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Tidsskrift For Den Norske Laegeforening... Feb 2024
Topics: Humans; Female; Depression, Postpartum; Antidepressive Agents; Pregnancy
PubMed: 38932736
DOI: 10.4045/tidsskr.24.0035 -
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 -
Nutrients Jun 2024Maternal obesity and/or Western diet (WD) is associated with an increased risk of metabolic dysfunction-associated steatotic liver disease (MASLD) in offspring, driven,...
Maternal obesity and/or Western diet (WD) is associated with an increased risk of metabolic dysfunction-associated steatotic liver disease (MASLD) in offspring, driven, in part, by the dysregulation of the early life microbiome. Here, using a mouse model of WD-induced maternal obesity, we demonstrate that exposure to a disordered microbiome from WD-fed dams suppressed circulating levels of endogenous ligands of the aryl hydrocarbon receptor (AHR; indole, indole-3-acetate) and TMAO (a product of AHR-mediated transcription), as well as hepatic expression of (an AHR target), in offspring at 3 weeks of age. This signature was recapitulated by fecal microbial transfer from WD-fed pregnant dams to chow-fed germ-free (GF) lactating dams following parturition and was associated with a reduced abundance of in GF offspring. Further, the expression of was downregulated in liver myeloid cells and in LPS-stimulated bone marrow-derived macrophages (BMDM) in adult offspring, suggestive of a hypo-responsive, or tolerant, innate immune response. BMDMs from adult mice lacking AHR in macrophages exhibited a similar tolerogenic response, including diminished expression of . Overall, our study shows that exposure to maternal WD alters microbial metabolites in the offspring that affect AHR signaling, potentially contributing to innate immune hypo-responsiveness and progression of MASLD, highlighting the impact of early life gut dysbiosis on offspring metabolism. Further investigations are warranted to elucidate the complex interplay between maternal diet, gut microbial function, and the development of neonatal innate immune tolerance and potential therapeutic interventions targeting these pathways.
Topics: Animals; Gastrointestinal Microbiome; Female; Pregnancy; Diet, Western; Immunity, Innate; Tryptophan; Mice; Receptors, Aryl Hydrocarbon; Mice, Inbred C57BL; Interleukin-10; Prenatal Exposure Delayed Effects; Obesity, Maternal; Liver; Maternal Nutritional Physiological Phenomena; Male; Macrophages; Disease Models, Animal
PubMed: 38931163
DOI: 10.3390/nu16121808 -
Medicina (Kaunas, Lithuania) Jun 2024Gabapentin has shown promise as a potential agent for the treatment of alcohol withdrawal syndrome. We aimed to evaluate the effectiveness of gabapentin as a...
Gabapentin has shown promise as a potential agent for the treatment of alcohol withdrawal syndrome. We aimed to evaluate the effectiveness of gabapentin as a benzodiazepine-sparing agent in patients undergoing alcohol withdrawal treatment in all the hospitals of a large tertiary healthcare system. Medical records of patients admitted to the hospital for alcohol withdrawal management between 1 January 2020 and 31 August 2022 were reviewed. Patients were divided into two cohorts: benzodiazepine-only treatment who received benzodiazepines as the primary pharmacotherapy and gabapentin adjunctive treatment who received gabapentin in addition to benzodiazepines. The outcomes assessed included the total benzodiazepine dosage administered during the treatment and the length of hospital stay. The statistical models were calibrated to account for various factors. A total of 4364 patients were included in the final analysis. Among these, 79 patients (1.8%) received gabapentin in addition to benzodiazepines, and 4285 patients (98.2%) received benzodiazepines only. Patients administered gabapentin required significantly lower average cumulative benzodiazepine dosages, approximately 17.9% less, compared to those not receiving gabapentin (median 2 mg vs. 4 mg of lorazepam equivalent dose ( < 0.01)). However, there were no significant differences in outcomes between the two groups. Our findings demonstrate that using gabapentin with benzodiazepine was associated with a reduction in the cumulative benzodiazepine dosage for alcohol withdrawal. Considering gabapentin as an adjunctive therapy holds promise for patients with comorbidities who could benefit from reducing benzodiazepine dose. This strategy warrants further investigation.
Topics: Humans; Gabapentin; Male; Benzodiazepines; Female; Middle Aged; Substance Withdrawal Syndrome; Adult; Retrospective Studies; Treatment Outcome; Aged; Length of Stay
PubMed: 38929621
DOI: 10.3390/medicina60061004 -
Medicina (Kaunas, Lithuania) Jun 2024Hyperprolactinemia, as a potential side-effect of some antipsychotic medications, is associated with decreased bone density and an increased risk of fractures. This...
Hyperprolactinemia, as a potential side-effect of some antipsychotic medications, is associated with decreased bone density and an increased risk of fractures. This study investigates whether calcium and vitamin D supplementation affects prolactin receptor ( gene expression in the duodenum, vertebrae, and kidneys of female rats with sulpiride-induced hyperprolactinemia. Twenty-one-week-old female Wistar rats were assigned to three groups: Group S consisted of ten rats who received sulpiride injections (10 mg/kg) twice daily for 6 weeks; Group D (10 rats) received daily supplementation of 50 mg calcium and 500 IU vitamin D along with sulpiride for the last 3 weeks; and Group C consisting of seven age-matched nulliparous rats serving as a control group. Real-time PCR was used to assess gene expression in the duodenum, vertebrae, and kidneys. In Group S, Prlr gene expression was notably decreased in the duodenum ( < 0.01) but elevated in the vertebrae and kidneys compared to Group C. Conversely, Group D exhibited significantly increased Prlr expression in the duodenum ( < 0.01) alongside elevated expression in the vertebrae and kidneys. In sulpiride-induced hyperprolactinemia, decreased Prlr gene expression in the duodenum may lead to reduced intestinal calcium absorption. Consequently, prolactin may draw calcium from the skeletal system to maintain calcium balance, facilitated by increased Prlr gene expression in the vertebrae. However, vitamin D supplementation in sulpiride-induced hyperprolactinemia notably enhances Prlr gene expression in the duodenum, potentially ameliorating intestinal calcium absorption and mitigating adverse effects on bone health.
Topics: Animals; Hyperprolactinemia; Sulpiride; Rats, Wistar; Female; Vitamin D; Rats; Calcium; Duodenum; Receptors, Prolactin; Gene Expression
PubMed: 38929559
DOI: 10.3390/medicina60060942 -
Children (Basel, Switzerland) May 2024This empirical research on children's poverty and the accompanying risk behavior was conducted in the Baktalórántháza micro-region, in one of the most disadvantaged...
This empirical research on children's poverty and the accompanying risk behavior was conducted in the Baktalórántháza micro-region, in one of the most disadvantaged micro-regions of Hungary. The study, completed in 2023, was conducted utilizing three methods, a questionnaire for families, interviews, and focus group interviews with social professionals working in the settlements. The region is one of the ten micro-regions with the highest poverty rate in the country. The majority of the population only has an elementary education, and the proportion of graduates is much lower than the national average. The proportion of households with three or more children is higher than the national average and the proportion of unemployed people in households with children is twice as high as the national average. Based on the experience of social workers working in the area, in addition to smoking and drinking alcohol, the consumption of psychoactive and psychotropic substances has increased among adolescents and young adults. Based on various indicators, children regularly consume illegal drugs. The origin and composition of these drugs are typically unknown. According to the reports by drug users, everyday life is easier, and they can escape from problems when under the influence of drugs. Based on the observations of experts, the consumption of various psychoactive substances has harmful effects on behavior, health, learning, and family life. School performance and the ability to think and learn decrease. Drug users are dissatisfied with their lives, have problems with social relationships, engage in partner violence, and may develop antisocial behavior in their lives.
PubMed: 38929204
DOI: 10.3390/children11060624 -
International Journal of Molecular... Jun 2024NMDA receptor antagonists have potential for therapeutics in neurological and psychiatric diseases, including neurodegenerative diseases, epilepsy, traumatic brain... (Review)
Review
NMDA receptor antagonists have potential for therapeutics in neurological and psychiatric diseases, including neurodegenerative diseases, epilepsy, traumatic brain injury, substance abuse disorder (SUD), and major depressive disorder (MDD). ()-ketamine was the first of a novel class of antidepressants, rapid-acting antidepressants, to be approved for medical use. The stereoisomer, ()-ketamine (arketamine), is currently under development for treatment-resistant depression (TRD). The compound has demonstrated efficacy in multiple animal models. Two clinical studies disclosed efficacy in TRD and bipolar depression. A study by the drug sponsor recently failed to reach a priori clinical endpoints but post hoc analysis revealed efficacy. The clinical value of ()-ketamine is supported by experimental data in humans and rodents, showing that it is less sedating, does not produce marked psychotomimetic or dissociative effects, has less abuse potential than ()-ketamine, and produces efficacy in animal models of a range of neurological and psychiatric disorders. The mechanisms of action of the antidepressant effects of ()-ketamine are hypothesized to be due to NMDA receptor antagonism and/or non-NMDA receptor mechanisms. We suggest that further clinical experimentation with ()-ketamine will create novel and improved medicines for some of the neurological and psychiatric disorders that are underserved by current medications.
Topics: Ketamine; Humans; Animals; Antidepressive Agents; Nervous System Diseases; Receptors, N-Methyl-D-Aspartate; Mental Disorders; Stereoisomerism
PubMed: 38928508
DOI: 10.3390/ijms25126804 -
International Journal of Molecular... Jun 2024The objective of this study was to assess the impact of acute and chronic treatment with oxcarbazepine on its anticonvulsant activity, neurological adverse effects, and...
The objective of this study was to assess the impact of acute and chronic treatment with oxcarbazepine on its anticonvulsant activity, neurological adverse effects, and protective index in mice. Oxcarbazepine was administered in four protocols: once or twice daily for one week (7 × 1 or 7 × 2) and once or twice daily for two weeks (14 × 1 or 14 × 2). A single dose of the drug was employed as a control. The anticonvulsant effect was evaluated in the maximal electroshock test in mice. Motor and long-term memory impairment were assessed using the chimney test and the passive avoidance task, respectively. The concentrations of oxcarbazepine in the brain and plasma were determined via high-performance liquid chromatography. Two weeks of oxcarbazepine treatment resulted in a significant reduction in the anticonvulsant (in the 14 × 1; 14 × 2 protocols) and neurotoxic (in the 14 × 2 schedule) effects of this drug. In contrast, the protective index for oxcarbazepine in the 14 × 2 protocol was found to be lower than that calculated for the control. No significant deficits in memory or motor coordination were observed following repeated administration of oxcarbazepine. The plasma and brain concentrations of this anticonvulsant were found to be significantly higher in the one-week protocols. Chronic treatment with oxcarbazepine may result in the development of tolerance to its anticonvulsant and neurotoxic effects, which appears to be dependent on pharmacodynamic mechanisms.
Topics: Animals; Oxcarbazepine; Mice; Anticonvulsants; Electroshock; Male; Disease Models, Animal; Seizures; Brain; Memory, Long-Term; Carbamazepine; Avoidance Learning
PubMed: 38928457
DOI: 10.3390/ijms25126751 -
International Journal of Molecular... Jun 2024Exposure to general anesthetics can adversely affect brain development, but there is little study of sedative agents used in intensive care that act via similar...
Exposure to general anesthetics can adversely affect brain development, but there is little study of sedative agents used in intensive care that act via similar pharmacologic mechanisms. Using quantitative immunohistochemistry and neurobehavioral testing and an established protocol for murine sedation, we tested the hypothesis that lengthy, repetitive exposure to midazolam, a commonly used sedative in pediatric intensive care, interferes with neuronal development and subsequent cognitive function via actions on the mechanistic target of rapamycin (mTOR) pathway. We found that mice in the midazolam sedation group exhibited a chronic, significant increase in the expression of mTOR activity pathway markers in comparison to controls. Furthermore, both neurobehavioral outcomes, deficits in Y-maze and fear-conditioning performance, and neuropathologic effects of midazolam sedation exposure, including disrupted dendritic arborization and synaptogenesis, were ameliorated via treatment with rapamycin, a pharmacologic mTOR pathway inhibitor. We conclude that prolonged, repetitive exposure to midazolam sedation interferes with the development of neural circuitry via a pathologic increase in mTOR pathway signaling during brain development that has lasting consequences for both brain structure and function.
Topics: Midazolam; Animals; TOR Serine-Threonine Kinases; Mice; Signal Transduction; Brain; Male; Hypnotics and Sedatives; Behavior, Animal; Female; Mice, Inbred C57BL; Maze Learning; Animals, Newborn
PubMed: 38928447
DOI: 10.3390/ijms25126743 -
International Journal of Molecular... Jun 2024Phytochemicals and tryptophan (Trp) metabolites have been found to modulate gut function and health. However, whether these metabolites modulate gut ion transport and...
Phytochemicals and tryptophan (Trp) metabolites have been found to modulate gut function and health. However, whether these metabolites modulate gut ion transport and serotonin (5-HT) metabolism and signaling requires further investigation. The aim of this study was to investigate the effects of selected phytochemicals and Trp metabolites on the ion transport and 5-HT metabolism and signaling in the ileum of mice in vitro using the Ussing chamber technique. During the in vitro incubation, vanillylmandelic acid (VMA) reduced ( < 0.05) the short-circuit current, and 100 μM chlorogenic acid (CGA) ( = 0.12) and perillic acid (PA) ( = 0.14) had a tendency to reduce the short-circuit current of the ileum. Compared with the control, PA and -acetylserotonin treatment upregulated the expression of tryptophan hydroxylase 1 (), while 100 μM cinnamic acid, indolelactic acid (ILA), and 10 μM CGA or indoleacetaldehyde (IAld) treatments downregulated ( < 0.05) the mRNA levels of . In addition, 10 μM IAld or 100 μM ILA upregulated ( < 0.05) the expression of monoamine oxidase A (). However, 10 μM CGA or 100 μM PA downregulated ( < 0.05) expression. All selected phytochemicals and Trp metabolites upregulated ( < 0.05) the expression of and compared to that of the control group. VMA and CGA reduced ( < 0.05) the ratios of / and /. These findings may help to elucidate the effects of phytochemicals and Trp metabolites on the regulation of gut ion transport and 5-HT signaling-related gut homeostasis in health and disease.
Topics: Animals; Serotonin; Mice; Ileum; Tryptophan; Signal Transduction; Cinnamates; Ion Transport; Male; Tryptophan Hydroxylase; Chlorogenic Acid
PubMed: 38928404
DOI: 10.3390/ijms25126694