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Journal of Cellular and Molecular... Jun 2024Stress triggers a comprehensive pathophysiological cascade in organisms. However, there is a substantial gap in the research regarding the effects of stress on liver...
Stress triggers a comprehensive pathophysiological cascade in organisms. However, there is a substantial gap in the research regarding the effects of stress on liver function. This study aimed to investigate the impact of restraint stress on hepatocellular damage and elucidate the underlying molecular mechanisms. An effective mouse restraint stress model was successfully developed, and liver function analysis was performed using laser speckle imaging, metabolomics and serum testing. Alterations in hepatocyte morphology were assessed using haematoxylin and eosin staining and transmission electron microscopy. Oxidative stress in hepatocytes was assessed using lipid reactive oxygen species and malondialdehyde. The methylation status and expression of GSTP1 were analysed using DNA sequencing and, real-time PCR, and the expression levels of GPX4, TF and Nrf2 were evaluated using real-time quantitative PCR, western blotting, and immunohistochemical staining. A stress-induced model was established in vitro by using dexamethasone-treated AML-12 cells. To investigate the underlying mechanisms, GSTP1 overexpression, small interfering RNA, ferroptosis and Nrf2 inhibitors were used. GSTP1 methylation contributes to stress-induced hepatocellular damage and dysfunction. GSTP1 is involved in ferroptosis-mediated hepatocellular injury induced by restraint stress via the TF/Nrf2 pathway. These findings suggest that stress-induced hepatocellular injury is associated with ferroptosis, which is regulated by TF/Nrf2/GSTP1.
PubMed: 38890797
DOI: 10.1111/jcmm.18494 -
BMC Oral Health Jun 2024Surgical extraction of impacted third molars (ITM) often leads to postoperative discomfort including pain, swelling, and limited function. Steroids like dexamethasone... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study Observational Study
Comparison of perineural and systemic dexamethasone use in impacted third molar surgeries in terms of anesthesia duration and postoperative complaints: a controlled, randomized observational study.
BACKGROUND
Surgical extraction of impacted third molars (ITM) often leads to postoperative discomfort including pain, swelling, and limited function. Steroids like dexamethasone (DXN) are commonly used in oral surgery to manage pain and inflammation. Various administration routes for DXN exist, including intravenous (IV), perineural (PN), and oral applications, each with its advantages. Previous studies have shown that adding DXN to local anesthetics can prolong anesthesia duration and reduce postoperative sequelae. However, comparative studies on IV and PN applications with inferior alveolar nerve block (IANB) of DXN in ITM surgeries are limited.
METHODS
This controlled, randomized observational study involved patients undergoing Class II position B ITM extraction. Patients were divided into three groups. IANB (1.8 ml of articaine hydrochloride + 1 ml of saline) was performed 1 h after IV-DXN (4 mg/ml DXN) was administered to the IV group. DXN along with IANB (1.8 ml of articaine hydrochloride + 1 ml of 4 mg/ml DXN) was applied to the PN group. Only IANB (1.8 ml of articaine hydrochloride + 1 ml of saline) was applied to the control group. Anesthesia duration was assessed as primary outcomes. Anesthesia duration was evaluated using a vitalometer from the molars. Secondary outcomes included postoperative pain and edema measured on the 1st, 3rd, and 7th days after surgery. Pain was evaluated postoperatively by using a visual analog scale. A p-value < 0.05 was considered statistically significant.
RESULTS
The study included 45 patients with similar demographic characteristics across groups. IV application significantly prolonged anesthesia duration compared to the control group. (p = 0.049) Both IV and PN administration of DXN reduced postoperative edema at 3rd (p = 0.048) and 7th day (p = 0.01). Post-procedure pain reduction was significant in the IV group (p = 0.011). On the other hand, it was observed that the pain did not decrease in the PN group at 3rd and 7th days compared to the control and IV groups.
CONCLUSIONS
PN and IV DXN administration prolonged anesthesia duration and reduced postoperative edema in ITM surgeries. However, PN DXN administration was associated with increased postoperative pain compared to IV DXN and control groups. Further studies comparing different doses and administration routes of DXN are needed to determine optimal strategies for managing postoperative discomfort in ITM surgeries.
TRIAL REGISTRATION
This study was conducted at Ahmet Keleşoğlu Faculty of Dentistry with the permission of Karamanoğlu Mehmetbey University Faculty of Medicine Ethics Committee (#04-2022/101). Trial registration is also available at clinicaltrail.gov. (NCT06318013, 26/05/2024).
Topics: Humans; Molar, Third; Dexamethasone; Tooth, Impacted; Male; Female; Pain, Postoperative; Tooth Extraction; Nerve Block; Adult; Anesthesia, Dental; Anesthetics, Local; Young Adult; Pain Measurement; Mandibular Nerve; Carticaine; Time Factors; Edema
PubMed: 38890655
DOI: 10.1186/s12903-024-04483-4 -
Scientific Reports Jun 2024Hand-foot syndrome (HFS) is a frequently occurring and treatment-requiring adverse effect of docetaxel. We previously reported that systemic dexamethasone (DEX) prevents...
Hand-foot syndrome (HFS) is a frequently occurring and treatment-requiring adverse effect of docetaxel. We previously reported that systemic dexamethasone (DEX) prevents the other docetaxel-induced adverse inflammatory effects in a dose-dependent manner. This study aimed to evaluate the dose-dependent efficacy of systemic DEX in attenuating HFS in patients with breast cancer receiving docetaxel. Patients with breast cancer receiving docetaxel (75 mg/m)-containing regimens (n = 111) were divided into 4 and 8 mg/day DEX groups, with each DEX dose administered on days 2-4, and analyzed retrospectively. Development of all-grade HFS in all treatment cycles was significantly lower in the 8 mg group (50.0%) than in the 4 mg group (73.0%, P = 0.03), with primary endpoint accomplishment. Moreover, its development in the first cycle was also lower in the 8 mg group than in the 4 mg group. These results were confirmed in a propensity score-matched population. Logistic regression analysis suggested higher DEX dosage as an independent preventive factor (adjusted odds ratio 0.35; 95% confidence interval 0.14-0.86, P = 0.02 for all cycles; 0.26, 0.11-0.63, P = 0.003 for the first cycle). Our study suggests that systemic DEX prevents the occurrence of docetaxel-induced HFS in patients with breast cancer in a dose-dependent manner in a real-world setting.
Topics: Humans; Docetaxel; Dexamethasone; Female; Breast Neoplasms; Hand-Foot Syndrome; Middle Aged; Retrospective Studies; Aged; Adult; Dose-Response Relationship, Drug; Antineoplastic Agents
PubMed: 38890326
DOI: 10.1038/s41598-024-64553-z -
Steroids Jun 2024Occupancy of prostate cancer (PCa) cell androgen receptors (AR) signals proliferation, therefore testosterone biosynthesis inhibitors and AR antagonists are important...
In silico studies on the molecular interactions of steroid hormones and steroid hormone mimicking drugs in the androgen receptor binding cleft - Implications for prostate cancer treatment.
Occupancy of prostate cancer (PCa) cell androgen receptors (AR) signals proliferation, therefore testosterone biosynthesis inhibitors and AR antagonists are important PCa treatments. Conversely, androgen mimics (e.g., prednisone) used in management of PCa might cause proliferation. The balance between PCa proliferation and inhibition predicts treatment success. We used in silico molecular modelling to explore interactions between ARs, androgens (testosterone, dihydrotestosterone (DHT)) and drugs used to treat (bicalutamide) and manage (dexamethasone, prednisone, hydrocortisone) PCa. We found that hydrogen (H-) bonds between testosterone, DHT and Arg752, Asn705 and Thr877 followed by ligand binding cleft hydrophobic interactions signal proliferation, whereas bicalutamide antagonism is via Phe764 interactions. Hydrocortisone, dexamethasone and prednisone H-bond Asn705 and Thr877, but not Arg752 in the absence of a water molecule. Studies with a bicalutamide agonist AR mutation showed different amino acid interactions, indicating testosterone and DHT would not promote proliferation as effectively as via the native receptor. However, hydrocortisone and bicalutamide form Arg752 and Asn705 H-bonds indicating agonism. Our results suggest that as PCa progresses the resulting mutations will change the proliferative response to androgens and their drug mimics, which have implications for the treatment of prostate cancer.
PubMed: 38889811
DOI: 10.1016/j.steroids.2024.109456 -
Stem Cell Research & Therapy Jun 2024There is a significant demand for intermediate-scale bioreactors in academic and industrial institutions to produce cells for various applications in drug screening...
BACKGROUND
There is a significant demand for intermediate-scale bioreactors in academic and industrial institutions to produce cells for various applications in drug screening and/or cell therapy. However, the application of these bioreactors in cultivating hiPSC-derived immune cells and other blood cells is noticeably lacking. To address this gap, we have developed a xeno-free and chemically defined intermediate-scale bioreactor platform, which allows for the generation of standardized human iPSC-derived hematopoietic organoids and subsequent continuous production of macrophages (iPSC-Mac).
METHODS
We describe a novel method for intermediate-scale immune cell manufacturing, specifically the continuous production of functionally and phenotypically relevant macrophages that are harvested on weekly basis for multiple weeks.
RESULTS
The continuous production of standardized human iPSC-derived macrophages (iPSC-Mac) from 3D hematopoietic organoids also termed hemanoids, is demonstrated. The hemanoids exhibit successive stage-specific embryonic development, recapitulating embryonic hematopoiesis. iPSC-Mac were efficiently and continuously produced from three different iPSC lines and exhibited a consistent and reproducible phenotype, as well as classical functionality and the ability to adapt towards pro- and anti-inflammatory activation stages. Single-cell transcriptomic analysis revealed high macrophage purity. Additionally, we show the ability to use the produced iPSC-Mac as a model for testing immunomodulatory drugs, exemplified by dexamethasone.
CONCLUSIONS
The novel method demonstrates an easy-to-use intermediate-scale bioreactor platform that produces prime macrophages from human iPSCs. These macrophages are functionally active and require no downstream maturation steps, rendering them highly desirable for both therapeutic and non-therapeutic applications.
Topics: Humans; Induced Pluripotent Stem Cells; Macrophages; Bioreactors; Organoids; Cell Differentiation; Cell Culture Techniques; Hematopoiesis
PubMed: 38886860
DOI: 10.1186/s13287-024-03785-2 -
JCI Insight Jun 2024Osteoporotic fractures are a major complication of long-term glucocorticoid therapy. Glucocorticoids transiently increase bone resorption, but they predominantly inhibit...
Osteoporotic fractures are a major complication of long-term glucocorticoid therapy. Glucocorticoids transiently increase bone resorption, but they predominantly inhibit bone formation and induce osteocyte apoptosis, leading to bone loss. Current treatments of glucocorticoid-induced osteoporosis aim mainly at reducing bone resorption and are therefore inadequate. We previously showed that signaling via the NO/cGMP/protein kinase G pathway plays a key role in skeletal homeostasis. Here, we show that pharmacological PKG activation with the guanylyl cyclase-1 activator cinaciguat or expression of a constitutively-active, mutant PKG2R242Q restored proliferation, differentiation, and survival of primary mouse osteoblasts exposed to dexamethasone. Cinaciguat treatment of wild type mice or osteoblast-specific expression of PKG2R242Q in transgenic mice prevented dexamethasone-induced loss of cortical bone mass and strength. These effects of cinaciguat and PKG2R242Q expression were due to preserved bone formation parameters and osteocyte survival. The basis for PKG2's effects appeared to be through recovery of Wnt/β-catenin signaling, which was suppressed by glucocorticoids but is critical for proliferation, differentiation, and survival of osteoblast-lineage cells. Cinaciguat reduced dexamethasone activation of osteoclasts, but this did not occur in the PKG2R242Q transgenic mice, suggesting a minor role in osteoprotection. We propose that existing PKG-targeting drugs could represent a novel therapeutic approach to prevent glucocorticoid-induced osteoporosis.
PubMed: 38885330
DOI: 10.1172/jci.insight.175089 -
European Review For Medical and... Jun 2024Laparoscopic sleeve gastrectomy (LSG) is a widely recognized effective bariatric surgery. However, variable weight loss outcomes post-surgery remained a clinical...
OBJECTIVE
Laparoscopic sleeve gastrectomy (LSG) is a widely recognized effective bariatric surgery. However, variable weight loss outcomes post-surgery remained a clinical challenge. Currently, there is no established consensus on the factors influencing weight loss failure following LSG. This study aimed to explore the association between preoperative cortisol secretion autonomy and postoperative weight loss in obese patients undergoing LSG.
PATIENTS AND METHODS
A cohort of 181 patients with simple obesity (BMI ≥ 28 kg/m2) who underwent LSG and were followed up for one year was analyzed. Weight loss was measured by the percentage of excess weight loss (%EWL), and cortisol secretion autonomy was evaluated using a 1 mg dexamethasone suppression test (DST). Regression models were used to analyze the correlation between preoperative 1 mg DST results and %EWL one year after laparoscopic sleeve gastrectomy (LSG).
RESULTS
Cortisol secretion autonomy was significantly lower in the %EWL ≥ 75% group and higher in the %EWL < 75% group, showing a negative correlation with %EWL (R = -0.336, p = 0.001). Logistic regression analysis indicated that high cortisol secretion autonomy was significantly correlated with %EWL < 75% after LSG. The likelihood of %EWL being < 75% was 10.47 times greater in patients with high cortisol secretion autonomy compared to those with low cortisol secretion autonomy (odds ratio 10.472, confidence interval: 1.660-66.048, p = 0.012).
CONCLUSIONS
Cortisol secretion autonomy emerges as an independent predictor of weight loss outcomes in Asian patients undergoing LSG. This finding suggests the potential for cortisol secretion autonomy to inform preoperative assessments and personalized treatment strategies in bariatric surgery.
Topics: Humans; Gastrectomy; Laparoscopy; Weight Loss; Prospective Studies; Female; Hydrocortisone; Male; Adult; Middle Aged; Bariatric Surgery; Asian People; Treatment Outcome; Cohort Studies; Obesity
PubMed: 38884507
DOI: 10.26355/eurrev_202406_36377 -
Clinical Case Reports Jun 2024Vincristine therapy can be effective in refractory Immune thrombocytopenia (ITP) following COVID-19 vaccination. Our case report highlights the need for further research...
KEY CLINICAL MESSAGE
Vincristine therapy can be effective in refractory Immune thrombocytopenia (ITP) following COVID-19 vaccination. Our case report highlights the need for further research to establish standard management guidelines for COVID-19-vaccine-associated ITP.
ABSTRACT
Adult immune thrombocytopenia (ITP) can occur as a rare complication following several viral infections or a rare adverse event or complication of vaccination. In this paper, we report a case of a 39-year-old male patient with severe refractory ITP that began 4-weeks after receiving his third (booster) dose of the COVID-19 vaccine (BNT162b2, Pfizer-BioNTech). He was given oral dexamethasone 40 mg daily for 4 days followed by prednisone at 1 mg/kg (85 mg daily) for 10 days. In the following weeks, we attempted several other lines of therapy to treat his ITP, including anti-RhD immunoglobulin, which, unfortunately, caused moderate hemolysis requiring packed red blood cell transfusion, intravenous immunoglobulin (given at a subtherapeutic dose of 0.4 g/kg for only 1 day since it was not available), rituximab, and eltrombopag. The patient, unfortunately, showed no response to any of these treatments. This was an indicator to initiate salvage therapy with vincristine 2 mg weekly for 3 weeks. The patient's platelet count started to increase remarkably during the third week of vincristine and normalized after 4 weeks. We review the findings, clinical characteristics, and management approaches that were reported in the literature regarding COVID-19-vaccine-induced ITP. More in-depth research is needed to delineate standard guidelines for the management of such cases. This report underscores the importance of resorting to vincristine and eltrombopag as great options for severe and refractory ITP related to the COVID-19 vaccine.
PubMed: 38883219
DOI: 10.1002/ccr3.9070 -
Journal of Pharmacy & Bioallied Sciences Apr 2024Surgical removal of the third molar often resulted in postoperative pain which affected the quality of life of the patients. Pharmacological management of pain includes...
Comparative Analgesic Efficacy of Intramuscular Dexamethasone, Ketorolac, Tramadol, and Butorphanol with Regard to Postoperative Pain After Mandibular Third Molar Surgery.
Surgical removal of the third molar often resulted in postoperative pain which affected the quality of life of the patients. Pharmacological management of pain includes NSAIDS or steroids. The present study compared four drugs, viz. Group 1 (4 mg dexamethasone injection); Group 2 (30 mg ketorolac); Group 3 (50 mg tramadol injection); and Group 4 (1 mg butorphanol injection) in the management of postoperative pain after third molar surgery. We observed that in comparison with the first and third postoperative pain between groups, it revealed the lowest mean pain score in the butorphanol group, followed by dexamethasone and tramadol group and the highest mean score in the ketorol group ( value <0.0001). We conclude that butorphanol with low dosage can be effectively used for reducing postoperative discomfort after surgery.
PubMed: 38882800
DOI: 10.4103/jpbs.jpbs_421_23 -
Mediterranean Journal of Hematology and... 2024
Impact of the Addition of Daratumumab to the Standard Bortezomib-Thalidomide-Dexamethasone Regimen on Hematopoietic Stem Cell Mobilization and Collection, Post-Transplant Engraftment and Infectious Complications: A Case-Control Multicentre Real-Life Analysis.
PubMed: 38882460
DOI: 10.4084/MJHID.2024.049