes activates LTB<sub>4</sub> pathway, and during COVID-19, it increases <i>ACE2/TMPRSS2</i> as well as <i>ALOX5</i> expression. Diabetes was also associated with COVID-19-related disorders, such as reduced SpO2/FiO2 and PaO2/FiO2 levels, and increased disease duration. In addition, the expression of <i>ACE2</i> and <i>ALOX5</i> are positively correlated, with increased expression in COVID-19 patients with diabetes requiring intensive care assistance. We confirmed these molecular results at the protein level, where plasma LTB<sub>4</sub> is significantly increased in individuals with diabetes. Besides, IL-6 serum levels are increased only in individuals with diabetes requiring intensive care assistance. Together, these results indicate that LTB<sub>4</sub> and IL-6 systemic levels, as well as, <i>ACE2</i><i>/ALOX5</i> blood expression could be early markers of severe COVID-19 in individuals with diabetes.

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