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Frontiers in Genetics 2024Previous studies have shown that endoplasmic reticulum stress (ERS) -induced apoptosis is involved in the pathogenesis of dilated cardiomyopathy (DCM). However, the...
Previous studies have shown that endoplasmic reticulum stress (ERS) -induced apoptosis is involved in the pathogenesis of dilated cardiomyopathy (DCM). However, the molecular mechanism involved has not been fully characterized. In total, eight genes were obtained at the intersection of 1,068 differentially expressed genes (DEGs) from differential expression analysis between DCM and healthy control (HC) samples, 320 module genes from weighted gene co-expression network analysis (WGCNA), and 2,009 endoplasmic reticulum stress (ERGs). These eight genes were found to be associated with immunity and angiogenesis. Four of these genes were related to apoptosis. The upregulation of MX1 may represent an autocompensatory response to DCM caused by a virus that inhibits viral RNA and DNA synthesis, while acting as an autoimmune antigen and inducing apoptosis. The upregulation of TESPA1 would lead to the dysfunction of calcium release from the endoplasmic reticulum. The upregulation of THBS4 would affect macrophage differentiation and apoptosis, consistent with inflammation and fibrosis of cardiomyocytes in DCM. The downregulation of MYH6 would lead to dysfunction of the sarcomere, further explaining cardiac remodeling in DCM. Moreover, the expression of genes affecting the immune micro-environment was significantly altered, including TGF-β family member. Analysis of the co-expression and competitive endogenous RNA (ceRNA) network identified XIST, which competitively binds seven target microRNAs (miRNAs) and regulates MX1 and THBS4 expression. Finally, bisphenol A and valproic acid were found to target MX1, MYH6, and THBS4. We have identified four ERS-related genes (MX1, MYH6, TESPA1, and THBS4) that are dysregulated in DCM and related to apoptosis. This finding should help deepen understanding of the role of endoplasmic reticulum stress-induced apoptosis in the development of DCM.
PubMed: 38699233
DOI: 10.3389/fgene.2024.1366087 -
FEBS Open Bio Jun 2024Myocardial infarction results in extensive cardiomyocyte apoptosis, leading to the formation of noncontractile scar tissue. Given the limited regenerative capacity of...
Myocardial infarction results in extensive cardiomyocyte apoptosis, leading to the formation of noncontractile scar tissue. Given the limited regenerative capacity of adult mammalian cardiomyocytes, direct reprogramming of cardiac fibroblasts (CFs) into cardiomyocytes represents a promising therapeutic strategy for myocardial repair, and small molecule drugs might offer a more attractive alternative to gene editing approaches in terms of safety and clinical feasibility. This study aimed to reprogram rat CFs into cardiomyocytes using a small molecular chemical mixture comprising CHIR99021, Valproic acid, Dorsomorphin, SB431542, and Forskolin. Immunofluorescence analysis revealed a significant increase in the expression of cardiomyocyte-specific markers, including cardiac troponin T (cTnT), Connexin 43 (Cx43), α-actinin, and Tbx5. Changes in intracellular calcium ion levels and Ca signal transfer between adjacent cells were monitored using a calcium ion fluorescence probe. mRNA sequencing analysis demonstrated the upregulation of genes associated with cardiac morphogenesis, myocardial differentiation, and muscle fiber contraction during CF differentiation induced by the small-molecule compounds. Conversely, the expression of fibroblast-related genes was downregulated. These findings suggest that chemical-induced cell fate conversion of rat CFs into cardiomyocyte-like cells is feasible, offering a potential therapeutic solution for myocardial injury.
Topics: Animals; Myocytes, Cardiac; Rats; Fibroblasts; Cellular Reprogramming; Cell Differentiation; Cells, Cultured; Small Molecule Libraries; Rats, Sprague-Dawley; Calcium
PubMed: 38693086
DOI: 10.1002/2211-5463.13811 -
Journal of Cancer Research and... Apr 2024There are emerging but inconsistent evidences about anti-epileptic drugs (AEDs) as radio- or chemo-sensitizers to improve survival in glioblastoma patients. We conducted...
INTRODUCTION
There are emerging but inconsistent evidences about anti-epileptic drugs (AEDs) as radio- or chemo-sensitizers to improve survival in glioblastoma patients. We conducted a nationwide population-based study to evaluate the impact of concurrent AED during post-operative chemo-radiotherapy on outcome.
MATERIAL AND METHODS
A total of 1057 glioblastoma patients were identified by National Health Insurance Research Database and Cancer Registry in 2008-2015. Eligible criteria included those receiving surgery, adjuvant radiotherapy and temozolomide, and without other cancer diagnoses. Survival between patients taking concurrent AED for 14 days or more during chemo-radiotherapy (AED group) and those who did not (non-AED group) were compared, and subgroup analyses for those with valproic acid (VPA), levetiracetam (LEV), or phenytoin were performed. Multivariate analyses were used to adjust for confounding factors.
RESULTS
There were 642 patients in the AED group, whereas 415 in the non-AED group. The demographic data was balanced except trend of more patients in the AED group had previous drug history of AEDs (22.6% vs. 18%, P 0.078). Overall, the AED group had significantly increased risk of mortality (HR = 1.18, P 0.016) compared to the non-AED group. Besides, an adverse dose-dependent relationship on survival was also demonstrated in the AED group (HR = 1.118, P 0.0003). In subgroup analyses, the significant detrimental effect was demonstrated in VPA group (HR = 1.29,P 0.0002), but not in LEV (HR = 1.18, P 0.079) and phenytoin (HR = 0.98, P 0.862).
CONCLUSIONS
Improved survival was not observed in patients with concurrent AEDs during chemo-radiotherapy. Our real-world data did not support prophylactic use of AEDs for glioblastoma patients.
Topics: Humans; Female; Anticonvulsants; Male; Glioblastoma; Middle Aged; Brain Neoplasms; Aged; Chemoradiotherapy, Adjuvant; Adult; Cohort Studies; Phenytoin; Registries; Levetiracetam; Valproic Acid
PubMed: 38687925
DOI: 10.4103/jcrt.jcrt_750_22 -
Cureus Mar 2024Valproic acid (VPA) is utilized in the management of a variety of seizure and mood disorders. A rare side effect of this medication is dose-dependent thrombocytopenia....
Valproic acid (VPA) is utilized in the management of a variety of seizure and mood disorders. A rare side effect of this medication is dose-dependent thrombocytopenia. In this case, we report a patient with a treatment-resistant epilepsy genetic variant phenotype who was admitted for sepsis and found to have significant thrombocytopenia with clinical manifestations of epistaxis and easy bruising, which was found to be due to VPA use rather than secondary to other clinical pathologies. The patient's clinical condition improved with supportive treatment including fluid rehydration. Platelet counts normalized after a transfusion and holding of her valproate. She experienced breakthrough seizures despite the initiation of diazepam. The decision was made to restart VPA per Neurology consult recommendations for better seizure control. She had no breakthrough seizures reported after restarting VPA in the hospital. This case highlights the importance of monitoring antiseizure medication side effects, especially in populations at higher risk due to treatment resistance.
PubMed: 38681313
DOI: 10.7759/cureus.57030 -
Journal of Clinical Medicine Apr 2024: Linezolid is used for Gram-positive bacterial infections. Thrombocytopenia is one of its main adverse effects resulting from myelosuppression. Several studies have...
: Linezolid is used for Gram-positive bacterial infections. Thrombocytopenia is one of its main adverse effects resulting from myelosuppression. Several studies have assessed risk factors that may increase the risk of this adverse effect. However, most studies included patients with hemato-oncologic diseases, which may confound such assessments. This study aimed to investigate risk factors for linezolid-associated thrombocytopenia in patients without hemato-oncologic diseases. : This was a multicenter retrospective case-control study of adult patients treated with linezolid twice daily for ≥3 days. Patients with hemato-oncologic diseases, active dengue fever, active COVID-19, baseline platelet count <100 × 10/mm, concurrent therapy with trimethoprim/sulfamethoxazole or valproic acid, and a recent platelet transfusion within 7 days were excluded. Thrombocytopenia was defined as a drop in platelet count below 100 × 10/mm. : Out of 158 evaluated patients, 33 developed thrombocytopenia, indicating an incidence rate of 20.9%. Of all the risk factors assessed, creatinine clearance of <60 mL/min and bacteremia/infective endocarditis were significantly associated with linezolid-associated thrombocytopenia (adjusted odds ratios, 3.25 and 5.95; 95% CI 1.12-9.45 and 1.23-28.66; = 0.031 and 0.026, respectively). End of therapy platelet counts were significantly lower in the cases than in the controls (79 vs. 243 × 10/mm; < 0.001). Similarly, the percentage of platelet count change was significantly different (-55.1% vs. -10.2%; < 0.001). : In our study, the incidence rate of linezolid-associated thrombocytopenia was 20.9%, and we found that patients with renal impairment and bacteremia may need close monitoring of platelet counts. Prospective studies are warranted to evaluate the potential need for renal dose adjustment.
PubMed: 38673653
DOI: 10.3390/jcm13082380 -
Biomolecules Apr 2024Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by severe deficits in social communication and interaction, repetitive movements, abnormal... (Review)
Review
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by severe deficits in social communication and interaction, repetitive movements, abnormal focusing on objects, or activity that can significantly affect the quality of life of the afflicted. Neuronal and glial cells have been implicated. It has a genetic component but can also be triggered by environmental factors or drugs. For example, prenatal exposure to valproic acid or acetaminophen, or ingestion of propionic acid, can increase the risk of ASD. Recently, epigenetic influences on ASD have come to the forefront of investigations on the etiology, prevention, and treatment of this disorder. Epigenetics refers to DNA modifications that alter gene expression without making any changes to the DNA sequence. Although an increasing number of pharmaceuticals and environmental chemicals are being implicated in the etiology of ASD, here, we specifically focus on the molecular influences of the abovementioned chemicals on epigenetic alterations in neuronal and glial cells and their potential connection to ASD. We conclude that a better understanding of these phenomena can lead to more effective interventions in ASD.
Topics: Autism Spectrum Disorder; Humans; Epigenesis, Genetic; Neuroglia; Valproic Acid; Propionates; Animals; Acetaminophen; Neurons; DNA Methylation
PubMed: 38672454
DOI: 10.3390/biom14040437 -
Cureus Mar 2024The vein of Galen aneurysmal malformation (VGAM) is a rare congenital arteriovenous fistula of the embryonic median prosencephalic vein of Markowski, resulting in its...
The vein of Galen aneurysmal malformation (VGAM) is a rare congenital arteriovenous fistula of the embryonic median prosencephalic vein of Markowski, resulting in its pathological dilation. If left untreated, it can lead to multiple severe complications in the neonatal period, among which obstructive hydrocephalus. We present a case report of a six-year-old male patient with severe status epilepticus and a clinical history of VGAM and obstructive hydrocephalus, diagnosed via an MRI and an MR-angiography. The hydrocephalus was treated via a ventriculostomy at the age of six months, while the VGAM underwent a partial transarterial endovascular embolization when the patient was four years old. The procedures were successful, and there were no significant post-operative complications observed. The epileptic seizures began at a later point and were successfully medicated with valproate. However, they resumed due to a lowering of the medication dosage by the patient's parents. The patient was given a new valproic acid regimen with an appropriate dosage, and his parents reported no further seizures. This case report emphasizes the use of appropriate prenatal and neonatal diagnostic methods for VGAM and explores the nature of the multi-procedural therapy approach towards the pathology and its complications in relation to a possibly idiopathic co-pathology, namely epilepsy.
PubMed: 38665762
DOI: 10.7759/cureus.56962 -
Frontiers in Neurology 2024Vestibular migraine (VM) is a newly defined clinical condition. Several vestibular abnormalities have been reported in patients with VM. However, to date, no specific...
INTRODUCTION
Vestibular migraine (VM) is a newly defined clinical condition. Several vestibular abnormalities have been reported in patients with VM. However, to date, no specific vestibular examinations are used to define VM. Therefore, the utility of vestibular examinations is limited. Currently, the role of vestibular examination has not been clearly defined. We speculated that the results of vestibular examinations could predict the prognosis of VM. We investigated the relationship between the vestibular examination results and clinical outcomes in patients with VM.
METHODS
This study included 25 patients with VM. Vestibular examinations, including the video head impulse test (V-HIT), cervical and ocular vestibular evoked myogenic potential (c-VEMP and o-VEMP), posturography, and several questionnaires, including the Dizziness Handicap Inventory (DHI), were conducted at the initial evaluation. Lifestyle modifications for VM and conventional pharmacological prophylactic treatments, including lomerizine, amitriptyline, and valproic acid, were performed. After 4 weeks of treatment, clinical improvements were evaluated using the Clinical Global Improvement Scale (CGI-s). The relationships among the CGI-S score, several clinical variables, and the results of several vestibular examinations were evaluated. Each patient was further classified into two subgroups according to treatment outcomes concerning vertigo and headache: CGI-S score from 0 to 2 (good response [GR]) and CGI-S score > 3 (poor response [PR]).
RESULTS
Overall, after treatment, most of the patients had improved dizziness and headache, and the CGI-s was 2.7 ± 1.3. There were 12 GRs, and 13 had PRs. Thus, neither V-HIT nor posturography predicted the prognosis. For c-VEMP, patients with GRs had significantly small AR concerning PR (19.2 ± 12.8 and 62.5 ± 42.5, respectively, [ < 0.01]). There were five normal, six unilateral, and 14 bilateral no response in 500hz o-VEMP. CGI-s of normal, unilateral, and bilateral no response was 1.4 ± 0.5, 2.8 ± 1.3, and 3.1 ± 1.2, respectively. There was a statistically significant difference between the normal and bilateral non-response o-VEMP groups ( < 0.05).
CONCLUSION
Patients with VM had improvements in both headache and vertigo through a combination of lifestyle changes and prophylactic medications. Vestibular examinations, especially o- or c-VEMP, are beneficial for predicting the treatment outcomes of VM. The pathophysiology of VM is closely related to vestibular abnormalities, particularly the otolith-related pathways.
PubMed: 38660093
DOI: 10.3389/fneur.2024.1370940 -
PloS One 2024Herpesviruses have two distinct life cycle stages, latency and lytic replication. Epstein-Barr virus (EBV), a gamma-herpesvirus, establishes latency in vivo and in...
Herpesviruses have two distinct life cycle stages, latency and lytic replication. Epstein-Barr virus (EBV), a gamma-herpesvirus, establishes latency in vivo and in cultured cells. Cell lines harboring latent EBV can be induced into the lytic cycle by treatment with chemical inducing agents. In the Burkitt lymphoma cell line HH514-16 the viral lytic cycle is triggered by butyrate, a histone deacetylase (HDAC) inhibitor. Butyrate also alters expression of thousands of cellular genes. However, valproic acid (VPA), another HDAC inhibitor with global effects on cellular gene expression blocks EBV lytic gene expression in Burkitt lymphoma cell lines. Valpromide (VPM), an amide derivative of VPA, is not an HDAC inhibitor, but like VPA blocks induction of the EBV lytic cycle. VPA and VPM are the first examples of inhibitors of initial stages of lytic reactivation. We compared the effects of VPA and VPM, alone and in combination with butyrate, on host cellular gene expression using whole transcriptome analysis (RNA-seq). Gene expression was analyzed 6 h after addition of the compounds, a time before the first EBV lytic transcripts are detected. The results address two alternative, yet possibly complementary, mechanisms for regulation of EBV lytic reactivation. First, cellular genes that were up- or down-regulated by butyrate, but no longer altered in the presence of VPA or VPM, represent genes that correlated with EBV lytic reactivation. Second, genes regulated similarly by VPA and VPM in the absence and presence of butyrate are candidates for suppressors of EBV reactivation. Two genes upregulated by the lytic cycle inhibitors, CHAC1 and SLC7A11, are related to redox status and the iron-dependent cell death pathway ferroptosis. This study generates new hypotheses for control of the latency to lytic cycle switch of EBV and provides the first description of effects of the anti-convulsant drug VPM on global human cellular gene expression.
Topics: Humans; Burkitt Lymphoma; Herpesvirus 4, Human; Histone Deacetylase Inhibitors; Epstein-Barr Virus Infections; Virus Activation; Gene Expression Profiling; Butyrates; Valproic Acid
PubMed: 38635661
DOI: 10.1371/journal.pone.0299198 -
Cureus Mar 2024We report a case involving a 31-year-old male without any known precipitating injuries presenting with involuntary finger movements and rare seizures. There was a noted...
We report a case involving a 31-year-old male without any known precipitating injuries presenting with involuntary finger movements and rare seizures. There was a noted family history of tremulous movements. Yet the characteristics of his finger movements were irregular and not typical of essential tremor (ET). Electrophysiological examinations, including video EEG, showed no epileptic discharges, and brain MRI results were normal. However, somatosensory evoked potentials (SEP) revealed the presence of giant SEP, and a positive cortical (C)-reflex was observed, leading to a clinical diagnosis of benign adult familial myoclonus epilepsy (BAFME). Management with valproic acid and perampanel resulted in a significant reduction of symptoms. This case highlights the necessity of considering BAFME in the differential diagnosis for atypical tremorous finger movements, especially with a relevant family history, and the critical role of electrophysiological findings indicative of cortical hyperexcitability.
PubMed: 38629017
DOI: 10.7759/cureus.56303