Mai Ahmed Salem

Background/Objectives: Manganese (Mn) is a neurotoxic trace element whose excessive accumulation in the brain can induce hippocampal damage via oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis. This study investigated whether honokiol (HNK) and its liposomal nanoformulation (HNK-LNPs) can ameliorate Mn-induced hippocampal neurotoxicity by modulating key antioxidant and mitochondrial regulatory pathways. Methods: Male Wistar rats were subjected to Mn exposure to induce hippocampal neurotoxicity and were treated with HNK or HNK-LNPs. We assessed oxidative status via NRF2/HO-1 signaling, antioxidant defenses (glutathione, GPx, SOD, CAT), and oxidative indices (ROS, MDA). Neuroinflammatory markers (NF-κB, TNF-α, IL-1β, IL-6, Iba-1), mitochondrial respiratory chain function and ATP levels, SIRT1/PGC-1α signaling, and neurotransmitter homeostasis were evaluated. We analyzed apoptosis using Bax, Bcl-2, caspase-3, and cytochrome c, along with histopathological and ultrastructural examination of the hippocampus. Results: Mn exposure was associated with NRF2/HO-1 downregulation, depleted endogenous antioxidants, increased ROS and MDA levels, and increased NF-κB–driven neuroinflammation and microglial Iba-1 expression. Mn was further associated with reduced ATP synthesis, dysregulation of SIRT1/PGC-1α signaling, and disrupted neurotransmitter balance, with a pro-apoptotic shift (elevated Bax, caspase-3, cytochrome c; reduced Bcl-2) and neuronal degeneration. Co-treatment with HNK, and more prominently with HNK-LNPs, was associated with reversing these alterations, restoring antioxidant and mitochondrial pathways, dampening inflammatory cascades, normalizing neurotransmitters, and favoring neuronal survival, with many indices approaching control values and consistently surpassing free HNK. Conclusions: Liposomal encapsulation significantly enhances honokiol’s neuroprotection against Mn-induced hippocampal neurotoxicity, likely via improved CNS bioavailability and coordinated modulation of NRF2/HO-1 and SIRT1/PGC-1α pathways. These findings support HNK-LNPs as a promising multi-mechanistic therapeutic strategy for metal-induced and related neurotoxic brain disorders.

Colorectal cancer (CRC) is driven by oxidative stress, chronic inflammation, and disruption of cytoprotective signaling pathways. This study aimed to evaluate whether poly(lactic-co-glycolic acid) (PLGA)-based nanoparticle delivery enhances the chemoprotective efficacy of paeonol against 1,2-dimethylhydrazine (DMH)-induced colorectal carcinogenesis, with a focus on modulation of the NRF2/HO-1 pathway. Sixty male Wistar rats were randomly assigned to six groups: control, paeonol (PNL), PNL-PLGA, DMH, DMH + PNL, and DMH + PNL-PLGA. CRC was induced using DMH over 10 weeks. Serum tumor biomarkers (AFP, CEA, CA19-9, CA125, CA15-3), oxidative stress markers (ROS, MDA, antioxidant enzymes), inflammatory cytokines, DNA damage, apoptosis- and autophagy-related gene expression, and hepatic and renal function were assessed. Histopathological and ultrastructural analyses of colonic tissues were performed. DMH exposure was markedly associated with increased tumor biomarkers, oxidative stress, and inflammatory mediators, DNA damage, and impaired liver and kidney function. It was also associated with the restoration of NRF2/HO-1 signaling, improved redox balance, suppression of inflammation, reduction in DNA damage, and preservation of regulated NRF2/HO-1 signaling, antioxidant defenses, autophagy markers, and apoptotic proteins, as well as severe histological and ultrastructural alterations. Free paeonol partially attenuated these changes. In contrast, PNL-PLGA was significantly associated with restoring NRF2/HO-1 signaling, improving redox balance, suppressing inflammation, reducing DNA damage, and preserving colonic architecture and ultrastructure. These findings demonstrate that a PLGA-based nanoformulation of paeonol markedly improves its chemopreventive efficacy against DMH-induced CRC, primarily by activating NRF2/HO-1 signaling and modulating oxidative stress, inflammation, apoptosis, and autophagy, highlighting its potential as a promising nanotherapeutic strategy for colorectal cancer.

Environmental neurotoxicants such as rotenone (RO) and 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) are known to induce cytotoxicity in neural cells. This study aimed to investigate the neuroprotective properties of active vitamin D3 against the cytotoxic effects of RO and MPTP on undifferentiated human neuroblastoma (SH‐SY5Y) cells. Exposure to these neurotoxins resulted in concentration‐ and time‐dependent reductions in cell viability. Cotreatment with vitamin D significantly mitigated the cytotoxic impact of both compounds. Furthermore, vitamin D attenuated disruptions in noradrenaline turnover and acetylcholinesterase activity caused by neurotoxin exposure. Mechanistic exploration revealed that vitamin D preserved cellular bioenergetics by maintaining ATP levels, supporting Mitochondrial Complexes I and III activities, stabilizing mitochondrial membrane potential and reducing lactate accumulation. Vitamin D also reduced oxidative stress, as evidenced by lower reactive species production and lipid peroxidation, while enhancing catalase (CAT) activity in treated cells. In addition, vitamin D counteracted the upregulation of neurodevelopmental genes CAMK2A and CAMK2B induced by neurotoxin exposure. Collectively, these findings demonstrate that vitamin D3 confers significant neuroprotection against RO‐ and MPTP‐induced toxicity in SH‐SY5Y cells by modulating mitochondrial function, oxidative stress and neurochemical balance. These results support the potential therapeutic use of vitamin D3 to prevent or ameliorate neurodegenerative conditions and other neurological disorders characterized by mitochondrial dysfunction and oxidative damage.

Background/Objectives: Nickel exposure is a significant environmental and occupational risk factor associated with the onset and progression of chronic liver diseases due to its capacity to induce persistent oxidative stress, inflammation, and hepatocellular injury. This study aimed to evaluate the enhanced hepatoprotective and antioxidant/anti-inflammatory effects of naringin-loaded nanoliposomes (NRG-NLPs), a novel nanoformulation designed to improve the bioavailability of naringin, a citrus-derived flavonoid phytochemical, against nickel sulfate (NiSO₄)-induced hepatotoxicity in male Wistar rats. Methods: Ninety rats were allocated into six groups (n = 15 each): control, NRG, NRG-NLPs, NiSO₄, NiSO₄ + NRG, and NiSO₄ + NRG-NLPs. Treatments consisted of oral administration of NRG or NRG-NLPs (80 mg/kg/day) and intraperitoneal injections of NiSO₄ (20 mg/kg/day) for three weeks. Endpoints included assessment of growth performance, serum biochemistry, hepatic antioxidant status, inflammatory mediators, apoptotic gene expression, nickel tissue accumulation, and histopathological and ultrastructural liver changes. Results: NiSO₄ exposure induced marked hepatic injury, evidenced by reduced body weight, adverse serum biochemical profiles, increased hepatic enzymes and bilirubin, elevated oxidative damage markers (MDA, protein carbonyls), increased proinflammatory cytokines, and upregulation of HMGB1, PI3K, mTOR, JAK/STAT, and proapoptotic genes, accompanied by aberrant nickel accumulation and severe histopathological alterations. Co-treatment with NRG-NLPs significantly ameliorated biochemical and histological disturbances, restored antioxidant defense systems (SOD, CAT, GPx, GSH, Nrf2, HO-1), and modulated key pathways of inflammation (NF-κB, TNF-α, IL-6), fibrosis (TGF-β), cell survival, and apoptosis more effectively than crude naringin. NRG-NLPs also substantially reduced hepatic nickel deposition and preserved near-normal liver architecture. Conclusions: These findings demonstrate that nanoformulated naringin confers superior hepatoprotective benefits against nickel-induced liver injury through enhanced bioavailability and multi-pathway modulation, supporting its translational potential as a citrus-derived medicinal phytochemical and dietary bioactive for the prevention and therapeutic intervention of oxidative and inflammatory chronic liver disease.

Background/Objectives: Rutin (RT), a promising bioflavonoid, faces clinical limitations due to its poor solubility and bioavailability. In this study, we formulated RT-loaded phytosome nanoparticles (RT-PNPs) via thin-layer hydration and characterized their morphology, size distribution, and zeta potential. Methods: We established a mouse model of Ehrlich ascites carcinoma (EAC), randomly allocating ninety female Swiss albino mice into six groups: untreated controls, RT-treated, RT-PNP-treated, EAC, EAC + RT, and EAC + RT-PNPs. Tumor induction and treatment protocols were controlled, with the oral administration of 25 mg/kg/day of RT or RT-PNPs for 20 days. We comprehensively assessed survival, body weight, ascitic fluid/tumor volume, and cell viability and performed detailed hematological, serum biochemical, and tumor marker analyses. Multiorgan (liver and kidney) function and redox homeostasis were evaluated through enzymatic assays for SOD, CAT, GSH-Px, and GSH, as well as lipid peroxidation assessment. Proinflammatory cytokines and tumor markers (AFP, CEA, CA19-9, CA125, and CA15-3) were quantified via ELISA. Results: Gene expression profiling (TP53, Bax, and Bcl-2) and flow cytometry (p53 and Ki-67) elucidated the modulation of apoptosis. Histopathological scoring documented organ protection, while advanced multivariate (heatmap and principal component) analyses revealed distinct treatment clusterings. The RT-PNPs demonstrated potent anti-tumor, antioxidant, anti-inflammatory, and apoptosis-inducing effects, outperforming free RT in restoring physiological markers and tissue integrity. Conclusions: The current results underscore the potential of RT-PNPs as a multifaceted therapeutic approach to EAC, leveraging nanoparticle technology to optimize efficacy and systemic protection.

Emerging studies show that long intergenic non-protein coding RNA, regulator of reprogramming (LINC-ROR) is aberrantly expressed in several types of cancer, including colon cancer (CC). LINC-ROR intronic variant rs1942347 may impact gene regulation and disease phenotype. We aimed to explore the potential association of LINC-ROR (rs1942347) with the clinicopathological features and outcome of CC cases. Archived FFPE (n = 180) CC samples were enrolled. Taq-Man allelic discrimination PCR was used for genotyping in propensity-matched cohorts with/without positive staining for mutant BRAF protein after eliminating confounders bias. The rs1942347*A allele variant was associated with high pathological grade, larger tumor size, distant metastasis, and mortality. Multiple logistic regression analysis adjusted by sex and BRAF mutation showed A/A genotype carriers to have 3 times more risk of early onset of cancer (OR = 3.13, 95%CI = 1.28–7.69, p = 0.034) than T/T genotype carriers. Overall analysis showed that rs1942347*A allele carriers had higher risk of mortality under heterozygote (OR = 2.13, 95%CI = 1.08–4.35, p = 0.003), homozygote (OR = 5.0, 95%CI = 1.69–14.29, p = 0.003), dominant (OR = 3.33, 95%CI = 1.20–9.09, p = 0.003), and recessive (OR = 2.63, 95%CI = 1.37–5.0, p = 0.011) models compared to T/T allele carriers. Stratified analysis by BRAF status revealed that the ancestor T/T allele conferred protection in BRAF mutant CC patients and was associated with a 73–93% reduced risk of mortality under heterozygote/homozygote comparison models. Using Kaplan–Meier curves, carriers of the A/A genotype had shorter survival times than T/T cohorts. The univariate Cox regression model revealed that the A/A genotype was associated with a 3.5 times greater mortality risk than the T/T genotype. However, after adjustment by multiple Cox regression analysis, the risk was insignificant. In conclusion, this is the first study identifying the potential association of the LINC-ROR (rs1942347) variant with CC prognosis.