A novel selenium analog of HDACi-based twin drug induces apoptosis and cell cycle arrest via CDC25A to improve prostate cancer therapy.

Cancer therapy has moved from single agents to more mechanism-based targeted approaches. In recent years, the combination of HDAC inhibitors and other anticancer chemicals has produced exciting progress in cancer treatment. Herein, we developed a novel prodrug via the ligation of dichloroacetate to selenium-containing potent HDAC inhibitors. The effect and mechanism of this compound in the treatment of prostate cancer were also studied. Methods: The concerned prodrug SeSA-DCA was designed and synthesized under mild conditions. This compound's preclinical studies, including the pharmacokinetics, cell toxicity, and anti-tumor effect on prostate cancer cell lines, were thoroughly investigated, and its possible synergistic mechanism was also explored and discussed. Results: SeSA-DCA showed good stability in physiological conditions and could be rapidly decomposed into DCA and selenium analog of SAHA (SeSAHA) in the tumor microenvironment. CCK-8 experiments identified that SeSA-DCA could effectively inhibit the proliferation of a variety of tumor cell lines, especially in prostate cancer. In further studies, we found that SeSA-DCA could also inhibit the metastasis of prostate cancer cell lines and promote cell apoptosis. At the animal level, oral administration of SeSA-DCA led to significant tumor regression without obvious toxicity. Moreover, as a bimolecular coupling compound, SeSA-DCA exhibited vastly superior efficacy than the mixture with equimolar SeSAHA and DCA both in vitro and in vivo. Our findings provide an important theoretical basis for clinical prostate cancer treatment. Conclusions: Our in vivo and in vitro results showed that SeSA-DCA is a highly effective anti-tumor compound for PCa. It can effectively induce cell cycle arrest and growth suppression and inhibit the migration and metastasis of PCa cell lines compared with monotherapy. SeSA-DCA's ability to decrease the growth of xenografts is a little better than that of docetaxel without any apparent signs of toxicity. Our findings provide an important theoretical basis for clinical prostate cancer treatment.

Molecular Mechanisms of the Therapeutic Effect of Selenium Nanoparticles in Hepatocellular Carcinoma.

This review describes and summarizes, for the first time, the molecular mechanisms of the cytotoxic effect of selenium nanoparticles of various origins on hepatocellular carcinoma cells. The text provides information from recent years indicating the regulation of various signaling pathways and endoplasmic reticulum stress by selenium nanoparticles; the pathways of cell death of liver cancer cells as a result of exposure to selenium nanoparticles are considered. Particular attention is paid to the participation of selenoproteins and selenium-containing thioredoxin reductases and glutathione peroxidases in these processes. Previously, there were no reviews that fully reflected the cytotoxic effects of selenium nanoparticles specifically in hepatocellular carcinoma, despite the fact that many reviews and experimental articles have been devoted to the causes of this disease and the molecular mechanisms of regulation of cytotoxic effects by other agents. The relevance of this review is primarily explained by the fact that despite the development of various drugs and approaches for the treatment and prevention of hepatocellular carcinoma, this disease is still the fourth leading cause of death in the world. For this reason, a complete understanding of the latest trends in the treatment of oncology of various etiologies, especially hepatocellular carcinoma, is extremely important.

Development potential of selenium in the prevention and treatment of bovine endometritis.

Endometritis is a common postpartum disease in cows. It delays uterine involution and impairs normal physiological function. This can result in long-term or even lifelong infertility and cause significant losses to the dairy farming industry. Traditional treatments like antibiotics possess certain shortcomings, such as antibiotic residues, the abuse of antibiotics, and increased antimicrobial resistance of pathogens. Alternative treatment strategies are needed to minimize the utilization of antibiotics in dairy production. As an essential trace element in animals, selenium (Se) plays a vital role in regulating immune function, the inflammatory response, and oxidative stress, affecting the speed and completeness of tissue repair. This paper reviewed previous studies to analyse the potential of Se in the prevention and treatment of bovine endometritis, aiming to provide a new direction to increase production capacity in the future.

Phase and Defect Engineering of MoSe2 Nanosheets for Enhanced NIR-II Photothermal Immunotherapy.

Inducing immunogenic cell death (ICD) during photothermal therapy (PTT) has the potential to effectively trigger photothermal immunotherapy (PTI). However, ICD induced by PTT alone is often limited by inefficient PTT, low immunogenicity of tumor cells, and a dysregulated redox microenvironment. Herein, we develop MoSe2 nanosheets with high-percentage metallic 1T phase and rich exposed active Mo centers through phase and defect engineering of MoSe2 as an effective nanoagent for PTI. The metallic 1T phase in MoSe2 nanosheets endows them with strong PTT performance, and the abundant exposed active Mo centers endow them with high activity for glutathione (GSH) depletion. The MoSe2-mediated high-performance PTT synergizing with efficient GSH depletion facilitates the release of tumor-associated antigens to induce robust ICD, thus significantly enhancing checkpoint blockade immunotherapy and activating systemic immune response in mouse models of colorectal cancer and triple-negative metastatic breast cancer.

Seleno-amino Acid Metabolism Reshapes the Tumor Microenvironment: from Cytotoxicity to Immunotherapy.

Selenium (Se) is an essential trace element for biological processes. Seleno-amino acids (Se-AAs), known as the organic forms of Se, and their metabolic reprogramming have been increasingly recognized to regulate antioxidant defense, enzyme activity, and tumorigenesis. Therefore, there is emerging interest in exploring the potential application of Se-AAs in antitumor therapy. In addition to playing a vital role in inhibiting tumor growth, accumulating evidence has revealed that Se-AA metabolism could reshape the tumor microenvironment (TME) and enhance immunotherapy responses. This review presents a comprehensive overview of the current progress in multifunctional Se-AAs for antitumor treatment, with a particular emphasis on elucidating the crosstalk between Se-AA metabolism and various cell types in the TME, including tumor cells, T cells, macrophages, and natural killer cells. Furthermore, novel applications integrating Se-AAs are also discussed alongside prospects to provide new insights into this emerging field.

Recent advances in the therapeutic applications of selenium nanoparticles.

Selenium nanoparticles (SeNPs) are an appealing carrier for the targeted delivery. The selenium nanoparticles are gaining global attention because of the potential therapeutic applications in several diseases e.g., rheumatoid arthritis (RA), inflammatory bowel disease (IBD), asthma, liver, and various autoimmune disorders like psoriasis, cancer, diabetes, and a variety of infectious diseases. Despite the fact still there is no recent literature that summarises the therapeutic applications of SeNPs. There are some challenges that need to be addressed like finding targets for SeNPs in various diseases, and the various functionalization techniques utilized to increase SeNP's stability while facilitating wide drug-loaded SeNP distribution to tumor areas and preventing off-target impacts need to focus on understanding more about the therapeutic aspects for better understanding the science behind it. Keeping that in mind we have focused on this gap and try to summarize all recent key targeted therapies for SeNPs in cancer treatment and the numerous functionalization strategies. We have also focused on recent advancements in SeNP functionalization methodologies and mechanisms for biomedical applications, particularly in anticancer, anti-inflammatory, and anti-infection therapeutics. Based on our observation we found that SeNPs could potentially be useful in suppressing viral epidemics, like the ongoing COVID-19 pandemic, in complement to their antibacterial and antiparasitic uses. SeNPs are significant nanoplatforms with numerous desirable properties for clinical translation.

Efficacy of selenium on patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials.

INTRODUCTION: Postoperative complications pose significant challenges in cardiac surgery and with the evolution of selenium as a potential anti-inflammatory agent, some studies reported its inefficiency. Thus, we conducted our meta-analysis to evaluate the impact of selenium supplementation on cardiac surgery patients. METHODS: Different databases such as PubMed, Embase, and Cochrane Library from inception till January 2024 were searched identifying a total of seven randomized-controlled trials involving selenium supplementation after cardiac surgery. Risk ratio (RR) and Mean difference (MD) were calculated with a 95% confidence interval (CI). RESULTS: The selenium intervention significantly raised the incidence of Acute Kidney injury (RR 0.76; 95% CI: 0.59, 0.98; P = 0.04) while significantly reducing the duration of hospital stay (MD -1.33; 95% CI: -2.51, -0.16; P = 0.03) and postoperative CRP levels (SMD -0.18; 95% CI: -0.34, -0.02; P = 0.03). The effect of selenium intervention on days spent in ICU (MD -0.01; 95% CI: -0.28, 0.25; P = 0.92), mortality (RR 1.07; 95% CI: 0.84, 1.37; P = 0.57) and incidence of hospital acquired infections (RR 0.98; 95% CI: 0.76, 1.26; P = 0.88) is insignificant. CONCLUSION: Selenium supplementation did not significantly reduce major postoperative complications in cardiac surgery patients. However, its ability to modulate inflammation, as reflected in decreased C-reactive protein levels, highlights its potential role in managing the inflammatory response. Future investigations should focus on optimized selenium supplementation strategies in conjunction with other antioxidants to enhance its benefits.

Nutritional Support: The Use of Antioxidants in Inflammatory Bowel Disease.

The problem of treating inflammatory bowel disease continues to be a topic of great interest for researchers. Despite the complexity surrounding their treatment and strategies to prolong periods of remission, there is a promising exploration of various compounds that have potential in combating inflammation and alleviating symptoms. Selenium, calcium, magnesium, zinc, and iron are among these compounds, offering a glimpse of hope in the treatment of IBD. These essential minerals not only hold the promise of reducing inflammation in these diseases, but also show the potential to enhance immune function and possibly influence the balance of intestinal microflora. By potentially modulating the gut microbiota, they may help support overall immune health. Furthermore, these compounds could play a crucial role in mitigating inflammation and minimising complications in patients with IBD. Furthermore, the protective effect of these compounds against mucosal damage in IBD and the protective effect of calcium itself against osteoporosis in this group of patients are notable.

The Preventive Effect of Preoperative and Postoperative Selenium on the Medication-Related Osteonecrosis of the Jaw: An Animal Study in Rats.

BACKGROUND: Medication-related osteonecrosis of the jaw (MRONJ) is a condition that can occur primarily in patients undergoing or have previously undergone therapy with bisphosphonates, particularly in the presence of risk factors, such as tooth extraction (TE). PURPOSE: This study aimed to evaluate the effect of selenium (SEL) administration on the prevention of osteonecrosis of the jaw in an MRONJ animal model. STUDY DESIGN, SETTING, AND SAMPLE: This study was a longitudinal in vivo animal study using a TE model in a sample of 48 Wistar rats. PREDICTOR VARIABLE: The predictor variables were SEL exposure, timing of SEL exposure, and zoledronic acid (ZOL) exposure. The animals were randomly assigned to 4 treatment groups (n = 12 per group): 1) saline (negative control), 2) ZOL (positive control), 3) SELpreop + ZOL, and 4) ZOL + SELpostop. The animals were administered saline (negative control) or ZOL (0.06 mg/kg, intraperitoneally) once a week for 5 weeks. All rats underwent TE at the end of the fifth week. SEL (0.3 mg/kg, intraperitoneally) was administered once daily for 15 days to the SELpreop + ZOL group before TE and to the ZOL + SELpostop group after TE. All animals were sacrificed at the end of the ninth week. MAIN OUTCOME VARIABLES: The primary outcome variables were new bone area, necrotic bone area, fibrosis, new connective tissue formation, and inflammatory cell infiltration in the histopathological analysis, as well as angiogenesis and percentage of osteoblasts in the immunohistochemical analysis. COVARIATES: There was none. ANALYSES: Statistical analysis was conducted using the Kruskal-Wallis test, followed by post hoc Bonferroni-corrected Mann-Whitney U tests, with a significance level of P ≤ .05. RESULTS: The new bone area was higher in the ZOL + SELpostop group (3.00 score) than in the saline group (0.58 ± 1.08 score, P < .001) and the ZOL group (0.82 ± 1.40 score, P = .001), while the necrotic bone area was lower in the ZOL + SELpostop group (0.08 ± 0.29 score) than in the ZOL group (2.82 ± 0.40 score, P < .001) and the SELpreop + ZOL group (1.67 ± 0.89 score, P = .007). The percentage of osteoblasts was higher in the ZOL + SELpostop group (18.73%) than in the saline group (8.63%, P < .001) and the ZOL group (0.07%, P < .001), and it was also higher in the SELpreop + ZOL group (18.49%) than in the ZOL group (0.07%, P < .001). CONCLUSION AND RELEVANCE: In conclusion SEL prevents MRONJ, with postoperative SEL demonstrating greater prevention effects. Given these findings, we hypothesize that SEL exposure may decrease the risk of MRONJ.

Tumor Microenvironment-Triggered Self-Adaptive Polymeric Photosensitizers for Enhanced Photodynamic Therapy.

Photodynamic therapy (PDT) employs photosensitizers to convert nearby oxygen into toxic singlet oxygen (1O2) upon laser light irradiation, showing great potential as a noninvasive approach for tumor ablation. However, the therapeutic efficacy of PDT is essentially impeded by π-π stacking and the aggregation of photosensitizers. Herein, we propose a tumor microenvironment-triggered self-adaptive nanoplatform to weaken the aggregation of photosensitizers by selenium-based oxidation at the tumor site. The selenide units in a selenium-based porphyrin-containing amphiphilic copolymer (PSe) could be oxidized into hydrophilic selenoxide units, leading to the nanoplatform self-expansion and stretching of the distance between intramolecular porphyrin units. This process could provide a better switch to greatly reduce the aggregation of photosensitive porphyrin units, generating more 1O2 upon laser irradiation. As verified in a series of in vitro and in vivo studies, PSe could be efficiently self-adapted at tumor sites, thus significantly enhancing the PDT therapeutic effect against solid tumors and minimizing side effects.

The effect of selenium supplementation on oxidative stress, clinical symptoms and mental health status in patients with migraine: a study protocol for a double-blinded randomized clinical trial.

BACKGROUND: Despite a number of recommended strategies, effective treatment of migraine remains elusive. Given the role of oxidative stress in the pathogenesis of migraine, selenium, as an antioxidant nutrient, may have a beneficial effect on migraine outcomes. However, no study has explored the effects of selenium supplementation on migraine symptoms, oxidative stress biomarkers, and mental health. Therefore, this randomized, double-blinded, placebo-controlled clinical trial aims to examine the effects of selenium supplementation among migraine patients. METHODS: Seventy-two migraine patients will receive either 200 µg/day selenium supplement (n = 36) or placebo (n = 36) for 12 weeks in a randomized, double-blinded, placebo-controlled study. The severity, frequency, and duration of headaches, mental health indices including depression, anxiety, and distress, and quality of life, as well as biomarkers of oxidative stress such as nitric oxide (NO), malondialdehyde (MDA), total antioxidant capacity (TAC), and total oxidant status (TOS), will be measured at the baseline and end of the study. The intention-to-treat (ITT) approach will be used to estimate missing values. One-way analysis of covariance (ANCOVA) will be performed to detect the effect of selenium supplementation on outcome variables. DISCUSSION: Oxidative stress is recognized as a key contributor to migraine pathogenesis. Selenium is an essential trace element with antioxidant properties, capable of crossing the blood-brain barrier (BBB), holding promise to alleviate the oxidative stress and neurotoxicity. Thus, selenium may beneficially affect clinical symptoms and oxidative stress as well as the quality of life in migraine patients. TRIAL REGISTRATION: This trial was registered in the Iranian Registry of Clinical Trials ( https://www.irct.ir/ ) on 27 May 2023 with the code number IRCT20121216011763N60.

Micronutrients as therapy in critical illness.

PURPOSE OF REVIEW: Recent large-scale randomized controlled trials (RCTs) challenged current beliefs about the potential role of micronutrients to attenuate the inflammatory response and improve clinical outcomes of critically ill patients. The purpose of this narrative review is to provide an overview and critical discussion about most recent clinical trials, which evaluated the clinical significance of a vitamin C, vitamin D, or selenium administration in critically ill patients. RECENT FINDINGS: None of the most recent large-scale RCTs could demonstrate any clinical benefits for a micronutrient administration in ICU patients, whereas a recent RCT indicated harmful effects, if high dose vitamin C was administered in septic patients. Following meta-analyses could not confirm harmful effects for high dose vitamin C in general critically ill patients and indicated benefits in the subgroup of general ICU patients with higher mortality risk. For vitamin D, the most recent large-scale RCT could not demonstrate clinical benefits for critically ill patients, whereas another large-scale RCT is still ongoing. The aggregated and meta-analyzed evidence highlighted a potential role for intravenous vitamin D administration, which encourages further research. In high-risk cardiac surgery patients, a perioperative application of high-dose selenium was unable to improve patients' outcome. The observed increase of selenium levels in the patients' blood did not translate into an increase of antioxidative or anti-inflammatory enzymes, which illuminates the urgent need for more research to identify potential confounding factors. SUMMARY: Current data received from most recent large-scale RCTs could not demonstrate clinically meaningful effects of an intervention with either vitamin C, vitamin D, or selenium in critically ill patients. More attention is needed to carefully identify potential confounding factors and to better evaluate the role of timing, duration, and combined strategies.

Protective effects of functional Nano-Selenium supplementation on spleen injury through regulation of p38 MAPK and NF-κB protein expression.

Selenium (Se) is a trace element necessary for humans to maintain normal physiological activities, and Se deficiency may lead to splenic injury, while Se supplementation can alleviate splenic injury. However, the mechanism is unclear. In this study, we constructed a Se deficiency animal model by feeding Sprague-Dawley (SD) rats with low Se feed. Meanwhile, we observed the repairing effect of Se supplementation on splenic injury with two doses of novel nano-selenium (Nano-Se) supplement by gavage. We measured the Se content in the spleens of the rats by atomic fluorescence spectroscopy (AFS) method and combined the results of hematoxylin-eosin (HE) and Masson staining to observe the splenic injury, comprehensively evaluating the construction of the animal model of low selenium-induced splenic injury. We measured the mRNA and protein expression levels of p38 mitogen-activated protein kinase (p38 MAPK), nuclear factor kappa-B (NF-κB), and interleukin-6 (IL-6) in the spleen by Real-time quantitative polymerase chain reaction (qPCR), western blot (WB), and immunohistochemistry (IHC). We found that the Se deficiency group exhibited lower Se content, splenic fibrosis, and high expression of p38 MAPK, NF-κB, and IL-6 compared to the normal group. The Se supplement groups exhibited higher Se content, attenuated splenic injury, and down-regulated expression of p38 MAPK, NF-κB, and IL-6 relative to the Se deficiency group. This study suggests that Se deficiency leads to splenic injury in rats, and Se supplementation may attenuate splenic injury by inhibiting the expression of p38 MAPK, NF-κB and IL-6.

Effects of postoperative antioxidants on the salivary glands in patients with thyroid cancer undergoing radioactive iodine-131 treatment.

OBJECTIVE: This study aimed to evaluate the effects of three antioxidants, selenium yeast capsule, vitamin E and vitamin C, alone or in combination, on the salivary glands of patients with differentiated thyroid cancer (DTC) treated with iodine-131 ( 131 I). METHODS: A total of 69 postoperative DTC patients were randomly divided into three groups: vitamin E combined with vitamin C group (21 cases); selenium yeast group (23 cases); and selenium yeast combined with vitamin C group (25 cases). Salivary gland functional changes were assessed by salivary gland dynamic imaging functional parameters in the enrolled patients before and 1 month after 131 I treatment. RESULTS: Comparison of salivary gland function parameters before and after 131 I treatment in the three groups were evaluated. In the vitamin E combined with the vitamin C group, the left parotid gland excretion fraction (EF) value was significantly higher than that before treatment. In the selenium yeast group, the left parotid gland excretion part, bilateral parotid gland excretion ratio (ER), left submandibular gland maximum uptake ratio within 20 min (UR20), and the right submandibular gland ER values were significantly higher than that before treatment, while in the selenium yeast combined with vitamin C group, the bilateral parotid gland EF, bilateral submandibular gland UR20, EF, and left submandibular gland ER values were significantly higher than that before treatment (all P < 0.05). CONCLUSION: During high-dose 131 I treatment, vitamin E combined with vitamin C improved the excretory function of parotid glands in DTC patients; selenium supplementation had a protective effect on salivary glands; and the combination of selenium and vitamin C had a better effect.

Porous Se@SiO2 nanospheres alleviate diabetic retinopathy by inhibiting excess lipid peroxidation and inflammation.

BACKGROUND: Lipid peroxidation is a characteristic metabolic manifestation of diabetic retinopathy (DR) that causes inflammation, eventually leading to severe retinal vascular abnormalities. Selenium (Se) can directly or indirectly scavenge intracellular free radicals. Due to the narrow distinction between Se's effective and toxic doses, porous Se@SiO2 nanospheres have been developed to control the release of Se. They exert strong antioxidant and anti-inflammatory effects. METHODS: The effect of anti-lipid peroxidation and anti-inflammatory effects of porous Se@SiO2 nanospheres on diabetic mice were assessed by detecting the level of Malondialdehyde (MDA), glutathione peroxidase 4 (GPX4), decreased reduced/oxidized glutathione (GSH/GSSG) ratio, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL) -1ß of the retina. To further examine the protective effect of porous Se@SiO2 nanospheres on the retinal vasculopathy of diabetic mice, retinal acellular capillary, the expression of tight junction proteins, and blood-retinal barrier destruction was observed. Finally, we validated the GPX4 as the target of porous Se@SiO2 nanospheres via decreased expression of GPX4 and detected the level of MDA, GSH/GSSG, TNF-α, IFN-γ, IL -1ß, wound healing assay, and tube formation in high glucose (HG) cultured Human retinal microvascular endothelial cells (HRMECs). RESULTS: The porous Se@SiO2 nanospheres reduced the level of MDA, TNF-α, IFN-γ, and IL -1ß, while increasing the level of GPX4 and GSH/GSSG in diabetic mice. Therefore, porous Se@SiO2 nanospheres reduced the number of retinal acellular capillaries, depletion of tight junction proteins, and vascular leakage in diabetic mice. Further, we identified GPX4 as the target of porous Se@SiO2 nanospheres as GPX4 inhibition reduced the repression effect of anti-lipid peroxidation, anti-inflammatory, and protective effects of endothelial cell dysfunction of porous Se@SiO2 nanospheres in HG-cultured HRMECs. CONCLUSION: Porous Se@SiO2 nanospheres effectively attenuated retinal vasculopathy in diabetic mice via inhibiting excess lipid peroxidation and inflammation by target GPX4, suggesting their potential as therapeutic agents for DR.

Ultrathin 2D As2Se3 Nanosheets for Photothermal-Triggered Cancer Immunotherapy.

Arsenic trioxide (As2O3) has achieved groundbreaking success in the treatment of acute promyelocytic leukemia (APL). However, its toxic side effects seriously limit its therapeutic application in the treatment of solid tumors. To detoxify the severe side effects of arsenic, herein we synthesized innovative 2D ultrathin As2Se3 nanosheets (As2Se3 NSs) with synergistic photothermal-triggered immunotherapy effects. As2Se3 NSs are biocompatible and biodegradable under physiological conditions and can release As(III) and Se(0). Furthermore, selenium increases the immunomodulatory efficacy of arsenic treatments, facilitating reprogramming of the tumor microenvironment by As2Se3 NSs by enhancing the infiltration of natural killer cells and effector tumor-specific CD8+ T cells. The synergistic combination of photothermal therapy and immunotherapy driven by As2Se3 NSs via a simple but effective all-in-one strategy achieved efficient anticancer effects, addressing the key limitations of As2O3 for solid tumor treatment. This work demonstrates not only the great potential of selenium for detoxifying arsenic but also the application of 2D As2Se3 nanosheets for cancer therapy.

The potential anti-Alzheimer's activity of Oxalis corniculata Linn. Methanolic extract in experimental rats: Role of APOE4/LRP1, TLR4/NF-κß/NLRP3, Wnt 3/ß-catenin/GSK-3ß, autophagy and apoptotic cues.

ETHNOPHARMACOLOGICAL RELEVANCE: Oxalis corniculata (O. corniculata) is a member of Oxalidaceae family, widely distributed in Asia, Europe, America, and Africa, used extensively as food and its traditional folkloric uses include management of epilepsy, gastric disorders, and neurodegenerative diseases, together with its use in enhancing health. Numerous pharmacological benefits of O. corniculata are linked to its anti-inflammatory and antioxidant abilities. One of the most prevalent neurodegenerative disorders is Alzheimer's disease (AD) in which neuroinflammation and oxidative stress are its main pathogenic processes. AIM OF THE STUDY: Our research aimed to study the neuroprotective effect of the methanolic extract of Oxalis corniculata Linn. (O. corniculata ME), compared to selenium (Se) against AlCl3-induced AD. MATERIALS AND METHODS: Forty male albino rats were allocated into four groups (Gps). Gp I a control group, the rest of the animals received AlCl3 (Gp II-Gp IV). Rats in Gp III and IV were treated with Se and O. corniculata ME, respectively. RESULTS: The chemical profile of O. corniculata ME was studied using ultraperformance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry, allowing the tentative identification of sixty-six compounds, including organic acids, phenolics and others, cinnamic acid and its derivatives, fatty acids, and flavonoids. AlCl3 showed deterioration in short-term memory and brain histological pictures. Our findings showed that O. corniculata ME and selenium helped to combat oxidative stress produced by accumulation of AlCl3 in the brain and in prophylaxis against AD. Thus, Selenium (Se) and O. corniculata ME restored antioxidant defense, via enhancing Nrf2/HO-1 hub, hampered neuroinflammation, via TLR4/NF-κß/NLRP3, along with dampening apoptosis, Aß generation, tau hyperphosphorylation, BACE1, ApoE4 and LRP1 levels. Treatments also promoted autophagy and modulated Wnt 3/ß-catenin/GSK3ß cue. CONCLUSIONS: It was noted that O. corniculata ME showed a notable ameliorative effect compared to Se on Nrf2/HO-1, TLR4/NF-κß/NLRP3, APOE4/LRP1, Wnt 3/ß-catenin/GSK-3ß and PERK axes.