Milica Vukojević

Naringenin (NAR) and hesperetin (HES) are citrus flavanones that have been shown to exert various geroprotective effects. However, key regulators of these processes remain unexplored. To address this gap, we investigated the mechanisms through which NAR and HES modulate hepatic redox control, persulfidation, and senescence‐associated pathways in 24‐month‐old male Wistar rats. Animals were treated orally with NAR or HES (15 mg/kg b.w.) for 4 weeks, while control groups remained physiologically intact or received vehicle. Liver tissue was analyzed using a dimedone‐based switch method to evaluate overall protein persulfidation (P‐SSH), Western blot, qPCR, and histological analysis, including quantification of IHC staining and IF labeling. Our results showed that both citrus flavanones increased total P‐SSH levels while exerting distinct regulatory effects on the H ₂ S metabolic network. Only HES upregulated gene expression of H ₂ S‐producing enzymes (cystathionine beta‐synthase CBS, cystathionine gamma‐lyase CSE, and mercaptopyruvate sulfurtransferase MST) and catabolic enzymes (sulfide:quinone oxidoreductase SQR and thiosulfate sulfurtransferase TST), together with CBS protein, whereas NAR decreased CSE protein expression. Both NAR and HES treatment activated the Nrf2 signaling pathway, as evidenced by increased nuclear translocation of Nrf2 in the treated groups. Concurrently, NAR and HES increased Sirt1 expression, which was accompanied by decreases in p16 and β‐galactosidase expression, indicating attenuation of hepatic senescence. Together, these findings highlight a synergistic interplay among persulfidation, H ₂ S metabolism, and Nrf2/Sirt1 signaling as a key mechanism by which citrus flavanones support hepatic resilience during aging.

Background and Aims: Restless legs syndrome (RLS) is frequently reported in peripheral neuropathies, but its prevalence and clinical correlates in Charcot–Marie–Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) remain poorly defined. We aimed to determine RLS prevalence in CMT1A and HNPP and to assess associations with disease severity, muscle strength, disability, and quality of life (QoL). Methods: Forty‐seven CMT1A and 18 HNPP patients were included. RLS was diagnosed according to the International Restless Legs Syndrome Study Group criteria, and RLS severity was assessed with the International Restless Legs Syndrome Severity Scale (IRLS‐SS). MRC Sum Score (MRC‐SS), Charcot–Marie‐Tooth Examination Score (CMTES), Overall Neuropathy Limitations Scale (ONLS), Beck Depression Inventory (BDI), Fatigue Severity Scale (FSS), and the 36‐Item Short Form Health Survey (SF‐36) were recorded. Results: RLS was present in 29.8% of CMT1A and 38.9% of HNPP patients. CMT1A patients with RLS had longer disease duration ( p = 0.05), worse muscle strength ( p = 0.014), higher disease severity ( p = 0.014), higher upper‐limb ( p = 0.005) and overall disability ( p = 0.011), and higher fatigue severity ( p = 0.011) compared with those without RLS. HNPP patients with RLS showed higher upper‐limb ( p = 0.034) and overall disability ( p = 0.032), higher depression ( p = 0.005), and fatigue severity ( p = 0.018) than those without RLS. QoL was significantly impaired in patients with RLS in both groups, and RLS severity negatively correlated with physical and mental QoL domains. Interpretation: RLS is common in CMT1A and HNPP and is associated with increased disease severity, greater functional disability, and reduced QoL. Clinicians should screen for RLS in PMP22 ‐related neuropathies and consider symptomatic management.

Background and Objectives: Chemical androgen deprivation and estrogenization are essential components of clinical treatment for advanced prostate cancer and male-to-female sex transition. The aim of this study was to determine the effects of these therapies on anthropometric parameters, liver histology, and biochemical parameters, with the goal of establishing experimental models that accurately represent current clinical practice. Materials and Methods: Young adult Wistar rats were divided into nine groups: intact control (IC), control vehicle (CV), cyproterone acetate-treated (CA), flutamide-treated (F), control sesame oil (CO), estradiol valerate-treated (E), combined control (CC), flutamide + estradiol valerate (F + E), and cyproterone acetate + estradiol valerate (CA + E)-treated groups. Treatments were administered by subcutaneous injection for four weeks. Results: The administration of estradiol valerate, alone or combined with antiandrogens, reduced final body mass and white adipose tissue mass. Notable changes were observed in absolute and relative pituitary, liver, prostate, and testis mass in the E, F + E and CA + E groups. There were no significant changes in liver histology or glycogen deposition; however, the combined treatment groups showed an increased volume density of binucleated hepatocytes and fibrotic tissue. Regarding biochemical parameters, androgen deprivation and/or estrogenization caused marked changes in serum triglyceride, LDL (low-density lipoproteins), ALP (alkaline phosphatase), AST (aspartate aminotransferase), ALT (alanine aminotransferase), Bil-T (bilirubin), creatinine, and urea levels. Conclusions: Given the importance of these therapies in clinical practice, providing a model based on the evaluated parameters offers a solid platform for future research.