BACKGROUND: High doses of the histone deacetylase inhibitor valproic acid (VPA, 150-400 mg/kg) improve outcomes in animal models of lethal insults. We are conducting a US Food and Drug Administration-approved Phase I, double-blind, placebo-controlled trial to evaluate the safety and tolerability of ascending doses of VPA in human volunteers. We hypothesized that VPA would induce significant changes in the proteome of healthy humans when given at doses lower than those used in prior animal studies. METHODS:Peripheral blood mononuclear cells were obtained from three healthy subjects randomized to receive VPA (120 mg/kg over 1 hour) at baseline and at 4 and 8 hours following infusion. Detailed proteomic analysis was performed using 1D gel electrophoresis, liquid chromatography, and mass spectrometry. Proteins with differential expression were chosen for functional annotation and pathway analysis using Ingenuity Pathway Analysis (Qiagen GmbH, Hilden, Germany) and Panther Gene Ontology. RESULTS: A total of 3,074 unique proteins were identified. The average number of proteins identified per sample was 1,716 ± 459. There were a total of 140 unique differentially expressed proteins (p < 0.05). There was a minor and inconsistent increase in histone and nonhistone protein acetylation. Functional annotation showed significant enrichment of apoptosis (p = 3.5E-43), cell death (p = 9.9E-72), proliferation of cells (p = 1.6E-40), dementia (p = 9.6E-40), amyloidosis (p = 6.3E-38), fatty acid metabolism (p = 4.6E-76), quantity of steroid (p = 4.2E-75), and cell movement (p = 1.9E-64). CONCLUSIONS:Valproic acid induces significant changes to the proteome of healthy humans when given at a dose of 120 mg/kg. It alters the expression of key proteins and pathways, including those related to cell survival, without significant modification of protein acetylation. In the next part of the ongoing Phase I trial, we will study the effects of VPA on trauma patients in hemorrhagic shock. LEVEL OF EVIDENCE: Therapeutic study, level V.
RCT Entities:
BACKGROUND: High doses of the histone deacetylase inhibitor valproic acid (VPA, 150-400 mg/kg) improve outcomes in animal models of lethal insults. We are conducting a US Food and Drug Administration-approved Phase I, double-blind, placebo-controlled trial to evaluate the safety and tolerability of ascending doses of VPA in human volunteers. We hypothesized that VPA would induce significant changes in the proteome of healthy humans when given at doses lower than those used in prior animal studies. METHODS: Peripheral blood mononuclear cells were obtained from three healthy subjects randomized to receive VPA (120 mg/kg over 1 hour) at baseline and at 4 and 8 hours following infusion. Detailed proteomic analysis was performed using 1D gel electrophoresis, liquid chromatography, and mass spectrometry. Proteins with differential expression were chosen for functional annotation and pathway analysis using Ingenuity Pathway Analysis (Qiagen GmbH, Hilden, Germany) and Panther Gene Ontology. RESULTS: A total of 3,074 unique proteins were identified. The average number of proteins identified per sample was 1,716 ± 459. There were a total of 140 unique differentially expressed proteins (p < 0.05). There was a minor and inconsistent increase in histone and nonhistone protein acetylation. Functional annotation showed significant enrichment of apoptosis (p = 3.5E-43), cell death (p = 9.9E-72), proliferation of cells (p = 1.6E-40), dementia (p = 9.6E-40), amyloidosis (p = 6.3E-38), fatty acid metabolism (p = 4.6E-76), quantity of steroid (p = 4.2E-75), and cell movement (p = 1.9E-64). CONCLUSIONS:Valproic acid induces significant changes to the proteome of healthy humans when given at a dose of 120 mg/kg. It alters the expression of key proteins and pathways, including those related to cell survival, without significant modification of protein acetylation. In the next part of the ongoing Phase I trial, we will study the effects of VPA on traumapatients in hemorrhagic shock. LEVEL OF EVIDENCE: Therapeutic study, level V.
Authors: Aaron M Williams; Umar F Bhatti; Isabel S Dennahy; Kiril Chtraklin; Panpan Chang; Nathan J Graham; Basil M Baccouche; Shalini Roy; Mohammed Harajli; Jing Zhou; Vahagn C Nikolian; Qiufang Deng; Yuzi Tian; Baoling Liu; Yongqing Li; Gregory L Hays; Julia L Hays; Hasan B Alam Journal: J Vis Exp Date: 2018-08-24 Impact factor: 1.355
Authors: Vahagn C Nikolian; Baihong Pan; Tomaz Mesar; Isabel S Dennahy; Patrick E Georgoff; Xiuzhen Duan; Baoling Liu; Xizi Wu; Michael J Duggan; Hasan B Alam; Yongqing Li Journal: Inflammation Date: 2017-08 Impact factor: 4.092
Authors: Simone E Dekker; Vahagn C Nikolian; Martin Sillesen; Ted Bambakidis; Patrick Schober; Hasan B Alam Journal: J Neurosci Res Date: 2017-07-25 Impact factor: 4.164
Authors: I F Duarte; J Caio; M F Moedas; L A Rodrigues; A P Leandro; I A Rivera; M F B Silva Journal: Cell Mol Life Sci Date: 2021-10-31 Impact factor: 9.261
Authors: Aaron M Williams; Isabel S Dennahy; Umar F Bhatti; Ben E Biesterveld; Nathan J Graham; Yongqing Li; Hasan B Alam Journal: Shock Date: 2019-09 Impact factor: 3.454
Authors: Ben E Biesterveld; Luke Pumiglia; Ariella Iancu; Alizeh A Shamshad; Henriette A Remmer; Ali Z Siddiqui; Rachel L O'Connell; Glenn K Wakam; Michael T Kemp; Aaron M Williams; Manjunath P Pai; Hasan B Alam Journal: J Trauma Acute Care Surg Date: 2020-12 Impact factor: 3.697