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Viruses May 2024Repression of human cytomegalovirus (HCMV) immediate-early (IE) gene expression is a key regulatory step in the establishment and maintenance of latent reservoirs. Viral...
cGAS-STING-TBK1 Signaling Promotes Valproic Acid-Responsive Human Cytomegalovirus Immediate-Early Transcription during Infection of Incompletely Differentiated Myeloid Cells.
Repression of human cytomegalovirus (HCMV) immediate-early (IE) gene expression is a key regulatory step in the establishment and maintenance of latent reservoirs. Viral IE transcription and protein accumulation can be elevated during latency by treatment with histone deacetylase inhibitors such as valproic acid (VPA), rendering infected cells visible to adaptive immune responses. However, the latency-associated viral protein UL138 inhibits the ability of VPA to enhance IE gene expression during infection of incompletely differentiated myeloid cells that support latency. UL138 also limits the accumulation of IFNβ transcripts by inhibiting the cGAS-STING-TBK1 DNA-sensing pathway. Here, we show that, in the absence of UL138, the cGAS-STING-TBK1 pathway promotes both IFNβ accumulation and VPA-responsive IE gene expression in incompletely differentiated myeloid cells. Inactivation of this pathway by either genetic or pharmacological inhibition phenocopied UL138 expression and reduced VPA-responsive IE transcript and protein accumulation. This work reveals a link between cytoplasmic pathogen sensing and epigenetic control of viral lytic phase transcription and suggests that manipulation of pattern recognition receptor signaling pathways could aid in the refinement of MIEP regulatory strategies to target latent viral reservoirs.
Topics: Humans; Valproic Acid; Myeloid Cells; Signal Transduction; Membrane Proteins; Cytomegalovirus; Nucleotidyltransferases; Protein Serine-Threonine Kinases; Cytomegalovirus Infections; Virus Latency; Transcription, Genetic; Cell Differentiation; Gene Expression Regulation, Viral; Genes, Immediate-Early; Interferon-beta
PubMed: 38932169
DOI: 10.3390/v16060877 -
Pharmaceuticals (Basel, Switzerland) May 2024(1) Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are extremely severe cutaneous adverse drug reactions which are relatively rare in...
(1) Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are extremely severe cutaneous adverse drug reactions which are relatively rare in routine clinical practice. An analysis of a national pharmacovigilance database may be the most effective method of obtaining information on SJS and TEN. (2) Methods: Design-a retrospective descriptive pharmacoepidemiologic study of spontaneous reports (SRs) with data on SJS and TEN retrieved from the Russian National Pharmacovigilance database for the period from 1 April 2019 to 31 December 2023. Descriptive statistics was used to assess the demographic data of patients and the structure of suspected drugs. (3) Results: A total of 170 SRs on SJS and TEN were identified, of which 32.9% were SJS and 67.1%-TEN. In total, 30% were pediatric SRs, 21.2%-SRs of the elderly. There were 12 lethal cases, and all cases were TEN. The leading culprit drugs were anti-infectives for systemic use and nervous system agents. The top 10 involved drugs are as follows: lamotrigine (23.5%), ibuprofen (12.9%), ceftriaxone (8.8%), amoxicillin and amoxicillin with beta-lactam inhibitors (8.8%), paracetamol (7.6%), carbamazepine (5.9%), azithromycin (4.1%), valproic acid (4.1%), omeprazole (3.5%), and levetiracetam (3.5%). (4) Conclusions: Our study was the first study in Russia aimed at the assessment of the structure of the drugs involved in SJS and TEN on the national level.
PubMed: 38931343
DOI: 10.3390/ph17060675 -
Antibiotics (Basel, Switzerland) May 2024Interactions between drugs are a common problem in Intensive Care Unit patients, as they mainly have a critical condition that often demands the administration of... (Review)
Review
Interactions between drugs are a common problem in Intensive Care Unit patients, as they mainly have a critical condition that often demands the administration of multiple drugs simultaneously. Antibiotics are among the most frequently used medications, as infectious diseases are often observed in ICU patients. In this review, the most important antibiotic-drug interactions, based on the pharmacokinetic and pharmacodynamic mechanisms, were gathered together and described. In particular, some of the most important interactions with main groups of antibacterial drugs were observed in patients simultaneously prescribed oral anticoagulants, NSAIDs, loop diuretics, and valproic acid. As a result, the activity of drugs can be increased or decreased, as dosage modification might be necessary. It should be noted that these crucial interactions can help predict and avoid negative consequences, leading to better patient recovery. Moreover, since there are other factors, such as fluid therapy or albumins, which may also modify the effectiveness of antibacterial therapy, it is important for anaesthesiologists to be aware of them.
PubMed: 38927170
DOI: 10.3390/antibiotics13060503 -
Nature Jun 2024Interindividual genetic variation affects the susceptibility to and progression of many diseases. However, efforts to study how individual human brains differ in normal...
Interindividual genetic variation affects the susceptibility to and progression of many diseases. However, efforts to study how individual human brains differ in normal development and disease phenotypes are limited by the paucity of faithful cellular human models, and the difficulty of scaling current systems to represent multiple people. Here we present human brain Chimeroids, a highly reproducible, multidonor human brain cortical organoid model generated by the co-development of cells from a panel of individual donors in a single organoid. By reaggregating cells from multiple single-donor organoids at the neural stem cell or neural progenitor cell stage, we generate Chimeroids in which each donor produces all cell lineages of the cerebral cortex, even when using pluripotent stem cell lines with notable growth biases. We used Chimeroids to investigate interindividual variation in the susceptibility to neurotoxic triggers that exhibit high clinical phenotypic variability: ethanol and the antiepileptic drug valproic acid. Individual donors varied in both the penetrance of the effect on target cell types, and the molecular phenotype within each affected cell type. Our results suggest that human genetic background may be an important mediator of neurotoxin susceptibility and introduce Chimeroids as a scalable system for high-throughput investigation of interindividual variation in processes of brain development and disease.
PubMed: 38926573
DOI: 10.1038/s41586-024-07578-8 -
Epilepsy & Behavior : E&B Jun 2024This study aimed to identify the factors associated with insomnia in MRI-negative epilepsy and uncover the underlying pathological mechanism driving insomnia within the...
OBJECTIVE
This study aimed to identify the factors associated with insomnia in MRI-negative epilepsy and uncover the underlying pathological mechanism driving insomnia within the context of epilepsy.
METHODS
We conducted a retrospective study of patients with MRI-negative epilepsy recruited consecutively from December 2021 to December 2022. All subjects completed the Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS), Self-rating Anxiety Scale (SAS), and Self-rating Depression Scale (SDS). Additionally, some subjects underwent the three-dimensional pseudo continuous arterial spin labeling(3D-pCASL) imaging examination. Bilateral frontal lobe, temporal lobe, hippocampus, thalamus, amygdala, caudate nucleus and lenticular nucleus were selected as regions of interest(ROI) and cerebral blood flow(CBF) values were measured in these regions. Subjects were classified into insomnia (ISI ≥ 10) or non-insomnia (ISI < 10) groups, and univariate and stepwise logistic regression analyses were employed to identify the factors associated with insomnia. Furthermore, CBF values in each ROI were compared between the two groups to identify the brain regions potentially related to the underlying pathological mechanism of insomnia in epilepsy.
RESULTS
A total of 73 patients with MRI-negative epilepsy were recruited in this study(men, 49.3 %). Among them, 14 patients(19.2 %) had insomnia. Univariate regression revealed that nocturnal seizures, number of anti-seizure medication(ASM), anxiety, use of valproic acid(VPA), depression, and excessive daytime sleepiness(EDS) may be associated with insomnia in MRI-negative epilepsy (all p<0.05). Stepwise regression demonstrated that nocturnal seizures, anxiety, and EDS were independently associated with insomnia in MRI-negative epilepsy (OR[95 %CI]P: 14.64[2.02-106.27]0.008,49.35[3.06-796.61]0.006, 13.28[1.25-140.66]0.032, respectively). Furthermore, CBF values in the left amygdala were significantly lower in patients with MRI- negative epilepsy who had insomnia.
CONCLUSION
The prevalence of insomnia in MRI-negative epilepsy is 19.2%. Nocturnal seizures, anxiety, and EDS were independently associated with insomnia in MRI-negative epilepsy. The noteworthy decrease in CBF values in the left amygdala might be connected to the underlying pathological mechanism of insomnia in epilepsy.
PubMed: 38924967
DOI: 10.1016/j.yebeh.2024.109903 -
International Journal of Developmental... Jun 2024Stigma maydis polysaccharide (SMPS) has regulatory effect on the intestinal microflora and promotes gastrointestinal peristalsis. Children with autism spectrum disorder...
Stigma maydis polysaccharide (SMPS) has regulatory effect on the intestinal microflora and promotes gastrointestinal peristalsis. Children with autism spectrum disorder (ASD) often experience gastrointestinal problems and dysbiosis in their gut microbiota. Our previous study revealed that SMPS interventions had an impact on the gut microbiota of valproic acid (VPA)-induced autism model rats. However, the effects of SMPS on the behavior and gut function of autism model rats remain poorly understood. Therefore, we gave different doses of SMPS intervention in the early stage of autism model rats to observe their developmental conditions and behavior performances. Through histological evaluation and real-time polymerase chain reaction (PCR), integrity of the intestinal structure and the expression of tight junction-related gene Zo-1 and Occludin were detected. The results indicated that SMPS intervention improved the physical development, learning and memory impairment, and social performance of autism model rats. Meanwhile, SMPS promoted intestinal peristalsis and restored the integrity of the intestinal structure, reduced the number of inflammatory cells, and increased the expression of the Zo-1 and Occludin genes. Furthermore, the expression levels of neurotransmitters (substance P, enkephalin, vasoactive intestinal peptide, and 5-hydroxytryptamine) in the hippocampal tissues were altered after SMPS treatment. In conclusion, SMPS could ameliorate ASD-like phenotypes and gut problems in autism model rats. Collectively, these results provide new evidence for the relationship between the gut-brain axis and ASD and suggest a novel therapeutic target for ASD treatment.
PubMed: 38923604
DOI: 10.1002/jdn.10354 -
CPT: Pharmacometrics & Systems... Jun 2024Significant pharmacokinetic (PK) differences exist between different forms of valproic acid (VPA), such as syrup and sustained-release (SR) tablets. This study aimed to...
Significant pharmacokinetic (PK) differences exist between different forms of valproic acid (VPA), such as syrup and sustained-release (SR) tablets. This study aimed to develop a population pharmacokinetic (PopPK) model for VPA in children with epilepsy and offer dose adjustment recommendation for switching dosage forms as needed. The study collected 1411 VPA steady-state trough concentrations (C) from 617 children with epilepsy. Using NONMEM software, a PopPK model was developed, employing a stepwise approach to identify possible variables such as demographic information and concomitant medications. The final model underwent internal and external evaluation via graphical and statistical methods. Moreover, Monte Carlo simulations were used to generate a dose tailoring strategy for typical patients weighting 20-50 kg. As a result, the PK characteristics of VPA were described using a one-compartment model with first-order absorption. The absorption rate constant (k) was set at 2.64 and 0.46 h for syrup and SR tablets. Body weight and sex were identified as significant factors affecting VPA's pharmacokinetics. The final PopPK model demonstrated acceptable prediction performance and stability during internal and external evaluation. For children taking syrup, a daily dose of 25 mg/kg resulted in the highest probability of achieving the desired target C, while a dose of 20 mg/kg/day was appropriate for those taking SR tablets. In conclusion, we established a PopPK model for VPA in children with epilepsy to tailor VPA dosage when switching between syrup and SR tablets, aiming to improve plasma VPA concentrations fluctuations.
PubMed: 38923247
DOI: 10.1002/psp4.13191 -
Molecular Neurobiology Jun 2024Evidence suggests that long non-coding RNAs (lncRNAs) play a significant role in autism. Herein, we explored the functional role and possible molecular mechanisms of...
Evidence suggests that long non-coding RNAs (lncRNAs) play a significant role in autism. Herein, we explored the functional role and possible molecular mechanisms of NEAT1 in valproic acid (VPA)-induced autism spectrum disorder (ASD). A VPA-induced ASD rat model was constructed, and a series of behavioral tests were performed to examine motor coordination and learning-memory abilities. qRT-PCR and western blot assays were used to evaluate target gene expression levels. Loss-and-gain-of-function assays were conducted to explore the functional role of NEAT1 in ASD development. Furthermore, a combination of mechanistic experiments and bioinformatic tools was used to assess the relationship and regulatory role of the NEAT1-YY1-UBE3A axis in ASD cellular processes. Results showed that VPA exposure induced autism-like developmental delays and behavioral abnormalities in the VPA-induced ASD rat model. We found that NEAT1 was elevated in rat hippocampal tissues after VPA exposure. NEAT1 promoted VPA-induced autism-like behaviors and mitigated apoptosis, oxidative stress, and inflammation in VPA-induced ASD rats. Notably, NEAT1 knockdown improved autism-related behaviors and ameliorated hippocampal neuronal damage. Mechanistically, it was observed that NEAT1 recruited the transcription factor YY1 to regulate UBE3A expression. Additionally, in vitro experiments further confirmed that NEAT1 knockdown mitigated hippocampal neuronal damage, oxidative stress, and inflammation through the YY1/UBE3A axis. In conclusion, our study demonstrates that NEAT1 is highly expressed in ASD, and its inhibition prominently suppresses hippocampal neuronal injury and oxidative stress through the YY1/UBE3A axis, thereby alleviating ASD development. This provides a new direction for ASD-targeted therapy.
PubMed: 38922486
DOI: 10.1007/s12035-024-04309-y -
Expert Opinion on Drug Metabolism &... Jun 2024The literature associates clozapine with pneumonia/aspiration pneumonia.
Investigating in VigiBase® over 6000 cases of pneumonia in clozapine-treated patients in the context of the literature: focus on high lethality and the association with aspiration pneumonia.
BACKGROUND
The literature associates clozapine with pneumonia/aspiration pneumonia.
RESEARCH DESIGN AND METHODS
The international pharmacovigilance database (VigiBase™) uses the information component (IC) as statistical signal. VigiBase clozapine reports were analyzed for pneumonia/aspiration pneumonia from introduction to 10 May 2023.
RESULTS
There were 6392 cases of all types of pneumonia (5572 cases of pneumonia, 775 of aspiration pneumonia, and 45 combined). The IC was 3.52 for aspiration pneumonia, introduced as a VigiBase label in 2003, and 1.91 for pneumonia. Patients were reclassified as 3628 with no signs of aspiration and 1533 with signs. Signs of aspiration were strongly associated with some co-medications: olanzapine, odds ratio (OR) = 23.8, 95% confidence interval (CI), 14.9-38.0; risperidone OR = 18.6, CI, 11.4-30.4; valproic acid, OR = 5.5, CI, 4.5-6.6; and benzodiazepines OR = 5.5, CI, 4.5-6.6. In 2415 cases with completed data, fatal outcomes made up 45% (signs of aspiration made no difference), but there was wide variability from 0% (females <45 years of age; duration ≤30 days) to 76% (males >64 years of age; duration >1 year). During the first week, pneumonia was associated with: 1) very high titration doses, 2) very small doses in Parkinson's disease and 3) Japan vs other countries.
CONCLUSIONS
In clozapine-treated patients: 1) at least 30% of pneumonia cases may be aspiration pneumonia, 2) stopping some co-medications may decrease the risk of aspiration pneumonia, 3) average lethality in pneumonia was 45% but may be around 75% in geriatric patients in long-term treatment, and 4) safer titrations may sometimes require 5-mg tablets.
PubMed: 38920369
DOI: 10.1080/17425255.2024.2373111 -
Naunyn-Schmiedeberg's Archives of... Jun 2024Ziprasidone is widely used in the treatment of psychiatric disorders. Despite its prevalence, there is a notable lack of population pharmacokinetics (PPK) studies on...
Ziprasidone is widely used in the treatment of psychiatric disorders. Despite its prevalence, there is a notable lack of population pharmacokinetics (PPK) studies on ziprasidone in serum, both domestically and internationally. This study aimed to comprehensively investigate the various factors influencing the PPK characteristics of Ziprasidone, thereby providing a scientific basis for personalized treatment strategies in clinical settings. This is a retrospective study. A non-linear mixed-effects modeling method was used for data analysis, with the ziprasidone PPK model established using the Phoenix NLME 8.1 software. Model evaluation employed goodness-of-fit plots, visual predictive checks, and Bootstrap methods to ensure reliability and accuracy. To further validate the model's applicability, data from an additional 30 patients meeting the same inclusion criteria but not included in the final model were collected for external validation. Simulations were performed to explore the personalized dosage regimens. This retrospective analysis collected 547 drug concentration data points from 185 psychiatric disorder patients, along with related medical records. The data included detailed demographic information (such as age, gender, weight), dosing regimens, laboratory test results, and concomitant medication details. In the final model, Ka was fixed at 0.5 h based on literature, and the population typical values for ziprasidone clearance (CL) and volume of distribution (V) were 18.74 L/h and 110.24 L, respectively. Co-administration of lorazepam and valproic acid significantly influenced the clearance of ziprasidone. Moreover, the model evaluation indicated good stability and predictive accuracy. A simple to use dosage regimen table was derived based on the results of simulations. This study successfully established and validated a PPK model for ziprasidone in Chinese patients with psychiatric disorders. The model provides a scientific reference for individualized dosing of ziprasidone and holds the potential to optimize treatment strategies, thereby enhancing therapeutic efficacy and safety.
PubMed: 38918237
DOI: 10.1007/s00210-024-03244-y