Using cell culture systems from the Persian Gulf Arabian yellowfin sea bream, Acanthopagrus arabicus, to assess the effects of dexamethasone on gonad and brain aromatase activity and steroid production.

Dexamethasone (DEX) is a synthetic glucocorticoid widely used as pharmaceutical and usually exists in effluents with varying degrees of concentrations. In this study, cultivated Brain, ovary and testis cells from Arabian Sea bream, Acanthopagrus arabicus, were treated by DEX at concentrations of 0, 0.3, 3.0, 30.0 and 300.0 µg/ml for 48 h. The aromatase activity and steroid (17-ß-estradiol (E2), progesterone (P) and testosterone (T)) production by cells were measured at 12, 24 and 48 h of the experiment. The results showed that the sensitivity of cultivated ovarian, testicular and brain cells to DEX increased dose dependently. DEX was potent inhibitor of aromatase activity at specially 30.0 and 300.0 µg/ml in the cultivated ovarian and testicular cells at different sampling time. On the other hand, DEX was found to stimulate the aromatase activity of fish brain. DEX also decreased E2, P and T production by cultivated ovarian and testicular cells during the experiment. While, DEX caused an increase in the production of E2 and P by brain cells, which seems logical considering the stimulating effect of this drug on brain aromatase activity. In conclusion, results highlight that DEX is able to change the activity of aromatase, and disrupt the biosynthesis of estrogens and thus affect reproduction in fish.

Multi-organ developmental toxicity and its characteristics in fetal mice induced by dexamethasone at different doses, stages, and courses during pregnancy.

Dexamethasone is widely used in pregnant women at risk of preterm birth to reduce the occurrence of neonatal respiratory distress syndrome and subsequently reduce neonatal mortality. Studies have suggested that dexamethasone has developmental toxicity, but there is a notable absence of systematic investigations about its characteristics. In this study, we examined the effects of prenatal dexamethasone exposure (PDE) on mother/fetal mice at different doses (0.2, 0.4, or 0.8 mg/kg b.i.d), stages (gestational day 14-15 or 16-17) and courses (single- or double-course) based on the clinical practice. Results showed that PDE increased intrauterine growth retardation rate, and disordered the serum glucose, lipid and cholesterol metabolic phenotypes, and sex hormone level of mother/fetal mice. PDE was further discovered to interfere with the development of fetal lung, hippocampus and bone, inhibits steroid synthesis in adrenal and testis, and promotes steroid synthesis in the ovary and lipid synthesis in the liver, with significant effects observed at high dose, early stage and double course. The order of severity might be: ovary > lung > hippocampus/bone > others. Correlation analysis revealed that the decreased serum corticosterone and insulin-like growth factor 1 (IGF1) levels were closely related to PDE-induced low birth weight and abnormal multi-organ development in offspring. In conclusion, this study systematically confirmed PDE-induced multi-organ developmental toxicity, elucidated its characteristics, and proposed the potential "glucocorticoid (GC)-IGF1" axis programming mechanism. This research provided an experimental foundation for a comprehensive understanding of the effect and characteristics of dexamethasone on fetal multi-organ development, thereby guiding the application of "precision medicine" during pregnancy.

Prenatal dexamethasone exposure impairs rat blood-testis barrier function and sperm quality in adult offspring via GR/KDM1B/FSTL3/TGFß signaling.

Both epidemiological and animal studies suggest that adverse environment during pregnancy can change the offspring development programming, but it is difficult to achieve prenatal early warning. In this study we investigated the impact of prenatal dexamethasone exposure (PDE) on sperm quality and function of blood-testis barrier (BTB) in adult offspring and the underlying mechanisms. Pregnant rats were injected with dexamethasone (0.1, 0.2 and 0.4 mg·kg-1·d-1, s.c.) from GD9 to GD20. After weaning (PW4), the pups were fed with lab chow. At PW12 and PW28, the male offspring were euthanized to collect blood and testes samples. We showed that PDE significantly decreased sperm quality (including quantity and motility) in male offspring, which was associated with impaired BTB and decreased CX43/E-cadherin expression in the testis. We demonstrated that PDE induced morphological abnormalities of fetal testicle and Sertoli cell development originated from intrauterine. By tracing to fetal testicular Sertoli cells, we found that PDE dose-dependently increased expression of histone lysine demethylases (KDM1B), decreasing histone 3 lysine 9 dimethylation (H3K9me2) levels of follistatin-like-3 (FSTL3) promoter region and increased FSTL3 expression, and inhibited TGFß signaling and CX43/E-cadherin expression in offspring before and after birth. These results were validated in TM4 Sertoli cells following dexamethasone treatment. Meanwhile, the H3K9me2 levels of FSTL3 promoter in maternal peripheral blood mononuclear cell (PBMC) and placenta were decreased and its expression increased, which was positively correlated with the changes in offspring testis. Based on analysis of human samples, we found that the H3K9me2 levels of FSTL3 promoter in maternal blood PBMC and placenta were positively correlated with fetal blood testosterone levels after prenatal dexamethasone exposure. We conclude that PDE can reduce sperm quality in adult offspring rats, which is related to the damage of testis BTB via epigenetic modification and change of FSTL3 expression in Sertoli cells. The H3K9me2 levels of the FSTL3 promoter and its expression in the maternal blood PBMC can be used as a prenatal warning marker for fetal testicular dysplasia.

Effects of prenatal dexamethasone exposure on adult C57BL/6J mouse metabolism and oxidative stress.

Prenatal glucocorticoid exposure has been shown to alter hypothalamic-pituitary-adrenal axis function resulting in altered fetal development that can persist through adulthood. Fetal exposure to excess dexamethasone, a synthetic glucocorticoid, has been shown to alter adult behaviour and metabolism. This study investigated the effects prenatal dexamethasone exposure had on adult offspring cardiac and liver metabolism and oxidative stress. Pregnant C57BL/6 mice received a dose of 0.4 mg/kg dexamethasone on gestational days 15-17. Once pups were approximately 7 months old, glucose uptake was determined using positron emission tomography and insulin resistance (IR) was determined by homeostatic model assessment (HOMA) IR calculation. Oxidative stress was assessed by measuring 4-hydroxynonenal protein adduct formation and total reactive oxygen species. Female dexamethasone group had significantly increased glucose uptake when insulin stimulated compared to vehicle-treated mice. HOMA IR revealed no evidence of IR in either male or female offspring. There was also no change in oxidative stress markers in either cardiac or liver tissues of male or female offspring. These data suggest that prenatal dexamethasone exposure in male mice does not alter oxidative stress or metabolism. However, prenatal dexamethasone exposure increased glucocorticoids, cardiac glucose uptake, and pAkt signaling in female heart tissues in adult mice, suggesting there are sex differences in prenatal dexamethasone exposure.

A physiologically based toxicokinetic model of P-glycoprotein transporter-mediated placenta perfusion of dexamethasone in the pregnant rat.

The present dosage of Dexamethasone (DEX) administered to pregnant women may pose a risk of toxicity to their unborn offspring. We aimed to develop a maternal-fetal physiologically based toxicokinetic (PBTK) model for DEX in pregnant rats, with a specific focus on the role of the P-glycoprotein (P-gp) transporter in placenta perfusion, and finally facilitate the optimization of clinical DEX dosage. We conducted animal experiments to determine DEX concentrations in various rat tissues, and constructed the PBTK model using MATLAB software. Sensitivity analysis was performed to assess input parameters and the model stability, with fold error (FE) values serving as evaluation indices. Our results indicate the successful construction of the PBTK model, with the fitting key parameters such as the absorption rate constant (Ka), intrinsic hepatic clearance (CLh,int) and intrinsic P-gp clearance (CLint,P-gp). The median concentration of DEX in maternal plasma, fetal plasma, fetal lung, and fetal brain were determined, which allowed us to fit the tissue-to-plasma partition coefficients for the fetal lung (Kp,lung,f) and fetal brain (Kp,brain,f). After making adjustments, all calculated FE values were found to be less than 2, demonstrating the acceptability and accuracy of our model's predictions. Our model integrated external literature data and internal animal experimentation to comprehensively evaluate the maternal-fetal PK characteristics of DEX. These findings provide valuable support for the optimization of clinical DEX dosing.

Influence of sex on chronic steroid-induced glaucoma: 24-Weeks follow-up study in rats.

The objective was to evaluate ocular changes based on sex in steroid-induced glaucoma models in rats comparing healthy controls, over 24 weeks follow-up. Eighty-nine Long-Evans rats (38 males and 51 females) with steroid-induced glaucoma were analysed. Two steroid-induced glaucoma models were generated by injecting poly-co-lactic-glycolic acid microspheres loaded with dexamethasone (MMDEX model) and dexamethasone-fibronectin (MMDEXAFIBRO model) into the ocular anterior chamber. Intraocular pressure was measured by rebound tonometer Tonolab®. Neuroretinal function was analysed using dark- and light-adapted electroretinography (Roland consult® RETIanimal ERG), and structure was analysed using optical coherence tomography (OCT Spectralis, Heidelberg® Engineering) using Retina Posterior Pole, Retinal Nerve Fibre Layer and Ganglion Cell Layer protocols over 24 weeks. Males showed statistically (p < 0.05) higher intraocular pressure measurements. In both sexes and models neuroretinal thickness tended to decrease over time. In the MMDEX model, males showed higher IOP values and greatest percentage thickness loss in the Ganglion Cell Layer (p = 0.015). Females receiving MMDEXAFIBRO experienced large fluctuations in thickness, a higher percentage loss (on average) in Retina Posterior Pole (p = 0.035), Retinal Nerve Fibre Layer and Ganglion Cell Layer than aged-matched males, and the highest thickness loss rate by mmHg. Although no difference was found by sex in dark- and light-adapted electroretinography, increased amplitude in photopic negative response was found in MMDEX males and MMDEXAFIBRO females at 12 weeks. Although both glaucoma models used dexamethasone, different intraocular pressure and neuroretinal changes were observed depending on sex and other influential cofactors (fibronectin). Both sex and the induced glaucoma model influenced neuroretinal degeneration.

The Effects of ROCK Inhibitor on Prevention of Dexamethasone-Induced Glaucoma Phenotype in Human Trabecular Meshwork Cells.

Purpose: This study investigated the effects of dexamethasone (Dex) on human trabecular meshwork (TM) cells, a model of glucocorticoid-induced glaucoma, and evaluated the impact of ripasudil (Rip) as a co-delivery or sequential dosing strategy. Methods: In vitro experiments were conducted to assess the effects of Dex and Rip on TM cells. Confocal microscopy was used to evaluate the impact of Dex and Rip on F-actin staining signals. Contractility of the TM cells upon Dex and Rip treatment mimicking co-delivery and sequential delivery was quantified using collagen gel contraction assay. Transepithelial electrical resistance (TEER) values and fluorescein isothiocyanate (FITC)-dextran permeability were also measured to assess the impact of Dex and Rip on TM cells. Results: Dex and Rip did not exhibit cytotoxicity at the maximum tested concentration (20 µM). Dex-treated TM cells exhibited higher F-actin staining signals compared to controls, which were reduced when co-treated with Rip. Rip inhibited Dex-induced collagen gel contraction activity in both co-delivery and sequential treatments. Dex resulted in increased TEER values as the dose increased, whereas TEER values were maintained when co-treated with Rip. Conclusions: Co-delivery of Rip has the potential to prevent glaucoma symptoms when patients are treated with Dex. This study highlights the importance of identifying strategies to reduce the side effects of prolonged use of glucocorticoids, such as Dex, in the treatment of various diseases. Translational Relevance: This study demonstrates the potential of co-delivering ripasudil with dexamethasone to mitigate glucocorticoid-induced ocular hypertension and a secondary glaucoma that resembles primary open-angle glaucoma, providing insights for the development of novel preventive strategies in clinical care.

Transgenerational inheritance of adrenal steroidogenesis inhibition induced by prenatal dexamethasone exposure and its intrauterine mechanism.

BACKGROUND: Adrenal gland is the synthesis and secretion organ of glucocorticoid, which is crucial to fetal development and postnatal fate. Recently, we found that prenatal dexamethasone exposure (PDE) could cause adrenal dysfunction in offspring rats, but its multigenerational genetic effects and related mechanisms have not been reported. METHODS: The PDE rat model was established, and female filial generation 1 (F1) rats mate with wild males to produce the F2, the same way for the F3. Three generation rats were sacrificed for the related detection. SW-13 cells were used to clarify the epigenetic molecular mechanism. RESULTS: This study confirmed that PDE could activate fetal adrenal glucocorticoid receptor (GR). The activated GR, on the one hand, up-regulated Let-7b (in human cells) to inhibit steroidogenic acute regulatory protein (StAR) expression directly; on the other hand, down-regulated CCCTC binding factor (CTCF) and up-regulated DNA methyltransferase 3a/3b (Dnmt3a/3b), resulting in H19 hypermethylation and low expression. The decreased interaction of H19 and let-7 can further inhibit adrenal steroidogenesis. Additionally, oocytes transmitted the expression change of H19/let-7c axis to the next generation rats. Due to its genetic stability, F2 generation oocytes indirectly exposed to dexamethasone also inhibited H19 expression, which could be inherited to the F3 generation. CONCLUSIONS: This cascade effect of CTCF/H19/Let-7c ultimately resulted in the transgenerational inheritance of adrenal steroidogenesis inhibition of PDE offspring. This study deepens the understanding of the intrauterine origin of adrenal developmental toxicity, and it will provide evidence for the systematic analysis of the transgenerational inheritance effect of acquired traits induced by PDE. Video Abstract.

Extract of Cimicifuga racemosa (L.) Nutt protects ovarian follicle reserve of mice against in vitro deleterious effects of dexamethasone.

The present study aims to investigate if Cimicifuga racemosa (L.) Nutt extract (CIMI) reduces deleterious effects of dexamethasone (DEXA) in ovaries cultured in vitro. Mouse ovaries were collected and cultured in DMEM+ only or supplemented with 5 ng/mL of CIMI, or 4 ng/mL DEXA, or both CIMI and DEXA. The ovaries were cultured at 37.5°C in 5% CO2 for 6 days. Ovarian morphology, follicular ultrastructure, and the levels of mRNA for Bax, Bcl-2, and Caspase-3 were evaluated. The results showed that DEXA reduced the percentage of morphologically normal follicles, while CIMI prevented the deleterious effects caused by DEXA. In addition, DEXA negatively affected the stromal cellular density, while CIMI prevented these adverse effects. Ovaries cultured with DEXA and CIMI showed similar levels of mRNA for Bax, Bcl-2, and Caspase-3 compared to those cultured in control medium, while ovaries cultured with DEXA had increased expression of the above genes. Additionally, the ultrastructure of the ovaries cultured with CIMI was well preserved. Thus, the extract of CIMI was able to prevent the deleterious effects caused by DEXA on cultured mouse ovaries.

Short-term exposure to dexamethasone at environmentally relevant concentrations impairs embryonic development in Cyprinus carpio: Bioconcentration and alteration of oxidative stress-related gene expression patterns.

In recent years and as a result of the Covid-19 pandemic, the consumption of dexamethasone (DXE) has increased. This favors that this corticosteroid is highly released in aquatic environments, generating deleterious effects in aquatic organisms. The information on the toxic effects of DXE in the environment is still limited. Thus, the objective of this work was to determine whether DXE at short-term exposure can cause alterations to embryonic development and alteration of oxidative stress-related gene expression patterns in Cyprinus carpio. For this purpose, common carp embryos (2 hpf) were exposed to realistic concentrations of DXE until 96 hpf. Alterations to embryonic development were evaluated at 12, 24, 48, 72 and 96 hpf. In addition, oxidative stress in carp embryos at 72 and 96 hpf was evaluated by cellular oxidation biomarkers (lipoperoxidation level, hydroperoxide and carbonyl protein content) and antioxidant enzymes activities (superoxide dismutase and catalase). Oxidative stress-related gene expression (sod, cat and gpx1) was also evaluated. Our results showed that DXE concentrations above 35 ng/L are capable of producing alterations to embryonic development in 50 % of the embryo population. Furthermore, DXE was able to induce alterations such as scoliosis, hypopigmentation, craniofacial malformations, pericardial edema and growth retardation, leading to the death of half of the population at 50 ng/L of DXE. Concerning oxidative stress, the results demonstrated that DXE induce oxidative damage on the embryos of C. carpio. In conclusion, DXE is capable of altering embryonic development and generating oxidative stress in common carp C. carpio.

Transcriptomic analysis of World Trade Center particulate Matter-induced pulmonary inflammation and drug treatments.

Over 400,000 people are estimated to have been exposed to World Trade Center particulate matter (WTCPM) since the attack on the Twin Towers in Lower Manhattan on September 11, 2001. Epidemiological studies have found that exposure to dust may cause respiratory ailments and cardiovascular diseases. However, limited studies have performed a systematic analysis of transcriptomic data to elucidate the biological responses to WTCPM exposure and the therapeutic options. Here, we developed an in vivo mouse exposure model of WTCPM and administered two drugs (i.e., rosoxacin and dexamethasone) to generate transcriptomic data from lung samples. WTCPM exposure increased the inflammation index, and this index was significantly reduced by both drugs. We analyzed the transcriptomics derived omics data using a hierarchical systems biology model (HiSBiM) with four levels, including system, subsystem, pathway, and gene analyses. Based on the selected differentially expressed genes (DEGs) from each group, WTCPM and the two drugs commonly affected the inflammatory responses, consistent with the inflammation index. Among these DEGs, the expression of 31 genes was affected by WTCPM exposure and consistently reversed by the two drugs, and these genes included Psme2, Cldn18, and Prkcd, which are involved in immune- and endocrine-related subsystems and pathways such as thyroid hormone synthesis, antigen processing and presentation, and leukocyte transendothelial migration. Furthermore, the two drugs reduced the inflammatory effects of WTCPM through distinct pathways, e.g., vascular-associated signaling by rosoxacin, whereas mTOR-dependent inflammatory signaling was found to be regulated by dexamethasone. To the best of our knowledge, this study constitutes the first investigation of transcriptomics data of WTCPM and an exploration of potential therapies. We believe that these findings provide strategies for the development of promising optional interventions and therapies for airborne particle exposure.

Autophagy inhibition mediated by intrauterine miR-1912-3p/CTSD programming participated in the susceptibility to osteoarthritis induced by prenatal dexamethasone exposure in male adult offspring rats.

Autophagy inhibition is known to be involved in the development of adult osteoarthritis. Dexamethasone, as a synthetic glucocorticoid, is widely used for premature delivery and related pregnancy diseases in clinics. We have previously shown that prenatal dexamethasone exposure (PDE) was associated with increased susceptibility to postnatal osteoarthritis in offspring. However, whether the occurrence of fetal-originated adult osteoarthritis induced by PDE is related to autophagy remains unclear. In this study, we first found that PDE could increase the mRNA and protein expression of cartilage matrix-degrading enzymes (MMP3, MMP13, and ADAMTS5) and decrease the cartilage matrix contents in adult offspring, and the in vitro results suggested that this might be related to the autophagy inhibition of chondrocytes. Further, we demonstrated a persistent autophagy inhibition with autolysosome accumulation, low expression of cathepsin D (CTSD), increased H3K9ac level, and expression of miR-1912-3p in the cartilage of PDE offspring from fetus to adulthood. In vitro experiments showed that dexamethasone inhibited autophagy flux and CTSD expression in fetal chondrocytes, while overexpression of CTSD could alleviate the inhibition of autophagic flux induced by dexamethasone. Finally, we confirmed that dexamethasone increased the H3K9ac level and expression of miR-1912-3p through activation of the glucocorticoid receptor (GR), resulting in the decreased expression of CTSD and inhibition of autophagy flux in fetal chondrocytes. In conclusion, intrauterine miR-1912-3p/CTSD programming-mediated autophagy inhibition promoted the susceptibility to osteoarthritis in PDE adult offspring rats. This study provides new ideas for exploring early prevention and therapeutic targets in fetal-originated osteoarthritis.

Coadministration of olanzapine causes minor impacts on the diabetogenic outcomes induced by dexamethasone treatment in rats.

AIMS: Investigate whether the coadministration of olanzapine exacerbates the diabetogenic effects of dexamethasone, two agents used in the antiemetic cocktails indicated to mitigate the adverse effects of chemotherapy. MAIN METHODS: Adult Wistar rats (both sexes) were treated daily with dexamethasone (1 mg/kg, body mass (b.m.), intraperitoneal (i.p.)) with or without olanzapine (10 mg/kg, b.m., orogastric (o.g.)) for 5 consecutive days. During and at the end of the treatment, we evaluated biometric data and parameters involving glucose and lipid metabolism. KEY FINDINGS: Dexamethasone treatment resulted in glucose and lipid intolerance, higher plasma insulin and triacylglycerol levels, higher content of hepatic glycogen and fat, and higher islet mass in both sexes. These changes were not exacerbated by concomitant treatment with olanzapine. However, coadministration of olanzapine worsened the weight loss and plasma total cholesterol in males, while in females resulted in lethargy, higher plasma total cholesterol, and higher hepatic triacylglycerol release. SIGNIFICANCE: Coadministration of olanzapine does not exacerbate any diabetogenic dexamethasone effect on glucose metabolism and exerts a minor impact on the lipid homeostasis of rats. Our data favor the addition of olanzapine in the antiemetic cocktail considering the low incidence of metabolic adverse effects for the period and dosage analyzed in male and female rats.

Physiological and transcriptional effects in the male western mosquitofish (Gambusia affinis) following exposure to dexamethasone.

Dexamethasone (DEX) is a synthetic glucocorticoid widely found in a variety of aquatic environments and has potential adverse effects on aquatic organisms. This study was to assess the toxic effects of exposure to different concentrations (0, 5 and 50 µg/L) of DEX for 60 days on adult male mosquitofish (Gambusia affinis). Morphological analyses of skeleton and anal fin, histological effects of testes and livers, and transcriptional expression levels of genes related to reproductive and immune system were determined. The results showed that exposure to DEX significantly increased 14L and 14D values of hemal spines, which suggested DEX could affect skeleton development and result in more masculine characteristics in male fish. In addition, the damage to testis and liver tissue was observed after DEX treatment. It also enhanced mRNA expression of Erß gene in the brain and Hsd11b1 gene in the testis. The findings of this study reveal physiological and transcriptional effects of DEX on male mosquitofish.

Molecular Cardiotoxic Effects of Proteasome Inhibitors Carfilzomib and Ixazomib and Their Combination with Dexamethasone Involve Mitochondrial Dysregulation.

With the development and approval of new proteasome inhibitors, proteasome inhibition is increasingly recognized in cancer therapy. Besides successful anti-cancer effects in hematological cancers, side effects such as cardiotoxicity are limiting effective treatment. In this study, we used a cardiomyocyte model to investigate the molecular cardiotoxic mechanisms of carfilzomib (CFZ) and ixazomib (IXZ) alone or in combination with the immunomodulatory drug dexamethasone (DEX) which is frequently used in combination therapies in the clinic. According to our findings, CFZ showed a higher cytotoxic effect at lower concentrations than IXZ. DEX combination attenuated the cytotoxicity for both proteasome inhibitors. All drug treatments caused a marked increase in K48 ubiquitination. Both CFZ and IXZ caused an upregulation in cellular and endoplasmic reticulum stress protein (HSP90, HSP70, GRP94, and GRP78) levels and DEX combination attenuated the increased stress protein levels. Importantly, IXZ and IXZ-DEX treatments caused upregulation of mitochondria fission and fusion gene expression levels higher than caused by CFZ and CFZ-DEX combination. The IXZ-DEX combination reduced the levels of OXPHOS proteins (Complex II-V) more than the CFZ-DEX combination. Reduced mitochondrial membrane potential and ATP production were detected with all drug treatments in cardiomyocytes. Our findings suggest that the cardiotoxic effect of proteasome inhibitors may be due to their class effect and stress response and mitochondrial dysfunction may be involved in the cardiotoxicity process.

Dexamethasone as an anti-cancer or hepatotoxic.

The linkage between inflammation and oxidative stress in liver damage has been proven and is undeniable; dexamethasone with some antioxidants can reduce the toxicity of liver tissue. Due to the importance of cancer treatment, glucocorticoids' synergistic effect in inhibiting cancer cell growth is also investigated. Dexamethasone alone and combined with etoposide were tested at concentrations of 1, 5, and 10 µM to evaluate the potency of dexamethasone in inhibiting the growth of A549 cells using oxidative stress factors and DNA damage. Also, intraperitoneal injection of dexamethasone in rats was used to induce liver toxicity. Coenzyme Q10 at different concentrations (1, 10, and 50 mg/kg) was used as an antioxidant to assess the oxidative stress factors and measure Caspase-3 activity. The results showed that dexamethasone combined with etoposide could significantly inhibit the growth of cancer cells and induce apoptosis. Treatment of A549 cells using dexamethasone also inhibits cancer cells' growth by inducing oxidative stress and DNA damage. Dexamethasone also, by inducing oxidative stress and activation of caspase 3, ultimately causes hepatotoxicity. Treatment with different concentrations of CoQ10 showed improved mitochondrial function, antioxidant defense, and liver enzyme. The best effect of coenzyme Q10 on dexamethasone-induced hepatotoxicity is 50 mg/kg. As a result, dexamethasone (alone and combined with etoposide) has an anti-cancer effect by damaging DNA and inducing oxidative stress. Also, CoQ10 has antioxidant effects against dexamethasone-induced hepatotoxicity by improving mitochondrial function and reducing caspase-3 activity.

MiR-133a-3p/Sirt1 epigenetic programming mediates hypercholesterolemia susceptibility in female offspring induced by prenatal dexamethasone exposure.

Mounting evidence indicates that adverse intrauterine conditions increase offspring's hypercholesterolemia susceptibility in adulthood. This study aimed to confirm prenatal dexamethasone exposure (PDE)-induced hypercholesterolemia susceptibility in female adult offspring rats, and elucidate its intrauterine programming mechanism. Pregnant Wistar rats were injected with dexamethasone subcutaneously (0, 0.1 and 0.2 mg/kg·d) from gestational day (GD) 9 to 20. Serum and liver of the female offspring were collected at GD21 and postnatal week (PW) 12 and 28. PDE offspring showed elevated serum total cholesterol (TCH) levels and a cholesterol phenotype of high cardiovascular disease risk at PW12 and PW28. The histone acetylation levels of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr) and its expression were consistently increased in the PDE offspring both in utero and after birth. Moreover, PDE promoted glucocorticoid receptor (GR) nuclear translocation and miR-133a-3p expression and inhibited sirtuin-1 (Sirt1) expression in the fetal liver. In vitro, dexamethasone increased intracellular and supernatant TCH levels and miR-133a-3p expression, decreased SIRT1 expression, and promoted HMGCR histone acetylation and expression in bone marrow mesenchymal stem cells (BMSCs) hepatoid differentiated cells and HepG2 cell line. GR siRNA, miR-133a-3p inhibitor or SIRT1 overexpression reversed dexamethasone-induced downstream molecular and phenotypic changes. Furthermore, elevated TCH levels in umbilical cord blood and increased HMGCR expression in peripheral blood mononuclear cells (PBMCs) were observed in human female neonates who had received dexamethasone treatment during pregnancy. In conclusion, PDE can cause persistent enhancement of hepatic cholesterol synthesis function before and after birth through GR/miR-133a-3p/Sirt1 pathway, eventually leading to increased hypercholesterolemia susceptibility in female offspring rats.

Prolonged Dexamethasone Exposure Enhances Zebrafish Lateral-Line Regeneration But Disrupts Mitochondrial Homeostasis and Hair Cell Function.

The synthetic glucocorticoid dexamethasone is commonly used to treat inner ear disorders. Previous work in larval zebrafish has shown that dexamethasone treatment enhances hair cell regeneration, yet dexamethasone has also been shown to inhibit regeneration of peripheral nerves after lesion. We therefore used the zebrafish model to determine the impact of dexamethasone treatment on lateral-line hair cells and primary afferents. To explore dexamethasone in the context of regeneration, we used copper sulfate (CuSO4) to induce hair cell loss and retraction of nerve terminals, and then allowed animals to recover in dexamethasone for 48 h. Consistent with previous work, we observed significantly more regenerated hair cells in dexamethasone-treated larvae. Importantly, we found that the afferent processes beneath neuromasts also regenerated in the presence of dexamethasone and formed an appropriate number of synapses, indicating that innervation of hair cells was not inhibited by dexamethasone. In addition to regeneration, we also explored the effects of prolonged dexamethasone exposure on lateral-line homeostasis and function. Following dexamethasone treatment, we observed hyperpolarized mitochondrial membrane potentials (ΔΨm) in neuromast hair cells and supporting cells. Hair cells exposed to dexamethasone were also more vulnerable to neomycin-induced cell death. In response to a fluid-jet delivered saturating stimulus, calcium influx through hair cell mechanotransduction channels was significantly reduced, yet presynaptic calcium influx was unchanged. Cumulatively, these observations indicate that dexamethasone enhances hair cell regeneration in lateral-line neuromasts, yet also disrupts mitochondrial homeostasis, making hair cells more vulnerable to ototoxic insults and possibly impacting hair cell function.

Geniposide ameliorates glucocorticoid-induced osteoblast apoptosis by activating autophagy.

Long-term exposure to glucocorticoid (GC) contributes to the development of osteoporosis (OP), which is correlated with the risk of fracture. Pathologically, GC-induced bone loss is associated with osteoblast apoptosis. Geniposide (GEN), a natural occurring compound derived from Eucommia ulmoides, has been reported to ameliorate dexamethasone (DEX)-induced OP. Our previous study shows that GEN exhibits protective activity against DEX-induced OP by attenuating endoplasmic reticulum stress and decreasing apoptosis in osteoblasts. However, the molecular mechanisms of GEN in inhibiting DEX-induced osteoblast apoptosis still need further elucidation. In this article, a molecular target network of GEN against OP was screened. It was found that GEN might interact with OP by mediating PI3K/AKT pathway, which is the upstream factor in regulating autophagy. GEN exhibited protective activity against DEX-induced apoptosis by activating autophagy in vivo and in vitro. Blockage of autophagy, activation of PI3K/AKT/mTOR pathway, or inhibition of GLP-1R activity could eliminate the protective effects of GEN against DEX-induced apoptosis. Collectively, GEN ameliorated DEX-induced osteoblast apoptosis by activating autophagy through GLP-1R/PI3K/AKT/mTOR pathway.

Chronic glucocorticoid exposure accelerates Aß generation and neurotoxicity by activating calcium-mediated CN-NFAT1 signaling in hippocampal neurons in APP/PS1 mice.

Glucocorticoid (GC) exposure can lead to deterioration of the structure and function of hippocampal neurons and is closely involved in Alzheimer's disease (AD). Amyloid-ß (Aß) overproduction is an important aspect of AD pathogenesis. Our study mainly investigated the mechanism of chronic GC exposure in accelerating Aß production in primary cultured hippocampal neurons from APP/PS1 mice. The results indicated that chronic dexamethasone (DEX, 1 µM) significantly accelerated neuronal damage and Aß accumulation in hippocampal neurons from APP/PS1 mice. Meanwhile, DEX exposure markedly upregulated APP, NCSTN, BACE1 and p-Tau/Tau expression in hippocampal neurons from APP/PS1 mice. Our study also indicated that chronic DEX exposure significantly increased intracellular Ca2+ ([Ca2+]i) levels and the expressions of p-PLC, CN and NFAT1 in hippocampal neurons from APP/PS1 mice. We further found that stabilizing intracellular calcium homeostasis with 2-APB (50 µM) and SKF-96365 (10 µM) significantly alleviated neuronal damage and Aß accumulation in chronic DEX-induced hippocampal neurons from APP/PS1 mice. Additionally, dual luciferase assays showed that NFAT1 upregulated NCSTN transactivation, which was further increased upon DEX treatment. This study suggests that chronic DEX exposure accelerates Aß accumulation by activating calcium-mediated CN-NFAT1 signaling in hippocampal neurons from APP/PS1 mice, which may be closely related to the acceleration of AD.