Biphasic release of betamethasone from an injectable HA hydrogel implant for alleviating lumbar disc herniation induced sciatica.

Epidural steroid injection (ESI) is a common therapeutic approach for managing sciatica caused by lumbar disc herniation (LDH). However, the short duration of therapeutic efficacy and the need for repeated injections pose challenges in LDH treatment. The development of a controlled delivery system capable of prolonging the effectiveness of ESI and reducing the frequency of injections, is highly significant in LDH clinical practice. In this study, we utilized a thiol-ene click chemistry to create a series of injectable hyaluronic acid (HA) based release systems loaded with diphasic betamethasone, including betamethasone dipropionate (BD) and betamethasone 21-phosphate disodium (BP) (BD/BP@HA). BD/BP@HA hydrogel implants demonstrated biocompatibility and biodegradability to matched neuronal tissues, avoiding artificial compression following injection. The sustained release of betamethasone from BD/BP@HA hydrogels effectively inhibited both acute and chronic neuroinflammation by suppressing the nuclear factor kappa-B (NF-κB) pathway. In a mouse model of LDH, the epidural administration of BD/BP@HA efficiently alleviated LDH-induced sciatica for at least 10 days by inhibiting the activation of macrophages and microglia in dorsal root ganglion and spinal dorsal horn, respectively. The newly developed HA hydrogels represent a valuable platform for achieving sustained drug release. Additionally, we provide a simple paradigm for fabricating BD/BP@HA for epidural injection, demonstrating greater and sustained efficiency in alleviating LDH-induced sciatica compared to traditional ESI and displaying potentials for clinical translation. This system has the potential to revolutionize drug delivery for co-delivery of both soluble and insoluble drugs, thereby making a significant impact in the pharmaceutical industry. STATEMENT OF SIGNIFICANCE: Lumbar disc herniation (LDH) is a common degenerative disorder leading to sciatica and spine surgery. Although epidural steroid injection (ESI) is routinely used to alleviate sciatica, the efficacy is short and repeated injections are required. There remains challenging to prolong the efficacy of ESI. Herein, an injectable hyaluronic acid (HA) hydrogel implant by crosslinking acrylated-modified HA (HA-A) with thiol-modified HA (HA-SH) was designed to achieve a biphasic release of betamethasone. The hydrogel showed biocompatibility and biodegradability to match neuronal tissues. Notably, compared to traditional ESI, the hydrogel better alleviated sciatica in vivo by synergistically inhibiting the neuroinflammation in central and peripheral nervous systems. We anticipate the injectable HA hydrogel implant has the potential for clinical translation in treating LDH-induced sciatica.

Reproductive endocrine disruption and gonadal intersex induction in male Japanese medaka chronically exposed to betamethasone at environmentally relevant levels.

The broad utilization of betamethasone in medical treatments may pose a significant ecotoxicological risk to aquatic organisms, yet its potential reproductive toxicity remains unclear. The present study examined the impacts of environmental exposure on male reproduction using Japanese medaka (Oryzias latipes). After 110 days of betamethasone exposure at environmentally relevant concentrations (0, 20 and 200 ng/L), LH/FSH synthesis and release in the pituitary was inhibited, and the production of sex hormones and their signaling pathways in the gonads of male medaka were greatly influenced. This synthetic glucocorticoid restrained testosterone (T) synthesis and gave rise to a significant increase in E2/T and E2/11-KT ratios. Furthermore, chronic betamethasone exposure (20 and 200 ng/L) led to the suppression of androgen receptor (AR) signaling and enhancement of estrogen receptors (ERs) signaling. An increase in hepatic vitellogenin contents was also detected, and testicular oocytes were observed in both 20 and 200 ng/L betamethasone-treated groups. It showed that 20 and 200 ng/L betamethasone could induce male feminization and even intersex, triggering abnormal spermatogenesis in medaka males. With its adverse effects on male fertility, betamethasone could potentially influence the fishery productivity and population dynamics in aquatic ecosystems.

Preventive effects of antenatal CDP-choline in a rat model of neonatal hyperoxia-induced lung injury.

Antenatal steroid administration to pregnant women at risk of prematurity provides pulmonary maturation in infants, while it has limited effects on incidence of bronchopulmonary dysplasia (BPD), the clinical expression of hyperoxia-induced lung injury (HILI). Cytidine-5'-diphosphate choline (CDP-choline) was shown to alleviate HILI when administered to newborn rats. Therefore, we investigated effects of maternal administration of CDP-choline, alone or in combination with betamethasone, on lung maturation in neonatal rats subjected to HILI immediately after birth. Pregnant rats were randomly assigned to one of the four treatments: saline (1 mL/kg), CDP-choline (300 mg/kg), betamethasone (0.4 mg/kg), or CDP-choline plus betamethasone (combination therapy). From postnatal day 1 to 11, pups born to mothers in the same treatment group were pooled and randomly assigned to either normoxia or hyperoxia group. Biochemical an d histopathological effects of CDP-choline on neonatal lung tissue were evaluated. Antenatal CDP-choline treatment increased levels of phosphatidylcholine and total lung phospholipids, decreased apoptosis, and improved alveolarization. The outcomes were further improved with combination therapy compared to the administration of CDP-choline or betamethasone alone. These results demonstrate that antenatal CDP-choline treatment provides benefit in experimental HILI either alone or more intensively when administered along with a steroid, suggesting a possible utility for CDP-choline against BPD.

The Effect of the Long-Term Calcipotriol/Betamethasone Dipropionate Local Therapy on Tissue Resident Memory Cells Markers in Psoriatic Eruptions.

BACKGROUND: The natural course of psoriasis is characterized by the long-term persistence of lesions and a predilection for relapse in the same area. It is caused by the inherence of TRM (tissue resident memory T cells) in apparently healthy skin. These cells are able to initiate an inflammatory cascade and induce relapse of the disease. These cells are characterized by high resistance to damaging factors and apoptosis, which determines their longevity. AIM: The aim of our study was to evaluate the presence of TRM in psoriatic plaques before, during and after 12 weeks of therapy in patients treated with topical calcipotriol and betamethasone dipropionate (Cal/BD) foam. METHODS: TRM markers (CD4, CD8, CD103, CD69, CD49, CXCR6) and tissue expression of cytokines (IL-17A, IL-22) in the lesional psoriatic skin from 10 patients compared to 10 healthy skin samples were estimated by immunohistochemistry. Biopsy samples from the area of the same psoriatic plaque were collected three times: before the initiation of therapy, 4 and 12 weeks after its initiation. RESULTS: The presence of TRM markers in the epidermis and dermis of psoriatic lesions was significantly higher when compared to the skin of control group patients. A reduction in the expression of the characteristic TRM markers (CD8, CD4, CD103, CD69, CXCR6, IL-17A and IL-22) was observed in the epidermis on week 12 of therapy, while a depletion in the expression of TRM in the dermis was demonstrated only in CD4 and IL-22. CONCLUSIONS: Topical treatment with Cal/BD foam significantly decreased the expression of TRM markers mainly in the epidermis, and to a lesser extent in the dermis, during the 12-week observation period. It probably results from a worse penetration of the drug into the dermis and the effect of the preparation mainly on the epidermis. The persistence of a high expression of TRM markers in the dermis may result in the rapid recurrence of lesions after discontinuation of topical treatment.

The RelB-BLNK Axis Determines Cellular Response to a Novel Redox-Active Agent Betamethasone during Radiation Therapy in Prostate Cancer.

Aberrant levels of reactive oxygen species (ROS) are potential mechanisms that contribute to both cancer therapy efficacy and the side effects of cancer treatment. Upregulation of the non-canonical redox-sensitive NF-kB family member, RelB, confers radioresistance in prostate cancer (PCa). We screened FDA-approved compounds and identified betamethasone (BET) as a drug that increases hydrogen peroxide levels in vitro and protects non-PCa tissues/cells while also enhancing radiation killing of PCa tissues/cells, both in vitro and in vivo. Significantly, BET increases ROS levels and exerts different effects on RelB expression in normal cells and PCa cells. BET induces protein expression of RelB and RelB target genes, including the primary antioxidant enzyme, manganese superoxide dismutase (MnSOD), in normal cells, while it suppresses protein expression of RelB and MnSOD in LNCaP cells and PC3 cells. RNA sequencing analysis identifies B-cell linker protein (BLNK) as a novel RelB complementary partner that BET differentially regulates in normal cells and PCa cells. RelB and BLNK are upregulated and correlate with the aggressiveness of PCa in human samples. The RelB-BLNK axis translocates to the nuclear compartment to activate MnSOD protein expression. BET promotes the RelB-BLNK axis in normal cells but suppresses the RelB-BLNK axis in PCa cells. Targeted disruptions of RelB-BLNK expressions mitigate the radioprotective effect of BET on normal cells and the radiosensitizing effect of BET on PCa cells. Our study identified a novel RelB complementary partner and reveals a complex redox-mediated mechanism showing that the RelB-BLNK axis, at least in part, triggers differential responses to the redox-active agent BET by stimulating adaptive responses in normal cells but pushing PCa cells into oxidative stress overload.

One percent of the clinical dose used for antenatal steroid therapy is sufficient to induce lung maturation when administered directly to the preterm ovine fetus.

Antenatal steroids (ANSs) are routinely administered to women judged to be at imminent risk of preterm delivery. Their principal benefit is precocious functional maturation of the preterm fetal lung. Current dosing regimens expose the mother and fetus to high steroid levels that may be unnecessary, increasing the potential risks of disruption to the maternal and fetal hypothalamic-pituitary-adrenal (HPA) axis and glucose regulation, alterations in placental function, and reduced fetal growth. Using a sheep model of pregnancy, we tested the hypothesis that direct fetal administration of an ultra-low dose course of betamethasone phosphate (∼0.33 mg) would be sufficient to elicit functional maturation of the fetal lung. A jugular catheter was installed in singleton ovine fetuses at 122-day gestation under general anesthesia. Animals were randomized to receive either: 1) fetal intravenous betamethasone phosphate to target fetal plasma betamethasone mean levels of 2 ng/mL for 26 h (fetal treatment group; n = 16); 2) fetal intravenous saline for 26 h and two maternal intramuscular injections of 0.25 mg/kg betamethasone phosphate + betamethasone acetate, simulating a standard clinical treatment (maternal treatment group; n = 12); or 3) fetal intravenous saline only for 26 h (negative control group; n = 10). Fetuses were delivered 48 h after surgery, ventilated for 30 min to allow the collection of lung function and physiological data, and euthanized. Quantitative PCR and Western blots were used to assess markers of lung maturation. The average total betamethasone phosphate dose for the fetal treatment group was 1% (0.3 mg) of the maternal treatment group (31-mg betamethasone phosphate + betamethasone acetate). At 30 min of ventilation, arterial [Formula: see text], pH, heart rate, and ventilation efficacy index (VEI) were significantly (P < 0.05) and equivalently improved in both the fetal treatment group and maternal treatment group, relative to the negative control group. Similarly, SP-A, SP-C, and AQ-5 mRNA expression was significantly higher in both the fetal treatment group and maternal treatment group, relative to negative control. Maternal steroid administration was not required to generate preterm fetal lung maturation in sheep. Using a low dose and targeting steroid treatments directly to the fetus has the potential to significantly reduce maternal exposures, while simultaneously reducing the potential risk of adverse outcomes associated with current clinical dosing regimens.

Fetal glucocorticoid exposure leads to sex-specific changes in drug-transporter function at the blood-brain barrier in juvenile guinea pigs.

Antenatal synthetic glucocorticoids (sGCs) are a life-saving treatment in managing pre-term birth. However, off-target effects of sGCs can impact blood-brain barrier (BBB) drug transporters essential for fetal brain protection, including P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (BCRP/Abcg2). We hypothesized that maternal antenatal sGC treatment modifies BBB function in juvenile offspring in a sex-dependent manner. Thus, the objective of this study was to determine the long-term impact of a single or multiple courses of betamethasone on P-gp/Abcb1 and BCRP/Abcg2 expression and function at the BBB. Pregnant guinea pigs (N = 42) received 3 courses (gestation days (GDs) 40, 50, and 60) or a single course (GD50) of betamethasone (1 mg/kg) or vehicle (saline). Cerebral microvessels and brain endothelial cells (BEC) were collected from the post-natal day (PND) 14 offspring to measure protein, gene expression, and function of the drug transporters P-gp/Abcb1 and BCRP/Abcg2. P-gp protein expression was decreased (p < .05) in microvessels from male offspring that had been exposed to multiple courses and a single course of sGC, in utero. Multiple courses of sGC resulted in a significant decrease in P-gp function in BECs from males (p < .05), but not females. There was a very strong trend for increased P-gp function in males compared to females (p = .055). Reduced P-gp expression and function at the BBB of young male offspring following multiple prenatal sGC exposures, is clinically relevant as many drugs administered postnatally are P-gp substrates. These novel sex differences in drug transporter function may underlie potential sexual dimorphism in drug sensitivity and toxicity in the newborn and juvenile brain.

A potential role of mesenchymal stem cells derived from human umbilical cord blood in ameliorating psoriasis-like skin lesion in the rats.

BACKGROUND: Psoriasis is a common autoimmune inflammatory skin disease, with no clear cause, treated with topical agents and phototherapy, conventional immunosuppressant drugs and biologic agents. Stem cell therapy has generated significant interest in regenerative medicine. The aim of this study was to use mesenchymal stem cell (MSC) therapy compared to the topical application of the standard conventional corticosteroid cream. MATERIALS AND METHODS: Forty male adult albino rats were used, divided into four groups, 10 rats each: group I (control), group II (psoriasis-like lesions induced by usage of Aldara cream), group III (treated with betamethasone) and group IV (treated with MSCs). Specimens were stained with haematoxylin and eosin, Masson's trichrome, immune-histochemical technique for CD4, CD8 and CD31. Ultra-sections were prepared for transmission electron microscope (TEM) examination. RESULTS: Mesenchymal stem cells demonstrated efficacy in reduction of disease severity in the form of uniform epidermal thickness covered by a very thin keratin layer. Normally arranged layers of epidermal layers, with a clear border demarcation, were seen between the epidermis and the dermis with apparently intact basement membrane. TEM showed absence of gaps between the tightly connected cells of the basal layer and the resting basement membrane. CONCLUSIONS: Application of MSCs raises hope for developing a new, safe and effective therapy for psoriatic patients, avoiding the side effects of betamethasone.

Betamethasone induces potent immunosuppression and reduces HIV infection in a PBMC in vitro model.

Genital inflammation is an established risk factor for increased HIV acquisition risk. Certain HIV-exposed seronegative populations, who are naturally resistant to HIV infection, have an immune quiescent phenotype defined by reduced immune activation and inflammatory cytokines at the genital tract. Therefore, the aim of this study was to create an immune quiescent environment using immunomodulatory drugs to mitigate HIV infection. Using an in vitro peripheral blood mononuclear cell (PBMC) model, we found that inflammation was induced using phytohemagglutinin and Toll-like receptor (TLR) agonists Pam3CSK4 (TLR1/2), lipopolysaccharide (LPS) (TLR4) and R848 (TLR7/8). After treatment with anti-inflammatory drugs, ibuprofen (IBF) and betamethasone (BMS), PBMCs were exposed to HIV NL4-3 AD8. Multiplexed ELISA was used to measure 28 cytokines to assess inflammation. Flow cytometry was used to measure immune activation (CD38, HLA-DR and CCR5) and HIV infection (p24 production) of CD4+ T cells. BMS potently suppressed inflammation (soluble cytokines, p<0.05) and immune activation (CD4+ T cells, p<0.05). BMS significantly reduced HIV infection of CD4+ T cells only in the LPS (0.98%) and unstimulated (1.7%) conditions (p<0.02). In contrast, IBF had minimal anti-inflammatory and immunosuppressive but no anti-HIV effects. BMS demonstrated potent anti-inflammatory effects, regardless of stimulation condition. Despite uniform immunosuppression, BMS differentially affected HIV infection according to the stimulation conditions, highlighting the complex nature of these interactions. Together, these data underscore the importance of interrogating inflammatory signaling pathways to identify novel drug targets to mitigate HIV infection.

Variability in the efficacy of a standardized antenatal steroid treatment was independent of maternal or fetal plasma drug levels: evidence from a sheep model of pregnancy.

BACKGROUND: Administration of antenatal steroids is standard of care for women assessed to be at imminent risk of preterm delivery. There is a marked variation in antenatal steroid dosing strategy, selection for treatment criteria, and agent choice worldwide. This, combined with very limited optimization of antenatal steroid use per se, means that treatment efficacy is highly variable, and the rate of respiratory distress syndrome is decreased to perhaps as low as 40%. In some cases, antenatal steroid use is associated with limited benefit and potential harm. OBJECTIVE: We hypothesized that individual differences in maternofetal steroid exposure would contribute to observed variability in antenatal steroid treatment efficacy. Using a chronically catheterized sheep model of pregnancy, we aimed to explore the relationship between maternofetal steroid exposure and antenatal steroid treatment efficacy as determined by functional lung maturation in preterm lambs undergoing ventilation. STUDY DESIGN: Ewes carrying a single fetus underwent surgery to catheterize a fetal and maternal jugular vein at 119 days' gestation. Animals recovered for 24 hours before being randomized to either (1) a single maternal intramuscular injection of 2 mL saline (negative control group, n=10) or (2) a single maternal intramuscular injection of 0.25 mg/kg betamethasone phosphate plus acetate (antenatal steroid group, n=20). Serial maternal and fetal plasma samples were collected from each animal after 48 hours before fetuses were delivered and ventilated for 30 minutes. Total and free plasma betamethasone concentration was measured by mass spectrometry. Fetal lung tissue was collected for analysis using quantitative polymerase chain reaction. RESULTS: One animal from the control group and one animal from the antenatal steroid group did not complete their treatment protocol and were removed from analyses. Animals in the antenatal steroid group were divided into a responder subgroup (n=12/19) and a nonresponder subgroup (n=7/19) using a cutoff of partial pressure of arterial CO2 at 30-minute ventilation within 2 standard deviations of the mean value from saline-treated negative control group animals. Although antenatal steroid improved fetal lung maturation in the undivided antenatal steroid group and in the responder subgroup both physiologically (blood gas- and ventilation-related data) and biochemically (messenger ribonucleic acid expression related to fetal lung maturation), these values did not improve relative to saline-treated control group animals in the antenatal steroid nonresponder subgroup. No differences in betamethasone distribution, clearance, or protein binding were identified between the antenatal steroid responder and nonresponder subgroups. CONCLUSION: This study correlated individual maternofetal steroid exposures with preterm lung maturation as determined by pulmonary ventilation. Herein, approximately 40% of preterm lambs exposed to antenatal steroids had lung maturation that was not significantly different to saline-treated control group animals. These nonresponsive animals received maternal and fetal betamethasone exposures identical to animals that had a significant improvement in functional lung maturation. These data suggest that the efficacy of antenatal steroid therapy is not solely determined by maternofetal drug levels and that individual fetal or maternal factors may play a role in determining treatment outcomes in response to glucocorticoid signaling.

Combination of agents modifying effects in hadrontherapy: modelization of the role of HO° free radicals.

Purpose: A study is presented of the irradiation of cancerous cervical cell line HeLa loaded with a platinum salt, betamethasone and deoxyglucose. The presence of the platinum increases the free-radical concentration and augments the cell death rate, whereas betamethasone or deoxyglucose induces radiosensitization by the alteration of metabolic pathways. Two by two combinations of these chemicals are made to investigate the possible benefit when two radiosensitizers are present. A model is proposed to understand the results of the presence of two modifying agents on the dose effects.Materials and methods: The cells were incubated for 6 h in the presence of the following molecules: dichloro terpyridine platinum, concentration C = 350 µM, betamethasone and deoxyglucose with concentrations of C = 0.2 µM and C = 6 mM, respectively. The cells were subsequently irradiated by carbon C6+ ion 290 MeV/amu up to a dose of 2.5 Gy, under atmospheric conditions.Results: The presence of the platinum salt or bethamethasone augments the cell death rate. The combination of betamethasone with the platinum salt also increases the cell death rate, but less than for the platinum salt alone. The explanation is that any radiosensitizer also behaves as a scavenger of free radicals. This dual behavior should be considered in any optimization of the design of radiosensitizers when different ionizing particles are used.

Sulfur mustard alkylates steroid hormones and impacts hormone function in vitro.

The chemical warfare agent sulfur mustard (SM) alkylates a multitude of biomacromolecules including DNA and proteins. Cysteine residues and nucleophilic nitrogen atoms in purine DNA bases are typical targets of SM but potentially every nucleophilic structure may be alkylated by SM. In the present study, we analyzed potential SM-induced alkylation of glucocorticoid (GC) hormones and functional consequences thereof. Hydrocortisone (HC), the synthetic betamethasone (BM) and dexamethasone (DEX) were chosen as representative GCs. Structural modifications were assessed by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. The hypothesized alkylation was verified and structurally allocated to the OH-group of the C21 atom. The biological function of SM-alkylated GCs was investigated using GC-regulated dual-luciferase reporter gene assays and an ex vivo GC responsiveness assay coupled with real-time quantitative polymerase chain reaction (RT-qPCR). For the reporter gene assays, HEK293-cells were transiently transfected with a dual-luciferase reporter gene that is transcriptional regulated by a GC-response element. These cells were then incubated either with untreated or SM-derivatized HC, BM or DEX. Firefly-luciferase (Fluc) activity was determined 24 h after stimulation. Fluc-activity significantly decreased after stimulation with SM-pre-exposed GC dependent on the SM concentration. The ex vivo RT-qPCR-based assay for human peripheral leukocyte responsiveness to DEX revealed a transcriptional dysregulation of GC-regulated genes (FKBP5, IL1R2, and GILZ) after stimulation with SM-alkylated DEX. Our results present GCs as new biological targets of SM associated with a disturbance of hormone function.

Effect of the Ratio of Betamethasone to TNF-α siRNA Coencapsulated in Solid Lipid Nanoparticles on the Acute Proinflammatory Activity of the Nanoparticles.

There is evidence that encapsulating glucocorticoids into nucleic acid-containing nanoparticles reduces the inflammatory toxicities of the nanoparticles. Herein, using betamethasone acetate (BA), a glucocorticoid, and a solid lipid nanoparticle formulation of siRNA, we confirmed that coencapsulating BA into the siRNA solid lipid nanoparticles significantly reduced the proinflammatory activity of the siRNA nanoparticles in a mouse model. Using TNF-α siRNA, we then showed that the BA and TNF-α siRNA coencapsulated into the solid lipid nanoparticles acted as a dual anti-inflammatory and synergistically reduced TNF-α release by mouse macrophages in culture following stimulation with lipopolysaccharide, as compared to solid lipid nanoparticles encapsulated with TNF-α siRNA or BA alone. Importantly, upon studying the effect of the ratio of BA and TNF-α siRNA on the proinflammatory activity of the resultant nanoparticles, we identified that BA and TNF-α siRNA coencapsulated solid lipid nanoparticles prepared with a BA to TNF-α siRNA weight ratio of 2:1 induced the lowest proinflammatory cytokine production by macrophages in culture. This result was in comparison to nanoparticles prepared with BA to TNF-α siRNA ratios both higher and lower than 2:1 (i.e., 4:1, 1:1, and 0.5:1) and is likely due to differences in molecular interactions among the various components in the BA and TNF-α-siRNA coencapsulated solid lipid nanoparticles at these ratios. Encapsulating glucocorticoids into siRNA-nanoparticles represents a viable strategy to reduce the proinflammatory activity of the nanoparticles; however, the ratio of the glucocorticoid to siRNA in the nanoparticles requires optimization.

Antenatal betamethasone enhanced the detrimental effects of postnatal dexamethasone on hyperoxic lung and brain injuries in newborn rats.

PURPOSE: To determine the effects of antenatal betamethasone and/or postnatal dexamethasone administration on hyperoxic lung and brain injuries in newborn rats. METHODS: Newborn Sprague-Dawley rats were divided into five experimental groups: normoxia-vehicle-vehicle group, hyperoxia-vehicle-vehicle group, hyperoxia-betamethasone-vehicle group, hyperoxia-vehicle-dexamethasone group, and hyperoxia-betamethasone-dexamethasone group according to (i) whether rats were exposed to normoxia or hyperoxia after birth to postnatal day (P) 14, (ii) whether antenatal betamethasone (0.2mg/kg) or vehicle was administered to pregnant rats at gestation days 19 and 20, and (iii) whether three tapering doses of dexamethasone (0.5, 0.3, 0.1mg/kg per day) or vehicle were administered on P5, 6 and 7, respectively. The lungs and brains were harvested for histological and biochemical analyses at P8 and P14. RESULTS: Postnatal dexamethasone but not antenatal betamethasone significantly enhanced hyperoxia-induced reduction in body weight gain and alveolarization and increased lung terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells both at P8 and P14, transiently increased hyperoxia-induced reductions in brain weight gain and angiogenesis, and increase in brain TUNEL-positive cells at P8 but not at P14. Co-administration of antenatal betamethasone significantly enhanced dexamethasone-induced impairments in alveolarization both at P8 and P14, transient increases in lung and brain oxidative stresses, and increases in brain TUNEL-positive cells at P8 but not at P14. CONCLUSION: Although postnatal dexamethasone but not antenatal betamethasone alone significantly increased hyperoxic lung and brain injuries, co-administration of antenatal betamethasone significantly enhanced the detrimental effects of postnatal dexamethasone on hyperoxic lung and brain injuries in newborn rats.

Long-Term Evaluation of Low-Dose Betamethasone for Ataxia Telangiectasia.

BACKGROUND: Ataxia telangiectasia is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Quality of life is severely impaired by neurological symptoms. However, curative options for the neurological symptoms are limited. Recent studies have demonstrated short-term improvement in neurological symptoms with betamethasone therapy. However, the long-term and adverse effects of betamethasone are unclear. The aim of this study was to evaluate the long-term effects, benefits, and adverse effects of low-dose betamethasone in ataxia telangiectasia. METHODS: Six patients with ataxia telangiectasia received betamethasone at 0.02 mg/kg/day for two years. After cessation of betamethasone, the patients were observed for two additional years. Neurological assessments were performed, and adverse effects were monitored every three months throughout the four-year study period. RESULTS: Transient improvement of neurological symptom was observed in five of the six patients. However, after two years betamethasone treatment, only one of the six patients showed a slight improvement in the neurological score, one patient showed no change, and the neurological scores of the remaining four patients deteriorated. After the cessation of betamethasone treatment, neurological symptoms worsened in all patients. As an adverse effect of betamethasone, transient adrenal dysfunction was observed in all cases. CONCLUSIONS: Although these findings are in agreement with previous studies suggesting that short-term betamethasone treatment transiently benefits patients with ataxia telangiectasia, the long-term benefits and risks should be carefully considered.

Oxidative stress-induced IL-15 trans-presentation in keratinocytes contributes to CD8+ T cells activation via JAK-STAT pathway in vitiligo.

Oxidative stress and effector memory CD8+ T cells have been greatly implicated in vitiligo pathogenesis. However, the crosstalk between these two crucial pathogenic factors has been merely investigated. IL-15 has been regarded as an important cytokine exerting its facilitative effect on memory CD8+ T cells function in various autoimmune diseases. In the present study, we initially discovered that the IL-15 expression was significantly increased in vitiligo epidermis and highly associated with epidermal H2O2 content. In addition, epidermal IL-15 expression was mainly derived from keratinocytes. Then, we showed that oxidative stress promoted IL-15 and IL-15Rα expression as well as IL-15 trans-presentation by activating NF-κB signaling in keratinocytes. What's more, the trans-presented IL-15, rather than the secreted one, was accounted for the potentiation of CD8+ TEMs activation. We further investigated the mechanism underlying trans-presented IL-15 in potentiating CD8+ TEMs activation and found that the blockage of IL-15-JAK-STAT signaling could be a potent therapeutic approach. Taken together, our results demonstrate that oxidative stress-induced IL-15 trans-presentation in keratinocytes contributes to the activation of CD8+ TEMs, providing a novel mechanism by which oxidative stress initiates autoimmunity in vitiligo.

The role of glucocorticoids in ovarian development of sleep deprived rats.

OBJECTIVE: Sleep deprivation (SD) adversely affects female reproductive function. In this study, we investigated the role of glucocorticoids in ovarian development in sleep deprived rats. MATERIALS AND METHODS: Female rats were subjected to SD for 1-4 days. Concentrations of serum estradiol and corticosterone were assessed. Betamethasone (BET) and/or recombinant human follicle-stimulating hormone (FSH) were administered to 21-day-old female rats for 2 days to evaluate ovarian status for follicular development. Intact preantral follicles were mechanically dissected from the rat's ovaries and cultured for 72 h with or without FSH in the presence or absence of BET to evaluate follicular development. RESULTS: SD led to a significant difference in serum estradiol concentrations between the sham and SD groups, and corticosterone concentrations were significantly elevated in groups with more than 2 days of SD (P < 0.05). FSH stimulated ovarian growth in immature rats, whereas BET inhibited ovarian development caused by the FSH treatment. Treatment of the preantral follicles with FSH induced an increase in both follicle size and follicular cell number, while follicular cell differentiation was accompanied by enhanced inhibin-α and connexin 43 expression. Inhibition of FSH-stimulated follicular growth through BET treatment exhibited a dose-dependent reciprocal trend; as the BET dose increased (0.001-1 µg/mL), preantral follicular growth decreased. This decrease was associated with a decrease in follicular cell numbers and suppression of a proliferating cell nuclear antigen, inhibin-α, and connexin 43 expression. CONCLUSION: The findings suggest that the adverse effects of SD may inhibit follicular development during ovarian hyperstimulation by corticosterone elevation in rat.

Intrathecal betamethasone for cancer pain: A study of its analgesic efficacy and safety.

BACKGROUND: A preliminary study has shown effective cancer pain relief by intrathecal betamethasone (ITB). However, further evidence is needed to support this new approach. METHODS: Cancer patients with opioid-resistant pain received lumbar intrathecal administration of betamethasone 2 or 3 mg once a week for 28 days. Immediate and short-term analgesia (using a percentage pain reduction scale and a numerical rating scale, NRS) and long-term analgesia (using NRS) were assessed. Patients were classified into two groups according to the most painful site of metastasis: vertebral column and/or surrounding nerve plexus metastases (group A) and other metastases distal from the vertebral column (group B). RESULTS: A total of 104 patients received ITB. Pain relief was observed not only in the lower half but also in the upper half of the body. The proportion of group A patients who experienced immediate analgesia was 81% (47/58), which was significantly greater than that of group B (P < 0.001). A decrease in NRS scores 1 day after ITB administration was observed in significantly more patients in group A than in group B (P < 0.001). Long-term analgesia was also recorded in a greater proportion of patients in group A than in group B in the 7-day (59%, 38/64 vs 6%, 2/33) and 28-day periods (71%, 40/56 vs 31%, 8/26) (P < 0.001). No adverse effects related to neurotoxicity were recorded. CONCLUSION: Intrathecal injection of betamethasone produced analgesia for opioid-resistant cancer pain, and may be a potent therapeutic option for intolerable pain from vertebral column and/or surrounding nerve plexus metastases.

Betamethasone prevents human rhinovirus- and cigarette smoke- induced loss of respiratory epithelial barrier function.

The respiratory epithelium is a barrier against pathogens and allergens and a target for therapy in respiratory allergy, asthma and chronic obstructive pulmonary disease (COPD). We investigated barrier-damaging factors and protective factors by real-time measurement of respiratory cell barrier integrity. Barrier integrity to cigarette smoke extract (CSE), house dust mite (HDM) extract, interferon-γ (IFN-γ) or human rhinovirus (HRV) infection alone or in combination was assessed. Corticosteroids, lipopolysaccharide (LPS), and nasal mucus proteins were tested for their ability to prevent loss of barrier integrity. Real-time impedance-based measurement revealed different patterns of CSE-, HDM-, IFN-γ- and HRV-induced damage. When per se non-damaging concentrations of harmful factors were combined, a synergetic effect was observed only for CSE and HDM. Betamethasone prevented the damaging effect of HRV and CSE, but not damage caused by HDM or IFN-γ. Real-time impedance-based measurement of respiratory epithelial barrier function is useful to study factors, which are harmful or protective. The identification of a synergetic damaging effect of CSE and HDM as well as the finding that Betamethasone protects against HRV- and CSE-induced damage may be important for asthma and COPD.

A novel model to study neonatal Escherichia coli sepsis and the effect of treatment on the human immune system using humanized mice.

PROBLEM: Neonatal sepsis is a serious threat especially for preterm infants. As existing in vitro and in vivo models have limitations, we generated a novel neonatal sepsis model using humanized mice and tested the effect of Betamethasone and Indomethacin which are used in the clinic in case of premature birth. METHOD OF STUDY: Humanized mice were infected with Escherichia coli (E. coli). Subsequently, the effect of the infection itself, and treatment with Betamethasone and Indomethacin on survival, recovery, bacterial burden, leukocyte populations, and cytokine production, was analyzed. RESULTS: The human immune system in the animals responded with leukocyte trafficking to the site of infection and granulopoiesis in the bone marrow. Treatment with Indomethacin had no pronounced effect on the immune system or bacterial burden. Betamethasone induced a decline of splenocytes. CONCLUSION: The human immune system in humanized mice responds to the infection, making them a suitable model to study neonatal E. coli sepsis and the immune response of the neonatal immune system. Treatment with Betamethasone could have potential negative long-term effects for the immune system of the child.