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Journal of Molecular and Cellular... Aug 2023Cerebrovascular disease is one of the leading causes of death worldwide. Middle cerebral artery (MCA) is the largest and most complex of cerebral arteries. The prenatal...
BACKGROUND
Cerebrovascular disease is one of the leading causes of death worldwide. Middle cerebral artery (MCA) is the largest and most complex of cerebral arteries. The prenatal period is a critical time for development, which largely determines lifelong health. Clinically, glucocorticoids (GCs) administration to accelerate preterm fetal lung maturation has become standard practice. Prenatal GCs administration increases cardiovascular risks in offspring, but little is known regarding the side effects on offspring MCA function.
OBJECTIVE
We investigated the alterations of MCA reactivity following prenatal GCs administration in postnatal offspring.
METHOD AND RESULTS
Pregnant Sprague-Dawley rats received synthetic GCs (dexamethasone, DEX) during the last week of pregnancy, and we examined vascular reactivity, cellular electrophysiology, and gene promoter epigenetic modifications in the male offspring MCA. Our results showed that prenatal DEX exposure increased the sensitivity of offspring MCA to Angiotensin II, which was resulted from the increased Cav1.2 (L-type Ca channels subunit alpha1 C). Mechanistically, prenatal DEX exposure resulted in a transcriptionally active chromatin structure at the Cav1.2 gene promoter by altering histone modifications. This activation led to increased expression of vascular Cav1.2 gene, ultimately resulting in increased MCA contractility in offspring.
CONCLUSION
The present study is the first to demonstrate that the adverse effects of prenatal GCs administration on cerebrovascular tone persist into adulthood, providing new insights into developmental origins of cerebrovascular disease.
Topics: Rats; Animals; Pregnancy; Humans; Female; Male; Rats, Sprague-Dawley; Prenatal Exposure Delayed Effects; Glucocorticoids; Cerebrovascular Disorders; Dexamethasone; Cerebral Arteries
PubMed: 37271369
DOI: 10.1016/j.yjmcc.2023.05.008 -
The Journal of Clinical Endocrinology... Feb 2024During treatment, children with acute lymphoblastic leukemia (ALL) receive high doses dexamethasone, which induce acute side effects.
CONTEXT
During treatment, children with acute lymphoblastic leukemia (ALL) receive high doses dexamethasone, which induce acute side effects.
OBJECTIVE
To determine the influence of a 5-day dexamethasone course on changes in leptin, fat mass, BMI, hunger, sleep, and fatigue and to explore associations between these changes.
METHODS
Pediatric ALL patients were included during maintenance treatment. Data were collected before (T1) and after (T2) a 5-day dexamethasone course (6 mg/m2/day). At both time points, BMI, fat mass (bioelectrical impedance analysis), and leptin were assessed, as well as parent-reported questionnaires regarding hunger, fatigue, and sleep problems. Changes between T1 and T2 were assessed using paired tests. Correlation coefficients were calculated to assess associations between these changes (Delta scores: T2-T1). Univariable regression models were estimated to study associations between covariates and elevated leptin.
RESULTS
We included 105 children, with median age 5.4 years (range, 3.0-18.8). Leptin and fat mass, as well as hunger scores, fatigue, and sleep deteriorated after 5 days of dexamethasone (P < .001), in contrast to BMI (P = .12). No correlations between delta leptin and delta fat mass, BMI, hunger, fatigue, or sleep were found. Elevated leptin on T1 was associated with older age (odds ratio [OR] 1.51; 95% CI, 1.28-1.77), higher fat mass (OR 1.19; 95% CI, 1.07-1.33), and earlier maintenance week (OR 0.96; 95% CI, 0.92-0.99).
CONCLUSION
Five days of high-dose dexamethasone treatment led to direct and significant changes in leptin, hunger scores, and fat mass. Since children with ALL are at increased risk for metabolic adverse events, understanding underlying mechanisms is important, and a dexamethasone-induced state of acute leptin resistance might play a role.
Topics: Child; Humans; Child, Preschool; Leptin; Dexamethasone; Hunger; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Fatigue
PubMed: 37878899
DOI: 10.1210/clinem/dgad621 -
Theranostics 2023Orbital inflammation is a prevalent and prolonged ocular disease that poses a significant challenge to clinicians. Glucocorticoid Dexamethasone sodium phosphate (Dex)...
Orbital inflammation is a prevalent and prolonged ocular disease that poses a significant challenge to clinicians. Glucocorticoid Dexamethasone sodium phosphate (Dex) has demonstrated efficacy in the clinical treatment of nonspecific orbital inflammation. However, frequent administration is required due to the short half-life of Dex, which may lead to drug waste and adverse side effects. In this study, we co-assembled Dex with a weak acid responsive hydrogelator Py-Phe-Phe-Lys-Lys-OH (K) to obtain a novel supramolecular hydrogel Dex/K that could release Dex in a slow manner to treat orbital inflammation. The therapeutic effect of Gel Dex/K on orbital inflammation was verified by and experiments. experiments indicated that co-assembly of Dex with K significantly increased mechanic strength of the hydrogel, enabling a continuous release of 40% of total Dex within 7 days. experiments further demonstrated that sustained release of Dex from Gel Dex/K could effectively alleviate the infiltration of inflammatory cells and the release of inflammatory factors in the orbit of mice, improving symptoms such as increased intraocular pressure and proptosis. Additionally, Gel Dex/K mitigated the degree of tissue fibrosis and fatty infiltration by reducing the development of local inflammation in the orbit. Our research results indicate that Gel Dex/K could more efficiently achieve responsive drug release in orbit, providing an innovative method for treating orbital inflammation.
Topics: Mice; Animals; Hydrogels; Dexamethasone; Inflammation; Eye; Glucocorticoids
PubMed: 37554273
DOI: 10.7150/thno.85627 -
Phytomedicine : International Journal... Jan 2024Although chronic treatment with glucocorticoids, such as dexamethasone, is frequently associated with muscle atrophy, effective and safe therapeutics for treating muscle...
BACKGROUND
Although chronic treatment with glucocorticoids, such as dexamethasone, is frequently associated with muscle atrophy, effective and safe therapeutics for treating muscle atrophy remain elusive. Jakyak-gamcho-tang (JGT), a decoction of Paeoniae Radix and Glycyrrhizae Radix et Rhizoma, has long been used to relieve muscle tension and control muscle cramp-related pain. However, the effects of JGT on glucocorticoid-induced muscle atrophy are yet to be comprehensively clarified.
PURPOSE
The objective of the current study was to validate the protective effect of JGT in dexamethasone-induced muscle atrophy models and elucidate its underlying mechanism through integrated in silico - in vitro - in vivo studies.
STUDY DESIGN AND METHODS
Differential gene expression was preliminarily analyzed using the RNA-seq data to determine the effects of JGT on C2C12 myotubes. The protective effects of JGT were further validated in dexamethasone-treated C2C12 myotubes by assessing cell viability, myotube integrity, and mitochondrial function or in C57BL/6 N male mice with dexamethasone-induced muscle atrophy by evaluating muscle mass and physical performance. Transcriptomic pathway analysis was also performed to elucidate the underlying mechanism.
RESULTS
Based on preliminary gene set enrichment analysis using the RNA-seq data, JGT regulated various pathways related to muscle differentiation and regeneration. Dexamethasone-treated C2C12 myotubes and muscle tissues of atrophic mice displayed substantial muscle protein degradation and muscle loss, respectively, which was efficiently alleviated by JGT treatment. Importantly, JGT-mediated protective effects were associated with observations such as preservation of mitochondrial function, upregulation of myogenic signaling pathways, including protein kinase B/mammalian target of rapamycin/forkhead box O3, inhibition of ubiquitin-mediated muscle protein breakdown, and downregulation of inflammatory and apoptotic pathways induced by dexamethasone.
CONCLUSION
To the best of our knowledge, this is the first report to demonstrate that JGT could be a potential pharmaceutical candidate to prevent muscle atrophy induced by chronic glucocorticoid treatment, highlighting its known effects for relieving muscle spasms and pain. Moreover, transcriptomic pathway analysis can be employed as an efficient in silico tool to predict novel pharmacological candidates and elucidate molecular mechanisms underlying the effects of herbal medications comprising diverse biologically active ingredients.
Topics: Male; Mice; Animals; Glucocorticoids; Paeonia; Mice, Inbred C57BL; Muscular Atrophy; Muscle Fibers, Skeletal; Muscle Proteins; Dexamethasone; Pain; Mammals; Drugs, Chinese Herbal; Glycyrrhiza
PubMed: 37984121
DOI: 10.1016/j.phymed.2023.155057 -
Neuropharmacology Nov 2023The molecular processes that underlie long-term memory formation involve signaling pathway activation by neurotransmitter release, which induces the expression of...
The molecular processes that underlie long-term memory formation involve signaling pathway activation by neurotransmitter release, which induces the expression of immediate early genes, such as Zif268, having a key role in memory formation. In this work, we show that the cannabinoid CB1 receptor signaling is necessary for the effects of dexamethasone on the behavioral response in an inhibitory avoidance task, on dexamethasone-induced ERK phosphorylation, and on dexamethasone-dependent Zif268 expression. Furthermore, we provide primary evidence for the mechanism responsible for this crosstalk between cannabinoid and glucocorticoid-mediated signaling pathways, showing that dexamethasone regulates endocannabinoid metabolism by inhibiting the activity of the Fatty acid amide hydrolase (FAAH), an integral membrane enzyme that hydrolyzes endocannabinoids and related amidated signaling lipids. Our results provide novel evidence regarding the role of the endocannabinoid system, and in particular of the CB1 receptor, as a mediator of the effects of glucocorticoids on the consolidation of aversive memories.
Topics: Endocannabinoids; Receptor, Cannabinoid, CB1; Memory Consolidation; Cannabinoids; Signal Transduction; Glucocorticoids; Dexamethasone; Amidohydrolases; Cannabinoid Receptor Modulators
PubMed: 37541383
DOI: 10.1016/j.neuropharm.2023.109674 -
International Journal of Biological... May 2024Oral ulceration is the most common oral mucosal disease. Oral mucosal ulcers are extremely painful, may interfere with eating and speaking, and potentially complicate...
Oral ulceration is the most common oral mucosal disease. Oral mucosal ulcers are extremely painful, may interfere with eating and speaking, and potentially complicate systemic symptoms in severe cases. The humid and highly dynamic environment of the oral cavity makes local drug administration for treating oral mucosal ulcers challenging. To overcome these challenges, we designed and prepared a novel dissolving microneedle (MN) patch containing multiple drugs in a core-shell to promote oral ulcer healing. The MNs contained a methacrylate gelatin shell layer of basic fibroblast growth factor (bFGF), a hyaluronic acid (HA) core loaded with dexamethasone (DXMS), and zeolite imidazoline framework-8 (ZIF-8) encapsulated in the HA-based backplane. Progressive degradation of gelatin methacryloyl (GelMA) from the tip of the MN patch in the oral mucosa resulted in sustained bFGF release at the lesion site, significantly promoting cell migration, proliferation, and angiogenesis. Moreover, the rapid release of HA and, subsequently, DXMS inhibited inflammation, and the remaining MN backing after the tip dissolved behaved as a dressing, releasing ZIF-8 for its antimicrobial effects. This novel, multifunctional, transmucosal core-shell MN patch exhibited excellent anti-inflammatory, antimicrobial, and pro-healing effects in vivo and in vitro, suggesting that it can promote oral ulcer healing.
Topics: Hyaluronic Acid; Gelatin; Animals; Oral Ulcer; Mouth Mucosa; Methacrylates; Needles; Wound Healing; Rats; Dexamethasone; Fibroblast Growth Factor 2; Male; Mice; Humans
PubMed: 38554926
DOI: 10.1016/j.ijbiomac.2024.131221 -
Clinical Oral Investigations May 2024To evaluate the efficacy of pregabalin and dexamethasone coadministration in preemptive analgesia and anxiety control in lower third molar surgery. (Randomized Controlled Trial)
Randomized Controlled Trial
Evaluation of the effects of pregabalin and dexamethasone coadministration on preemptive multimodal analgesia and anxiety in third molar surgeries: a triple-blind randomized clinical trial.
OBJECTIVE
To evaluate the efficacy of pregabalin and dexamethasone coadministration in preemptive analgesia and anxiety control in lower third molar surgery.
MATERIALS AND METHODS
A triple-blind, split-mouth clinical trial conducted with patients divided into two groups: control group, receiving placebo and dexamethasone, and test group, receiving pregabalin and dexamethasone preoperatively. The evaluated variables were pain, measured by the Visual Analog Scale (VAS), anxiety assessed through the State-Trait Anxiety Inventory (STAI) questionnaires, hemodynamic parameters [Blood Pressure (BP), Heart Rate (HR), Oxygen Saturation (SpO)], and sedation assessed by the Ramsay scale.
RESULTS
A total of 31 patients were included. The test group exhibited a significant reduction in pain at 2,4,6,8,12,16,24, and 48 h after surgery and in the consumption of rescue analgesics. Anxiety, evaluated by STAI and VAS, showed a significant decrease in the test group (p < 0.001). Additionally, there was a significant decrease in BP at most of the assessed time points (p < 0.05) and a significant reduction in HR at two different time intervals (p = 0.003 and p = 0.009), indicating a positive effect in the test group. There was no significant difference in SpO between the groups. Sedation assessment revealed a significant difference at all time points favoring the test group (p < 0.05). There were no significant postoperative adverse effects.
CONCLUSIONS
Pregabalin coadministered with dexamethasone demonstrated significant efficacy in controlling postoperative pain and anxiety, as well as a sedative effect.
CLINICAL RELEVANCE
The coadministration of pregabalin with dexamethasone may presents potential advantages in both pain modulation and psychological well-being of individuals undergoing third molar surgeries.
TRIAL REGISTRATION
Brazilian Clinical Trials Registry (REBEC), No. RBR-378h6t6.
Topics: Humans; Pregabalin; Dexamethasone; Molar, Third; Male; Female; Pain, Postoperative; Pain Measurement; Analgesics; Tooth Extraction; Adult; Drug Therapy, Combination; Dental Anxiety; Treatment Outcome; Surveys and Questionnaires; Pain Management
PubMed: 38717697
DOI: 10.1007/s00784-024-05700-8 -
BMC Infectious Diseases Dec 2023Currently, some meta-analyses on COVID-19 have suggested that glucocorticoids use can reduce the mortality rate of COVID-19 patients, utilization rate of invasive... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Currently, some meta-analyses on COVID-19 have suggested that glucocorticoids use can reduce the mortality rate of COVID-19 patients, utilization rate of invasive ventilation, and improve the prognosis of patients. However, optimal regimen and dosages of glucocorticoid remain unclear. Therefore, the purpose of this network meta-analysis is to analyze the efficacy and safety of glucocorticoids in treating COVID-19 at regimens.
METHODS
This meta-analysis retrieved randomized controlled trials from the earliest records to December 30, 2022, published in PubMed, Embase, Cochrane Library, CNKI Database and Wanfang Database, which compared glucocorticoids with placebos for their efficacy and safety in the treatment of COVID-19, Effects of different treatment regimens, types and dosages (high-dose methylprednisolone, very high-dose methylprednisolone, Pulse therapy methylprednisolone, medium-dose hydrocortisone, high-dose hydrocortisone, high-dose dexamethasone, very high-dose dexamethasone and placebo) on 28-day all-caused hospitalization mortality, hospitalization duration, mechanical ventilation requirement, ICU admission and safety outcome were compared.
RESULTS
In this network meta-analysis, a total of 10,544 patients from 19 randomized controlled trials were finally included, involving a total of 9 glucocorticoid treatment regimens of different types and dosages. According to the analysis results, the 28-day all-cause mortality rate was the lowest in the treatment with pulse therapy methylprednisolone (OR 0.08, 95% CI 0.02, 0.42), but the use of high-dose methylprednisolone (OR 0.85, 95% CI 0.59, 1.22), very high-dose dexamethasone (OR 0.95, 95% CI 0.67, 1.35), high-dose hydrocortisone (OR 0.64, 95% CI 0.34, 1.22), medium-dose hydrocortisone (OR 0.80, 95% CI 0.49, 1.31) showed no benefit in prolonging the 28-day survival of patient. Compared with placebo, the treatment with very high-dose methylprednisolone (MD = -3.09;95%CI: -4.10, -2.08) had the shortest length of hospital stay, while high-dose dexamethasone (MD = -1.55;95%CI: -3.13,0.03) and very high-dose dexamethasone (MD = -1.06;95%CI: -2.78,0.67) did not benefit patients in terms of length of stay.
CONCLUSIONS
Considering the available evidence, this network meta‑analysis suggests that the prognostic impact of glucocorticoids in patients with COVID-19 may depend on the regimens of glucocorticoids. It is suggested that pulse therapy methylprednisolone is associated with lower 28-day all-cause mortality, very high-dose methylprednisolone had the shortest length of hospital stay in patients with COVID-19.
TRIAL REGISTRATION
PROSPERO CRD42022350407 (22/08/2022).
Topics: Humans; Glucocorticoids; COVID-19; Hydrocortisone; Network Meta-Analysis; Methylprednisolone; Dexamethasone
PubMed: 38124031
DOI: 10.1186/s12879-023-08874-w -
Journal of Pediatric... 2023The purpose of this research was to understand the experience of parenting a child receiving dexamethasone during maintenance chemotherapy for acute lymphoblastic...
The purpose of this research was to understand the experience of parenting a child receiving dexamethasone during maintenance chemotherapy for acute lymphoblastic leukemia (ALL). Previous research has shown that dexamethasone's high level of toxicity causes many physical, behavioral, and emotional side effects, which reduce the quality of life during ALL treatment. Less is known about the experience of parenting a child receiving dexamethasone and the impact on the parent-child relationship. In-depth semi-structured interviews were conducted with 12 parents and data was analyzed using Interpretative Phenomenological Analysis. Four superordinate themes emerged: "a child on steroids is not your child": the behavioral and emotional changes in the child and their relationships; "you have to do what you have to do": adapting parenting to manage dexamethasone; "it breaks your heart … it's a horrible medicine": the emotional impact of parenting a child on dexamethasone; and, "it's the worst week ever": finding ways to cope with the challenges of dexamethasone. A preparatory intervention for parents beginning the dexamethasone journey focused on likely challenges, managing boundary setting and discipline, and their own emotional struggles, could be beneficial. Research into the impact on siblings could further understand the systemic influence of dexamethasone and help develop further interventions.
Topics: Humans; Parenting; Quality of Life; Maintenance Chemotherapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Dexamethasone
PubMed: 37194310
DOI: 10.1177/27527530221147877 -
Experimental Brain Research Jan 2024The purpose of the study was to which investigate whether dexamethasone, which has anti-inflammatory and immune response suppression roles, could treat noise-induced...
The purpose of the study was to which investigate whether dexamethasone, which has anti-inflammatory and immune response suppression roles, could treat noise-induced hearing loss caused by damage to hair cells in the cochlea. The experiment used 8-week-old CBA mice exposed to white noise at an intensity of 110 dB SPL for 2 h, with hearing loss confirmed by the auditory brainstem response test. Dexamethasone was administered by intraperitoneal injection for 5 days, and the therapeutic effect was investigated for 3 weeks. The experimental groups were 3 mg/kg of dexamethasone (3 mpk) and 10 mg/kg of dexamethasone (10 mpk), and the control group was a saline-administered group. The results showed that compared to the control group, the hearing threshold value was recovered by 10 dB SPL compared to the saline group from the 14th day in the 3 mpk group. In the 10 mpk group, thresholds were recovered from the 7th day compared to the saline group. This difference was similar at 4 kHz, and in the case of the 10 mpk group, the threshold was recovered by 20 dB SPL compared to the saline group. The study also confirmed the restoration of nerve cell activity and showed a recovery effect of about 20 µV in the amplitude value change in the 10 mpk group. In conclusion, the study suggests that dexamethasone has a therapeutic effect for noise-induced hearing loss by increasing the activity of nerve cells and showing a recovery effect from hair cells damaged by noise.
Topics: Mice; Animals; Hearing Loss, Noise-Induced; Auditory Threshold; Mice, Inbred CBA; Cochlea; Disease Models, Animal; Dexamethasone; Evoked Potentials, Auditory, Brain Stem
PubMed: 38010535
DOI: 10.1007/s00221-023-06742-2