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Calcium (Ca[sup.2+])signaling dysfunction is a central contributor to neuronal hyperexcitability and seizure propagation in epilepsy, yet the intracellular mechanisms underlying the actions of valproic acid (VPA) remain incompletely understood. In this study, we investigated whether VPA modulates Ca[sup.2+] homeostasis at the level of the endoplasmic reticulum (ER) and how this action influences cytosolic Ca[sup.2+] dynamics associated with epileptiform activity. ER Ca[sup.2+] levels were directly measured using ER-targeted aequorin in HeLa and PC12 cells, while cytosolic Ca[sup.2+] signals were monitored by fura-2 fluorescence imaging in bovine chromaffin cells exposed to veratridine, a model of sustained sodium channel activation and Ca[sup.2+] oscillations. VPA induced a concentration-dependent release of Ca[sup.2+] from the ER, with an IC[sub.50] of approximately 17 µM. This effect was preserved in permeabilized cells and exhibited activation kinetics comparable to those elicited by inositol 1,4,5-trisphosphate (InsP[sub.3]). Pharmacological inhibition of InsP[sub.3] receptors (InsP[sub.3]Rs), but not ryanodine receptors or SERCA, abolished VPA-induced ER Ca[sup.2+] release, supporting a selective InsP[sub.3]R-mediated mechanism. Functionally, VPA suppressed the repetitive cytosolic Ca[sup.2+] oscillations induced by veratridine, while simultaneously producing a sustained elevation of cytosolic Ca[sup.2+] originating from ER stores and facilitating depolarization-evoked catecholamine secretion. Together, these results support the conclusion that VPA induces InsP[sub.3]R-mediated Ca[sup.2+] mobilization from the endoplasmic reticulum and identify ER Ca[sup.2+] release as a previously unrecognized intracellular mechanism contributing to its modulatory effects on Ca[sup.2+] signaling and excitability in epilepsy.

Abdominal aortic aneurysm (AAA) is a multifactorial cardiovascular disease with a high risk of death, and it occurs in the infrarenal aorta with vascular dilatation. High blood pressure acts on the aortic wall, resulting in rupture and causing life-threatening intra-abdominal hemorrhage. Vascular smooth muscle cell (VSMC) dysregulation and extracellular matrix (ECM) degradation, especially elastin breaks, contribute to structural changes in the aortic wall. The pathogenesis of AAA includes the occurrence of oxidative stress, inflammatory cell infiltration, elastic fiber fragmentation, VSMC apoptosis, and phenotypic transformation. Tributyrin (TB) is decomposed by intestinal lipase and has a function similar to that of butyrate. Whether TB has a protective effect against AAA remains uncertain. In the present study, we established an AAA murine model by angiotensin II (AngII) induction in low-density lipoprotein receptor knockout (LDLR[sup.-/-]) mice and investigated the effects of orally administered TB on the AAA size, ratio of macrophage infiltration, levels of matrix metalloproteinase (MMP) expression, and epigenetic regulation. TB attenuates AngII-induced AAA size and decreases elastin fragmentation, macrophage infiltration, and MMP expression in the medial layer of the aorta and reduces the levels of SBP (systolic blood pressure, p < 0.001) and MMP-2 (p < 0.02) in the serum. TB reduces the AngII-stimulated expression levels of MMP2 (p < 0.05), MMP9 (p < 0.05), MMP12, and MMP14 in human aortic smooth muscle cells (HASMCs). Moreover, TB and valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, suppress AngII receptor type 1 (AT1R, p < 0.05) activation and increase the expression of acetyl histone H3 by HDAC activity inhibition (p < 0.05). Our findings suggest that TB exerts its protective effect by suppressing the activation of HDAC to attenuate the AngII-induced AT1R signaling cascade.

Valproic acid (VPA) is a drug that has various therapeutic applications; however, it has been associated with liver damage. Furthermore, it is interesting to propose new compounds derived from VPA as N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA). The HO-AAVPA has better antiproliferative activity than the VPA in different cancer cell lines. The purpose of this study was to evaluate the liver injury of HO-AAVPA by acute treatment (once administration) and repeated doses for 7 days under intraperitoneal administration. The median lethal dose value (LD[sub.50]) was determined in rats and mice (females and males) using OECD Guideline 425. In the study, male rats were randomly divided into 4 groups (n = 7), G1: control (without treatment), G2: vehicle, G3: VPA (500 mg/kg), and G4: HO-AAVPA (708 mg/kg, in equimolar ratio to VPA). Some biomarkers related to hepatotoxicity were evaluated. In addition, macroscopic and histological studies were performed. The LD[sub.50] value of HO-AAVPA was greater than 2000 mg/kg. Regarding macroscopy and biochemistry, the HO-AAVPA does not induce liver injury according to the measures of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, glutathione peroxidase, glutathione reductase, and catalase activities. Comparing the treatment with HO-AAVPA and VPA did not show a significant difference with the control group, while malondialdehyde and glutathione-reduced levels in the group treated with HO-AAVPA were close to those of the control (p ≤ 0.05). The histological study shows that liver lesions caused by HO-AAVPA were less severe compared with VPA. Therefore, it is suggested that HO-AAVPA does not induce hepatotoxicity at therapeutic doses, considering that in the future it could be proposed as an antineoplastic drug.

Drug interactions with vitamin K antagonist may involve antiepileptic drug. Numerous antiepileptic drugs are strong inducers or inhibitors of liver enzymes and affect warfarin metabolism, including valproic acid, which is capable of displacing warfarin from the protein binding site. Although this type of drug interaction is less widely recognized, it is a phenomenon that causes significant changes in the INR. We report a case of severe subconjunctival bleeding in patient with concomitant use of warfarin and valproic acid. The management include cessation of the drug, conservative eye treatment, and vitamin K. The case was fully resolved.

Colorectal cancer is the predominant and recurring cancer leading to the second largest cause of mortality, globally. Abnormal regulation of oncogenes and deactivation of tumor suppressor genes over an extended period were key mechanisms underlying colon tumorigenesis. As a result, an effective drug targeting these genes should be explored to combat this disease. We aim to explore the effects of Valproic acid (VPA), a histone deacetylase inhibitor (HDACi), and Zebularine (ZEB), DNA methyltransferase inhibitor, on the expression of the Krüppel-like factor 4 (KLF4) and CTNNB1 ([beta]-catenin) in an early-stage colon cells (SW480 cells) and a late-stage colon cell (DLD-1 cells). Using several in-vitro assays including cell viability, proliferation assay, single cell imaging and analysis and molecular assays including qPCR, protein expression analysis, we have assessed the anticancer properties of both drugs, VPA and ZEB. The synergistic effect of VPA and ZEB could effectively inhibit the proliferation of colon cells than their independent doses. The gene expression profile revealed 2-fold increase in the expression of KLF4 in SW480 cells, with increase to about 22-fold in DLD-1 cells. Notably, CTNNB1 was downregulated than KLF4 in a dose dependent manner, potentially leading to antitumorigenic and anti-proliferative properties of the combinatorial drug. Cellular localization of KLF4 and CTNNB1 protein expression in cytoplasm and nucleus with morphological changes of the cancer cells revealed the onset of programmed cell death. qPCR analysis also showed the downregulation of KLF4 and CTNNB1 upon synergistic activity of ZEB and VPA treated colon cancer cells. Microscopic analysis confirmed the upregulation of KLF4 in ZEB treatment cells leading to DNA methylation. Finally, single cell image analysis has shown the reduced expression of both KLF4 and CTNNB1. Overall, the analysis confirmed that synergistic effect of ZEB and VPA served as a potential anti-colon cancer agent.

BackgroundMany patients with bipolar I disorder do not respond to monotherapy treatment with mood-stabilizing medications, and combination regimens are commonly used in both inpatient and outpatient settings for the acute and maintenance treatment of bipolar disorder. We studied whether combination therapy is more effective than monotherapy for the acute treatment of subjects with bipolar I disorder currently experiencing manic symptoms. The primary hypothesis was that combination treatments would be associated with greater reductions in symptoms of mania and hypomania than monotherapy alone. The secondary hypothesis was that combination therapies would be associated with lower depression levels than monotherapy alone. Last, a post-hoc exploratory aim was used to examine whether the effect of side effect severity on risk-of-dropout would be greater in combination therapies than in monotherapy alone.ResultsIn this 12-week, double-blind, placebo-controlled ambulatory pilot trial, participants (n = 75) with bipolar I disorder were randomly assigned to: (1) monotherapy divalproex plus placebo (DVP + PBO), (2) combination therapy of divalproex plus blinded lithium (DVP + Li) or (3) divalproex plus blinded quetiapine (DVP + QTP). Combination therapies (vs. monotherapy) were not associated with improved symptoms of mania, hypomania or depression. The effect of side effect severity on study retention did not differ between combination therapies and monotherapy. However, the risk-of-dropout was significantly greater in the DVP + Li arm versus the DVP + PBO arm.ConclusionsNo longitudinal differences in mania, hypomania or depression were found between combination therapies and monotherapy. The effect of side effect severity on study retention did not differ between groups. Due to the small sample size and differential rates of attrition between treatment arms, results of this pilot trial must be interpreted with caution.Trial registration ClinicalTrials.gov identifier: NCT00183443

Valproic acid (VPA) is a widely prescribed drug to treat epilepsy, bipolar disorder, and migraine. If taken during pregnancy, however, exposure to the developing embryo can cause birth defects, cognitive impairment, and autism spectrum disorder. How VPA causes these developmental defects remains unknown. We used embryonic mice and human organoids to model key features of VPA drug exposure, including exencephaly, microcephaly, and spinal defects. In the malformed tissues, in which neurogenesis is defective, we find pronounced induction of cellular senescence in the neuroepithelial (NE) cells. Critically, through genetic and functional studies, we identified p19.sup.Arf as the instrumental mediator of senescence and microcephaly, but, surprisingly, not exencephaly and spinal defects. Together, these findings demonstrate that misregulated senescence in NE cells can contribute to developmental defects.

Mutations in genes encoding chromatin modifiers are enriched among mutations causing intellectual disability. The continuing development of the brain postnatally, coupled with the inherent reversibility of chromatin modifications, may afford an opportunity for therapeutic intervention following a genetic diagnosis. Development of treatments requires an understanding of protein function and models of the disease. Here, we provide a mouse model of Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) (OMIM 603736) and demonstrate proof-of-principle efficacy of postnatal treatment. SBBYSS results from heterozygous mutations in the KAT6B ( MYST4/MORF/QFK ) gene and is characterized by intellectual disability and autism-like behaviors. Using human cells carrying SBBYSS-specific KAT6B mutations and Kat6b heterozygous mice ( Kat6b +/– ), we showed that KAT6B deficiency caused a reduction in histone H3 lysine 9 acetylation. Kat6b +/– mice displayed learning, memory, and social deficits, mirroring SBBYSS individuals. Treatment with a histone deacetylase inhibitor, valproic acid, or an acetyl donor, acetyl-carnitine (ALCAR), elevated histone acetylation levels in the human cells with SBBYSS mutations and in brain and blood cells of Kat6b +/– mice and partially reversed gene expression changes in Kat6b +/– cortical neurons. Both compounds improved sociability in Kat6b +/– mice, and ALCAR treatment restored learning and memory. These data suggest that a subset of SBBYSS individuals may benefit from postnatal therapeutic interventions.