Polystyrene microplastics (PS-MPs) are emerging environmental contaminants with increasing evidence of systemic toxicity; however, the mechanisms underlying their hepatic effects remain incompletely understood. The present study investigated the hepatotoxic effects of PS-MPs, focusing on hepatic bioaccumulation, mitochondrial homeostasis, inflammation, apoptosis, and liver functional impairment. Experimental animals were exposed to increasing concentrations of PS-MPs, after which liver tissues were subjected to GC-MS, biochemical, histopathological, and molecular analyses. GC-MS confirmed hepatic accumulation of PS-MPs predominantly in the higher exposure groups (20 and 40 μg), which were subsequently selected for mechanistic investigations. PS-MP exposure induced marked hepatic dysfunction, evidenced by elevated bilirubin, ALT, AST, and GGT levels together with significant reductions in total protein, albumin, and globulin concentrations. Histopathological examination revealed progressive hepatocellular degeneration, inflammatory infiltration, cytoplasmic vacuolation, and necrotic alterations. In parallel, inflammatory and apoptotic signaling were significantly activated, as demonstrated by increased NF-κB and caspase-3 levels. Mechanistically, PS-MPs were associated with transcriptional dysregulation of genes involved in mitochondrial homeostasis, including suppression of mitochondrial biogenesis markers (PGC-1α and TFAM), downregulation of mitochondrial fusion regulators (MFN2 and OPA1), increased DRP1 expression, and reduced PINK1 expression, suggesting altered mitophagy-related signaling. Principal Component Analysis further demonstrated clear separation between control and exposed groups, strongly associating PS-MP exposure with hepatic injury, transcriptional dysregulation of mitochondrial homeostasis-related genes, inflammation, and apoptosis. Collectively, these findings demonstrate that PS-MPs induce significant hepatotoxicity, accompanied by coordinated transcriptional dysregulation of mitochondrial homeostasis-related genes and activation of inflammatory and apoptotic pathways. These findings highlight the liver as a major target of microplastic toxicity and emphasize the need for further studies incorporating protein-level validation, functional mitochondrial assessments, and long-term exposure models to better understand the implications for human health.

Polystyrene microplastics (PS-MPs), widely used in commercial and pharmaceutical products, are emerging endocrine-disrupting pollutants with potential reproductive toxicity. This study evaluated the dose-dependent effects of PS-MPs on adult male rats by assessing semen quality, reproductive hormones, oxidative stress, mitochondrial and inflammatory markers, and testicular histology. Rats were assigned to six groups: a control group and five groups receiving PS-MPs orally (0.1, 1, 10, 20, or 40 µg/kg BW) for 45 days. PS-MP exposure reduced sperm count and motility, increased abnormal sperm, decreased testosterone, and elevated FSH and LH. Mitochondrial biogenesis/function markers (PGC-1α, UCP1, TFAM) were downregulated, while NF-κB, caspase-3, and TBARS were increased, accompanied by significant depletion of antioxidant defenses (GSH, GR, GPx, SOD, GST, CAT, TAC) and pronounced testicular histopathology. These effects were dose-dependent, and PS-MPs were detected in testicular tissue by pyrolysis-GC/MS at the doses of 10 µg/kg and higher. Collectively, the data identify mitochondrial dysfunction–driven oxidative stress and associated inflammation as a key mechanism by which PS-MPs induce spermatogenic failure, hormonal disruption, and testicular damage, highlighting their potential as potent male reproductive toxicants.

Geraniol (GO), a traditional plant-derived medicine, has demonstrated anti-osteoclastogenic properties that preserve bone integrity and inhibit bone resorption. This study aimed to evaluate the effect of GO in the adjuvant arthritis rat model, alone and combined with methotrexate (MX), with emphasis on miR-124 and miR-30a effect on the inflammasome (NLRP3)-related disease progression pathways. Fourteen days post-adjuvant injection, male Sprague–Dawley rats were treated with methotrexate (MX, 1 mg/kg/week), low-dose GO (100 mg/kg/day), high-dose GO (200 mg/kg/day), or a combination of MX and high-dose GO for 14 days. Arthritis progression was assessed using the arthrogram score and hind paw swelling. Tibiotarsal joint tissue was analyzed for inflammatory and autophagy markers, angiogenic factors, miR-124, and miR-30a. Radiological and histopathological examination of the ankle joint was performed, as well as immunohistochemistry for NLRP3. Increased hind paw swelling and changes in radiological and histopathological characteristics confirmed the development of AA. Biochemical analysis of synovial tissue revealed decreased expression of miR-124 and miR-30a, accompanied by increased NLRP3 expression, as well as enhanced autophagy, angiogenesis, and inflammatory markers. Geraniol, in a dose-dependent manner, could reverse inflammatory parameters without any significant toxicological signs. These findings suggest that GO modulates the NLRP3 pathway through miRNA regulation. The synergistic effect of the GO and MX combination uncovers a novel therapeutic strategy in RA.

Non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastric ulcers remain a significant clinical challenge. Aloe vera (Av), a natural, eco-friendly agent, is recognized for its gastroprotective properties, while pentoxifylline (Px) is known to improve gastric microcirculation. This study aimed to investigate the synergistic gastroprotective effects of Av and Px, when co-delivered into a floating gastroretentive raft system with Px incorporated as solid lipid nanoparticles (SLNs), enhancing both bioavailability and therapeutic efficacy. SLNs containing Px were formulated using varying concentrations of lipid excipients and incorporated into alginate based floating rafts. The formulations were subjected to in vitro characterization, including drug release profiles and physicochemical properties. Network pharmacology analysis identified key therapeutic targets for anti-ulcer activity. In vivo, gastric ulcers were induced in rats via high-dose ibuprofen (IBU, 400 mg/kg). Animals were divided into treatment groups receiving different drug combinations for seven days. Gastric tissue was assessed for ulcer index, histopathological changes, and biochemical markers of inflammation, oxidative stress, and apoptosis. Gastric juice and serum were also evaluated for toxicity markers. The optimized formulation demonstrated favorable in vitro properties, including sustained release of Px. In vivo findings revealed significant gastroprotection with the combined Av and Px-SLN raft system, evidenced by reduced ulcer scores, suppressed inflammatory and oxidative stress markers, and apoptotic regulation compared to controls. The co-delivery of Av and Px-loaded SLNs in a floating raft system presents a novel and promising approach for treating NSAID-induced gastric ulcers, with enhanced therapeutic effects and targeted gastric retention.

Astaxanthin (ATX) is a potent natural antioxidant that shows promise against hepatocellular carcinoma (HCC). We investigated the therapeutic potential of ATX and its impact on Wnt/β-catenin pathway in a rat model, inducing HCC by nitrosodiethylamine (DEN) and carbon tetrachloride (CCl4). Rats were divided into five groups; I: control, II: HCC, III: HCC rats received ATX (5 days/week), IV: HCC rats received doxorubicin (DOX) weekly, V: HCC rats received combination therapy, for 4 weeks. Our results indicate that combination therapy significantly improved serum biomarkers, reducing alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alpha-fetoprotein (AFP) levels by 45%, 35%, 49%, respectively compared to untreated HCC rats. Histopathological examination revealed the absence of hepato-carcinogenic nodules in the DOX- and combination-treated groups. Furthermore, combination therapy downregulated Wnt/β-catenin pathway components, decreasing frizzled-7 (FZD-7) by 56%, low-density lipoprotein receptor-related proteins 5/6 (LRP5/6) by 62%, β-catenin by 58%, and upregulating glycogen synthase kinase-3β (GSK3β) by 41% compared to untreated HCC rats. Consequently, the expression of key proteins such as cyclin D1 was ameliorated by 46%. While DOX monotherapy upregulated multidrug resistance protein-1 (MDR1) by 65%, combination therapy mitigated this increase by 36%. These findings highlight that ATX has potential therapeutic benefits in HCC treatment in rats.

Abstract Hydroxyapatite nanoparticles (HANPs) are increasingly utilized in biomedical and technological fields due to their biocompatibility and structural similarity to bone mineral. However, accumulating evidence indicates that prolonged exposure to HANPs may adversely affect the male reproductive system through oxidative stress, inflammation, apoptosis, and dysregulated autophagy. This study investigated the protective role of Monascus purpureus red pigments (RP), naturally derived bioactive compounds with antioxidant and anti-inflammatory properties, against HANP-induced testicular damage in adult male rats. Animals were orally treated with HANPs (88.3 mg/kg), RP (10, 20, or 40 mg/kg), or their combination for 50 days. Reproductive toxicity was assessed by analyzing semen quality, serum reproductive hormones, oxidative and inflammatory markers, apoptotic activity, expression of key autophagy-related genes (Beclin-1, LC3B, ULK1, and ATG9), and testicular histopathology. HANPs exposure caused significant reproductive impairment, evidenced by deteriorated semen parameters, disrupted testosterone, follicle-stimulating hormone and luteinizing hormone levels, elevated oxidative stress, increased NF-κB and caspase-3 activity, and upregulation of autophagy-related genes, accompanied by marked histopathological damage. Co-administration of RP markedly attenuated these alterations in a dose-dependent manner, with the highest dose (40 mg/kg) restoring reproductive function, redox balance, inflammatory and apoptotic status, autophagy signaling, and testicular architecture toward near-control levels. Molecular docking analysis revealed strong binding affinities of the major RP components, monascorubramine and rubropunctamine, to the autophagy-related protein LC3B, supporting a potential mechanistic role in autophagy modulation. Collectively, these findings demonstrate that M. purpureus RPs effectively protect against HANP-induced testicular toxicity through coordinated antioxidant, anti-inflammatory, anti-apoptotic, and autophagy-regulatory mechanisms.

Breast cancer (BC) is the second most frequently diagnosed malignancy worldwide and the most common cancer among Egyptian women, accounting for 38.8

Instigating novel therapeutic strategies to combat breast cancer has become an urgent need. Astaxanthin (ASX), a keto-carotenoid, has been confirmed to possess antitumor activity, yet studies on breast cancer are still limited. The present study was deployed to unveil ASX's antitumor effects, alone or combined with doxorubicin (DOX), on 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors in Sprague‒Dawley female rats. Five groups of rats were assigned (n = 10), including normal group, which received the vehicle only, whereas other groups received DMBA for tumor induction, after which: group 3 received ASX (25 mg/kg/day; orally), group 4 received DOX (2 mg/kg/week; i.p.), and group 5 received both drugs. This study focused on assessing the role of Notch-1 signaling with some miRNAs orchestrating the pathway. Herein, ASX boosted miR-34a expression, which decreased the level of Notch-1 protein. In addition, miR-34a upregulation halted cell cycle progression by augmenting p21 protein level and triggering apoptosis by decreasing survivin and increasing Bax protein levels. Moreover, the downregulated miR-146a and miR-210 were escorted by decreased NF-κB and VEGF protein levels, respectively, suggesting their potential role in angiogenesis. Remarkably, ASX/DOX combination showed greater effects than either agent alone. Correlation and bioinformatics analyses manifested a significant relationship among all studied parameters. The ASX's restorative effect was further confirmed by histopathological examination. To the best of our knowledge, this study verified ASX's ability to abrogate DMBA-induced mammary tumors by impeding Notch-1 pathway, thus mitigating cell cycle progression and angiogenesis and augmenting apoptosis, exemplifying the interplay between Notch-1 and its downstream targets with different miRNAs.

Long term use of Flunixin meglumine produces many gastric and hepatic hazards. The current study aimed to investigate using Alpha lipoic acid (ALA) for treating flunixin meglumine (FM)-induced liver and gastrointestinal problems in male rats. FM alternated with ALA for 14 and 56 days in the experiment. This study divided 72 male rats into six groups, 12 rats for each group. Group 1 (control) received saline and distilled water, Group 2 (ALA) received alpha lipoic acid orally at 100 mg/kg bwt, Group 3 (FM-2.5) received Flunixin meglumine subcutaneously at 2.5 mg/kg bwt, Group 4 (FM-5) received Flunixin meglumine subcutaneously, Group 5 (FM-2.5 and ALA) received FM and ALA, and Group 6 received FM and ALA. Elevated white blood cell (WBC) concentrations, ALT, AST, ALP, pro-inflammatory cytokines (NF-κB, TNF-α, HMG), malonaldehyde (MDA), and significant reductions in hepatic and gastric total antioxidant capacity (TAC) were observed. At weeks 4 and 8, FM-5-treated groups had a lower stomach index weight. These changes improved when Groups 5 and 6 used ALA and FM. ALA treatment reduced WBCs, ALT, AST, ALP, NF-κB, TNF-α, HMG, MDA, TAC, and stomach index weight gains in FM-5-treated groups. Finally, biochemical markers and stomach index volume showed liver and stomach dysfunctions in male rats after FM injections. The simultaneous administration of ALA greatly reduced these deficits, suggesting it may prevent FM-related hepatic and gastrointestinal diseases.

The treatment of chronic disease (CKD) is a great challenge in healthcare that requires an innovative approach to address its complex nature. RNA nanotechnology has emerged rapidly and received attention in the last few years because of its significant aptitude for therapies. Hence, the present study aimed to design, construct, and characterize a multifunctional (anti-miR-34a DNA aptamer-kidney targeted) RNA nanoparticle (RNPs) based on bacteriophage phi29 packaging RNA three-way junction (pRNA-3WJ), and then explore their in vivo toxicity and therapeutic potentials in mice model of CKD. After confirming the safety and specific targeting capability of the prepared core 3WJ (3WJ) and the therapeutic 3WJ (3WJ-Kapt/anti-miR-34a) RNPs to renal tissue using healthy mice, CKD was induced in C57BL/6 mice using adenine. CKD mice were treated with a single intravenous injection of 3WJ or 3WJ-Kapt/anti-miR-34a. Every week, 5 mice of each group were selected randomly for sample collection for 4 weeks post-treatment. The anti-miR-34a 3WJ-RNPs have shown stability, safety, and efficacy in renal targeting using DNA aptamer, by targeting miR-34a in renal tissue, 3WJ-Kapt/anti-miR-34a suppressed profibrotic gene expression and induced anti-fibrotic pathways’ expression. Our present study provides preliminary and pioneering evidence for the promising treatment of renal fibrosis and CKD through targeting miR-34a in the renal tissue by 3WJ-RNPs.

Aging has emerged as a prominent area of academic inquiry. Brain aging is a complex physiological process characterized by features such as enhanced apoptosis, oxidative stress, neuroinflammation, mitochondrial dysfunction, and impaired autophagy. Currently, effective preventative or therapeutic approaches for age-related neurodegenerative disorders remain elusive. Ectoine, a naturally occurring compatible solute, possesses diverse applications in biological engineering, cosmetics, medicine, and the food industry. Ectoine is reported to exhibit anti-inflammatory, antioxidant, and anti-apoptotic properties, making it a potential anti-aging agent. Consequently, the present study investigated the potential neuroprotective effects of Ectoine against d-galactose (D-gal)-induced brain aging. Accelerated aging was induced by subcutaneous injection of D-gal. Rats were subsequently divided into a control group, an aged group, and Ectoine-supplemented groups, receiving daily doses of 10, 20, and 40 mg/kg, respectively. Our findings revealed that Ectoine effectively and dose-dependently protected against D-gal-induced brain aging by inhibiting oxidative stress, enhancing the antioxidant system, decreasing neuroinflammation, restoring autophagy and mitochondrial homeostasis, and inhibiting apoptosis. Furthermore, Ectoine significantly restored the expression of miR-124 and its target genes; however, this effect is correlative and warrants further mechanistic validation. Additionally, while Ectoine’s neuroprotective effects were observed at the tissue level, its cell-type specificity remains to be determined. These findings suggest that Ectoine may exert multi-pathway neuroprotective effects in brain aging. However, the current data are exploratory and warrant further validation to define causality and translational applicability.

Introduction:Epilepsy is a common neurological disorder; seizures and hyperexcitability are its defining features in the central nervous system (CNS). The condition known as status epilepticus (SE) can be fatal, as it involves seizures occurring. Epilepsy is typically treated with antiepileptic drugs (AEDs) like carbamazepine (CBZ). The present study aimed to establish a rat model of SE-like disease using the LiCl-pilocarpine and then utilize these rat models to evaluate the therapeutic potential of AST and/or CBZ in a solution form or loaded on NLCs via intranasal administration. Additionally, to investigate the potential molecular targets of AST and AST + CBZ-nanoformulations. Methods:After the treatment was completed, the rats underwent behavioral tests, including the rotarod and Morris Water Maze (MWM). They are then sacrificed and their brains were dissected to obtain the cerebral cortex and hippocampus for the assessment of neurotransmitters such as gamma-aminobutyric acid (GABA), serotonin, and dopamine; gene expression of GABA type A (GABAA) receptors subunits and gephyrin; indicators of inflammation like nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and High-Mobility Group Box 1 (HMGB1); antioxidant markers, including nuclear factor transcription factor E2-related factor 2 (Nrf2) and hem oxygenase-1 (HO-1). Results:The rats treated with the combination of AST and CBZ in nano-formulations seeing the best results. Discussion:Astaxanthin (AST) may reduce epilepsy-induced oxidative stress and neuronal cell death in the brain. Nano lipid carriers (NLCs) serve as better drug delivery carriers for lipophilic drugs such as CBZ and AST. AST exhibited potential anti-epileptic effects on its own, particularly as NLC-nanoformulations and when combined with conventional AEDs (CBZ).

Acute myocardial infarction (MI), a serious manifestation of ischemic heart disease, remains the culprit for mortality among coronary heart disease patients. Astaxanthin has demonstrated the ability to alleviate inflammation-induced myocardial damage while maintaining a balance between oxidants and antioxidants. This study investigates the cardioprotective potential of astaxanthin (ASX), particularly when encapsulated in nanostructured lipid carriers (NLCs), in isoprenaline (ISO)-induced myocardial infarction in rats. The study involved 48 rats separated into 6 groups. ASX and Nano-ASX (5 mg/kg) were administrated orally for 21 days before MI induction (isoprenaline, 85 mg/kg, subcutaneously). Blood and cardiac tissue samples were taken 24 h following the last isoprenaline injection for biochemical and histopathological investigation. The findings reveal that nano-formulated ASX significantly reduces oxidative stress and cardiac injury markers, including CK-MB, Troponin-I, and LDH. Additionally, it enhances antioxidant enzyme activities (GSH, GPx, and GSH-RD) and decreases inflammatory markers (COX-2 and VEGF). The study further demonstrates that nano-ASX stimulates autophagy by upregulating critical genes such as Beclin-1, ULK1, and LC3B, which are vital for cardiac protection and repair. Histological analysis confirms these biochemical outcomes, showing reduced myocardial damage and inflammation in the nano-ASX-treated groups. This study concludes the potential of ASX nano-formulations as an advanced therapeutic approach for myocardial infarction, leveraging improved bioavailability and targeting oxidative stress, inflammation, and autophagic mechanisms.

Parkinson's disease (PD) is a prevalent neurodegenerative disease. As the disease advances, patients become less receptive to levodopa and disease progression continues. So, there is a need for alternative treatment. Green synthesis of silver nanoparticles using Nigella sativa (NS-AgNPs) gives AgNPs additional pharmacological properties. We aimed to explore the possible therapeutic and/or protective effects of NS-AgNPs on PD-like model rats at different levels: histological, behavioral, α-synuclein (α-syn) aggregation, redox, neurotransmitters, apoptosis, and microRNAs (miR-34c and miR-124). The PD-like model was induced in rats by subcutaneous injection of rotenone (2 mg/kg) daily for 30 days. Then, PD-like rats were divided into the Nanotreated group, receiving NS-AgNPs (orally, 10 mg/kg daily for 30 days); Sinemet-treated group, receiving Sinemet 25 mg/250 mg (orally 10 mg/kg daily for 30 days); and Nanoprotected group, receiving rotenone and NS-AgNPs (10 mg/kg daily for 30 days) simultaneously. The PD-like rats disturbed the striatal histoarchitecture, increased α-syn content, oxidative stress, inflammation, and apoptosis, and decreased neurotransmission and microRNAs (miRs) levels. The Sinemet-treated group showed moderate histoarchitectural improvement and partially enhanced behavioral performance, neurotransmission, inflammation, and oxidative stress. In contrast, the NS-AgNPs ameliorated these effects and targeted multiple key pathways in the development and progression of PD, mainly through the modulation of miR-34a and miR-124 expression and significant elevation in dopamine content. It also decreased α-syn aggregation, inhibited microglial activation and apoptosis, decreased oxidative stress levels, and upregulated vesicular monoamine transporter 2 (VMAT2). This goes accordingly with the histopathological examination of the striatum and improvement in the behavioral performance of the PD-like rats. All of these effects, together with no adverse effects of NS-AgNPs, make it a promising therapeutic and neuroprotective agent for PD management.

Hydroxyapatite nanoparticles (HANPs) are widely used in biomedical applications due to their biocompatibility and structural similarity to human bones. However, like other nanoparticles, HANPs circulate in the bloodstream and accumulate in organs such as the liver, raising toxicity concerns. This study investigated the hepatic effects of oral HANPs exposure at a dose of 88.3 mg/kg body weight in male rats and evaluated the protective potential of varying doses of Monascus purpureus red pigment (RP; 10, 20, 40 mg/kg body weight). HANPs exposure led to significant disruptions, including elevated liver function biomarkers, altered lipid profiles, increased oxidative stress, reduced antioxidant enzyme activity, and heightened inflammatory responses, along with the suppression of key metabolic regulators. Histopathological analysis further revealed substantial liver tissue alterations. However, co-treatment with M. purpureus RP effectively mitigated these adverse effects, restoring biochemical parameters to near-normal levels, with higher RP doses offering greater preservation of liver histoarchitecture. These findings underscore M. purpureus RP as a promising hepatoprotective agent against HANPs-induced liver toxicity.