Methotrexate (MTX) is a widely used chemotherapeutic and immunosuppressive agent, but its clinical utility is limited by oxidative stress-mediated renal toxicity. This study evaluated the nephroprotective potential of the dietary polyphenolic bioactive molecule piceatannol (PIC) in its crude and liposomal nanoparticle (PIC-LNP) forms against MTX-induced kidney injury in rats. Sixty rats were allocated into six groups and received vehicle, PIC, PIC-LNPs, MTX, or combinations of MTX with PIC or PIC-LNPs. MTX administration induced marked renal dysfunction and oxidative/nitrosative stress, reflected by elevated serum urea, creatinine, and uric acid, together with increased renal ROS, MDA, protein carbonyls, 8-OHdG, and nitric oxide, in parallel with suppression of the Nrf2/HO-1 antioxidant pathway. These disturbances were accompanied by activation of TLR4/NF-κB and MAPK signaling, upregulation of pro-inflammatory cytokines, and a shift toward apoptosis, as evidenced by increased Bax and caspase-3 and reduced Bcl-2 expression. Histological and ultrastructural analyses confirmed extensive glomerular and tubular damage with mitochondrial disruption and cytoplasmic vacuolations. PIC treatment attenuated these MTX-induced alterations, whereas the liposomal formulation conferred superior protection. PIC-LNPs restored Nrf2/HO-1 signaling, enhanced endogenous antioxidant defenses, reduced oxidative/nitrosative and inflammatory responses, and normalized apoptotic markers, accompanied by substantial preservation of renal architecture and cellular integrity. Immunohistochemistry demonstrated strong Nrf2 expression with minimal NF-κB activation in the PIC-LNP group. Collectively, these findings highlight liposomal piceatannol as a promising bioactive-molecule-based strategy for controlling oxidative stress and mitigating chemotherapy-associated oxidative-stress-related renal injury.

Methotrexate (MTX) is widely used for its chemotherapeutic and immunosuppressive properties, but is limited by oxidative stress-mediated hepatotoxicity. Nanoantioxidant delivery systems can enhance the stability, solubility, and in vivo efficacy of natural antioxidants. This study investigated the hepatoprotective effects of myricetin (MYR), a flavonoid with potent antioxidant activity, and its liposomal nanoantioxidant formulation (MYR-loaded liposomal nanoparticles, MYR-LNPs) against MTX-induced liver injury in male albino Sprague Dawley rats. Sixty rats were randomly allocated to six groups: control, MTX, MYR, MYR-LNPs, and combinations of MTX with MYR-LNPs. MYR-LNPs were successfully formulated and physicochemically characterized, exhibiting a mean particle size of 95.6 nm, a zeta potential of −32 mV, and a narrow polydispersity index, collectively confirming their colloidal stability and suitability for hepatic delivery. MTX markedly disrupted liver function, increasing serum AST, ALT, ALP, and bilirubin and decreasing total protein, albumin, and globulin, whereas co-treatment with MYR-LNPs substantially restored these parameters and outperformed free MYR. MTX-induced oxidative stress, reflected by depleted hepatic GSH and antioxidant enzymes (GPx, SOD, CAT, GST), elevated reactive oxygen species (ROS), malondialdehyde (MDA), and protein carbonyls and downregulated NRF2/HO-1, was significantly counteracted by MYR-LNPs. In addition, MYR-LNPs mitigated MTX-evoked inflammation and nitrosative stress by reducing NF-κB, TNF-α, IL-1β, nitric oxide, and iNOS expression. They corrected apoptotic imbalance by lowering Bax and caspase 3 while increasing Bcl-2. Histopathological and ultrastructural assessments confirmed that MYR-LNPs preserved hepatic architecture and mitochondrial integrity. These findings indicate that MYR-loaded liposomal nanoantioxidants provide superior protection against MTX-induced hepatotoxicity by modulating oxidative stress, inflammation, and apoptosis, supporting their potential as an advanced nanodrug delivery strategy for antioxidant therapy.

Background and Objectives: Thyroid dysfunction and dysglycemia often coexist, but cross-sectional associations may reflect the populations sampled rather than a graded biochemical relationship. We compared the glycemic profile of adults with abnormal thyroid function tests with that of a euthyroid comparison group and examined whether thyrotropin (TSH), free thyroxine (FT4) and free triiodothyronine (FT3) were associated with glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG) within groups. Materials and Methods: This cross-sectional study included 331 adults from Jazan, Saudi Arabia: 230 with abnormal thyroid function tests from three hospital laboratories and 101 patients selected for normal thyroid function tests and normal glucose values. Participants were classified by TSH as euthyroid (n = 102), hyperthyroid pattern (n = 56) or hypothyroid pattern (n = 173). Spearman correlations, Kruskal–Wallis tests and robust linear regression were used, with multiple-imputation, threshold, restriction and sex-stratified sensitivity analyses. Results: In the whole cohort, TSH correlated with HbA1c (ρ = 0.59) and FPG (ρ = 0.63; both p < 0.001); median HbA1c was 5.1%, 5.8% and 6.6% in the euthyroid, hyperthyroid pattern and hypothyroid pattern groups. Within the hypothyroid pattern group, TSH was unrelated to HbA1c (ρ = 0.00) and FPG (ρ = 0.07), and overt and subclinical patterns had the same median HbA1c (6.6%). Thyroid function group alone explained 46% of HbA1c variance; continuous thyroid parameters, age, sex and body mass index explained 18%. Conclusions: The between-group differences and pooled correlations reflect a two-source design in which the comparison group was selected for normal glucose values. No graded relationship between thyroid function and glycemia was detectable within groups, and causal or directional inference is not supported.

Background/Objectives: Thyroid hormone regulates erythropoiesis, but most population studies have used thyrotropin (TSH) alone and have not examined whether the erythroid association differs by red cell phenotype. We examined this in a population where inherited microcytosis and iron deficiency are both common. Methods: We analyzed 3871 adults of both sexes with paired free triiodothyronine (FT3), free thyroxine, TSH, and complete blood count from three hospitals in Jazan, Saudi Arabia (3673 with FT3 within the reference interval formed the primary analysis). All three analytes were entered simultaneously in models adjusted for age and sex; mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) were pre-specified comparison (negative control) outcomes; red cell discriminant indices were used to assign a normocytic, acquired microcytic, or presumed inherited-trait pattern, which was compared against linked ferritin and transferrin saturation. Results: FT3 was associated with erythrocyte count (standardized β 0.097, 95% confidence interval (CI) 0.066–0.128, p < 0.001) and hemoglobin (+2.7 g/L per pmol/L); TSH was not (p = 0.547). The erythrocyte count association was present in normocytic (β 0.101) and acquired microcytic records (β 0.099) but absent in the presumed trait pattern (β −0.017; interaction p = 0.002) and remained absent under a stricter trait definition, whereas the hemoglobin association did not differ by phenotype (interaction p = 0.639). FT3 was unrelated to iron status, and the association survived adjustment for ferritin and restriction to same-episode iron measurements. In an exploratory comparison, both associations were strongest in iron-replete normocytic patients (hemoglobin +3.6 g/L per pmol/L, p < 0.001) and attenuated in measured iron deficiency. Conclusions: FT3, not TSH, was associated with erythrocyte count and hemoglobin. The count association was absent in the index-defined trait pattern, in which erythrocyte number is already high, and both associations were blunted where iron was limited. These observations are consistent with, but do not demonstrate, a limit on the marrow’s count response, since erythropoietic activity was not measured; they are hypothesis-generating and require replication with confirmed hemoglobin genotype, measured iron status, and reticulocyte or erythropoietin data.

Background/Objectives: Thyroid hormone regulates erythropoiesis, but most population studies have used thyrotropin (TSH) alone and could not ask whether the erythroid response depends on the marrow's capacity to respond. We examined this in a population where inherited microcytosis and iron deficiency are both common. Methods: We analyzed 3871 adults of both sexes with paired free triiodothyronine (FT3), free thyroxine, TSH, and complete blood count from three hospitals in Jazan, Saudi Arabia (3673 with FT3 within the reference interval formed the primary analysis). All three analytes were entered simultaneously in models adjusted for age and sex; mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) were pre-specified negative controls; discriminant indices assigned red cell phenotypes, validated against linked ferritin and transferrin saturation. Results: FT3 was associated with erythrocyte count (standardized β 0.097, 95% confidence interval (CI) 0.066–0.128, p < 0.001) and hemoglobin (+2.7 g/L per pmol/L); TSH was not (p = 0.547). The erythrocyte count association was present in normocytic (β 0.101) and acquired microcytic records (β 0.099) but absent in the inherited-trait pattern (β −0.017; interaction p = 0.002) and remained absent under a stricter trait definition. FT3 was unrelated to iron status, and the association survived adjustment for ferritin. In an exploratory comparison, both the count and hemoglobin associations were strongest in iron-replete normocytic patients (hemoglobin +3.6 g/L per pmol/L, p < 0.001) and attenuated in measured iron deficiency. Conclusions: FT3, not TSH, was associated with the erythron, and the response was absent where erythrocyte number is constitutionally elevated and blunted where hemoglobinization is iron-limited. These hypothesis-generating findings require replication with confirmed hemoglobin genotype.

Cadmium (Cd) is an environmentally pervasive toxic metal that accumulates in the kidney and promotes oxidative stress, inflammation, and apoptosis. This study evaluated the renoprotective effects of free pterostilbene (PTS) and PLGA-encapsulated PTS (PTS-PLGA) in male Sprague–Dawley rats with Cd-induced nephrotoxicity. Rats received CdCl₂ (2 mg/kg/day, intraperitoneally) for 3 weeks and oral free PTS or PTS-PLGA at a nominal PTS-equivalent dose of 50 mg/kg/day. The formulation dose was calculated from encapsulation efficiency; however, systemic and renal PTS exposure were not measured. Renal function, kidney injury molecule-1 (Kim-1), oxidative stress, inflammatory, and apoptosis-related markers were assessed together with histopathological, ultrastructural, and immunohistochemical changes. Cd exposure impaired renal function and increased Kim-1, reactive oxygen species, malondialdehyde, protein carbonyls, 8-hydroxy-2′-deoxyguanosine, inflammatory mediators, caspase activities, Bax/Bcl-2 ratio, and p53 expression. These changes were accompanied by reduced antioxidant defenses and Nrf2/HO-1-related markers, as well as marked histological and ultrastructural injury. Both PTS formulations attenuated Cd-associated renal alterations. Under the present dosing conditions, PTS-PLGA was associated with greater improvement than free PTS across most endpoints. PLGA-encapsulated PTS therefore warrants further preclinical investigation as a potential approach to mitigate Cd-induced nephrotoxicity; pharmacokinetic, biodistribution, and empty-carrier control studies are needed to define the basis of the observed formulation-related differences.