Type 2 diabetes mellitus (T2DM) is a major global health problem for which a wide range of antidiabetic medications are available. Adverse effects of antidiabetic medications may negatively affect patients’ health and treatment adherence. In Egypt, limited data are available regarding the adverse-effect profiles of antidiabetic agents. This study aimed to compare safety profiles, treatment-related adverse effects, and diabetes-related complications associated with commonly prescribed antidiabetic medications. A multicenter, cross-sectional observational study was conducted across diabetes outpatient clinics in Egypt from February 2024 to May 2024. Adult patients with type 2 diabetes on antidiabetic regimens were enrolled. Data was collected through medical records and patient interviews, including demographics, clinical history, laboratory results, diabetes complications, and treatment-related adverse events. Univariate logistic regression analyses were performed to assess the associations between antidiabetic medications and diabetes-related complications and adverse outcomes. Unadjusted odds ratios (ORs) with 95
Arsenic (AR) is an environmental and mining occupational toxicant with reported hepatotoxic effects. Ferroptosis has recently emerged as a critical mechanism involved in arsenic-induced hepatotoxicity. This study investigated the hepatoprotective effects of puerarin (PU) and its PLGA-loaded nanoparticle formulation (PU-PLGA) against arsenic-induced liver injury in rats, with particular emphasis on ferroptosis pathways modulation. Sixty adult male Sprague–Dawley rats were randomly assigned into six groups: control, PU, PU-PLGA, arsenic (AR), AR + PU, and AR + PU-PLGA. Subacute hepatotoxicity was induced by oral administration of arsenic (10 mg/kg) for 14 days. Oxidative stress, ferroptosis-related biomarkers, inflammatory mediators, apoptotic markers, fibrotic indicators, DNA damage, histopathological alterations, and ultrastructural changes were evaluated. Arsenic exposure induced marked hepatic injury characterized by Fe²⁺ accumulation, increased lipid peroxidation markers (MDA and 4-HNE), upregulation of ACSL4, and suppression of GPX4 and SLC7A11, indicating enhanced ferroptotic activity. These alterations were accompanied by oxidative stress, inflammatory activation (NF-κB, TNF-α, IL-6, IL-1β, and COX-2), apoptotic signaling (Bax and caspase-3), DNA damage (8-OHdG and DNA fragmentation), and fibrotic responses (TGF-β and collagen I). Treatment with PU and PU-PLGA significantly attenuated arsenic-induced hepatic injury by reducing iron accumulation and lipid peroxidation, restoring GPX4 and SLC7A11 expression, and suppressing ACSL4 upregulation. Notably, PU-PLGA demonstrated greater efficacy than free PU in modulating ferroptosis-related biomarkers, restoring antioxidant and survival signaling (Nrf2, p-AKT, and Bcl-2), and improving hepatic histopathological and ultrastructural integrity. P PU-PLGA nanoparticles exerted potent hepatoprotective effects against arsenic-induced liver injury, associated with modulation of ferroptosis-related pathways, oxidative stress, inflammatory responses, apoptosis-associated signaling, and profibrotic alterations. These findings highlight PU-PLGA as a promising nanotherapeutic strategy for arsenic-associated hepatotoxicity, although further mechanistic and translational validation is warranted.
Abstract Background Parenteral vancomycin is essential for the treatment of certain gram-positive infections but is associated with acute kidney injury (AKI). The 2020 IDSA guideline recommends AUC 24 -based dosing for MRSA to increase treatment safety. Due to the low MRSA prevalence at the University Hospital of Würzburg (UKW), this study investigated the impact of model-informed precision dosing (MIPD) of vancomycin on AKI incidence and target attainment in MRSA and non-MRSA infections. Methods This pre-post intervention study compared a retrospective group (January 1, 2019 - June 30, 2021) with a prospective group (October 17, 2022 - December 31, 2023), including critically ill patients from intensive and intermediate care units. The prospective group received AUC 24 -based MIPD using Bayesian pharmacometric modeling performed by a clinical pharmacist. The primary outcome was the incidence of AKI. Secondary outcomes included vancomycin therapeutic target attainment and the proportions of therapies within, below, and above the therapeutic range. Results AKI occurred in 27.8% of the retrospective group and 14.0% of the prospective group ( p = 0.04). The AUC-based group achieved therapeutic targets more frequently (70.2% vs. 55.1%, p = 0.049) and had fewer supratherapeutic levels (8.8% vs. 24.5%, p = 0.01). Conclusions AUC 24 -based MIPD for vancomycin improved therapeutic target attainment and was associated with a lower observed incidence of AKI. These findings support further evaluation of AUC-guided dosing for both MRSA and non-MRSA infections.
Synthetic musk ketone (MK) is extensively used in perfumes, cosmetics, and detergents. Due to its high lipophilicity, persistence, and limited removal efficiency in wastewater treatment, MK has been detected in various environmental matrices and human tissues. However, the ecotoxicity of MK remains poorly characterized. This study aimed to systematically evaluate the toxicological effects of MK and elucidate its underlying mechanisms using Caenorhabditis elegans (C. elegans) as a model organism. Wild-type C. elegans (strain N2) were exposed to MK at concentrations ranging from 0.4 to 20 mg/L for 24 h. Physiological endpoints including body size, locomotor activity, lifespan, and brood size were assessed. Biochemical markers comprising reactive oxygen species (ROS) levels and lipofuscin accumulation were quantified. Acute heat-stress tolerance was evaluated to assess stress resistance. Transcriptome sequencing (RNA-seq) and quantitative real-time PCR (qRT-PCR) were employed to investigate molecular mechanisms. Differential gene expression analysis was performed using DESeq2, and functional enrichment analyses were conducted for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. MK exposure significantly and concentration-dependently reduced body length and width, locomotor activity (head thrash and body bend frequencies), brood size, and lifespan. Lipofuscin accumulation and intracellular ROS levels were markedly elevated. Acute heat-stress tolerance was significantly impaired. Transcriptomic analysis identified 159 differentially expressed genes (DEGs) at 2 mg/L MK (19 up-regulated, 140 down-regulated) and 136 DEGs at 20 mg/L MK (30 up-regulated, 106 down-regulated). Key DEGs included ugt-30 (detoxification), Y9C9A.16 (oxidation-reduction), msp-59 (spermatogenesis), and acdh-8 (lipid metabolism). GO enrichment revealed significant alterations in spermatogenesis, protein catabolism, and kinase activity. KEGG pathway analysis identified perturbations in sulfur metabolism, branched-chain amino acid metabolism, fatty acid metabolism, and apoptosis. Protein-protein interaction network analysis identified cyc-2.2 and acdh-8 as hub genes. MK exposure induces multi-faceted toxicity in C. elegans, including developmental impairment, neurotoxicity, reproductive toxicity, accelerated aging, and diminished stress resilience. These adverse outcomes are strongly associated with oxidative stress, germline impairment, and disrupted lipid metabolism, suggesting that these pathways play central roles in MK-induced toxicity. Our findings indicate that environmental exposure to MK may pose significant toxicological risks to living organisms and warrant further assessment of its ecological and health impacts.
Diabetic hepatopathy is a major complication of type 2 diabetes mellitus characterized by metabolic dysregulation, oxidative stress, inflammation, and emerging evidence of ferroptosis-mediated liver injury. Icariin (IC), a bioactive flavonoid, exhibits hepatoprotective potential; however, its clinical applicability is limited by poor bioavailability. Liposomal nanoformulation represents a potential approach to modify IC delivery and enhance its pharmacological efficacy. Ninety rats were randomly assigned to six groups (n = 15/group): Control, IC, IC-LNPs, NA–STZ, NA–STZ + IC, and NA–STZ + IC-LNPs. Type 2 diabetes was induced by nicotinamide (120 mg/kg, i.p.) followed 15 min later by streptozotocin (60 mg/kg, i.p.). Five days after diabetes confirmation, diabetic treatment groups received IC or IC-LNPs at an IC-equivalent dose of 80 mg/kg/day, i.p., for eight consecutive weeks. Hepatic injury was assessed through biochemical parameters, oxidative stress markers, inflammatory cytokines, ferroptosis-related markers, and histopathological and ultrastructural analyses. NA–STZ administration induced significant metabolic dysfunction, including hyperglycemia, insulin depletion, dyslipidemia, weight loss, and elevated hepatic enzyme levels. IC treatment significantly improved these parameters, while IC-LNPs produced a more pronounced protective effect. Diabetic induction was associated with reduced hepatic NRF2 and HO-1 levels, accompanied by reduced levels of GSH, SOD, CAT, and GPX, and increased oxidative stress markers (MDA and H₂O₂). IC-LNPs more effectively restored antioxidant defenses and redox homeostasis than free IC. Moreover, NA–STZ increased NF-κB and COX-2 expression and the inflammatory mediators TNF-α, IL-6, and IL-1β, which were markedly reduced by IC-LNP treatment. Importantly, diabetic hepatopathy was associated with alterations in ferroptosis-related markers, evidenced by iron accumulation (Fe²⁺), upregulation of ACSL4 and TFR1, and downregulation of GPX4 and SLC7A11. IC-LNPs significantly attenuated these alterations, consistent with modulation of ferroptosis-related processes. Histopathological and ultrastructural analyses confirmed severe hepatic damage in diabetic rats, whereas IC-LNPs markedly preserved hepatic architecture. IC-LNPs provided greater protection than free IC against NA–STZ-induced diabetic hepatopathy, associated with attenuation of oxidative stress and inflammation and modulation of NRF2/HO-1, NF-κB/COX-2, and ferroptosis-related markers. These findings support the potential of liposomal IC as a preclinical approach for diabetic liver injury; however, pharmacokinetic, biodistribution, safety, and further mechanistic studies are required before its therapeutic or translational potential can be established.
