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Directional differentiation is a key factor determining the result of stem cell therapy. Herein, we developed a polyethylenimine (PEI)-coated poly(lactic- co -glycolic) acid (PLGA) nanoparticle (mPDN) carrying both nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA and dexamethasone (Dex) to human mesenchymal stem cells (hMSCs). The combination of Dex and Nrf2-mRNA delivered by mPDN promoted the osteogenic differentiation of hMSCs. In particular, Nrf2-mRNA rapidly reduced the DNA damage caused by ROS due to early and efficient gene expression at 3 h after treatment, which was not achieved in traditional pDNA systems. High and rapid transfection, effective ROS-scavenging effect, and protection of mitochondrial dynamics were observed in hMSCs after treatment with the resulting Nrf2-mPDN. Osteogenic differentiation was also observed in 3D pellets for up to 5 weeks. Finally, the effects of rapid DNA repair in hMSCs by Nrf2-mPDN and on in vivo bone regeneration were evaluated in a rat femoral bone defect model using CT. This study demonstrated the potential of an NP-based codelivery system and efficient transfection of mRNA at early stages in hMSCs for bone regeneration and stem cell therapy.

Psoriasis is a prevalent, inflammatory skin disease without cure. Further research is required to unravel dysregulated processes and develop new therapeutic interventions. The lack of suitable in vivo and in vitro preclinical models is an impediment in the psoriasis research. Recently, the development of 3D skin models has progressed including replicas with disease-like features. To investigate the use of in vitro models as preclinical test tools, the study focused on treatment responses of 3D skin replicas. Cytokine-priming of skin organoids induced psoriatic features like inflammation, antimicrobial peptides (AMP), hyperproliferation and impaired differentiation. Topical application of dexamethasone (DEX) or celastrol (CEL), a natural anti-inflammatory compound reduced the secretion of pro-inflammatory cytokines. DEX and CEL decreased the gene expression of inflammatory mediators. DEX barely affected the psoriatic AMP transcription but CEL downregulated psoriasis-driven AMP genes. Subcutaneous application of adalimumab (ADM) or bimekizumab (BMM) showed anti-psoriatic effects via protein induction of the differentiation marker keratin-10. Dual blockage of TNF-α and IL-17A repressed the inflammatory psoriasis phenotype. BMM inhibited the psoriatic expression of AMP genes and induced KRT10 and cell-cell contact genes. The present in vitro model provides a 3D environment with in vivo-like cutaneous responses and represents a promising tool for preclinical investigations., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Ethnopharmacological Relevance: Euonymus alatus (Thunb.) Siebold. (EA), a traditional Chinese medicine, is widely used in the treatment of diabetes. Our group has previously found that EA could treat diabetic retinopathy (DR) and stigmast-4-en-3-one (Numbered E6) is the active substance responsible for inhibiting angiogenesis in vitro by EA. However, the effects and mechanisms of E6 in the treatment of DR is still unknown., Aim of the Study: The aim of this study was to investigate the effects and mechanisms of E6 in EA on DR. Additionally, a comparison was made between the effects of E6 and triamcinolone acetonide (TA), as well as the side effects of E6 and dexamethasone., Materials and Methods: Ocular affinity assessment and pharmacokinetic parameter prediction were conducted to evaluate the potential of E6 to treat DR. Retinal endothelial cells were used to investigate the in vitro inhibitory effect of E6 on vascular proliferation. Additionally, chicken embryos, zebrafish, and mice were used to investigate the in vivo anti-vascular proliferation effect of E6. Finally, diabetic mice were used to investigate whether E6 improves diabetic retinopathy and to compare its efficacy with that of TA. We then used network pharmacology to study the targets of E6 and performed molecular docking; followed by immunofluorescence experiments, ELISA, Western blot, and tube formation experiments to further investigate its mechanism. Finally, we compared the side effects of E6 with those of dexamethasone., Results: E6 was found to have an affinity for the eye and to inhibit vascular proliferation both in vivo and in vitro. Moreover, E6 was found to be more efficacious than TA in the treatment of DR. Molecular docking experiments predicted that the glucocorticoid receptor (GR) is a potential target of E6, and immunofluorescence analyses confirmed that E6 upregulated the expression of the GR in the retina of hyperglycemic mice. In addition, western blotting results and tube formation experiments showed that E6 also attenuated angiogenesis by inhibiting the Hippo and VEGF pathways. Finally, by comparing the effects of E6 and dexamethasone on glucose regulation and osteoporosis, E6 was found to have fewer side effects., Conclusions: E6 is a highly effective drug for the treatment of DR, superior to TA and with fewer side effects than dexamethasone. Its mechanism involves the activation of glucocorticoid receptor and inhibition of Hippo and VEGF pathways to alleviate angiogenesis and inflammation. This study is the first to investigate the role and mechanism of E6 in improving DR. The findings suggest that E6 has unique advantages in the treatment of DR., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Stress, a risk factor for major depressive disorder and Alzheimer disease, leads to the release of high-mobility group box-1 (HMGB1) protein, which in turn causes neuroinflammation. The mechanism underlying stress-induced HMGB1 release is unknown, but stress-associated glucocorticoids could be involved. Primary cultured rat cortical microglia and neurons were treated with corticosterone, a stress-associated glucocorticoid, and HMGB1 release was measured by ELISA and western blotting to test this hypothesis. With corticosterone treatment, significant HMGB1 was released in microglia but not in neuronal cell cultures. HMGB1 mRNA expression and HMGB1 protein expression in microglia were not affected by corticosterone treatment. Thus, the source of extracellular HMGB1 released into the medium is likely to be existing nuclear HMGB1 rather than newly synthesized HMGB1. Corticosterone-induced HMGB1 release in microglia culture was significantly attenuated by blocking glucocorticoid receptors but not mineralocorticoid receptors. Dexamethasone, a selective glucocorticoid receptor agonist, and dexamethasone-bovine serum albumin (BSA), a membrane-impermeable glucocorticoid receptor agonist used to confirm the membrane receptor-mediated effects of glucocorticoids, increased the release of HMGB1. Immunocytochemistry showed that HMGB1 translocated from the nucleus to the cytoplasm following dexamethasone or dexamethasone-BSA treatment through glucocorticoid receptors. The present findings suggest that glucocorticoids stimulate microglial membrane glucocorticoid receptors and trigger cytoplasmic translocation and extracellular release of nuclear HMGB1. Thus, under stress conditions, glucocorticoids induce microglial HMGB1 release, leading to a neuroinflammatory state that could mediate neurological disorders., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Takahisa Shimoda is working in Laboratory for Pharmacology, Pharmaceuticals Research Center, Asahi Kasei Pharma Co. Ltd.. This study was conducted fully independent of the project in the Asahi Kasei Pharma Co., Ltd. The other authors declare no conflict of interest., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Different therapeutic modalities, including steroids, have been used to treat corneal scarring. However, the ability of steroids to reduce corneal scarring is limited and associated with numerous side effects. Our previous studies have demonstrated that topical hepatocyte growth factor (HGF) after corneal injury suppresses the development of stromal scars. Here, we investigated whether HGF can re-establish corneal clarity and normalize tissue structure in corneas with pre-existing scars. Corneal scarring was induced by mechanically removing the corneal epithelium and the anterior third of the stroma using a hand-held Algerbrush II in C57BL/6 mice. Substantial scar tissue formed by day 10 post-injury, at which time the epithelium was debrided and treated with 0.1% recombinant mouse HGF, 0.1% dexamethasone (steroid) or 0.1% control protein thrice a day for 10 days. Corneal clarity was significantly restored in the HGF treatment group, compared to both the steroid and control protein treatment groups. Moreover, HGF treatment downregulated the expression of αSMA and upregulated the expression of extracellular matrix-remodeling matrix metalloproteinases 1 and 10 (MMP1 and MMP10), suggesting HGF upregulates tissue remodeling molecule MMP1 and 10 to promote tissue restoration. These findings offer novel insights into the mechanisms by which HGF re-establishes corneal clarity, and promotes epithelial regeneration in corneas with pre-existing stromal scarring., (© 2024. The Author(s).)

Delayed endothelialization, the excessive proliferation of smooth muscle cells (SMCs), and persistent inflammation are the main reasons for the implantation failure of blood-contacting materials. To overcome this problem, an inflammation-responsive, core-shell structured microfiber scaffold is developed using polycaprolactone (PCL), selenocystamine-modified gelatin (Gel-Se), L-ascorbyl 6-palmitate (AP), and dexamethasone as the fiber shell, with poly (l-lysine) (PLL) and heparin incorporated in the fiber core. Superhydrophilic microfiber scaffolds exhibit antifouling properties that inhibit protein adsorption and blood cell adhesion, thereby effectively mitigating the risk of acute thrombosis. The continuous release of heparin and sustained generation of nitric oxide (NO) through the catalytic decomposition of S-nitrosothiols by selenocystamine lead to a biomimetic endothelial function for the enhancement of blood compatibility. The inflammation-responsive compound AP can detoxify excess reactive oxygen species (ROS) while controlling the release of dexamethasone to reduce chronic inflammation. We demonstrate the ability of microfiber scaffolds to reduce thrombotic and inflammatory complications, inhibit SMC proliferation, and promote rapid endothelialization both in vitro and ex vivo. Hence, microfiber scaffolds are robust and promising for blood-contacting implants with enhanced antithrombogenicity and anti-inflammatory capabilities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Adipocyte enhancer-binding protein 1 (AEBP1) is closely implicated in osteoblastic differentiation and bone fracture; this research aimed to investigate the effect of AEBP1 on restoring osteoblastic differentiation under dexamethasone (Dex) treatment, and its interaction with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. Pre-osteoblastic MC3T3-E1 cells were cultured in osteogenic medium and treated by Dex to mimic steroid-induced osteonecrosis cellular model. They were then further transfected with control or AEBP1-overexpressed lentiviral vectors. Finally, cells were treated with the PI3K inhibitor LY294002, with or without AEBP1-overexpressed lentiviral vectors. AEBP1 expression showed a downward trend in MC3T3-E1 cells under Dex treatment in a dose-dependent manner. AEBP1-overexpressed lentiviral vectors increased relative cell viability, alkaline phosphatase (ALP) staining, Alizarin red staining and osteoblastic differentiation markers including osteocalcin (OCN), osteopontin (OPN), collagen type I alpha 1 (COL1A1), runt-related transcription factor 2 (RUNX2) and bone morphogenetic protein 2 (BMP2), but decreased cell apoptosis rate in MC3T3-E1 cells under Dex treatment; besides, AEBP1-overexpressed lentiviral vectors positively regulated p-PI3K and p-AKT expressions. Furthermore, LY294002 treatment decreased relative cell viability, Alizarin red staining, osteoblastic differentiation markers including OCN, OPN, RUNX2 and BMP, increased cell apoptosis rate and did not affect ALP staining in MC3T3-E1 cells under Dex treatment; meanwhile, LY294002 treatment weakened the effect of AEBP1 overexpression vectors on the above cell functions. AEBP1 restores osteoblastic differentiation under Dex treatment by activating the PI3K/AKT pathway., (© 2024 John Wiley & Sons Australia, Ltd.)

Pathological neovascularization in retinopathy of prematurity (ROP) can cause visual impairment in preterm infants. Current ROP treatments which are not preventative and only address late neovascular ROP, are costly and can lead to severe complications. We showed that topical 0.1% dexamethasone eye drops administered prior to peak neovessel formation prevented neovascularization in five extremely preterm infants at high risk for ROP and suppressed neovascularization by 30% in mouse oxygen-induced retinopathy (OIR) modeling ROP. In contrast, in OIR, topical dexamethasone treatment before any neovessel formation had limited efficacy in preventing later neovascularization, while treatment after peak neovessel formation had a non-statistically significant trend to exacerbating disease. Optimally timed topical dexamethasone suppression of neovascularization in OIR was associated with increased retinal mitochondrial gene expression and decreased inflammatory marker expression, predominantly found in immune cells. Blocking mitochondrial ATP synthetase reversed the inhibitory effect of dexamethasone on neovascularization in OIR. This study provides new insights into topical steroid effects in retinal neovascularization and into mitochondrial function in phase II ROP, and suggests a simple clinical approach to prevent severe ROP., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Elevated glucocorticoids alter the skeletal muscle transcriptome to induce a myopathy characterized by muscle atrophy, muscle weakness, and decreased metabolic function. These effects are more likely to occur and be more severe in aged muscles. Resistance exercise can blunt the development of glucocorticoid myopathy in young muscle, but the potential to oppose the signals initiating myopathy in aged muscle is unknown. To answer this, young (4-mo-old) and aged (24-to 25-mo-old) male C57BL/6 mice were randomized to receive either an intraperitoneal (IP) injection of dexamethasone (DEX; 2 mg/kg) or saline as a control. Two hours postinjections, the tibialis anterior (TA) muscles of mice were subjected to unilateral high-force contractions. Muscles were harvested 4 h later. The glucocorticoid- and contraction-sensitive genes were determined by RNA sequencing. The number of glucocorticoid-sensitive genes was similar between young and aged muscle. Contractions opposed changes to more glucocorticoid-sensitive genes in aged muscle, with this outcome primarily occurring when hormone levels were elevated. Glucocorticoid-sensitive gene programs opposed by contractions were primarily related to metabolism in young mice and muscle size regulation and inflammation in aged mice. In silico analysis implied peroxisome proliferator-activated receptor gamma-1 (PPARG) contributed to the contraction-induced opposition of glucocorticoid-sensitive genes in aged muscle. Increasing PPARG expression in the TA of aged mice using adeno-associated virus serotype 9 partially counteracted the glucocorticoid-induced reduction in runt-related transcription factor 1 ( Runx1 ) mRNA content, recapitulating the effects observed by contractions. Overall, these data contribute to our understanding of the contractile regulation of the glucocorticoid transcriptome in aged skeletal muscle. NEW & NOTEWORTHY We establish the extent to which muscle contractions oppose changes to the glucocorticoid-sensitive transcriptome in both young and aged muscle. We also identify peroxisome proliferator-activated receptor gamma (PPARG) as a transcription factor likely contributing to contraction-induced opposition to the glucocorticoid transcriptome in aged muscle. Overall, these data contribute to our understanding of the contractile regulation of the glucocorticoid transcriptome.

Sunitinib, a novel anti-tumor small molecule targeting VEGFR, is prescribed for advanced RCC and GISTs. Sunitinib is primarily metabolized by the CYP3A enzyme. It is well-known that dexamethasone serves as a potent inducer of this enzyme system. Nonetheless, the effect of dexamethasone on sunitinib metabolism remains unclear. This study examined the effect of dexamethasone on the pharmacokinetics of sunitinib and its metabolite N-desethyl sunitinib in rats. The plasma levels of both compounds were measured using UHPLC-MS/MS. Pharmacokinetic parameters and metabolite ratio values were calculated. Compare to control group, the low-dose dexamethasone group and high-dose dexamethasone group decreased the AUC (0-t) values of sunitinib by 47 % and 45 %, respectively. Meanwhile, the AUC (0-t) values of N-desethyl sunitinib were increased by 2.2-fold and 2.4-fold in low-dose dexamethasone group and high-dose dexamethasone group, respectively. The CL values for sunitinib were both approximately 45 % higher in the two dexamethasone groups. Remarkably, metabolite ratio values increased over 5-fold in both low-dose dexamethasone group and high-dose dexamethasone group, indicating a significant enhancement of sunitinib metabolism by dexamethasone. Moreover, the total levels of sunitinib and its metabolite are also significantly increased. The impact of interactions on sunitinib metabolism, as observed with CYP3A inducers such as dexamethasone, is a crucial consideration for clinical practice. To optimize the dosage and prevent adverse drug events, therapeutic drug monitoring can be employed to avoid the toxicity from such interactions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Many chemotherapeutic and molecular targeted drugs have been used to treat brain metastases, e.g., anti-angiogenic vandetanib. However, the blood-brain barrier and brain-specific resistance mechanisms make these systemic therapeutic approaches inefficacious. Brain metastatic cancer cells could mimic neurons to upregulate multiple serpins and secrete them into the extracellular environment to reduce local plasmin production to promote L1CAM-mediated vessel co-option and resist anti-angiogenesis therapy. Here, we developed brain-tumor-seeking and serpin-inhibiting outer membrane vesicles (DE@OMVs) to traverse across the blood-brain barrier, bypass neurons, and specially enter metastatic cancer cells via targeting GRP94 and vimentin. Through specific delivery of dexamethasone and embelin, reduced serpin secretion, restored plasmin production, significant L1CAM inactivation and tumor cell apoptosis were specially found in intracranial metastatic regions, leading to delayed tumor growth and prolonged survival in mice with brain metastases. By combining the brain-tumor-seeking properties with the regulation of the serpin/plasminogen activator/plasmin/L1CAM axis, this study provides a potent and highly-selective systemic therapeutic option for brain metastases., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Collagen and hyaluronic acid are essential components of the dermis that collaborate to maintain skin elasticity and hydration due to their unique biochemical properties and interactions within the extracellular matrix. Prolonged exposure to glucocorticoids can induce skin aging, which manifests as diminished collagen content and hyaluronic acid levels in the dermis. Nerol, a monoterpene alcohol found in essential oils, was examined in this study for its potential to counteract glucocorticoid-induced skin aging and the underlying mechanism behind its effects. Our findings reveal that non-toxic concentrations of nerol treatment can reinstate collagen content and hyaluronic acid levels in human dermal fibroblasts treated with dexamethasone. Mechanistically, nerol mitigates dexamethasone-induced oxidative stress by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. The protective effects of nerol were significantly abrogated when the Nrf2 pathway was inhibited using the specific inhibitor ML385. In conclusion, nerol protects human dermal fibroblasts against glucocorticoid-induced skin aging by ameliorating oxidative stress via activation of the Nrf2 pathway, thereby highlighting its potential as a therapeutic agent for preventing and treating glucocorticoid-induced skin aging., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Pathologic bidirectional interactions between the extracellular matrix (ECM) and cells within the human trabecular meshwork (hTM) contribute to ocular hypertension. An in vitro model is needed to study these cell-matrix interactions and their effect on outflow homeostasis. This study aimed to determine whether pathogenic ECM derived from dexamethasone (DEX)-treated hTM cultures induces clinically relevant glaucoma-like changes in healthy hTM cells at the transcriptional level. Corneoscleral rims from non-glaucoma donors were used to isolate primary hTM cells after validation according to the consensus recommendations for TM culture. Normal hTM cells (n = 5) were plated on a coverslip and treated with 100 nM DEX or ethanol for four weeks. These cultures were then decellularized, plated with primary hTM cells, and allowed to grow for another 72 h. RNA was extracted from these hTM cells for stranded total RNA-Seq. Sequencing libraries prepared using the Zymo-Seq RiboFree Total RNA library kit were pooled and sequenced using Illumina NovaSeq 6000. After quality control, sequence reads were aligned to the human genome build hg19. Differential expression (DE) analyses were performed using paired multi-factorial ANOVA. The expression of several DE genes associated with glaucoma (ANGPTL2, PDE7B, C22orf23, COL4A1, ADAM12, IFT122, SEMA6C) was validated using EvaGreen-based Droplet Digital PCR (ddPCR) assays. Gene ontology analyses of the DE genes were performed using the PANTHER and NDEx IQA databases, and functional analyses were performed with the DAVID Bioinformatics software. Using a cutoff of p-value <0.05 and fold change ≥2.0, our differential analysis identified 267 up- and 135 down-regulated genes in DEX-induced ECM-treated cells compared to the control. These differentially expressed genes were found to play a significant role in pathways such as cytokine and oxidative stress-induced inflammation, integrin signaling, matrix remodeling, and angiogenesis. These findings were further supported by previously performed proteomics studies using the same model. Using ddPCR, we validated the expression of seven genes associated with the risk of primary open-angle glaucoma. These results not only provide support for the pathogenic ECM model of steroid-induced glaucoma, but also demonstrate that the pathologic changes induced by this model are indeed found at the transcriptional level. These findings further demonstrate that matrix changes significantly influence cell expression profiles, which enable further understanding of the molecular mechanisms underlying glaucomatous changes in the TM. However, future studies with a larger and more diverse set of samples and longer time points are needed to confirm the utility of this model for mechanistic studies., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Ulcerative colitis has been associated with psychological distress and an aberrant immune response. The immunomodulatory role of systemic cytokines produced during experimental intestinal inflammation in tonic immobility (TI) defensive behavior remains unknown. The present study characterized the TI defensive behavior of guinea pigs subjected to colitis induction at the acute stage and after recovery from intestinal mucosa injury. Moreover, we investigated whether inflammatory mediators (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8, IL-10, and prostaglandins) act on the mesencephalic nucleus, periaqueductal gray matter (PAG). Colitis was induced in guinea pigs by intrarectal administration of acetic acid. The TI defensive behavior, histology, cytokine production, and expression of c-FOS, IBA-1, and cyclooxygenase (COX)-2 in PAG were evaluated. Colitis reduced the duration of TI episodes from the first day, persisting throughout the 7-day experimental period. Neuronal c-FOS immunoreactivity was augmented in both columns of the PAG (ventrolateral (vlPAG) and dorsal), but there were no changes in IBA-1 expression. Dexamethasone, infliximab, and parecoxib treatments increased the duration of TI episodes, suggesting a modulatory role of peripheral inflammatory mediators in this behavior. Immunoneutralization of TNF-α, IL-1β, and IL-8 in the vlPAG reversed all effects produced by colitis. In contrast, IL-10 neutralization further reduced the duration of TI episodes. Our results reveal that peripherally produced inflammatory mediators during colitis may modulate neuronal functioning in mesencephalic structures such as vlPAG., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Glucocorticoid-induced osteoporosis (GIOP) commonly accelerates bone loss, increasing the risk of fractures and osteonecrosis more significantly than traditional menopausal osteoporosis. The extracellular environment influenced by glucocorticoids heightens fracture and osteonecrosis risks. Fraxin (Fra), a key component of the traditional Chinese herbal remedy Cortex Fraxini, is known for its wide-ranging pharmacological effects, but its impact on GIOP remains unexplored. This investigation aims to delineate the effects and underlying mechanisms of Fra in combating dexamethasone (Dex)-induced ferroptosis and GIOP. We established a mouse model of GIOP via intraperitoneal injections of Dex and cultured osteoblasts with Dex treatment for in vitro analysis. We evaluated the impact of Fra on Dex-treated osteoblasts through assays such as C11-BODIPY and FerroOrange staining, mitochondrial functionality tests, and protein expression analyses via Western blot and immunofluorescence. The influence of Fra on bone microarchitecture of GIOP in mice was assessed using microcomputerized tomography, hematoxylin and eosin staining, double-labeling with Calcein-Alizarin Red S, and immunohistochemistry at imaging and histological levels. Based on our data, Fra prevented Dex-induced ferroptosis and bone loss. In vitro, glutathione levels increased and malondialdehyde, lipid peroxidation, and mitochondrial reactive oxygen species decreased. Fra treatment also increases nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), and COL1A1 expression and promotes bone formation. To delve deeper into the mechanism, the findings revealed that Fra triggered the activation of Nrf2/GPX4 signaling. Moreover, the use of siRNA-Nrf2 blocked the beneficial effect of Fra in osteoblasts cultivated with Dex. Fra effectively combats GIOP by activating the Nrf2/GPX4 signaling pathway to inhibit ferroptosis., (© 2024 John Wiley & Sons, Ltd.)

Purpose: Corneal epithelial defects from trauma or surgery heal as new epithelial cells grow centripetally from the limbus and replenish the epithelium. Corneal wound healing requires cell signalling molecules. However, a topical treatment with these components is not available. Human breast milk (HBM) offers a potential, novel treatment as it contains bioactive molecules important in epithelial cell healing. This study seeks to investigate the potential of HBM in cornea wound healing., Methods: Balb/c mice, 8-12 weeks old, were anesthetized prior to creating a 2 mm central cornea epithelial defect. Mice were randomly assigned to a treatment group: HBM, ophthalmic ointment containing neomycin, polymyxin B, dexamethasone (RxTx), or saline and treated 4x/day for 2 days. Wound area was quantified by fluorescein and ImageJ at 0, 8, 24, and 48 h post wounding and eyes used for histology, RT-qPCR, and ELISA., Results: Wounded corneas treated with HBM demonstrated increased re-epithelialization at 8 h post injury compared to saline treatments. ELISA showed significantly higher Ki67 in HBM treated eyes vs. saline control at 8 h ( p =  0.0278). Additionally, immunohistology revealed more Ki67 positive cells in the HBM group compared to saline at 8 h and 24 h ( p  = 0.0063 8 h; p  = 0.0007 24 h). For inflammatory analysis, HBM group IL-1β levels were similar to the saline group, and higher than RxTx treated eyes ( p  < 0.05). Immunohistochemical staining for CD11b (macrophage marker) revealed HBM-treated eyes had significantly more positive cells vs. saline. RT-qPCR of limbal stem cell markers (LESCs) revealed upregulation of Integrin αV at 8 h with HBM vs. saline., Conclusions: HBM treatment on corneas with debridement of epithelium demonstrated improved healing, cellular proliferation, and upregulation of the LESC gene transcript, integrin αV, after wounding. Future studies could investigate LESC response to different signalling molecules in HBM to better understand the efficacy of this potential therapy.

The relief of joint pain is one of the main objectives in the clinical management of arthritis. Although significant strides have been made in improving management of rheumatoid and related forms of inflammatory arthritis, there are still major unmet needs for therapies that selectively provide potent, sustained and safe joint pain relief, especially among patients with osteoarthritis (OA), the most common form of arthritis. We have recently developed ProGel-Dex, an N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based thermoresponsive dexamethasone (Dex) prodrug, which forms a hydrogel upon intra-articular administration and provides sustained improvement in pain-related behavior and inflammation in rodent models of arthritis. The focus of the present study was to investigate the impact of ProGel-Dex formulation parameters on its physicochemical properties and in vivo efficacy. The results of this study provide essential knowledge for the future design of ProGel-Dex that can provide more effective, sustained and safe relief of joint pain and inflammation., Competing Interests: Declaration of competing interest D. Wang, S. R. Goldring, G. Zhao, and X. Wei are co-inventors of a PCT patent application covering ProGel technology. D. Wang and S. R. Goldring hold equity positions in Ensign Pharmaceutical, Inc., a start-up company which has licensed ProGel technology for further preclinical and translational development. The other coauthors declare no competing interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Zoledronic acid (ZOL) is a type of bisphosphonate with good therapeutic effects on orthopaedic diseases. However, the pharmacological functions of ZOL on steroid-induced avascular necrosis of femoral head (SANFH) and the underlying mechanism remain unclear, which deserve further research., Methods: SANFH models both in vivo and in vitro were established by dexamethasone (Dex) stimulation. Osteoclastogenesis was examined by TRAP staining. Immunofluorescence was employed to examine autophagy marker (LC3) level. Cell apoptosis was analyzed by TUNEL staining. The interaction between Foxhead box D3 protein (FOXD3) and Annexin A2 (ANXA2) promoter was analyzed using ChIP and dual luciferase reporter gene assays., Results: Dex aggravated osteoclastogenesis and induced osteoclast differentiation and autophagy in vitro, which was abrogated by ZOL treatment. PI3K inhibitor LY294002 abolished the inhibitory effect of ZOL on Dex-induced osteoclast differentiation and autophagy. FOXD3 overexpression neutralized the downregulation effects of ZOL on Dex-induced osteoclasts by transcriptionally activating ANXA2. ANXA2 knockdown reversed the effect of FOXD3 overexpression on ZOL-mediated biological effects in Dex-treated osteoclasts. In addition, ZOL improved SANFH symptoms in rats., Conclusion: ZOL alleviated SANFH through regulating FOXD3 mediated ANXA2 transcriptional activity and then promoting PI3K/AKT/mTOR pathway, revealing that FOXD3 might be a target for ZOL in SANFH treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Oxidative stress is a frequent concern in the breeding of laying hens, and limit the healthy development of poultry. Dexamethasone (DXM) has been demonstrated to induce oxidative stress. Conversely, betaine is an alkaloid with a potent antioxidant activity. The study was designed to investigate the ameliorative effect of betaine on DXM-induced oxidative stress in laying hens. The results revealed that DXM treatment significantly decreased laying rate, shell strength, albumen height, Haugh unit, egg weight, folk weight and albumen weight, alongside increased malondialdehyde (MDA) and decreased total antioxidant capacity (T-AOC) in serum and liver (P < 0.05). In contrast, dietary betaine addition reversed those parameters mentioned above (P < 0.05). Hepatic RNA-seq analysis showed that there existed 110 up- and 88 down-regulated genes in DXM group when compared with the control. Meanwhile there were 117 upregulation and 169 downregulation genes in BT group when compared with DXM group. Besides, we found that dietary betaine addition significantly down-regulated cell adhesion molecules, glycerolipid metabolism and glycolysis gluconeogenesis pathways. In addition, a total of 44 and 94 differential metabolites were identified respectively from Con vs. DXM and DXM vs BT. More importantly, dietary betaine addition significantly increased the levels of pantothenic acid, gamma-Aminobutyric acid, equol and choline, all of which were related to antioxidant and anti-inflammatory properties. Furthermore, gut microbiota analysis indicated that the Chao and Observed&#95;species indexes were remarkably higher in BT group (P<0.05). Heatmap analysis revealed that Subdoligranulum, Prevotella, Blautia, YRC22, Bacteroides, Ruminococcus and Coprococcus were notably restored in BT group (P<0.05). Taken together, our findings collectively illustrate that dietary betaine addition could attenuate DXM-induced oxidative stress, improve egg quality and gut microbes of laying hens., Competing Interests: DISCLOSURES The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Fabricating injectable hydrogel with multiple functions and effective promotion of wound repair has a great prospect in treatment of bacterial infected wounds. Herein, a pH/reactive oxygen species (ROS) dual responsive injectable hydrogel (PVBDL-gel) was constructed, the PVBDL-gel was cross-linked by dynamic Schiff base bonds and borate ester bonds between poly(vanillin acrylate-co-3 acrylamide phenylboronic acid-co-N,N-dimethylacrylamide) (P(VA-co-AAPBA-co-DMA)), oligolysines and polyvinyl alcohol (PVA). The anti-inflammatory drug, dexamethasone sodium phosphate (DEX), was encapsulated in this hydrogel. The hydrogel exhibited excellent degradability, stable rheology and suitable tissue adhesion, more importantly, which showing pH/ROS responsive ability and controllable releasing of DEX. In vitro and in vivo experiment results showed that the PVBDL-gel with good biocompatibility and efficient anti-infection ability can effectively eradicate 99.9 % of pathogenic bacteria within 3 h and promote the repair and regeneration of bacterial infection wounds. This novel multifunctional injectable hydrogel has great application in the field of bacterial infection wound repair., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Systemic Lupus Erythematosus (SLE) is characterized by dysregulated immune responses, with neutrophil extracellular traps (NETs) playing a significant role. NETs are recognized by autoantibodies in SLE patients, exacerbating pathology. Both excessive NET formation and impaired degradation contribute to SLE pathophysiology., Objective: To investigate the immunomodulatory effects of Dexamethasone-primed Wharton's jelly (WJ) derived MSCs CM (DW) and IFN-γ-primed WJ-MSCs-CM (IW) on NETosis and associated protein markers in SLE patients' LPS or ribonucleoprotein immune complexes (RNP ICs) induced neutrophils and in pristane induced lupus (PIL) model. And to elucidate the mechanism involved therein., Methods: We investigated the immunomodulatory effects of DW and IW on NETosis in SLE. Utilizing ex vivo and in vivo models, we assessed the impact of preconditioned media on NET formation and associated protein markers neutrophil elastase (NE), citrullinated histone (citH3), myeloperoxidase (MPO), cytoplasmic and mitochondrial ROS production. We also examined the involvement of key immunomodulatory factors present in DW and IW, including prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase (IDO), and transforming growth factor-beta (TGF-β)., Results: Preconditioned media effectively suppressed NETosis and reduced ROS generation in SLE neutrophils, indicating their immunomodulatory potential. Inhibition studies implicated IDO and PGE2 in mediating this effect. Combined treatment with DW or IW together with hydroxychloroquine (HCQ) demonstrated superior efficacy over HCQ alone, a standard SLE medication. In PIL mouse model, DW and IW treatments reduced NETosis, ROS generation, as evidenced by decreased NET-associated protein expression in vital organs., Conclusion: Our study highlights the multifaceted impact of IW and DW on NETosis, ROS dynamics, and lupus severity in SLE. These findings underscore the potential of preconditioned media for the development of targeted, personalized approaches for SLE treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Priya, Thacker, Chaubey, Rai, Singh, Rawat, Giri, Mohanty and Rai.)

Steroid-resistant asthma is a common cause of refractory asthma. Type 2 inflammation is the main inflammatory response in asthma, and the mechanism underlying the steroid-resistance of type 2 inflammation has not been completely elucidated. Tumor-necrosis-factor-like apoptosis-inducing factor (TWEAK) and transforming growth factor (TGF)-β1 are involved in epithelial-mesenchymal transition (EMT) and the production of thymic stromal lymphopoietin (TSLP) and C-C motif chemokine ligand 5 (CCL5). We herein hypothesize that the combined exposure to TWEAK and TGF-β1 may result in the development of steroid resistance in bronchial epithelial cells. The bronchial epithelial cell line BEAS-2B was cultured with or without TGF-β1 or TWEAK, in the presence or absence of dexamethasone (DEX). The roles of Smad-independent pathways and MAP kinase phosphatase 1 (MKP-1) were also explored. Co-stimulation of TWEAK and TGF-β1 induced E-cadherin reduction, N-cadherin upregulation, and TSLP and CCL5 production, which were not suppressed by DEX. Inhibition of the nuclear factor kappa beta (NF-κB) and mitogen-activated protein kinase pathways downregulated steroid-unresponsive TSLP and CCL5 production, whereas knockdown of MKP-1 improved steroid-unresponsive TSLP production, induced by co-stimulation with TWEAK and TGF-β1. Therefore, co-stimulation with TWEAK and TGF-β1 can induce the steroid-insensitive production of TSLP and CCL5 in the bronchial epithelium and may contribute to airway inflammation.

Sepsis is characterized by a dysregulated immune response and is very difficult to treat. In the cecal ligation and puncture (CLP) mouse model, we show that nanomedicines can effectively alleviate systemic and local septic events by targeting neutrophils. Specifically, by decorating the surface of clinical-stage dexamethasone liposomes with cyclic arginine-glycine-aspartic acid (cRGD) peptides, we promote their engagement with neutrophils in the systemic circulation, leading to their prominent accumulation at primary and secondary sepsis sites. cRGD-targeted dexamethasone liposomes potently reduce immature circulating neutrophils and neutrophil extracellular traps in intestinal sepsis induction sites and the liver. Additionally, they mitigate inflammatory cytokines systemically and locally while preserving systemic IL-10 levels, contributing to lower IFN-γ/IL-10 ratios as compared to control liposomes and free dexamethasone. Our strategy addresses sepsis at the cellular level, illustrating the use of neutrophils both as a therapeutic target and as a chariot for drug delivery.

Glucocorticoid-induced osteoporosis serves as a primary cause for secondary osteoporosis and fragility fractures, representing the most prevalent adverse reaction associated with prolonged glucocorticoid use. In this study, to elucidate the impact and underlying mechanisms of fluid shear stress (FSS)-mediated Piezo1 on dexamethasone (Dex)-induced apoptosis, we respectively applied Dex treatment for 6 h, FSS at 9 dyne/cm 2 for 30 min, Yoda1 treatment for 2 h, and Piezo1 siRNA transfection to intervene in MLO-Y4 osteocytes. Western blot analysis was used to assess the expression of Cleaved Caspase-3, Bax, Bcl-2, and proteins associated with the PI3K/Akt pathway. Additionally, qRT-PCR was utilized to quantify the mRNA expression levels of these molecules. Hoechst 33258 staining and flow cytometry were utilized to evaluate the apoptosis levels. The results indicate that FSS at 9 dyne/cm 2 for 30 min significantly upregulates Piezo1 in osteocytes. Following Dex-induced apoptosis, the phosphorylation levels of PI3K and Akt are markedly suppressed. FSS-mediated Piezo1 exerts a protective effect against Dex-induced apoptosis by activating the PI3K/Akt pathway. Additionally, downregulating the expression of Piezo1 in osteocytes using siRNA exacerbates Dex-induced apoptosis. To further demonstrate the role of the PI3K/Akt signaling pathway, after intervention with the PI3K pathway inhibitor, the activation of the PI3K/Akt pathway by FSS-mediated Piezo1 in osteocytes was significantly inhibited, reversing the anti-apoptotic effect. This study indicates that under FSS, Piezo1 in MLO-Y4 osteocytes is significantly upregulated, providing protection against Dex-induced apoptosis through the activation of the PI3K/Akt pathway., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yayi Xia reports financial support was provided by National Natural Science Foundation of China and Natural Science Foundation of Gansu Province. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The objective of this study was to develop two lipid nanoparticle (LNP) formulations capable of efficiently expressing a reporter mRNA while co-delivering the anti-inflammatory drug dexamethasone (DX) to reduce inflammatory side effects in protein replacement therapies. Two types of LNPs were developed, in which 25% of cholesterol was replaced by DX. These LNPs contained either 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) as a helper lipid. The resulting LNPs exhibited high stability, homogeneity, and near-neutral Zeta potentials. SAXS experiments confirmed DX incorporation into the LNP core, with slow in vitro DX release observed over 48 h. The LNPs achieved high mRNA encapsulation efficiency (95-100%) and effectively transfected HepG2 cells, dendritic cells, and hPBMCs. While LNPs increased cytokine release (IL-1β, TNF-α, MCP-1), LNPs-DX significantly reduced cytokine levels, demonstrating enhanced anti-inflammatory properties while maintaining mRNA expression levels. In vivo biodistribution showed predominant liver localization post-intramuscular injection, regardless of the DSPC or DOPE composition. LNPs co-loaded with mRNA and DX are promising candidates for continuous protein replacement. Due to their ability to reduce treatment-related inflammation while maintaining significant mRNA expression levels, these LNPs are perfectly suited for the treatment of liver-related metabolic diseases.

Background: The pivotal responsibility of GABAergic interneurons is inhibitory neurotransmission; in this way, their significance lies in regulating the maintenance of excitation/inhibition (E/I) balance in cortical circuits. An abundance of glucocorticoids (GCs) exposure results in a disorder of GABAergic interneurons in the prefrontal cortex (PFC); the relationship between this status and an enhanced vulnerability to neuropsychiatric ailments, like depression and anxiety, has been identified, but this connection is still poorly understood because systematic and comprehensive research is lacking. Here, we aim to investigate the impact of dexamethasone (DEX, a GC receptor agonist) on GABAergic interneurons in the PFC of eight-week-old adult male mice., Methods: A double-blind study was conducted where thirty-two mice were treated subcutaneously either saline or DEX (0.2 mg/10 ml per kg of body weight) dissolved in saline daily for 21 days. Weight measurements were taken at five-day intervals to assess the emotional changes in mice as well as the response to DEX treatment. Following the 21-day regimen of DEX injections, mice underwent examinations for depression/anxiety-like behaviours and GABAergic marker expression in PFC., Results: In a depression/anxiety model generated by chronic DEX treatment, we found that our DEX procedure did trigger depression/anxiety-like behaviors in mice. Furthermore, DEX treatment reduced the expression levels of a GABA-synthesizing enzyme (GAD67), Reelin, calcium-binding proteins (parvalbumin and calretinin) and neuropeptides co-expressed in GABAergic neurons (somatostatin, neuropeptide Y and vasoactive intestinal peptide) in the PFC were reduced after 21 days of DEX treatment; these reductions were accompanied by decreases in brain size and cerebral cortex thickness., Conclusion: Our results indicate that a reduction in the number of GABAergic interneurons may result in deficiencies in cortical inhibitory neurotransmission, potentially causing an E/I imbalance in the PFC; this insight suggests a potential breakthrough strategy for the treatment of depression and anxiety., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hu, Qiu, Fan, Wang, Liu, Liu, Liu, Shen, Zheng, Liu, Jia, Wang and Fang.)

Background: The T cell-mediated delayed-type hypersensitivity (DTH) response is critical for elucidating cellular immune mechanisms, especially the role of memory T cells upon antigen re-exposure. This study aimed to investigate the specific effects of the immunosuppressive drugs Cyclophosphamide (CY) and Dexamethasone (DEX) on intestinal immunity and microbiota in a DTH mouse model, contributing to a more nuanced understanding of their immunomodulatory mechanisms., Methods: Female BALB/c mice were sensitized to 2,4-dinitrofluorobenzene (DNFB) and randomly allocated into control, CY, and DEX groups. The impact of CY and DEX on immune function was assessed through measurement of thymus and spleen indices, lymphocyte proliferation in mesenteric lymph nodes (MLNs) using MTT assay, and flow cytometric analysis of T cell subsets and TCR expression. Intestinal secretory IgA (sIgA) was quantified by ELISA, and gut microbiota diversity was evaluated using 16S rRNA gene sequencing., Results: CY and DEX significantly reduced the immune function in DNFB-induced sensitized mice, as indicated by decreased thymus and spleen indices, MLN enlargement, intestinal sIgA content, and ear swelling degree. Flow cytometry revealed that CY increased the proportion of total CD3+ T cells but reduced CD3+CD69+ activated T cells and CD3+TCRγ/δ+ T cells, while DEX increased CD3+CD4+ helper T cells. Both drugs induced distinct changes in gut microbiota diversity and structure, with CY enhancing α diversity and DEX reducing it., Conclusions: The study demonstrates that CY and DEX have distinct regulatory effects on the immune organ index, distribution of T cell subsets, and diversity and structure of gut microbiota on DTH-induced immune responses mice, suggesting their differential influence on intestinal mucosal immunity. These findings have implications for the development of targeted immunotherapies and understanding the interplay between immunosuppressive drugs and gut microbiota., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

We demonstrate the role of signaling via the glucocorticoid receptor, NR3C1, in differentiation of CD8+ T cell memory. Pharmacological inhibition as well as the short hairpin RNA-mediated knockdown of the receptor hindered memory transition and limited the homeostatic turnover of the activated CD8+ T cells. Dexamethasone exposure of CD8+ T cells expanded during a resolving infection with influenza A virus or a γ-herpesvirus promoted conversion of effector cells into memory cells by modulating cellular metabolism and lowering the accumulation of reactive oxygen species. Reduced reactive oxygen species levels in the responding effector cells upregulated Bcl2 and enhanced survival. The generated virus-specific memory CD8+ T cells were efficiently recalled following challenge of animals with a secondary infection to control it better. The memory-enhancing effect was predominantly evident at low doses of dexamethasone. Therefore, controlled glucocorticoid signaling within the effector CD8+ T cells is crucial for optimal memory differentiation., (Copyright © 2024 by The American Association of Immunologists, Inc.)

We fabricated three-dimensional (3D)-printed polycaprolactone (PCL) and PCL/graphene oxide (GO) (PGO) scaffolds for bone tissue engineering. An anti-inflammatory and pro-osteogenesis drug dexamethasone (DEX) was adsorbed onto GO and a 3D-printed PGO/DEX (PGOD) scaffold successfully improved drug delivery with a sustained release of DEX from the scaffold up to 1 month. The physicochemical properties of the PCL, PGO, and PGOD scaffolds were characterized by various analytical techniques. The biological response of these scaffolds was studied for adherence, proliferation, and osteogenic differentiation of seeded rabbit adipose-derived stem cells (ASCs) from DNA assays, alkaline phosphatase (ALP) production, calcium quantification, osteogenic gene expression, and immunofluorescence staining of osteogenic marker proteins. The PGOD scaffold was demonstrated to be the best scaffold for maintaining cell viability, cell proliferation, and osteogenic differentiation of ASCs in vitro. In vivo biocompatibility of PGOD was confirmed from subcutaneous implantation in nude mice where ASC-seeded PGOD can form ectopic bones, demonstrated by microcomputed tomography (micro-CT) analysis and immunofluorescence staining. Furthermore, implantation of PGOD/ASCs constructs into critical-sized cranial bone defects in rabbits form tissue-engineered bones at the defect site, observed using micro-CT and histological analysis.

Our previous research revealed a close association between the acetylation of peroxisome proliferator-activated receptor γ (PPARγ) histone H3K27 and the adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). We preliminarily explored the epigenetic mechanism of steroid-induced avascular necrosis of the femoral head (SANFH) development, but the specific histone deacetylase (HDAC) involved in this regulatory process remains unknown. In this study, we combined cell, animal, and clinical specimen experiments to screen for specific HDAC genes that could regulate BMSC adipogenic differentiation and to explore their roles. The results showed that dexamethasone (DEX) significantly exacerbated the imbalance between the adipogenic and osteogenic differentiation of BMSCs, and there were differences in HDAC expression in the adipogenic differentiation cell models, with histone deacetylase 10 (HDAC10) showing the most significant decrease in expression. Subsequent use of a chromatin immunoprecipitation assay kit and quantitative polymerase chain reaction (ChIP‒qPCR) revealed a decrease in HDAC10 expression at predicted potential sites within the PPARγ promoter, indicating a significant decrease in HDAC10 enrichment in the PPARγ promoter region of BMSCs, thereby promoting sustained PPARγ expression. Additionally, immunohistochemistry of samples collected from mice and humans with SANFH and normal femoral heads revealed an imbalance between adipogenic and osteogenic differentiation in the necrotic area of femoral heads, with a significant decrease in the relative expression of HDAC10 in the necrotic area of femoral heads with SANFH. In summary, we speculate that HDAC10 affects the progression of SANFH by regulating BMSC adipogenic differentiation, a process possibly related to PPARγ histone acetylation. These findings provide a promising direction for the treatment of SANFH., (© 2024. The Author(s).)

Lenalidomide (LEN) is widely used immunomodulatory drug (IMiD). Nonetheless, despite its efficacy, over time patients become resistant to LEN and relapse. Due to high clinical relevance, drug resistance in MM is being thoroughly investigated. However, less is known about predictors of good response to LEN-based treatment. The aim of this study was to identify molecular pathways associated with good and long response to LEN. The study included newly diagnosed MM patients (NDMM) and MM patients treated with first-line LEN and dexamethasone (RD) who achieved and least very good partial remission (VGPR). RNA was isolated from MM cells and new-generation sequencing was performed. Obtained results were validated with qRT-PCR. A global increase in gene expression was found in the RD group compared to NDMM, suggesting the involvement of epigenetic mechanisms. Moreover, upregulation of genes controlling the interaction within MM niche was detected. Next, genes controlling immune response were upregulated. In particular, the gene encoding the IL-17 receptor was overexpressed in the RD group which is a novel finding. This should be emphasized because IL-17-related signaling can potentially be targeted, providing the rationale for future research. Establishing the molecular background associated with long-lasting and profound response to LEN may improve LEN-based chemotherapy regimens and facilitate the development of adjuvant therapies to enhance its anti-MM activity., (© 2024. The Author(s).)

To evaluate the therapeutic effect and mechanism of rapamycin (RAPA) on pulmonary fibrosis induced by chlormethine in C57BL/6N mice. Based on body weight, the 18-20 g C57BL/6N mice were randomly divided into five groups: control group, chlormethine group, chlormethine+dexamethasone (1 mg/kg) group, chlormethine+RAPA (1 mg/kg) group and chlormethine+RAPA (2 mg/kg) group, with ten mice in each group. Mice were put to death on the 21st day after the first administration of chlormethine. HE staining and Masson staining were used to observe the pathological changes and degree of fibrosis in the lung tissue of mice, and RT-PCR was used to detect collagen Ⅰ, E-cadherin, vimentin, and α-SMA mRNA expression. After 21 days of administration of chlormethine to mice, significant pulmonary fibrosis characteristics were observed in the lung tissue of the mice. Compared with the chlormethine group, the weight of mice in the chlormethine+dexamethasone (1 mg/kg) group, chlormethine+RAPA (1 mg/kg) group and chlormethine+RAPA (2 mg/kg) group, significantly increased ( P <0.05). Compared with the chlormethine group, the expression of pulmonary fibrosis-related indicators (collagen Ⅰ, E-cadherin, vimentin, and α-SMA) significantly improved ( P <0.05) in the chlormethine+dexamethasone (1 mg/kg) group, chlormethine+RAPA (1 mg/kg) group and chlormethine+RAPA (2 mg/kg) group. Compared with the chlormethine group, the pathological changes and collagen deposition in the lung tissue of mice in the chlormethine+dexamethasone (1 mg/kg) group, chlormethine+RAPA (1 mg/kg) group and chlormethine+RAPA (2 mg/kg) group, were significantly improved. Transcriptome analysis of the lung tissue of mice revealed that RAPA treatment of chlormethine-induced pulmonary fibrosis might be related to NF-kappa B signaling pathway. Compared with the chlormethine group, the mRNA expression of p65 in the lung tissue of mice in the chlormethine+dexamethasone (1 mg/kg) group, chlormethine+RAPA (1 mg/kg) group and chlormethine+RAPA (2 mg/kg) group, significantly decreased ( P <0.01). RAPA has a protective effect on pulmonary fibrosis induced by chlormethine in mice. Its efficacy is comparable to that of dexamethasone, which is currently being used in clinical practice. It is a new alternative therapy, and its mechanism may be related to inhibiting the activation of the NF-kappa B signaling pathway.

Objective: To investigate the effects of Araucaria sp. brown propolis (ABP) against trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats., Methods: Animals received vehicle (1% DMSO, 1 ml/kg) or hydroalcoholic extract of ABP (hydroalcoholic extract of Araucaria sp. brown propolis (HEABP), 30, 100, and 300 mg/kg) orally, or dexamethasone (25 mg/kg, s.c.) for 5 days. On day 4, the animals received intracolonic TNBS (150 mg/kg), on day 6 they were euthanized. The weight of the animals, the macroscopic and microscopic colonic damage, reduced glutathione (GSH) and malondialdehyde (MDA) levels, and the activity of glutathione S-transferase (GST), catalase (CAT), superoxide dismutase (SOD), and myeloperoxidase (MPO) were measured in colon homogenate. The action of HEABP and two isolated compounds in neutrophil migration was recorded., Key Findings: HEABP (100 and 300 mg/kg), but not dexamethasone, decreased colonic lesion, and increased colonic mucin staining. In parallel, HEABP decreased MDA and restored GSH levels and the activity of SOD, CAT, and GST in the colon. A dose-dependent inhibition of MPO activity was observed (LogIC50 = 1.9). Moreover, HEBPA and the junicedric and abietic acids inhibited the neutrophil chemotaxis in vitro and HEBPA reduced neutrophil migration in vivo., Conclusion: HEABP may be promising in the therapies for inflammatory bowel diseases, reducing oxidative and inflammatory damage, especially mediated by neutrophils., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Acute kidney injury (AKI) is a frequent and challenging clinical condition associated with high morbidity and mortality and represents a common complication in critically ill patients with COVID-19. In AKI, renal tubular epithelial cells (TECs) are a primary site of damage, and recovery from AKI depends on TEC plasticity. However, the molecular mechanisms underlying adaptation and maladaptation of TECs in AKI remain largely unclear. Here, our study of an autopsy cohort of patients with COVID-19 provided evidence that injury of TECs by myoglobin, released as a consequence of rhabdomyolysis, is a major pathophysiological mechanism for AKI in severe COVID-19. Analyses of human kidney biopsies, mouse models of myoglobinuric and gentamicin-induced AKI, and mouse kidney tubuloids showed that TEC injury resulted in activation of the glucocorticoid receptor by endogenous glucocorticoids, which aggravated tubular damage. The detrimental effect of endogenous glucocorticoids on injured TECs was exacerbated by the administration of a widely clinically used synthetic glucocorticoid, dexamethasone, as indicated by experiments in mouse models of myoglobinuric- and folic acid-induced AKI, human and mouse kidney tubuloids, and human kidney slice cultures. Mechanistically, studies in mouse models of AKI, mouse tubuloids, and human kidney slice cultures demonstrated that glucocorticoid receptor signaling in injured TECs orchestrated a maladaptive transcriptional program to hinder DNA repair, amplify injury-induced DNA double-strand break formation, and dampen mTOR activity and mitochondrial bioenergetics. This study identifies glucocorticoid receptor activation as a mechanism of epithelial maladaptation, which is functionally important for AKI.

Cultured fat is an important part of cultured meat, and the ability of adipose-derived mesenchymal stem cells (ADSCs) to differentiate into mature adipose tissue affects the quality of cultured fat. Thus, the primary aim of this study was to screen for combinations of differentiation-inducing factors (DIF) using single-factor experiment and orthogonal experimental design under two-dimensional culture conditions for ADSCs. The results showed that a combination of DIF consisting of 1 μmol/L dexamethasone, 0.1 mmol/L 3-isobutyl-1-methylxanthine, 10 μg/mL insulin, 0.1 mmol/L indomethacin, and 2 μmol/L rosiglitazone was a good choice for the differentiation of ADSCs. An combination of DIF was applied to the preparation of cultured fat with collagen as scaffolds. Forty-eight fatty acids were detected in cultured fat by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Among them, the content of twenty-one fatty acids in cultured fat was significantly higher than that of conventional porcine subcutaneous adipose tissue (P < 0.05), and the content of 14 fatty acids was not significantly different (P > 0.05). The ratio of ω-6 polyunsaturated fatty acids content to ω-3 polyunsaturated fatty acids content was 1.23:1, which meant cultured fat was beneficial for human health. This study provides a method to improve the differentiation ability of ADSCs while also providing a reference for indicating the nutritional value of cultured fat., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Shi-Jie Ding is the co-founder of Joes Future Food company, which is committed to the commercialization of cultured meat. Other authors have no conflict of interest.], (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The aim of the study was to assess glucocorticoid sensitivity in survivors of childhood acute lymphoblastic leukemia using in vivo and in vitro tests. Thirty leukemia survivors of both sexes aged ≥18 years participated in the study and at least two years after therapy withdrawal. In vivo tests comprised: a) a very low dose intravenous dexamethasone suppression test for measurement of serum cortisol before, after, and % suppression, compared with 32 age-matched controls; and b) 0.25 mg overnight oral dexamethasone suppression test for assessment of salivary cortisol before, after, and % suppression. In vitro methods comprised: c) glucocorticoid receptor polymorphisms: BcI1-NR3C1 and A3669G; and d) splicing variant of glucocorticoid receptor GR-α mRNA by real-time quantitative polymerase chain reaction, compared with 32 controls. There was a reduction in salivary cortisol, and 73.3% of leukemia survivors showed high sensitivity according to % suppression after oral dexamethasone (p<0.05). Serum cortisol at baseline, after the test, % suppression after intravenous dexamethasone, and the percentage of high sensitivity were reduced in the leukemia group (%F=36.7; p<0.05). The BcI1-NR3C1 and A3669G polymorphisms were present in 11/30 (36.7%) and 5/30 (16.7%) patients, respectively. GR-α mRNA levels were lower in the leukemia group than in the controls (p<0.05). Survivors of acute lymphoblastic leukemia presented with reduced glucocorticoid sensitivity. Glucocorticoid sensitivity allows individualized treatment to avoid adverse effects and may be involved in cardiovascular disease risk among this particular group of cancer survivors., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Lenalidomide (R), bortezomib (V), and dexamethasone (d) is a standard-of-care regimen in newly diagnosed multiple myeloma (NDMM); however, characteristics and outcomes for nontransplanted patients receiving frontline RVd are not well understood., Patients: The Connect Ⓡ MM Registry is a large, US, multicenter, prospective observational cohort study of NDMM patients., Methods: This analysis investigated characteristics and outcomes of patients who received RVd alone or followed by Rd or R (RVd ± Rd/R) who did not undergo frontline autologous stem cell transplantation., Results: As of August 2021, 314 of 1979 nontransplanted patients received RVd ± Rd/R as initial therapy. Of these, 135 were aged ≤ 65 years and 179 were > 65 years. 108 patients had time to relapse (TTR) of ≤ 12 months and 182 had TTR > 12 months. Baseline characteristics were comparable regardless of TTR and age group except renal function, which was more commonly impaired in older patients. Among patients aged ≤ 65 and > 65 years, median duration of first-line treatment was 6.3 and 9.0 months, median time to next line for those who received second-line therapy was 15.5 and 15.2 months, median progression-free survival (PFS) was 19.3 and 23.0 months, and median overall survival was 60.0 and 59.1 months, respectively. High-risk disease (per IMWG criteria) and high serum calcium were associated with higher hazard of progression or death; the adjusted PFS hazard ratio with respect to age (≤ 65 vs. > 65 years) based on multivariable analysis was 1.18 (0.89-1.57; P = .25)., Conclusion: These results indicate RVd is active across age groups and provide a better understanding of outcomes with RVd in NDMM., (Copyright © 2024. Published by Elsevier Inc.)

Seizures are neurological disorders triggered by an imbalance in the activity of excitatory and inhibitory neurotransmitters in the brain. When triggered chronically, this imbalance can lead to epilepsy. Critically, many of the affected individuals are refractory to treatment. Given this, anti-inflammatory drugs, in particular glucocorticoids, have been considered as a potential antiepileptogenic therapy. Glucocorticoids are currently used in the treatment of refractory patients, although there have been contradictory results in terms of their use in association with antiepileptic drugs, which reinforces the need for a more thorough investigation of their effects. In this context, the present study evaluated the effects of dexamethasone (DEX, 0.6 mg/kg) on the electroencephalographic (EEG) and histopathological parameters of male Wistar rats submitted to acute seizure induced by pentylenetetrazol (PTZ). The EEG monitoring revealed that DEX reduced the total brainwave power, in comparison with PTZ, in 12 h after the convulsive episode, exerting this effect in up to 36 h (p < 0.05 for all comparisons). An increase in the accommodation of the oscillations of the delta, alpha, and gamma frequencies was also observed from the first 12 h onwards, with the accommodation of the theta frequency occurring after 36 h, and that of the beta frequency 24 h after the seizure. The histopathological analyses showed that the CA3 region and hilum of the hippocampus suffered cell loss after the PTZ-induced seizure (control vs. PTZ, p < 0.05), although DEX was not able to protect these regions against cell death (PTZ vs. DEX + PTZ, p > 0.05). While DEX did not reverse the cell damage caused by PTZ, the data indicate that DEX has beneficial properties in the EEG analysis, which makes it a promising candidate for the attenuation of the epileptiform wave patterns that can precipitate refractory seizures., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Acute kidney injury (AKI) increases the risk of in-hospital death, adds to expense of care, and risk of early chronic kidney disease. AKI often follows an acute event such that timely treatment could ameliorate AKI and potentially reduce the risk of additional disease. Despite therapeutic success of dexamethasone in animal models, clinical trials have not demonstrated broad success. To improve the safety and efficacy of dexamethasone for AKI, we developed and characterized a novel, kidney-specific nanoparticle enabling specific within-kidney targeting to proximal tubular epithelial cells provided by the megalin ligand cilastatin. Cilastatin and dexamethasone were complexed to H-Dot nanoparticles, which were constructed from generally recognized as safe components. Cilastatin/Dexamethasone/H-Dot nanotherapeutics were found to be stable at plasma pH and demonstrated salutary release kinetics at urine pH. In vivo, they were specifically biodistributed to the kidney and bladder, with 75% recovery in the urine and with reduced systemic toxicity compared to native dexamethasone. Cilastatin complexation conferred proximal tubular epithelial cell specificity within the kidney in vivo and enabled dexamethasone delivery to the proximal tubular epithelial cell nucleus in vitro. The Cilastatin/Dexamethasone/H-Dot nanotherapeutic improved kidney function and reduced kidney cellular injury when administered to male C57BL/6 mice in two translational models of AKI (rhabdomyolysis and bilateral ischemia reperfusion). Thus, our design-based targeting and therapeutic loading of a kidney-specific nanoparticle resulted in preservation of the efficacy of dexamethasone, combined with reduced off-target disposition and toxic effects. Hence, our study illustrates a potential strategy to target AKI and other diseases of the kidney., (Published by Elsevier Inc.)

Tissue engineering is a steadily growing field of research due to its wide-ranging applicability in the field of regenerative medicine. Application-dependent mechanical properties of a scaffold material as well as its biocompatibility and tailored functionality represent particular challenges. Here the properties of fibrin-based hydrogels reinforced by functional cytocompatible poly(N-vinylcaprolactam)-based (PVCL) microgels are studied and evaluated. The employment of temperature-responsive microgels decorated by epoxy groups for covalent binding to the fibrin is studied as a function of cross-linking degree within the microgels, microgel concentration, as well as temperature. Rheology reveals a strong correlation between the mechanical properties of the reinforced fibrin-based hydrogels and the microgel rigidity and concentration. The incorporated microgels serve as cross-links, which enable temperature-responsive behavior of the hydrogels, and slow down the hydrogel degradation. Microgels can be additionally used as carriers for active drugs, as demonstrated for dexamethasone. The microgels' temperature-responsiveness allows for triggered release of payload, which is monitored using a bioassay. The cytocompatibility of the microgel-reinforced fibrin-based hydrogels is demonstrated by LIVE/DEAD staining experiments using human mesenchymal stem cells. The microgel-reinforced hydrogels are a promising material for tissue engineering, owing to their superior mechanical performance and stability, possibility of drug release, and retained biocompatibility., (© 2024 The Author(s). Small published by Wiley‐VCH GmbH.)

Purpose: Hair cell damage is a common side effect caused by the anticancer drug cisplatin (CDDP), which reduces patient quality of life. One CDDP resistance mechanism that occurs in recurrent cancers is heavy metal detoxification by metallothionein-2 (mt2). Here, we show that in zebrafish larvae, dexamethasone (DEX) reduces CDDP-induced hair cell damage by enhancing mt2 expression., Methods: Transgenic zebrafish (cldn: gfp; atoh1: rfp) that express green and red fluorescent proteins in neuromasts and hair cells, respectively, were used. The zebrafish were pretreated with DEX at 52 h post-fertilization (hpf) for 8 h, followed by CDDP treatment for 12 h. The lateral line hair cells of CDDP-treated zebrafish at 72 hpf were observed by fluorescence microscopy., Results: Reporting odds ratio (ROR) analysis using an adverse event database indicated an association between a decrease in CDDP-induced ototoxicity and DEX as an antiemetic treatment for cancer chemotherapy. Pretreatment with DEX protected 72 hpf zebrafish hair cells from CDDP-induced damage. The expression of mt2 mRNA was significantly increased by the combination of 10 µM DEX with CDDP. Gene editing of mt2 reversed the protective effect of DEX against CDDP-induced damage in hair cells., Conclusion: DEX protects hair cells from CDDP-induced damage through increased mt2 expression, which is a resistance mechanism for platinum-based anticancer drugs., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Although several studies have shown that glucocorticoids exert diuretic effects in animals and humans, the underlying mechanism responsible for the acute diuretic effect remains obscure. Here we examined the mechanism in terms of gene-expression. We observed that glucocorticoids, including dexamethasone (Dex) and prednisolone (PSL), acutely induced diuresis in rats in a dose-dependent manner. Free water clearance values were negative after Dex or PSL treatment, similar to those observed after treatment with osmotic diuretics (furosemide and acetazolamide). Dex significantly increased the urinary excretion of sodium, potassium, chloride, glucose, and inorganic phosphorus. Renal microarray analysis revealed that Dex significantly altered the renal expression of genes related to transmembrane transport activity. The mRNA levels of sodium/phosphate (NaPi-2a/Slc34a1, NaPi-2b/Slc34a2, and NaPi-2c/Slc34a3) and sodium/glucose cotransporters (Sglt2/Slc5a2) were significantly reduced in the Dex-treated kidney, being negatively correlated with the urinary excretion of their corresponding solutes. Dex did not affect renal expression of the natriuretic peptide receptor 1 (Npr1) gene, or the expression, localization, and phosphorylation of aquaporin-2 (AQP2), a water channel protein. These findings suggest that the acute diuretic effects of glucocorticoids might be mediated by reduced expression of sodium-dependent cotransporter genes., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Osteoarthritis (OA) management remains challenging because of its intricate pathogenesis. Intra-articular injections of drugs, such as glucocorticoids and hyaluronic acid (HA), have certain limitations, including the risk of joint infection, pain, and swelling. Hydrogel-based therapeutic strategies have attracted considerable attention because of their enormous therapeutic potential. Herein, a supramolecular nanofiber hydrogel is developed using dexamethasone sodium phosphate (DexP) as a vector to deliver lentivirus-encoding hyaluronan synthase 2 (HAS2) (HAS2@DexP-Gel). During hydrogel degradation, HAS2 lentivirus and DexP molecules are slowly released. Intra-articular injection of HAS2@DexP-Gel promotes endogenous HA production and suppresses synovial inflammation. Additionally, HAS2@DexP-Gel reduces subchondral bone resorption in the anterior cruciate ligament transection-induced OA mice, attenuates cartilage degeneration, and delays OA progression. HAS2@DexP-Gel exhibited good biocompatibility both in vitro and in vivo. The therapeutic mechanisms of the HAS2@DexP-Gel are investigated using single-cell RNA sequencing. HAS2@DexP-Gel optimizes the microenvironment of the synovial tissue by modulating the proportion of synovial cell subpopulations and regulating the interactions between synovial fibroblasts and macrophages. The innovative nanofiber hydrogel, HAS2@DexP-Gel, effectively enhances endogenous HA production while reducing synovial inflammation. This comprehensive approach holds promise for improving joint function, alleviating pain, and slowing OA progression, thereby providing significant benefits to patients., (© 2024 Wiley‐VCH GmbH.)

The osseointegration of titanium implants within the host tissue holds crucial importance. The introduction of functional coatings at tissue-implant interface enhances the bioactivity of titanium implants, improves their therapeutic outcomes, and enhances the effectiveness of treatments. In this study, we focused on enhancing the bioactivity of titanium-based implant materials by coating the titanium surfaces with chitosan microspheres, which are loaded with osseointegration-promoting agent dexamethasone (DEX). Initially, chitosan microspheres were successfully produced, followed by DEX loading through diffusion, resulting in a drug loading efficiency of around 50.2 (wt %). The subsequent drug release profile displayed a 24-hour duration, releasing approximately 32.6 (wt %) of the loaded DEX. In cell proliferation assays using human osteosarcoma (SAOS-2) cells, Ti surfaces coated with DEX-loaded chitosan microspheres initially exhibited lower cell numbers compared with DEX-free ones. This observation was attributed to transient osteogenic differentiation effects of DEX, since a notable increase in cell proliferation was observed on the 7th day. Von Kossa staining revealed mineralization beginning on the 14th day, particularly evident in DEX-loaded samples. Moreover, alkaline phosphatase (ALP) activity displayed a pattern of initial increase and subsequent decrease, with DEX release from chitosan microspheres showing a clear influence on the osteogenic differentiation, especially on the 7th day. These findings align with literature, highlighting DEX's potential to enhance osteogenic differentiation and cellular behavior on chitosan microsphere-coated titanium surfaces. This study emphasizes the promising implications for functionalizing surfaces of implant materials with DEX-loaded chitosan microspheres to improve their biocompatibility and bioactivity., (© 2024 The Authors. Journal of Biomedical Materials Research Part A published by Wiley Periodicals LLC.)

The objective of the study was to evaluate the effect of photobiomodulation (PBM) with laser on the inflammatory process in an experimental in vitro model of ACO. The groups were: (1) human bronchial epithelial cells (BEAS-2B); (2) BEAS-2B cells treated with dexamethasone; (3) BEAS-2B cells irradiated with laser; (4) BEAS-2B cells stimulated with cigarette smoke extract (CSE) + House Dust Mite (HDM); (5) BEAS-2B cells stimulated with CSE + HDM and treated with dexamethasone; (6) BEAS-2B cells incubated with CSE + HDM and irradiated with laser. After 24 h, cytokines were quantified. There was a reduction in TNF-α, IL-1β, IL-6, IL-4, IL-5, IL-13, IL-17, IL-21, IL-23, and an increase in IL-10 and IFN-γ in cells from the laser-irradiated ACO group compared to only ACO group. With these results, we can suggest that photobiomodulation acts in the modulation of inflammation observed in ACO, and may be a treatment option., (© 2024 Wiley‐VCH GmbH.)

Steroid-induced osteonecrosis of the femoral head (SONFH) is a prevalent form of osteonecrosis in young individuals. More efficacious clinical strategies must be used to prevent and treat this condition. One of the mechanisms through which SONFH operates is the disruption of normal differentiation in bone marrow adipocytes and osteoblasts due to prolonged and extensive use of glucocorticoids (GCs). In vitro, it was observed that atorvastatin (ATO) effectively suppressed the impact of dexamethasone (DEX) on bone marrow mesenchymal stem cells (BMSCs), specifically by augmenting their lipogenic differentiation while impeding their osteogenic differentiation. To investigate the underlying mechanisms further, we conducted transcriptome sequencing of BMSCs subjected to different treatments, leading to the identification of Wnt5a as a crucial gene regulated by ATO. The analyses showed that ATO exhibited the ability to enhance the expression of Wnt5a and modulate the MAPK pathway while regulating the Wnt canonical signaling pathway via the WNT5A/LRP5 pathway. Our experimental findings provide further evidence that the combined treatment of ATO and DEX effectively mitigates the effects of DEX, resulting in the upregulation of osteogenic genes (Runx2, Alpl, Tnfrsf11b, Ctnnb1, Col1a) and the downregulation of adipogenic genes (Pparg, Cebpb, Lpl), meanwhile leading to the upregulation of Wnt5a expression. So, this study offers valuable insights into the potential mechanism by which ATO can be utilized in the prevention of SONFH, thereby holding significant implications for the prevention and treatment of SONFH in clinical settings., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Glucocorticoids are a major class of therapeutic anti-inflammatory and immunosuppressive drugs prescribed to patients with inflammatory diseases, to avoid transplant rejection, and as part of cancer chemotherapy. However, exposure to these drugs increases the risk of opportunistic infections such as with the fungus Aspergillus fumigatus, which causes mortality in >50% of infected patients. The mechanisms by which glucocorticoids increase susceptibility to A. fumigatus are poorly understood. In this article, we used a zebrafish larva Aspergillus infection model to identify innate immune mechanisms altered by glucocorticoid treatment. Infected larvae exposed to dexamethasone succumb to infection at a significantly higher rate than control larvae. However, both macrophages and neutrophils are still recruited to the site of infection, and dexamethasone treatment does not significantly affect fungal spore killing. Instead, the primary effect of dexamethasone manifests later in infection with treated larvae exhibiting increased invasive hyphal growth. In line with this, dexamethasone predominantly inhibits neutrophil function rather than macrophage function. Dexamethasone-induced mortality also depends on the glucocorticoid receptor. Dexamethasone partially suppresses NF-κB activation at the infection site by inducing the transcription of IκB via the glucocorticoid receptor. Independent CRISPR/Cas9 targeting of IKKγ to prevent NF-κB activation also increases invasive A. fumigatus growth and larval mortality. However, dexamethasone treatment of IKKγ crispant larvae further increases invasive hyphal growth and host mortality, suggesting that dexamethasone may suppress other pathways in addition to NF-κB to promote host susceptibility. Collectively, we find that dexamethasone acts through the glucocorticoid receptor to suppress NF-κB-mediated neutrophil control of A. fumigatus hyphae in zebrafish larvae., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Objective: To analyze the expression of platelet membrane glycoprotein sialylation in primary immune thrombocytopenia and provide a reference for clinical diagnosis and treatment of the disease., Methods: 100 children with primary immune thrombocytopenia diagnosed and treated in the Children's Hospital of Yunhe District Central Hospital of Cangzhou City, Hebei Province from January 2020 to June 2022 were included in the study group. All children were treated with dexamethasone (DXMS) shock therapy; Another 20 healthy children who underwent routine physical examination at the same time were selected and included in the control group. The study measured the platelet membrane surface in plasma using flow cytometry in two groups: the comparative study group and the control group. The study measured the positive rates of α 2,3-sialic acid (α 2, 3-sa) and α 2,6-sialic acid (α 2, 6-sa) in both groups. The study also measured the positive rates of α 2,3-sialic acid (α 2, 3-sa) and α 2,6-sialic acid (α 2, 6-sa) before and after treatment in the comparative study group. At the same time, an enzyme-linked immunosorbent assay was used to determine the content of sialic acid and sialidase activity and content in the serum. The detection values of α2, 3-SA, and α2, 6-SA expression of children in the study group and the control group were compared, and the detection values of α2, 3-SA, and α2, 6-SA expression of children in the study group before and after treatment were compared., Results: There was no significant difference in the positive rate of α 2, 3-sa between the study group and the control group (t=0.852, P > .05); Study Group: The positive rate of α 2,6-sa was significantly lower than that of the control group (P < .05). In the study group, there was no significant difference in the positive rate of α 2,3-sa before and after treatment (P > .05). However, after treatment, the positive rate of α 2,6-sa was significantly higher than before (P < .05). The study found that the children in the study group had significantly higher levels of serum sialic acid content, sialidase activity, and content than those in the control group (P < .05). After treatment, the children in the study group showed a decrease in serum sialic acid content, sialidase activity, and content, which was statistically significant (P < .05) compared to before treatment., Conclusion: The sialylation of platelet membrane glycoprotein is abnormally expressed in primary immune thrombocytopenia. The sialylation of platelet membrane glycoprotein may be involved in the occurrence and development of the disease. It is of great practical significance to diagnose and evaluate the therapeutic effect of the disease by detecting the sialylation of platelet membrane glycoprotein.

Background: Postnatal systemic corticosteroids reduce the risk of bronchopulmonary dysplasia but the effect depends on timing, dosing, and type of corticosteroids. Animal studies may provide valuable information on these variable effects. This systematic review summarizes the effects of postnatal systemic corticosteroids on lung development in newborn animals., Methods: A systematic search was performed in PubMed and Embase in December 2022. The protocol was published on PROSPERO (CRD42021177701)., Results: Of the 202 eligible studies, 51 were included. Only newborn rodent studies met the inclusion criteria. Most studies used dexamethasone (98%). There was huge heterogeneity in study outcome measures and corticosteroid treatment regimens. Reporting of study quality indicators was mediocre and risk of bias was unclear due to poor reporting of study methodology. Meta-analysis showed that postnatal corticosteroids caused a decrease in body weight as well as persistent alveolar simplification. Subgroup analyses revealed that healthy animals were most affected., Conclusion: In newborn rodents, postnatal systemic corticosteroids have a persistent negative effect on body weight and lung development. There was huge heterogeneity in experimental models, mediocre study quality, unclear risk of bias, and very small subgroups for meta-analysis which limited firm conclusions., Impact: Postnatal corticosteroids reduce the risk of bronchopulmonary dysplasia but the effect depends on timing, dosing, and type of corticosteroids while the underlying mechanism of this variable effect is unknown. This is the first systematic review and meta-analysis of preclinical newborn animal studies reviewing the effect of postnatal systemic corticosteroids on lung development. In newborn rodent models, postnatal corticosteroids have a persistent negative effect on body weight and lung alveolarization, especially in healthy animals., (© 2024. The Author(s).)

Photothermal therapy (PTT) encounters challenges in addressing deep tissue infections, characterized by limited penetration or potential hyperthermal damage to surrounding tissues, initiating undesirable inflammatory cascades. Inspired by polar bear thermal regulation, we present a "bio-based endogenic thermal-adaptive booster" implant coating. This coating integrates a photothermal poly(tannic acid) (pTA) layer, mimicking the "polar bear dark skin", securely linked with anti-inflammatory dexamethasone (Dex), resembling the "secretion", and a red blood cell membrane (RBCM) layer, forming the insulating "transparent fur". The RBCM "fur" demonstrates unexpectedly superior local heat storage, amplifying the photothermal effect of the pTA "skin" by 1.30 times and boosting localized photothermal antibacterial efficiency by 1.30-fold (approximately 99%) compared to those without RBCM. Furthermore, RBCM sustains Dex release and offers additional protection against thermal inflammation, releasing Dex 1.90 times more under NIR irradiation than under non-photothermal conditions. In a rat infectious bone model, the photothermal-boosting implant coating provides a favorable biological interface and achieves a 99.97% photothermal antibacterial ratio, enhancing osseointegration without evident tissue harm, evidenced by a 2.47-fold increase in bone volume fraction and a 2.24-fold reduction in pro-inflammatory cytokines compared to those lacking a RBCM. Insights derived from cell membrane-based thermal-adaptive coatings herald a paradigm shift in efficient and safe PTT.