Mona Magdy Saber

Doxorubicin (Dox) is a highly effective chemotherapeutic agent whose clinical utility is limited by dose-dependent cardiotoxicity, largely driven by iron overload-dependent cell death (ferroptosis) and excessive reactive oxygen species (ROS). Targeting ferroptosis represents a promising strategy for cardioprotection. This study investigated the cardioprotective potential of liraglutide (Lira), deferoxamine (DFO), and their combination in a rat model of Dox-induced cardiotoxicity. Male Wistar rats received Dox (20 mg/kg, i.p.) following pretreatment with Lira (200 μg/kg/day), DFO (50 mg/kg/week), or their combination for 3 weeks. Cardiac injury markers, iron homeostasis, oxidative stress indices, ferroptosis-related gene expression, and histopathological alterations were evaluated. Dox administration induced marked cardiac dysfunction, elevated CK-MB and troponin-T, disrupted iron regulation, increased lipid peroxidation, suppressed Nrf-2/GPX-4 signaling, and triggered ferroptosis. Both Lira and DFO significantly attenuated these alterations; however, combined therapy produced superior restoration of ventricular function, normalization of iron parameters, enhancement of antioxidant defenses, and preservation of myocardial architecture. These findings demonstrate that simultaneous targeting of iron overload and antioxidant signaling confers enhanced cardioprotection against Dox-induced injury. The Lira–DFO combination may represent a promising adjunct strategy to mitigate anthracycline-associated cardiotoxicity.

Purpose: Doxorubicin (Dox) is a widely used anthracycline antibiotic with dose-dependent cardiotoxicity. Cardiac myocytes are highly energy-demanding cells that harbour a dense and well-structured mitochondrial network, which facilitates the accumulation of reactive Dox metabolites, causing disturbance of the mitophagy/biogenesis balance. We investigated the potential cardioprotective properties of liraglutide, a GLP-1 receptor agonist, either alone or in combination with pravastatin, in Dox-induced cardiotoxicity (DIC). Methods: Thirty-five male Sprague-Dawley rats were allocated into five groups (n= 7/group): normal control, doxorubicin, pravastatin & doxorubicin, liraglutide & doxorubicin, and pravastatin-liraglutide & doxorubicin groups. Cardiac histopathological assessment, as well as, echocardiography was performed at the end of the experiment to asses cardiac function along with measurement of CK-MB and troponin-T levels using ELISA. PINK1, Parkin, and PGC-1α gene expression levels were quantified using qRT-PCR while oxidative stress markers were analyzed biochemically. Results: Our findings demonstrated significant improvement in cardiac function, evidenced by the reduction in serum levels of cardiac injury markers, CK-MB and troponin-T, and restoration of mitophagy/biogenesis balance. This was supported by increased expression of PINK1, Parkin, and PGC-1α. Furthermore, co-administration of both drugs enhanced myocardial antioxidant capacity and reduced mitochondrial lipid peroxidation levels. Echocardiographic imaging and histopathological evaluations revealed preserved cardiac architecture and improved ventricular performance and fractional shortening, particularly in the combination therapy group. Conclusion: The enhanced effects highlight the therapeutic promise of combining pravastatin with liraglutide to counteract DIC, restoring mitochondrial dynamics, and strengthening antioxidant activity. Such modification of chemotherapeutic regimens may help safeguard cardiac health, improve quality of life, and reduce treatment-related complications.

Hyperpigmentation is often driven by UV-induced inflammation and melanogenesis. This study aimed to develop a novel, eco-friendly niacinamide nano-delivery system to overcome the skin barrier and effectively target both inflammation and pigmentation associated with UVB damage.Employing a Quality-by-Design (QbD) approach, we utilized a D-optimal response surface design to fabricate and optimize solvent-free niacinamide niosomes (NIA-NIs). Particle size (PS) was minimized and zeta potential (ZP) maximized for enhanced stability and skin penetration using novel complete solvent-free ultrasonication method. Morphology was confirmed by transmission electron microscopy (TEM). The therapeutic efficacy of the optimized formulation was validated in a rat-UVB-induced skin-damage model, with outcomes assessed through histopathological examination and inflammatory cytokines quantification.The optimized NIA-NIs exhibited a nano-size of 272nm ± 9.5 and a high negative charge ZP of -26.9mV ± 1.2. TEM confirmed spherical morphology and nano-scale size. The niosomal formulation demonstrated profound in-vivo superiority in suppressing inflammation, reducing TNF-α and IL-6 levels by 54% and 29%, respectively. Histopathology confirmed near-complete skin architecture restoration, markedly reducing hyperkeratosis, inflammatory infiltration, and collagen disruption, effects that were only partial using the free drug. Niosomes significantly enhance niacinamide's efficacy through targeted delivery, establishing them as a promising and sustainable nano-therapy for effectively treating hyperpigmentation and photo-damaged skin.

Osteoarthritis (OA), a degenerative joint condition, affects entire joints, including the tissues around it, causing pain, swelling and stiffness. This study explored the combined therapeutic effects of metformin and pravastatin on knee OA induced by monosodium iodoacetate (MIA) in rats. The study encompassed five animal groups (n = 10 per group) which were allocated as follows: group 1 received 100 µL of sterile saline injected intra-articularly into the left knee joint (control group) while groups 2–5 were injected with 2 mg MIA in 100µL normal saline into the intraarticular space. After 2 weeks, group 3 received oral metformin (100 mg/kg) for 2 weeks, group 4 received oral pravastatin (10 mg/kg) for 2 weeks and group 5 received both metformin 100 mg/kg and pravastatin 10 mg/kg orally for 2 weeks. The combination of metformin and pravastatin showed to be the most effective in terms of improving radiologic and histologic findings in knee OA. This combination also reduced both serum C reactive protein (CRP) and cartilage oligomeric matrix protein (COMP), while increasing serum collagen type II (COL2). Combining metformin and pravastatin also reduced AKT1, PI3K, STAT3 and IL-6 in the knee joint homogenate. TREM-1 levels showed the greatest reduction with the combination therapy. Furthermore, improvement was noted in oxidative stress markers with an increase in non-protein thiols and a decrease in malondialdehyde. In conclusion, the current study shows a therapeutic potential effect of combining metformin and pravastatin in OA, which could be partly attributed to TREM-1 signaling pathway. Graphical abstract

Objectives: Rhabdomyosarcoma (RMS) accounts for 50% of soft tissue sarcomas and 7% of pediatric malignancies. Cyclophosphamide (CPA) is the cornerstone of therapy and is a prodrug that is activated by the highly polymorphic drug-metabolizing enzyme CYP3A5. We aim to examine the possible CYP3A5 polymorphism association with CPA efficacy, survival outcomes, and toxicity in Egyptian pediatric RMS patients. Methods: The three non-functional SNPs, CYP3A5*3 rs776746 (C_26201809_30), CYP3A5*6 rs10264272 (C_30203950_10), and CYP3A5*7 rs41303343 (C_32287188_10) were genotyped by real-time PCR. We conducted a cohort retrospective study of 150 pediatric RMS patients treated with CPA-based first-line treatment to analyze the association between these genotypes and CPA efficacy/toxicities in RMS patients. Key findings: The frequency of having normal, intermediate, and poor metabolizers was 4.7%, 34%, and 61.3%, respectively. There was an association between these different phenotypes, genotypes, and CPA efficacy/toxicity. Hemorrhagic cystitis and pancytopenia were present in all patients, while nephrotoxicity incidence was 87.3%. There was a notable difference in the occurrence of hemorrhagic cystitis among CYP3A5 intermediate metabolizers *1/*3, *1/*6, and poor metabolizers *3/*3, *3/*6 with a significance level of p<0.05. Neither CYP3A5*7 polymorphism nor *6/*6 genotype was identified in our study. Conclusion: Our results demonstrate that CYP3A5*3 (rs776746) and CYP3A5*6 (rs10264272) have a great association with CPA efficacy and toxicity in RMS patients.

Background: Rhabdomyosarcoma (RMS) is a rare cancer that develops in soft tissue, particularly skeletal muscle tissue and occasionally hollow organs like the bladder or uterus. Vincristine (VCR) is the main therapy used in treatment of RMS, it is an alkaloid produced from vinca and it is one of the most commonly prescribed drugs in pediatric oncology for the treatment of a number of tumors. The CYP3A5 enzyme is responsible for vincristine metabolism. The effect of CYP3A5 genetic polymorphism on the efficacy and toxicity of VCR on RMS patients still needs further research. Methods: Genotyping for CYP3A5 SNPs rs776746, rs10264272 and rs41303343 was performed using Taqman Real-Time PCR assays in a retrospective cohort study of 150 RMS pediatric patients treated with vincristine. The relationship between these genotypes and RMS survival was then examined. Results: We found that patients with CYP3A5*3/*3 had the highest incidence of vincristine-induced neuropathy reaching 61.3%. Patients with CYP3A5*1/*3, CYP3A5*3/*6 and the normal metabolizers with CYP3A5*1/*1 had frequencies of 22%, 10.7%, and 4.7%. patients with the lowest frequency of 1.3% were those with the CYP3A5*1/*6 genotype. There was no correlation between the genotypes of CYP3A5*3, CYP3A5*6, CYP3A5*7, and RMS survival. Initial risk, metastasis, response, convulsions, unsteady gait and hepatotoxicity grade had a significant effect on overall survival with p<0.05. Conclusion: CYP3A5*1/*1 have less severe vincristine-induced neuropathy than CYP3A5 *1/*3, CYP3A5 *1/*6 and CYP3A5 *3/*3, CYP3A5 *3/*6. There is a significant influence of CYP3A5 mutation on neuropathy grade and assist of ADL as a part of neurotoxicity.