Evaluation of Cross-Linked Actin Networks (CLANs) in Human Trabecular Meshwork Cells and Tissues.

Elevated intraocular pressure (IOP) is a major risk factor for the development and progression of glaucoma, the leading cause of irreversible vision loss and blindness. An overall increase in resistance to aqueous humor outflow causes sustained elevation in IOP. Glaucomatous insults in the aqueous humor outflow pathway, including the trabecular meshwork (TM), precede such chronic physiological changes in IOP. These insults include ultrastructural changes with excessive extracellular matrix deposition and actin cytoskeletal reorganization that leads to pathological stiffening of the ocular tissues. One of the most common cytoskeletal changes associated with TM tissue stiffness in glaucoma is the increased prevalence of cross-linked actin networks (CLANs) in cells of the trabecular meshwork (TM) and lamina cribrosa (LC). In glaucomatous cells, rearrangement of linear actin stress fibers leads to formation of polygonal arrays within the cytoplasm, resembling a geodesic dome-like structure, that we identified as CLANs. In addition to increased amounts of CLANs in POAG TM cells and tissues, we also discovered that glucocorticoid (GC) and TGFß2 signaling pathways associated with the development of ocular hypertension (OHT) and glaucoma also induced CLANs in the TM. Despite a clear association, we are yet to completely understand the mechanisms involved in CLAN formation and their direct relevance to disease pathology. In this chapter, we will describe methods to identify and characterize CLANs using fluorescent microscopy in primary TM cell cultures, ex vivo perfusion cultured human anterior segments, and in situ in human donor eyes.

Should intravitreal dexamethasone implant in refractory diabetic macular edema be used as an adjuvant therapy or switch therapy?

ABSTRACT Purpose: To compare the outcomes of intravitreal dexamethasone implant used as either an adjuvant or a switching therapy for diabetic macular edema in patients with poor anatomic response after three consecutive monthly injections of ranibizumab. Methods: This retrospective study included patients with diabetic macular edema who received three consecutive doses of ranibizumab as initial therapy and demonstrated poor response. A single dose of intravitreal de xamethasone implant was administered to these patients. The patients were divided into two groups according to the treatment modalities: the adjuvant therapy group, consisting of patients who continued treatment with ranibizumab injection after receiving intravitreal dexamethasone implant, and the switch therapy group, consisting of patients who were switched from ranibizumab treatment to intravitreal dexamethasone implant as needed. The main outcome measurements were best corrected visual acuity and central retinal thickness at baseline and at 3, 6, 9, and 12 months of follow-up. Results: In this study that included 64 eyes of 64 patients, the best corrected visual acuity and central retinal thickness values did not significantly differ between the groups at baseline and at 6 months of follow-up (p>0.05). However, at 12 months, the best corrected visual acuity values in the adjuvant and switch therapy groups were 0.46 and 0.35 LogMAR, respectively (p=0.012), and the central retinal thickness values were 344.8 and 270.9, respectively (p=0.007). Conclusions: In a real-world setting, it seems more reasonable to use intravitreal dexamethasone implant as a switch therapy rather than an adjuvant therapy for diabetic macula edema refractory to ranibizumab despite three consecutive monthly injections of ranibizumab. Patients switched to intravitreal dexamethasone implant were found to have better anatomic and visual outcomes at 12 months than those who continued ranibizumab therapy despite their less-than-optimal responses.

Who and how to screen for endogenous hypercortisolism in type 2 diabetes mellitus or obesity.

PURPOSE: The current review aims to summarize and discuss the prevalence of confirmed hypercortisolism in patients with diabetes mellitus or obesity, analysing the screening tests used and their accuracy, in order to better identify whether patients with diabetes mellitus and obesity should be screened for Cushing's syndrome (CS) and how. METHODS: A narrative review was performed including publications focusing on the current knowledge on prevalence of confirmed hypercortisolism in patients with type 2 diabetes mellitus (T2DM) or obesity and on screening tests used to detect CS. RESULTS: The studies reviewed suggest that the prevalence of CS in patients with T2DM is variable, ranging from 0.6 to 9.3%. The most used screening test is the overnight cortisol after 1 mg of dexamethasone suppression test (DST), with a false positive rate ranging from 3.7 to 21%. The prevalence of CS among obese patients is generally about 1%, except for two studies which reported higher prevalence. For obese patients, 1 mg DST and late-night salivary cortisol are the most accurate screening tests for CS. CONCLUSIONS: Clinical expertise remains the mainstay to identify which subjects should be screened for CS. The evaluation of the clinical stigmata of CS and the combination with clinical comorbidities typical of CS are the stronger predictors of CS. In addition, we could hypothesize that in patients with T2DM, overnight 1 mg DST is the more accurate screening test for CS. By contrast, in patients with obesity both LNSC and overnight 1 mg DST could be equally used for the screening of hypercortisolism.

A randomized phase III study evaluating dexamethasone-based mouthwash to prevent chemotherapy-induced stomatitis in patients with breast cancer.

Stomatitis, which is a common side effect of chemotherapy, currently lacks a standardized approach for its prevention. Therefore, this multicenter, randomized, open-label, controlled phase III trial aims to assess the efficacy and safety of a dexamethasone-based mouthwash for preventing chemotherapy-induced stomatitis in patients with early breast cancer. We will randomly assign 230 patients with early breast cancer scheduled to receive chemotherapy in a 1:1 ratio to either the dexamethasone-based mouthwash group (10 ml, 0.1 mg/ml; swish for 2 min and spit 4 times daily for 8 weeks) or the mouthwash-with-tap-water group. The incidence of stomatitis, measured using electronic patient-reported outcomes, is the primary endpoint.

Impact of baseline steroids on the efficacy of neoadjuvant immunochemotherapy in locally advanced esophageal squamous cell carcinoma.

BACKGROUND: Immunochemotherapy involving the combination of programmed cell death 1/programmed cell death ligand 1 inhibitors with chemotherapy has advanced the treatment of locally advanced esophageal squamous cell carcinoma (ESCC). The use of corticosteroids as pretreatment might reduce immunotherapy efficacy. AIM: To investigate the impact of baseline corticosteroid use on neoadjuvant immunochemotherapy (nIC) outcomes in locally advanced ESCC patients. METHODS: Patients with locally advanced ESCC who received nIC at Sun Yat-sen University Cancer Center and the Third Affiliated Hospital of Sun Yat-sen University were included. Patients were divided into dexamethasone and antihistamine groups on the basis of the administered pretreatment. Antiallergic efficacy and safety were evaluated, as well as its impact on short-term efficacy [complete pathological response (pCR), major pathological response (MPR)] and long-term efficacy [overall survival (OS), progression-free survival (PFS)] of nIC. RESULTS: From September 2019 to September 2023, 142 patients were analyzed. No severe treatment-related adverse events or deaths were observed. Allergy occurrence was greater in the antihistamine group (P = 0.014). Short-term efficacy was not significantly different: The pCR rates were 29.9% and 40.0%, and the MPR rates were 57.9% and 65.7% in the dexamethasone and antihistamine groups, respectively. The long-term efficacy was not significantly different: The 2 years OS rates were 95.2% and 93.5%, and the 2 years PFS rates were 90.3% and 87.8%. Subgroup analysis revealed no difference in OS between the 20 mg dexamethasone group and the < 20 mg dexamethasone group, but PFS was significantly greater in the 20 mg dexamethasone group (93.9% vs 56.4%, P = 0.001). CONCLUSION: Dexamethasone or antihistamines can be used before nIC in locally advanced ESCC without affecting short- or long-term efficacy. Administering 20 mg dexamethasone before nIC may improve PFS in ESCC.

A Comparative Study of Post Operative Pain Following Tonsillectomy with Local Infilteration of Dexamethasone vs Triamcinolone.

Tonsillectomy till date continues to be the most frequently performed surgery by ENT surgeons, and with that comes the most challenging complication of post-tonsillectomy pain and its management that affects the patient morbidity and alters the hospital course. Various methods and techniques have been implicated in the post-operative pain management in patients undergoing tonsillectomy. To compare the post operative pain following local infiltration of Dexamethasone and Triamcinolone in patients undergoing Tonsillectomy. Total of 50 patients were selected and randomized into two groups- Group 1 and Group 2, who underwent local infiltration of Dexamethasone and Triamcinolone respectively to maintain uniformity. Baseline scoring (0 h post operatively) and follow up scoring after 6 h and 24 h was done using the Visual Analogue Scale and were evaluated and documented as per their response to treatment. A significant reduction was observed in the severity of pain in both groups with an average reduction of mean score from 9.50 to 5.92 in Group 1 and from 9.04 to 3.90 in Group 2 at the end of 24 h post-operatively. The mean score of Group 2 was greater and showed better improvements in VAS pain score and was statistically significant (p < 0.001). Usage of steroidal preparations locally during tonsillectomy helps combat the post-operative pain. Usage of Triamcinolone locally has proved beneficial in reducing the post-operative tonsillectomy pain.

IS Intra-masseteric Dexamethasone Better than Intra-deltoid Injection in Reducing Post-operative Sequelae Following Impacted Third Molar Surgery?: A Randomized Clinical Study.

Aim: The post-operative sequelae of third molar surgical extractions need to be controlled in order to reduce patient morbidity. Dexamethasone is a well-researched drug which has established its merit as an anti-inflammatory agent. The aim of this randomized clinical study was to compare the patient-centric outcomes after pre-emptive intramuscular injection of dexamethasone into the masseter and deltoid, respectively. Materials and Methods: The outcomes measured were pain, facial swelling and mouth-opening postoperatively on Day 1, 3 and 7. The subjects were randomly divided into two groups. Group 1 received an intra-oral injection of 8 mg of dexamethasone into the masseter muscle and a placebo injection of distilled-water into the deltoid muscle 2 h before surgical removal of impacted mandibular third molar. Group 2 received an intra-oral placebo injection of distilled-water into masseter muscle and an 8 mg injection of dexamethasone into deltoid muscle. Results: On comparison, Group 1 patients experienced statistically significant less pain (VAS score on day 1, 3, and 7), facial swelling (day 1, 3), and restricted mouth-opening (day 1, 3). Conclusion: The study concluded that pre-emptive dexamethasone injection, at masseter or deltoid, is helpful in reducing post-operative sequelae of mandibular third molar extraction. However, the immediate post-operative outcomes were found to be better mitigated when the injection was administered locally into masseter muscle.

Dexamethasone versus 5-HT3 receptor antagonists in preventing nausea during awake craniotomy: a propensity score matching study.

BACKGROUND: Nausea and vomiting during awake craniotomy (AC) can increase cerebral pressure and cause asphyxia and aspiration. 5-HT3 receptor antagonists, such as granisetron, are often administered before awakening to prevent nausea during AC. Recently, dexamethasone was reported to prevent nausea and vomiting during AC; however, the efficacy of both drugs in preventing nausea has not yet been investigated. METHODS: We examined the frequency of nausea and vomiting in AC patients (n = 170) treated at our hospital until the end of September 2019. We divided patients as those who received dexamethasone (n = 71) and or granisetron (n = 99) before awakening and examined the frequency of nausea and vomiting after propensity score (PS) matching. RESULT: Eighty-two patients were selected after PS matching. The incidence of nausea was significantly lower in the dexamethasone group than in the granisetron group (9.8% vs 41.5%, p = 0.002). In the logistic regression analysis after matching, the incidence of nausea significantly reduced with dexamethasone treatment (odds ratio: 0.12, 95% confidence interval: 0.029-0.499, p = 0.03). CONCLUSION: In conclusion, dexamethasone was more effective than granisetron in preventing nausea during AC.

Intravitreal Dexamethasone Implants for Macular Edema Secondary to Acute Retinal Necrosis.

PURPOSE: To assess the effectiveness and risk of intravitreal injection of dexamethasone implants in treating macular edema (ME) secondary to acute retinal necrosis (ARN). METHODS: In this retrospective, noncomparative case series study, five patients who developed secondary ME after ARN and received an intravitreal dexamethasone implant injection were enrolled. The features of secondary ME on OCT and the outcomes of dexamethasone intravitreal implanting were presented. RESULTS: The mean age of the patients was 59 years (range, 51-61 years). All patients had unilateral involvement, and all 5 eyes showed mild to moderate anterior uveitis, retinal necrosis, and vasculitis. Herpes zoster virus was detected in all eyes using PCR, and timely antiviral and anti-inflammatory treatment was performed. Aqueous humor samples were negative for herpes zoster virus DNA, and resolution of viral retinitis was noted upon the occurrence of ME. Additionally, three eyes received pars plana vitrectomy with silicone oil prior to ME development. All eyes presented with intraretinal fluid, hyper-reflective foci, and impairments of the external limiting membrane/ellipsoid zone at varying degrees on OCT images. Epiretinal membrane was exhibited in 80% of eyes, but no vitreoretinal traction was detected. Subretinal fluid was visible in 60% of eyes. ME was relieved effectively in all eyes after intravitreal dexamethasone implanting. One of these patients experienced three episodes of ME. No recurrence of retinal necrosis or corticosteroid-associated ocular hypertension was observed during the follow-up period. CONCLUSION: Intravitreal injection of dexamethasone implants can effectively alleviate ME secondary to ARN and improve visual acuity with no adverse reactions.

Macular edema secondary to acute retinal necrosis was characterized by the presence of intraretinal fluid, hyper-reflective foci, and external limiting membrane/ellipsoid zone fracture. The intravitreal injection of dexamethasone implants effectively alleviated this type of edema with no adverse reactions.

Encapsulation of Dexamethasone into mRNA-Lipid Nanoparticles Is a Promising Approach for the Development of Liver-Targeted Anti-Inflammatory Therapies.

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-1ß, 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.

Mutual associations among responsiveness to differential diagnostic tests for Cushing's disease, tumor size, and somatostatin receptor 5 expression in corticotroph tumors.

There are differences in the responsiveness to differential diagnostic tests for Cushing's disease (CD), corticotroph tumor size, and the somatostatin receptor (SSTR) 5 expression in corticotroph tumors between CD patients. The differences in SSTR5 expression are particularly significant for identifying therapeutic targets for CD. However, prospective predictors of SSTR5 expression remain unclear. Thus, our objective was to elucidate the relationships among these clinical characteristics of CD, including SSTR5 expression. In 27 hospitalized patients with CD at Osaka University Hospital, Osaka, Japan, associations between corticotroph tumor diameter, the response of ACTH and cortisol to differential diagnostic tests for CD (CRH, desmopressin [DDAVP], and high-dose dexamethasone suppression test [HDDST]), the ACTH/cortisol index, and the SSTR5 immunoreactive score were retrospectively investigated. The response to differential diagnostic tests, ACTH/cortisol index, tumor diameter, and SSTR5 expression were significantly related (vs. tumor diameter [CRH: r = -0.54; DDAVP: r = -0.54; HDDST r = -0.67; ACTH/cortisol index: r = 0.76; SSTR5: r = -0.61], vs. CRH [DDAVP: r = 0.63, HDDST: r = 0.72, ACTH/cortisol index: r = -0.45; SSTR5: r = 0.56], vs. DDAVP [HDDST: r = 0.66; ACTH/cortisol index: r = -0.46; SSTR5: r = 0.76], vs. HDDST [ACTH/cortisol index: r = -0.62; SSTR5: r = 0.77], ACTH/cortisol index vs. SSTR5: r = -0.67). The areas under the receiver operating characteristic curve for the prediction of high SSTR5 expression via the CRH test, DDAVP test, HDDST, ACTH/cortisol index, and tumor diameter were 0.79, 0.87, 0.80, 0.71, and 0.71, respectively. Tests for differential diagnosis of CD, the ACTH/cortisol index, and the corticotroph tumor diameter have the potential for identifying SSTR5 expression in corticotroph tumors. These parameters may reflect the biological characteristics of corticotroph tumors.

Mastoid approach for local drug delivery to the inner ear for treating hearing loss.

Hearing loss is a prevalent disability worldwide. Dexamethasone (Dex) is commonly used to treat hearing loss, administered either systemically or locally. However, targeted delivery of Dex to the inner ear remains challenging, which limits its therapeutic efficacy. This study aimed to develop new methods to improve Dex delivery to the inner ear and enhance its treatment effect. Mastoid, intraperitoneal, and intratympanic delivery routes for Dex were investigated in guinea pig cochlea. Liquid chromatography-mass spectrometry and immunohistochemistry were employed to compare the distribution of Dex in the perilymph and tissue uptake. Poly (lactic-co-glycolic acid) nanoparticles loaded with Dex (PLGA-NPs-Dex) were prepared, and their transport mechanism across the round window membrane (RWM) was explored. Among the three delivery routes, mastoid administration produced the highest Dex concentration in the perilymph. Compared to the control, PLGA-NPs-Dex provided significantly enhanced protection against lipopolysaccharide- and noise-induced hearing damage following mastoid administration. Mastoid delivery provides an accessible route for drug delivery to the inner ear and nanoparticle-based systems via this route represent a viable strategy for treating inner ear diseases. This approach caused less damage to the inner ear, making it a promising option for clinical use in treating hearing loss.

Safety and efficacy of intravitreal dexamethasone implantation along with phacoemulsification and intraocular lens implantation in children with uveitis.

PURPOSE: To evaluate the safety and efficacy of intravitreal dexamethasone implantation during phacoemulsification and intraocular lens implantation in pediatric uveitis. METHODS: A retrospective analysis was conducted on pediatric uveitis patients undergoing phacoemulsification and intraocular lens implantation with intravitreal dexamethasone implantation. Patients with a minimum follow-up of 6 months were included. Primary outcome measures included ocular inflammation, intraocular pressure (IOP), best-corrected visual acuity (BCVA), and worsening of uveitis. RESULTS: 36 eyes of 28 patients were ultimately included in this study. The mean preoperative BCVA was 1.00 (0.40-1.50) LogMAR. BCVA significantly improved to 0.40 (0.20-0.54) LogMAR at 1 month postoperatively (P = 0.006), further improving to 0.30 (0.20-0.40) LogMAR at 3 months postoperatively (P = 0.001). BCVA remained stable at 0.30 (0.20-0.70) LogMAR at 6 months postoperatively (P = 0.005). Mean IOP showed no statistically significant difference during the follow-up period of three to six months after surgery. Eight children experienced recurrence of ocular inflammation during the 6-month follow-up period. No cases of worsening macular edema, glaucoma, or elevated IOP were observed in any patient. CONCLUSION: Intravitreal dexamethasone implantation during phacoemulsification and intraocular lens implantation is a safe and effective method for preventing and treating postoperative inflammation in children with uveitis.

Impact of Aflibercept vs Dexamethasone Treatment on Epiretinal Membrane Formation in Eyes with Diabetic Macular Edema.

INTRODUCTION: This study aimed to investigate the impact of aflibercept and dexamethasone (DEX) on the formation of epiretinal membrane (ERM) and their treatment outcomes in eyes with diabetic macular edema (DME). METHODS: In this retrospective cohort study, medical records of 124 eyes from 429 patients diagnosed with DME were reviewed between June 2017 and June 2019. Patients were categorized into two groups: the aflibercept group (67 eyes) and the DEX group (57 eyes). The primary endpoint was the secondary ERM incidence following intravitreal treatments and its correlation across different medications. Secondary endpoints included longitudinal changes in best-corrected visual acuity (BCVA) and central macular thickness (CMT). RESULTS: Over a 24-month follow-up, eyes treated with DEX had approximately a fourfold higher incidence of ERM development compared to aflibercept [hazard ratio (HR) = 3.97, p = 0.02]. These eyes also showed worse BCVA (p = 0.059) and increased CMT (p = 0.004), despite requiring fewer total injections (p = 0.000) in the survival analysis model. The cumulative probability of ERM formation was 13.7%. Additionally, DME eyes exhibited poor functional and anatomical outcomes after developing ERM, while age, A1c level, DR severity, initial BCVA and CMT, lens status, and previous laser treatment were not associated with an elevated incidence of ERM formation. CONCLUSION: Intravitreal DEX implantation in DME eyes resulted in a higher incidence of secondary ERM formation compared to aflibercept over a 2-year period. The therapeutic efficacy for DME was diminished following ERM development, leading to worse anatomical outcomes. New therapeutic approaches should be explored to prevent ERM formation while maintaining both anatomical and functional outcomes in DME treatment.

Combination of different local anesthetic adjunct for supraclavicular brachial plexus block after arthroscopic shoulder surgery: a prospective randomized controlled trial.

BACKGROUND: Acute pain is a major concern after arthroscopic shoulder surgery, supraclavicular brachial plexus blockade has shown favorable postoperative analgesic effects. However, its duration of analgesia does not meet clinical needs. We aimed to explore whether the combination of different local anesthetic adjunct can prolong the analgesic duration of supraclavicular brachial plexus block for arthroscopic shoulder surgery. METHODS: In this prospective randomized controlled trial, we allocated 80 patients into four groups: Group DMD (dexamethasone 10 mg + ropivacaine 100 mg + dexmedetomidine 50 µg + magnesium sulfate 250 mg), Group DM (ropivacaine 100 mg + dexmedetomidine 50 µg + magnesium sulfate 250 mg), Group M (ropivacaine 100 mg + magnesium sulfate 250 mg) and Group D (ropivacaine 100 mg + dexmedetomidine 50 µg). The primary outcome was the time to first request for analgesia. Secondary outcome measures included cumulative opioid consumption at 6, 12, 18, 24, and 48 h postoperatively, VAS scores at 6, 12, 18, 24, and 48 h postoperatively and so on. RESULTS: The time to first request for analgesia in Group DMD was significantly longer than Group DM (P = 0.011) and Group M (P = 0.003). The cumulative opioid consumption at 18 h postoperatively in Group DMD was significantly lower than in Group DM (P = 0.002) and Group M (P = 0.007). The cumulative opioid consumption at 24 h postoperatively in Group DMD was significantly lower than in Group DM (P = 0.016). The VAS score at 6 h postoperatively in Group DMD was significantly lower than in Group DM and Group M. The VAS score at 12 h postoperatively in Group DMD was significantly lower than in Group M. For American Shoulder and Elbow Surgeons Score, Group DMD had a better score than Group DM and Group D. CONCLUSIONS: The analgesic efficacy of supraclavicular brachial plexus blockade combined with dexamethasone, magnesium sulfate, and dexmedetomidine is significantly superior to the combination of magnesium sulfate and dexmedetomidine, and significantly superior to the use of magnesium sulfate alone. TRIAL REGISTRATION: This trial was registered in Chinese Clinical Trial Registry. (ChiCTR2200061181, Date of registration: June 15, 2022, http://www.chictr.org.cn ).

Dexamethasone as an emerging environmental pollutant: Disruption of cholesterol-dependent synaptogenesis in the hippocampus and subsequent neurobehavioral impacts in offspring.

When fetuses are exposed to abnormally high levels of glucocorticoids in utero, irreversible damage to neuronal synaptogenesis occurs, leading to long-term cognitive and emotional behavioral abnormalities after birth. In this study, we investigated how maternal exposure to a novel environmental pollutant-synthetic glucocorticoid dexamethasone-affects offspring cognitive and emotional behaviors enduringly. We noted that offspring subjected to maternal dexamethasone exposure (MDE) displayed cognitive and emotional neurobehavioral deficits beginning in infancy, and these impairments persisted into adulthood. The principal mechanism involves MDE-induced damage to hippocampal neuronal synapse formation in the offspring, primarily due to a cholesterol deficiency which destabilizes neuronal membranes, thereby affecting normal synapse formation and ultimately leading to cognitive and emotional deficiencies. Specifically, we demonstrated abnormal activation of glucocorticoid receptors in hippocampal astroglial cells of MDE offspring, which triggers changes in the miR-450a-3p/HAT1/ABCG1 signaling axis, causing impaired cholesterol efflux in astroglial cells and insufficient cholesterol supply to neurons, further impairing synaptogenesis. This research not only underscores the significant impact of prenatal environmental pollutants on long-term health outcomes in offspring but also broadens our understanding of how prenatal exposure to glucocorticoids affects brain development in the progeny, providing new insights for interventions in neurodevelopmental and psychiatric disorders of fetal origin.

Spectroscopic Screening of Dexamethasone and Cyproheptadine Adulteration in Weight Gaining Products Marketed in Aden, Yemen.

Background: Weight-gaining (WG) products are either medicine or herbal products that have been used intensively by the young and adolescents in Yemen. These products may contain undeclared potentially toxic ingredients that can lead to several health problems and diseases on long-term usage. This study was intended to evaluate the presence of some undeclared pharmaceuticals, dexamethasone (DX) and cyproheptadine (CPR), in WG products in Aden, Yemen. Methods: The detection of DX & CPR in WG products was evaluated using UV& Fourier transform infrared (FT-IR) spectroscopy. Also, phytochemical analysis was carried out for herbal products. Findings: The study indicated the presence of CPR in Tab-II, honey mixture, and capsules in the range between 0.10%-102.6%. A lower percentage was detected in the honey mixture and a higher percentage in Tab-2. DX was only detected in Tab-I (102.87%). Conclusion: It can be concluded that WG products may contain undeclared amounts of DX and CPR. Stricter regulations must be implemented for the usage and distribution of these products to avoid potential long-term adverse consequences.

Mouse liver sinusoidal endothelial cell responses to the glucocorticoid receptor agonist dexamethasone.

Liver sinusoidal endothelial cells (LSECs) which make up the fenestrated wall of the hepatic sinusoids, are active scavenger cells involved in blood waste clearance and liver immune functions. Dexamethasone is a synthetic glucocorticoid commonly used in the clinic and as cell culture supplement. However, the response is dependent on tissue, cell type, and cell state. The aim of this study was to investigate the effect of dexamethasone on primary mouse LSECs (C57BL/6J); their viability (live-dead, LDH release, caspase 3/7 assays), morphology (scanning electron microscopy), release of inflammatory markers (ELISA), and scavenging functions (endocytosis assays), and associated biological processes and pathways. We have characterized and catalogued the proteome of LSECs cultured for 1, 10, or 48 h to elucidate time-dependent and dexamethasone-specific cell responses. More than 6,000 protein IDs were quantified using tandem mass tag technology and advanced mass spectrometry (synchronous precursor selection multi-notch MS3). Enrichment analysis showed a culture-induced upregulation of stress and inflammatory markers, and a significant shift in cell metabolism already at 10 h, with enhancement of glycolysis and concomitant repression of oxidative phosphorylation. At 48 h, changes in metabolic pathways were more pronounced with dexamethasone compared to time-matched controls. Dexamethasone repressed the activation of inflammatory pathways (IFN-gamma response, TNF-alpha signaling via NF-kB, Cell adhesion molecules), and culture-induced release of interleukin-6, VCAM-1, and ICAM-1, and improved cell viability partly through inhibition of apoptosis. The mouse LSECs did not proliferate in culture. Dexamethasone treated cells showed upregulation of xanthine dehydrogenase/oxidase (Xdh), and the transcription regulator Foxo1. The drug further delayed but did not block the culture-induced loss of LSEC fenestration. The LSEC capacity for endocytosis was significantly reduced at 48 h, independent of dexamethasone, which correlated with diminished expression of several scavenger receptors and C-type lectins and altered expression of proteins in the endocytic machinery. The glucocorticoid receptor (NR3C1) was suppressed by dexamethasone at 48 h, suggesting limited effect of the drug in prolonged LSEC culture. Conclusion: The study presents a detailed overview of biological processes and pathways affected by dexamethasone in mouse LSECs in vitro.

Establishment of a dexamethasone-induced zebrafish skeletal muscle atrophy model and exploration of its mechanisms.

BACKGROUND: Skeletal muscle atrophy is one of the main side effects of high-dose or continuous use of glucocorticoids (such as dexamethasone). However, there are limited studies on dexamethasone-induced skeletal muscle atrophy in zebrafish and even fewer explorations of the underlying molecular mechanisms. This study aimed to construct a model of dexamethasone-induced skeletal muscle atrophy in zebrafish and to investigate the molecular mechanisms. METHODS: Zebrafish soaked in 0.01 % dexamethasone solution for 10 days. Loli Track (Denmark) and Loligo Swimming Respirometer were used to observe the effect of dexamethasone on swimming ability. The effects of dexamethasone on zebrafish skeletal muscle were observed by Transmission electron microscopy, H&E, and wheat germ agglutinin techniques. Enriched genes and signaling pathways were analyzed using Transcriptome sequencing. Further, the levels of mitochondrial and endoplasmic reticulum-related proteins were examined to investigate possible mechanisms. RESULTS: 0.01 % dexamethasone reduced zebrafish skeletal muscle mass (p < 0.05), myofibre size and cross-sectional area (p < 0.001), and increased protein degradation (ubiquitination and autophagy) (p < 0.05). In addition, 0.01 % dexamethasone reduced the swimming ability of zebrafish, as evidenced by the reluctance to move, fewer movement trajectories, decreased total distance traveled (p < 0.001), average velocity of movement (p < 0.001), oxygen consumption (p < 0.001), critical swimming speed (p < 0.01) and increased exhaustive swimming time (p < 0.001). Further, 0.01 % dexamethasone-induced mitochondrial dysfunction (decreased mitochondrial biogenesis, disturbs kinetic homeostasis, increased autophagy) and endoplasmic reticulum stress. CONCLUSIONS: 0.01 % dexamethasone induces skeletal muscle atrophy and impairs the swimming ability of zebrafish through mitochondrial dysfunction and endoplasmic reticulum stress.