Early postnatal GABAergic signaling is crucial for brain development and circuit formation. While Gamma-aminobutyric acid (GABA) regulates sleep-wake cycles, sleep deprivation causes cognitive impairment and oxidative stress. Although blocking GABA-A receptors has been shown to improve cognition, the effect of such blockade during development on sleep-loss-induced cognitive deficits remains unknown. Accordingly, this study was designed to investigate the effects of early-life inhibition of GABA-A receptors on sleep deprivation-induced cognitive impairments in adulthood. Thirty-two male neonatal rats were randomly assigned to four equal-sized groups (n = 8/group): Control, Bicuculline (300 µg/kg subcutaneously on postnatal days 7, 9, and 11), Sleep Deprivation (24-h SD at postnatal days (PNDs) 60–70), and Bicuculline + SD. In young adulthood (PNDs 60–70), anxiety-like behavior was assessed using the Elevated plus maze (EPM), while the Morris water maze (MWM) was used to evaluate spatial learning and memory. We then measured superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, as well as malondialdehyde (MDA) levels in hippocampal tissue. SD alone significantly increased anxiety-like behaviors, impaired spatial learning and short-term memory, reduced hippocampal SOD and GPx activities, and elevated MDA. Remarkably, early-life bicuculline pretreatment prevented SD-induced cognitive deficits, attenuated anxiety-like responses, and restored antioxidant enzyme activities while normalizing MDA levels. Early postnatal transient blockade of GABA-A receptors was associated with decreased vulnerability to cognitive deficits, anxiety-like behaviors, and oxidative stress induced by acute sleep deprivation in adulthood. This reveals a novel developmental role of early GABAergic signaling in defense against sleep loss-induced neuropsychiatric and cognitive deficits.
Activation of brown adipose tissue (BAT) has emerged as a promising strategy for combating obesity due to its thermogenic capacity. However, chronic high-fat diet (HFD) exposure impairs BAT function and promotes a “whitening” phenotype characterized by lipid droplet enlargement and reduced thermogenic activity. Bifidobacterium adolescentis (B. adolescentis) has been reported to improve lipid metabolism and energy balance. This study investigated whether B. adolescentis supplementation attenuates HFD-induced BAT whitening, evaluated at transcriptional and histological levels, and examined its association with thermogenic and lipolytic gene expression. Twenty-four six-weeks-old male Sprague-Dawley rats were allocated into four groups for 16 weeks: control (standard chow diet), HFD, HFD-B. adolescentis–8 W (4 × 10¹⁰ CFU/day from week 8 to week 16), and HFD-B. adolescentis–16 W (4 × 10¹⁰ CFU/day for 16 weeks). Probiotic supplementation was administered via drinking water. Metabolic parameters, serum lipid profile, BAT histomorphmetery assessed by hematoxylin and eosin staining, and mRNA expression of thermogenesis- and lipolysis-related genes (Ucp1, Prdm16, Pgc-1α, Sirt1, Ampk, Atgl, and Hsl) were evaluated. B. adolescentis supplementation significantly attenuated HFD-induced weight gain and improved serum lipid parameters. These effects were accompanied by increased mRNA expression of Sirt1, Ampk, and key thermogenic and lipolytic genes in BAT. Histological analysis revealed partial preservation of multilocular adipocyte morphology and reduced cytoplasmic hypertrophy compared with the HFD group. B. adolescentis supplementation mitigated HFD-induced metabolic disturbances and attenuated BAT whitening. These effects were associated with the upregulation of thermogenesis- and lipolysis-related genes, including Sirt1 and Ampk. Further mechanistic studies are required to determine whether these molecular changes play a causal role in mediating the protective effects of this probiotic.
A dihydrofolate reductase inhibitor, pyrimethamine has an emerging anticancer potential but is not well soluble in aqueous and bioavailable. The D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS)-based micellar nanoformulation was developed to overcome these challenges to improve its therapeutic performance. The D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS)-based micellar nanoformulation was developed to overcome these challenges to improve its therapeutic performance. TPGS micelles containing pyrimethamine were developed through solvent casting-rehydration and studied through DLS, AFM, SEM and TEM. The maximally efficient expression generated homogeneous spherical micelles with an average diameter of about 74 nm and a low polydispersity (0.20) that is very homogeneous and stable. Persistent bi-phasic drug delivery was seen in physiological conditions. TPGS-Stabilized Pyrimethamine Micelles Promote ROS-Associated Apoptosis. In MDA-MB-231 breast cancer cells, the nanoformulation increased cytotoxicity and intracellular uptake compared with free pyrimethamine. The experiment showed that in mechanistic studies, there was high production of reactive oxygen species, high Annexin V-positive populations of apoptotic cells and G2/M phase arrest, which were associated with increased ROS generation, apoptosis, and cell-cycle arrest. In the murine lymphoma model, the nanoformulation reduced tumour progression and resulted in 100
Sensorineural hearing loss (SNHL) is a prevalent clinical disorder in otorhinolaryngology, with cochlear ischemia/reperfusion (I/R) injury-induced hair cell apoptosis being a core pathogenic mechanism. Ginsenoside Rb1 (Rb1), a major active component of Panax ginseng, exhibits potent anti-apoptotic and neuroprotective effects, but its role and underlying mechanism in cochlear I/R injury remain elusive. The hair cell-like HEI-OC1 cell line was employed to establish an in vitro cochlear I/R injury model via oxygen-glucose deprivation/reperfusion (OGD/R). Cell viability was evaluated using the CCK-8 assay to screen for the non-cytotoxic concentration of Rb1. LIMK1 knockdown was achieved by transfection with si-LIMK1, and the knockdown efficiency was verified by RT-qPCR and Western blot. Flow cytometry with Annexin V-FITC/PI staining was used to detect cell apoptosis. Western blot was performed to measure the protein expression levels of key molecules in the RhoA/ROCK/LIMK1 pathway and Fas system. The Rho/ROCK pathway inhibitor Y-27,632, the RhoA activator LPA, and Fas agonist antibody Jo2 were used to validate the regulatory relationships among the pathways. OGD/R significantly induced HEI-OC1 cell apoptosis, accompanied by activation of the RhoA/ROCK/LIMK1 pathway and Fas system. Rb1 pretreatment attenuated the OGD/R-induced reduction in cell viability and increase in apoptosis, while inhibiting the activation of the RhoA/ROCK/LIMK1 pathway and Fas system. LIMK1 knockdown attenuated OGD/R-induced Fas system activation and cell apoptosis. Notably, LPA attenuated the protective effects of Rb1 and restored RhoA/ROCK/LIMK1-related protein expression, whereas Jo2 attenuated Rb1-mediated protection without affecting the upstream pathway. Ginsenoside Rb1 protects HEI-OC1 cells against OGD/R-induced apoptosis, and this protective effect is associated with reduced activation of the RhoA/ROCK/LIMK1 pathway and Fas system. Ginsenoside Rb1 attenuates OGD/R-induced apoptosis in HEI-OC1 cells. LIMK1 knockdown suppresses OGD/R-induced Fas system activation and apoptosis. The RhoA/ROCK/LIMK1-Fas axis is a potential target of ginsenoside Rb1 in cochlear I/R-like injury.
Capecitabine (Cap) is widely used in the treatment of advanced gastric cancer; however, the emergence of acquired resistance remains a major obstacle to its long-term efficacy. Although several gastric cancer models resistant to 5-fluorouracil (5-FU) have been reported, experimentally characterized gastric cancer models of Cap resistance remain limited. This study aimed to establish and characterize a Cap-resistant MKN-45 gastric cancer cell model. with a focus on phenotypic alterations associated with acquired drug adaptation. A Cap-resistant MKN-45 subline (MKN-45/R-CapIC₆₀) was generated through exposure of parental MKN-45 cells to gradually increasing concentrations of Cap. Cell viability was evaluated using the MTT assay. Morphological alterations were examined by phase-contrast microscopy, while apoptosis, cell-cycle distribution, and surface c-Met expression were analyzed by flow cytometry. The established resistant subline exhibited a moderate level of Cap resistance, with an approximately 2- to 4-fold increase in the resistance index (RI) compared with the parental cells. Resistant cells showed morphological remodeling characterized by an elongated spindle-like morphology and increased adherence to the culture surface compared with parental cells. Surface c-Met expression was altered in resistant cells and further decreased following Cap exposure. Despite the acquisition of a resistance phenotype, Cap exposure retained biological activity in resistant cells by reducing proliferation, altering cell-cycle distribution through impaired G1/S transition, and increasing late apoptotic/necrotic populations. The findings suggest that the established Cap-resistant gastric cancer cell model retains responsiveness to Cap exposure despite the acquisition of a resistance phenotype. This model may provide a useful platform for investigating early phenotypic adaptations associated with the development of drug resistance in gastric cancer.
The emergence of antifungal resistance among Candida albicans strains poses a growing clinical challenge, underscoring the urgent need for alternative therapeutic strategies. Drug repositioning of non-steroidal anti-inflammatory drugs (NSAIDs) has attracted attention due to their reported antimicrobial properties and well-established safety profiles. This study aimed to synthesize and characterize water-soluble sodium salts of ibuprofen (IBU-Na), ketoprofen (KET-Na), and indomethacin (IM-Na), and to evaluate their antifungal activity and toxicity profiles, individually and in combination with fluconazole (FLU), against C. albicans strains. NSAID sodium salts were synthesized and characterized, and their antifungal activity, synergistic interactions with FLU, and toxicity profiles were evaluated against FLU-susceptible and -resistant C. albicans strains. IBU-Na and KET-Na exhibited inhibitory and fungicidal activities against both FLU-susceptible and -resistant C. albicans strains, whereas IM-Na was inactive. Combination assays revealed strong synergistic interactions with FLU (FICI = 0.008–0.009), resulting in marked reductions in fungal viability. Neither hemolytic activity nor genotoxic effects were detected at the tested concentrations. Water-soluble NSAID salts, particularly IBU-Na, demonstrate potent synergistic antifungal activity with FLU and favorable safety profiles, supporting their potential as candidates for antifungal drug repurposing. These findings emphasize the importance of reassessing sodium salt derivatives rather than assuming equivalence with their acidic precursors.
Diabetic nephropathy (DN) is a leading cause of end-stage renal disease, with proximal tubular injury and oxidative stress playing pivotal roles in its progression. The AMPK–Nrf2 signaling axis is a key regulator of antioxidant defense, but its modulation by Aloin in DN-relevant renal models remains insufficiently characterized. Aloin, a natural anthraquinone glycoside from Aloe species, exhibits antioxidant, anti-inflammatory, and anti-fibrotic properties in non-renal systems. This study investigated whether Aloin protects renal cells from high-glucose–induced injury and whether AMPK and Nrf2 contribute to these protective responses. Human renal proximal tubular epithelial cells (HK-2) and human renal glomerular endothelial cells (HRGECs) were exposed to high glucose (HG, 30 mM) for 48 h with or without Aloin (25 or 50 µM). Functional assays included CCK-8 cell viability, colony formation, and wound healing migration analysis. mRNA expression of oxidative stress–related, inflammatory, fibrotic, and phenotype-associated markers, including VIM and CDH1, was quantified by reverse transcription–quantitative polymerase chain reaction (RT-qPCR). siRNA-mediated knockdown of PRKAA1 (AMPK) or NFE2L2 (Nrf2) was performed to assess mechanistic involvement, with gene silencing confirmed by RT-qPCR and Western blotting. For exploratory in vivo validation, male db/db mice received oral Aloin at 25 mg/kg/day for 8 weeks, while age-matched db/m and db/db mice received vehicle (n = 6 per group). HG exposure reduced proliferation and clonogenic capacity while increasing wound closure under serum-free conditions in both HK-2 cells and HRGECs, accompanied by upregulation of TNF, CCL2, TGFB1, COL1A1, and VIM, and downregulation of NFE2L2, SOD1, PRKAA1, and CDH1. Aloin treatment dose-dependently restored proliferation, reduced migration, and normalized gene expression patterns, with 50 µM producing near-complete reversal toward normal glucose controls. PRKAA1 knockdown in HK-2 cells and NFE2L2 knockdown in HRGECs substantially attenuated Aloin-associated protective responses, supporting the functional involvement of AMPK and Nrf2 in these cell-specific effects. Aloin attenuated high-glucose-induced injury in cultured renal tubular epithelial and glomerular endothelial cells, with loss-of-function experiments supporting the involvement of AMPK and Nrf2 in these responses. Exploratory validation in db/db mice further showed reductions in albuminuria, serum creatinine, and mesangial matrix expansion, accompanied by restoration of renal AMPK–Nrf2 signaling. However, the 25 and 50 µM concentrations used in vitro cannot be directly equated with the 25 mg/kg/day oral dose used in mice, and plasma exposure, renal tissue concentrations, pharmacokinetics, and systemic safety were not determined. Additional pharmacokinetic, dose-ranging, and toxicological studies are required before the therapeutic relevance of Aloin can be established.
Trehalose is a promising therapeutic candidate for Alzheimer’s disease (AD) that is known to induce autophagy and facilitate misfolded proteins clearance such as amyloid-β and hyperphosphorylated tau. Despite there is emerging evidence that trehalose has a wider range of molecular mechanisms and thus has a greater neuroprotective profile. To summarize the emerging molecular mechanisms underlying the neuroprotective effects of trehalose beyond classical autophagy and discuss its therapeutic potential in AD. Published evidence from preclinical studies including in-vitro and in-vivo models, along with hypothetical and emerging findings from early clinical investigations was reviewed to evaluate the molecular mechanisms, therapeutic effects, and translational challenges associated with trehalose in AD. In addition to classical autophagy signalling, recent studies have demonstrated that autophagy can also regulate the stability of neuronal membrane microdomains, prevent lipid bilayers disruption by amyloid proteins, and regulate stress granules dynamics that affect the function of RNA-binding proteins. Other discoveries indicate that interactions with nutrient-sensing pathways and glucose transporter systems that simulate metabolic stress, which may activate protective mechanisms separate from the inhibition of mTOR. Trehalose could also involve in lysosomal-autophagosome fusion and modulate the microglia and astrocytes activation, suggesting an important immunometabolic function. Trehalose often connects to the gut-brain axis and show their effect in gut microbiota composition, microbial metabolite signalling and gut barrier function. These effects can influence systemic inflammation, availability of short-chain fatty acids, bile acid profiles and vagus-mediated gut-to-brain communication, all of which can influence neuroinflammation networks in AD. Although promising results have been reported, primarily from preclinical studies, with early human investigations now beginning to emerge, opportunities remain to address, such as poor oral bioavailability, penetration into the brain and long-term safety in elderly patients. Mechanistic dissection in multi-omics approaches, microbiome-stratified models and early-phase clinical testing are the areas that need to be targeted in future research. A broader understanding of the mechanisms of action of trehalose provides a good chance to reimagine its therapeutic implications and develop novel approaches to AD.
Anticoagulant knowledge, medication adherence, time in therapeutic range (TTR), and potential drug–drug interactions (pDDIs) are poorly understood, but they can increase the risk of thromboembolic events, major bleeding, and mortality. This study examined the relationship between oral anticoagulation knowledge and adherence in adults on long-term warfarin therapy, and their associations with TTR, clinical and demographic factors, bleeding risk, and pDDIs. This cross-sectional study included adults on chronic warfarin therapy at a university-affiliated cardiology clinic. Turkish versions of the validated Oral Anticoagulation Knowledge (OAK) and Anticoagulant Therapy Adherence Scale (ATAS) assessed oral anticoagulation knowledge and adherence. Clinical, laboratory, and treatment data were obtained from health records, and lifestyle information via patient interviews. pDDIs were evaluated using UpToDate® and Micromedex®. TTR was calculated using the Roosendaal method, and bleeding risk was assessed using the ATRIA score. The study included 126 adults on warfarin therapy, with a median TTR of 31.9
Vaccine adjuvants enhance immune responses to weak antigens. Natural compounds such as glycyrrhizin and glucomannan show immunomodulatory potential, but their combined effects on human cytokine expression as an adjuvant remain unclear. To evaluate the immunomodulatory effects of glucomannan (GA) from Amorphophallus konjac and glycyrrhizin (GL) from Glycyrrhiza glabra on cytokine gene expression in human peripheral blood mononuclear cells (PBMCs), assessing their potential to promote Th1 polarization as candidate vaccine adjuvants. PBMCs isolated from ten healthy donors were treated with GA and GL at 25 and 50 µg/mL, either individually or in combination. Cell viability was assessed using the MTT assay. Gene expression levels of pro-inflammatory cytokines (IL-6, TNF-α), the Th1 cytokine (IFN-γ), and Th2/regulatory cytokines (IL-10, TGF-β) were quantified using RT-qPCR. GA and GL significantly increased IL-6, TNF-α, and IFN-γ expression in a dose-dependent manner (p < 0.05 to p < 0.001), while significantly reducing IL-10 and TGF-β expression compared with the control group (p < 0.05 to p < 0.001). The combined treatment produced the strongest immunomodulatory response, characterized by enhanced expression of pro-inflammatory and Th1-associated cytokines and greater suppression of Th2/regulatory cytokines relative to individual treatments (p < 0.001). The MTT assay identified 25 and 50 µg/mL as safe and effective GA concentrations for subsequent experiments, based on cell proliferation and cytotoxicity assessments. In human PBMCs, GA and GL promote a Th1-biased cytokine response at the mRNA expression level under in vitro conditions, suggesting their implications for vaccine adjuvant development. However, these results are limited to in vitro gene expression data and have not been validated at the protein level, a gap that warrants further investigation.
To critically synthesize current mechanistic and clinical evidence on the role of hepatic stellate cells (HSCs) in alcoholic liver cirrhosis, with emphasis on fibrogenesis, cellular plasticity, fibrosis regression, and emerging diagnostic implications. A narrative review of literature was conducted using PubMed, Scopus, and Web of Science to identify relevant studies on hepatic stellate cells and their role in liver cirrhosis, with emphasis on recent mechanistic and translational research. HSCs are central mediators of fibrogenesis in alcoholic liver disease, contributing to extracellular matrix remodeling, immune signaling, and vascular alterations. Emerging evidence highlights the dynamic and potentially reversible nature of HSC activation, with distinct roles for apoptosis, senescence, and inactivation pathways. Recent studies also emphasize the influence of metabolic stress, gut–liver axis interactions, and micronutrient imbalances on HSC behavior. These insights support the development of targeted antifibrotic strategies and biomarker-driven approaches for disease monitoring. HSCs are central drivers of fibrogenesis, vascular remodeling, and immune metabolic crosstalk in alcoholic liver cirrhosis. Integrating HSC-focused molecular profiling with non-invasive diagnostics and robust clinical endpoints is essential for the development of effective antifibrotic strategies.
Systemic sclerosis (SSc) is driven by persistent inflammation and microvascular damage. Statins are hypothesized to offer vasculoprotective effects beyond lipid-lowering. We systematically evaluated the efficacy and safety of statins in SSc across biochemical, vascular, and patient-centred outcomes. Following PRISMA guidelines, a systematic search of four electronic databases was conducted up to August 2025. Ten studies involving 323 patients were included. Pooled estimates were calculated using a random-effects model. Heterogeneity and sensitivity analyses were performed, and study quality was assessed using standardized appraisal tools. Statin therapy was associated with significant biochemical improvements. Compared with baseline or placebo, CRP decreased by an average of 0.70 mg/L, IL-6 by 5.56 pg/mL, and fibrinogen by 40 mg/dL. Endothelial markers showed similar reductions: 0.85 pg/mL for ET-1, 23.17 IU/dL for vWF, and 25 ng/mL for ICAM-1. Total cholesterol and LDL decreased by mean differences of 0.93 mmol/L and 0.76 mmol/L, respectively, while HDL showed no meaningful change. Statins improve inflammatory and endothelial pathways in systemic sclerosis, but these findings should be interpreted cautiously, as clinical benefits remain minimal. Randomized trials are required to further study statins’ therapeutic role beyond biochemical modulation.
Poor aqueous solubility and low permeability limit the oral bioavailability of Nilotinib, a second-generation tyrosine kinase inhibitor used in chronic myeloid leukemia. Nanosponges prepared using cyclodextrin derivatives offer a scalable and efficient platform for enhancing solubility, controlling release, and improving bioavailability. Therefore, this study aimed to formulate Nilotinib-loaded hydroxypropyl β-cyclodextrin nanosponges to enhance oral absorption. Hydroxypropyl β-cyclodextrin nanosponges were synthesized using diphenyl carbonate as a cross-linker. Box–Behnken Design, under a Quality-by-Design framework, was applied to optimize critical parameters including mixing speed, reaction time, and molar ratio. The optimized formulation was characterized for particle size, zeta potential, entrapment efficiency, morphology, compatibility, drug release, permeability, and pharmacokinetic performance in rats. The optimized nanosponges showed a particle size of 203.1 ± 3.1 nm, zeta potential of − 24.0 ± 2.55 mV, and entrapment efficiency of 66.88 ± 2.66
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are established therapies across the cardiovascular–renal continuum. Although the excess risk of external genital infection is well recognized, the association between SGLT2 inhibition and urinary tract infection (UTI), particularly serious/complicated urinary infection, remains uncertain. We conducted a systematic review and meta-analysis of randomized placebo-controlled trials of empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, and bexagliflozin in adults with type 2 diabetes, chronic kidney disease, or heart failure. Co-primary urinary safety outcomes were any UTI and serious/complicated urinary infection, the latter defined using directly reported serious UTI endpoints or the closest reported severe urinary phenotype. Sensitivity analysis, subgroup analyses by drug and population, leave-one-out analyses, and exploratory meta-regression were performed. A total of 14 studies were included. For the primary any-UTI analysis, 11 studies contributed data, comprising 62,542 participants and 4,685 events. SGLT2 inhibitors were associated with a pooled RR of 1.14 (95
Exosome-mediated delivery of small interfering RNA (siRNA) has emerged as a promising therapeutic strategy for cancer treatment, offering precise gene silencing with minimal off-target effects. Exosomes, naturally secreted extracellular vesicles, provide biocompatible carriers that protect siRNA from enzymatic degradation and facilitate efficient uptake by tumor cells. Their natural tropism, driven by surface proteins such as integrins and tetraspanins, promotes cellular adhesion and interactions within the tumor microenvironment, facilitating the delivery of therapeutic cargo. Preclinical studies have demonstrated that exosome-delivered siRNAs can suppress oncogenes, inhibit tumor growth, reverse chemoresistance, and modulate immune responses by targeting stromal and immune components. Engineering approaches, including surface functionalization and hybrid exosome–nanoparticle systems, further enhance stability, payload capacity, and tumor-homing efficiency. Combination strategies with chemotherapy, immunotherapy, or phototherapy have shown synergistic effects, allowing simultaneous inhibition of survival pathways, promotion of apoptosis, and remodeling of the immunosuppressive microenvironment. Early-phase clinical studies indicate safety, effective biodistribution, and functional gene silencing, highlighting the translational potential of exosome-mediated siRNA therapeutics. Challenges such as scalable production, cargo heterogeneity, and regulatory considerations remain, but ongoing advances in exosome engineering and patient-derived vesicles are poised to overcome these barriers. This review aims to comprehensively summarize the current state, therapeutic applications, and translational prospects of exosome-mediated siRNA delivery in cancer.
Isoquercitrin (ISO), a neuroprotective flavonoid, alleviates ischemic stroke (IS) by inhibiting ferroptosis. In present study, we explored the mechanism of ISO attenuates neuronal ferroptosis in IS. HT22 cells and primary neurons underwent oxygen-glucose deprivation/reoxygenation (OGD/R) to mimic in vitro IS. Dual‑luciferase reporter assays detected luciferase activity. H3K9 acetylation levels at the RBM15 promoter were assessed by ChIP. The m6A modification of SLC25A28 mRNA was analyzed by MeRIP. The binding of RBM15 and IGF2BP3 to SLC25A28 mRNA was examined via RIP. Lipid and intracellular ROS levels were measured by C11-BODIPY and DCFH-DA staining. The levels of ferroptosis-related indicators were determined with commercial kits. Cell viability was examined using the CCK-8 assay. In vivo, the middle cerebral artery occlusion (MCAO) rat model was used to explore the effect of ISO. ISO protected against OGD/R-induced ferroptosis and restored viability. ISO inhibited neuronal ferroptosis by reducing RBM15 expression. ISO suppressed RBM15 via SIRT1-mediated H3K9 deacetylation. Subsequently, RBM15 promoted m6A modification of SLC25A28 mRNA to enhance its stability. Reversal of ISO-mediated ferroptosis suppression by SLC25A28 overexpression was partly counteracted by RBM15 knockdown. In the MCAO model, ISO reduced infarct volume, lowered MDA levels, and restored GPX4 expression, which were partly reversed by RBM15 overexpression. ISO promoted SIRT1-mediated H3K9 deacetylation at the RBM15 promoter to suppress its transcription. RBM15 downregulation inhibited SLC25A28 stability by m6A-IGF2BP3-dependent, ultimately attenuating neuronal ferroptosis in IS.
Conjunctivitis is the most prevalent ocular disorder and characterized by irritation, swelling and inflammation of the conjunctiva. Fluoroquinolones are the most promising classes of antibiotics and among them; ciprofloxacin (CFX) is used to treat conjunctivitis. To provide a controlled-release approach for extended antibacterial action, CFX-loaded thiolated gum ghatti (TGG) nanoparticles were developed to overcome the drawbacks of traditional eye medications (rapid elimination, low bioavailability). Gum ghatti (GG) was thiolated with 3-mercaptopropionic acid (3-MPA) to enhance the mucoadhesion. The nanoprecipitation technique was applied to produce nanoparticles of TGG loaded with CFX. Particle size, zeta potential, FTIR, DSC, TGA, and XRD were employed to characterize GG, TGG, and nanoparticles. Permeation, mucoadhesion, ocular irritation and pharmacokinetics were performed. TGG and nanoparticles contained 0.09 and 0.13 mmoL of thiol groups/mg of polymer, respectively. Nanoparticles showed a diameter of < 200 nm and PDI of < 0.3, and showed improved CFX penetration by 80
Ovarian cancer remains a major clinical challenge, largely because many patients eventually develop resistance to cisplatin. In this study, gold nanoparticles (AuNPs) were synthesized using Artemisia chamaemelifolia extract through a green chemistry approach, and their antiproliferative activity was evaluated in cisplatin-resistant A2780cp ovarian cancer cells. The aqueous extract of the plant was used as both the reducing and stabilizing agent during nanoparticle formation. The synthesized AuNPs were characterized using UV–Vis spectroscopy, FTIR, FESEM, TEM, and DLS. Cytotoxic effects were assessed using the MTT assay, while apoptosis was evaluated by Annexin V/PI flow cytometry. Changes in the expression of BAX, BCL-2, TP53, and CCND1 were assessed by RT-qPCR. HEK293 cells were included as a comparator cell line for cytotoxicity. UV–Vis spectroscopy showed a surface plasmon resonance peak near 530 nm, confirming nanoparticle formation. FESEM and TEM analyses revealed well-dispersed nanoparticles with predominantly spherical to slightly cubic morphology, an average size of 15.13 nm, and a relatively narrow size distribution. The MTT assay demonstrated dose-dependent cytotoxicity, with an IC₅₀ of 38.83 µg/mL(95
Breast cancer remains a leading cause of cancer-related mortality among women, with prolonged exposure to endogenous estrogens recognized as a major risk factor. This study aimed to design, synthesize, and pharmacologically evaluate novel 3,3′-diindolylmethane (DIM) derivatives as multi-target modulators of estrogen-related pathways in breast cancer. A series of DIM derivatives was synthesized and structurally characterized. Their biological activities were assessed through aromatase (CYP19A1) and CYP1B1 inhibition assays, E-screen assay for estrogen receptor activity, cytotoxicity assays in breast cancer (MCF-7 BUS, MDA-MB-231) and normal breast epithelial (MCF-10 A) cells, and scratch assay for cell migration. Molecular docking and in silico ADME analyses were conducted to support experimental findings. The derivatives demonstrated significant antiestrogenic activity by targeting multiple components of estrogen signaling. One compound exhibited potent aromatase inhibition (IC₅₀ = 0.79 µM), while two derivatives showed strong CYP1B1 inhibition (IC₅₀ = 0.37 µM and 0.71 µM). Selective cytotoxicity was observed in estrogen receptor-positive cells, with reduced effects on normal cells. Additionally, selected compounds significantly inhibited cell migration. Molecular modeling revealed favorable binding interactions within target enzymes, and ADME analysis indicated acceptable drug-like properties. These findings suggest that DIM derivatives act as selective, multi-target modulators of estrogen-related pathways and may serve as promising adjuvant candidates for hormone-dependent breast cancer therapy.
The PAOLA-1 trial demonstrated that olaparib plus bevacizumab (OB) significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to bevacizumab monotherapy (BM) as first-line maintenance therapy for patients with advanced ovarian cancer (AOC) who had homologous recombination deficiency (HRD)-positive status at high risk of disease progression (HRisk-HRD+), including both the breast cancer susceptibility gene mutated (BRCAm) subgroup and the BRCA wild-type (BRCAwt) subgroup. This study aimed to assess its cost-effectiveness from the perspective of the Chinese healthcare system. A state-transition Markov model over a 20-year lifetime horizon was developed to evaluate the cost-effectiveness of OB compared to BM. The willingness-to-pay (WTP) thresholds were set at 1 to 3 times the gross domestic product per capita of China in 2024 (13444.68 to40334.05/QALY). The primary outcomes included total costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). Subgroup analysis, sensitivity analysis and scenario analyses were performed to validate the robustness of the study. Compared with BM, the ICERs of OB were 10806.70/QALY,10478.80/QALY and 25114.44/QALY in the HRisk-HRD+ population, BRCAm subgroup and BRCAwt subgroup, respectively. OB demonstrated potential cost-effectiveness for patients with HRisk-HRD+ AOC, particularly those with a BRCA mutation. One-way sensitivity analysis indicated that the discount rate and the price of olaparib were the primary factors influencing the ICER. The results of the probabilistic sensitivity analysis and scenario analysis were generally consistent with those of the base-case analysis. Compared to BM, OB demonstrated superior cost-effectiveness as first-line maintenance therapy for patients with HRisk-HRD+ AOC, particularly those with a BRCA mutation in China.
