Hypericum perforatum L. Nanoemulsion Mitigates Cisplatin-Induced Chemobrain via Reducing Neurobehavioral Alterations, Oxidative Stress, Neuroinflammation, and Apoptosis in Adult Rats.

Cisplatin (Cis) is a potent chemotherapeutic agent; however, it is linked with oxidative stress, inflammation, and apoptosis, which may harmfully affect the brain. Hypericum perforatum L. (HP L.) is a strong medicinal plant, but its hydrophobic polyphenolic compounds limit its activity. Therefore, our study aimed to investigate the neuroprotective action of HP L. and its nanoemulsion (NE) against Cis-induced neurotoxicity. The prepared HP.NE was subjected to characterization. The droplet size distribution, surface charge, and morphology were evaluated. In addition, an in vitro dissolution study was conducted. Compared to Cis-intoxicated rats, HP L. and HP.NE-treated rats displayed improved motor activity and spatial working memory. They also showed an increase in their antioxidant defense system and a reduction in the levels of pro-inflammatory cytokines in the brain. Moreover, they showed an increase in the expression levels of the PON-3 and GPX genes, which are associated with a reduction in the brain levels of COX-2 and TP-53. These findings were confirmed by reducing the immunohistochemical expression of nuclear factor kappa (NF-ƘB) and enhanced Ki-67 levels. In conclusion, HP L. is a promising herb and could be used as an adjuvant candidate to ameliorate chemotherapeutic-induced neurotoxicity. Moreover, HP.NE has superior activity in lessening Cis-induced oxidative stress, inflammation, and apoptosis in brain tissue.

Assessment of the neuroprotective effect of selenium-loaded chitosan nanoparticles against silver nanoparticles-induced toxicity in rats.

BACKGROUND: With the recent growth in the applications of silver nanoparticles (Ag-NPs), worries about their harmful effects are increasing. Selenium plays a vital role in the antioxidant defense system as well as free radical scavenging activity. OBJECTIVES: This study aims to inspect the neuroprotective effect of selenium-loaded chitosan nanoparticles (CS-SeNPs) against the adverse impact of Ag-NPs on brain tissue in adult rats. DESIGN: Rats were divided into four groups: group I (control) was administered distilled water (0.5 mL/kg), group II was administered Ag-NPs (100 mg/kg), group III was administered Ag-NPs (100 mg/kg) and CS- SeNPs (0.5 mg/kg) and group IV received only CS- SeNPs (0.5 mg/kg) daily by oral gavage. After 60 days, rats were subjected to behavioral assessment and then euthanized. Brain tissues were obtained for estimation of total antioxidant capacity (TAC), malondialdehyde (MDA), 8-hydroxy-2-deoxy Guanosine (8-OHdG), and Nuclear Factor Erythroid 2 Like Protein 2 (Nrf2). Also, histological examination of the brain and immunohistochemical detection of glial fibrillary acidic protein (GFAP) were investigated RESULTS: exposure to Ag-NPs induced marked neurotoxicity in the brain tissue of rats that was manifested by decreased levels of TAC and Nrf2 with increased levels of MDA and 8-OHdG. Also, various pathological lesions with an increase in the number of GFAP immunoreactive cells were detected. While brain tissue of rats received Ag-NPs plus CS-SeNPs group (III) revealed significantly fewer pathological changes. CONCLUSION: Co-administration of CS-SeNPs significantly ameliorates most of the Ag-NPs-induced brain damage.

Ashwagandha-loaded nanocapsules improved the behavioral alterations, and blocked MAPK and induced Nrf2 signaling pathways in a hepatic encephalopathy rat model.

Ashwagandha (ASH), a vital herb in Ayurvedic medicine, demonstrated potent preclinical hepato- and neuroprotective effects. However, its efficacy is limited due to low oral bioavailability. Accordingly, we encapsulated ASH extract in chitosan-alginate bipolymeric nanocapsules (ASH-BPNCs) to enhance its physical stability and therapeutic effectiveness in the gastrointestinal tract. ASH-BPNC was prepared by emulsification followed by sonication. The NCs showed small particle size (< 220 nm), zeta-potential of 25.2 mV, relatively high entrapment efficiency (79%), physical stability at acidic and neutral pH, and in vitro release profile that extended over 48 h. ASH-BPNC was then investigated in a thioacetamide-induced hepatic encephalopathy (HE) rat model. Compared with free ASH, ASH-BPNC improved survival, neurological score, general motor activity, and cognitive task-performance. ASH-BPNC restored ALT, AST and ammonia serum levels, and maintained hepatic and brain architecture. ASH-BPNC also restored GSH, MDA, and glutathione synthetase levels, and Nrf2 and MAPK signaling pathways in liver and brain tissues. Moreover, ASH-BPNC downregulated hepatic NF-κB immunohistochemical expression. Moreover, the in vivo biodistribution studies demonstrated that most of the administered ASH-BPNC is accumulated in the brain and hepatic tissues. In conclusion, chitosan-alginate BPNCs enhanced the hepatoprotective and neuroprotective effects of ASH, thus providing a promising therapeutic approach for HE.

Salix subserrata Bark Extract-Loaded Chitosan Nanoparticles Attenuate Neurotoxicity Induced by Sodium Arsenate in Rats in Relation with HPLC-PDA-ESI-MS/MS Profile.

Pollution is a worldwide environmental risk. Arsenic (As) is an environmental pollutant with a major health concern due to its toxic effects on multiple body organs, including the brain. Humans are exposed to As through eating contaminated food and water or via skin contact. Salix species (willow) are plants with medicinal efficacy. Salix subserrata Willd bark extract-loaded chitosan nanoparticles (SBE.CNPs) was formulated, characterized, and evaluated against As-induced neurotoxicity. The stem bark was selected for nanoparticle formulation based on HPLC-PDA-ESI-MS/MS profiling and in vitro antioxidant assessment using free radical scavenging activity. SBE.CNPs demonstrated an average un-hydrated diameter of 193.4 ± 24.5 nm and zeta potential of + 39.6 ± 0.4 mV with an encapsulation efficiency of 83.7 ± 4.3%. Compared to As-intoxicated rats, SBE.CNP-treated rats exhibited anxiolytic activity and memory-boosting as evidenced in open field test, light-dark activity box, and Y-maze. Also, it increased the antioxidant biomarkers, including superoxide dismutase and glutathione peroxidase associated with reducing the malondialdehyde levels and apoptotic activity. Besides this, SBE.CNPs maintained the brain architecture and downregulated both nuclear factor-kappa B and heme oxygenase-1 expression. These results suggest that SBE.CNP administration showed promising potent neuroprotective and antioxidative efficiencies against arsenic-induced oxidative threats.

Antidepressant and Cardioprotective Effects of Self-Nanoemulsifying Self-Nanosuspension Loaded with Hypericum perforatum on Post-Myocardial Infarction Depression in Rats.

Hypericum perforatum (HP) is characterized by potent medicinal activity. However, the poor water solubility of many HP constituents limits their therapeutic effectiveness. Self-nanoemulsifying self-nanosuspension loaded with HP (HP.SNESNS) was formulated to improve the bioefficacy of HP. It was prepared using 10% triacetin, 57% Tween 20, and 33% PEG 400 and then incorporated with HP extract (100 mg/mL). HP.SNESNS demonstrated a bimodal size distribution (258.65 ± 29.35 and 9.08 ± 0.01 nm) corresponding to nanosuspension and nanoemulsion, respectively, a zeta potential of -8.03 mV, and an enhanced dissolution profile. Compared to the unformulated HP (100 mg/kg), HP.SNESNS significantly improved cardiac functions by decreasing the serum myocardial enzymes, nitric oxide (NO), and tumor necrosis factor- α (TNF-α) as well as restoring the heart tissue's normal architecture. Furthermore, it ameliorates anxiety, depressive-like behavior, and cognitive dysfunction by decreasing brain TNF-α, elevating neurotransmitters (norepinephrine and serotonin), and brain-derived neurotrophic factor (BDNF). In addition, HP.SNESNS augmented the immunohistochemical expression of cortical and hippocampal glial fibrillary acidic protein (GFAP) levels while downregulating the cortical Bcl-2-associated X protein (Bax) expression levels. Surprisingly, these protective activities were comparable to the HP (300 mg/kg). In conclusion, HP.SNESNS (100 mg/kg) exerted antidepressant and cardioprotective activities in the post-MI depression rat model.

Impact of different processing methods on the phenolics and neuroprotective activity of Fragaria ananassa Duch. extracts in a D-galactose and aluminum chloride-induced rat model of aging.

Age-related diseases, including dementia, are a major health concern affecting daily human life. Strawberry (Fragaria ananassa Duch.) is the most eaten fruit worldwide due to its exceptional aroma and flavor. However, it's rapid softening and decay limit its shelf-life. Freezing and boiling represent the well-known conservation methods to extend its shelf-life. Therefore, we aimed to discover the phytochemical content differences of fresh and processed strawberries associated with investigating and comparing their neuroprotective effects in a rat model of aging. Female Wistar rats were orally pretreated with fresh, boiled, and frozen F. ananassa methanolic extracts (250 mg kg-1) for 2 weeks, and then these extracts were concomitantly exposed to D-galactose [65 mg kg-1, subcutaneously (S/C)] and AlCl3 (200 mg kg-1, orally) for 6 weeks to develop aging-like symptoms. The results of UPLC/ESI-MS phytochemical profiling revealed 36 secondary metabolites, including phenolics, flavonoids, and their glycoside derivatives. Compared with boiled and frozen extracts, the fresh extract ameliorated the behavioral deficits including anxiety and cognitive dysfunction, upregulated brain HO-1 and Nrf2 levels, and markedly reduced caspase-3 and PPAR-γ levels. Moreover, LDH and miRNA-9, 124 and 132 protein expressions were reduced. The histological architecture of the brain hippocampus was restored and glial fibrillary acidic protein (GFAP) immunoexpression was downregulated. In conclusion, the fresh extract has neuroprotective activity that could have a promising role in ameliorating age-related neurodegeneration.

Selenium nanoparticles impart robust neuroprotection against deltamethrin-induced neurotoxicity in male rats by reversing behavioral alterations, oxidative damage, apoptosis, and neuronal loss.

This study investigated the neuroprotective role of selenium nanoparticles (SeNPs) on deltamethrin-induced neurotoxicity in rats. A total of 32 adult male Wister rats were allocated into the following four groups: 1) control, 2) deltamethrin (0.6 mg/kg), 3) SeNPs (0.5 mg/kg), and 4) deltamethrin + SeNPs. All agents were administered orally three times per week for 2 months. Locomotor behavior, anxiety-like behavior, biochemical parameters, including brain oxidative damage biomarkers (Malondialdehyde (MDA) and reduced glutathione (GSH)), brain acetylcholinesterase (AChE), and brain genotoxicity were evaluated. The gene expression levels of IGF-1 and Bcl2 were also determined. Moreover, a brain histopathological examination associated with the immunohistochemical determination of Bax in brain tissue was performed. Deltamethrin-intoxicated rats showed a reduction in the locomotor activity associated with a highly anxious state. They also displayed a disturbance in the brain redox state with a decrease in the brain AChE levels and a high DNA fragmentation percentage. Furthermore, they showed a decrement in the immunohistochemical GFAP levels as well as IGF-1 and Bcl2 gene expression levels with an increase in the immunohistochemical Bax levels. All these changes were confirmed by brain histopathology. Interestingly, SeNPs ameliorated all these changes and restored the normal brain architecture. In conclusion. SeNPs possess a potent medicinal activity due to their antioxidant and anti-inflammatory activity. Therefore, SeNPs can be a potential agent in ameliorating deltamethrin-induced neurotoxicity.

Ashwagandha (Withania somnifera) root extract attenuates hepatic and cognitive deficits in thioacetamide-induced rat model of hepatic encephalopathy via induction of Nrf2/HO-1 and mitigation of NF-κB/MAPK signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Ashwagandha (ASH) is one of the medicinal plants used in traditional Indian, Ayurvedic, and Unani medicines for their broad range of pharmacological activities including, tonic, aphrodisiac, energy stimulant, and counteracting chronic fatigue. Besides, it is used in the treatment of nervous exhaustion, memory-related conditions, insomnia, as well as improving learning ability and memory capacity. ASH is preclinically proven to be efficient in hepatoprotection and improving cognitive impairment, however, its beneficial effects against hepatic encephalopathy (HE) is still unclear. Therefore, this study aimed at investigating the protective effects of ASH root extract against thioacetamide (TAA)-induced HE and delineate the underlying behavioral and pharmacological mechanisms. MATERIALS AND METHODS: ASH metabolites were identified using UPLC-HRMS. Rats were pretreated with ASH (200 and 400 mg/kg) for 29 days and administrated TAA (i.p, 350 mg/kg) in a single dose. Then, behavioral (open field test, Y-maze, modified elevated plus maze and novel object recognition test), and biochemical (ammonia and hepatic toxicity indices) assessments, as well as oxidative stress markers (MDA and GSH) were evaluated. The hepatic and brain levels of glutamine synthetase (GS), nuclear factor erythroid 2-related factor 2 (Nrf2), heme-oxygenase (HO)-1, inducible nitric oxide synthase (iNOS) were detected by enzyme-linked immunosorbent assay (ELISA). The mRNA expressions of p38/ERK½ were determined using real-time polymerase chain reaction (PCR). Moreover, histopathological investigations and immunohistochemical (NF-κB and TNF-α immunohistochemical expressions) examinations were performed. RESULTS: Metabolite profiling of ASH revealed more than 45 identified metabolites including phenolic acids, flavonoids and steroidal lactone triterpenoids. Compared to the TAA-intoxicated group, ASH improved the locomotor and cognitive deficits, serum hepatotoxicity indices and ammonia levels, as well as brain and hepatic histopathological alterations. ASH reduced hepatic and brain levels of MDA, GS, and iNOS, and increased their GSH, Nrf2, and HO-1 levels. Also, ASH downregulated p38 and ERK½ mRNA expressions, and NF-κB and TNF-α immunohistochemical expressions in brain and hepatic tissues. CONCLUSIONS: Our results provided insights into the promising hepato- and neuroprotective effects of ASH, with superiority to 400 mg/kg ASH, to ameliorate HE with its sequential hyperammonemia and liver/brain injuries. This could be attributed to the recorded increase in the spontaneous alternation % and recognition index, antioxidant and anti-inflammatory activities, as well as upregulation of Nrf2 and downregualtion of MAPK signaling pathways.

Nano selenium protects against deltamethrin-induced reproductive toxicity in male rats.

Greater understanding of the efficiency of nanoparticles will assist future research related to male reproductive performance. The current study was performed to assess the potency of selenium nanoparticles (SeNPs) in alleviating deltamethrin (DLM)-induced detrimental effects on sperm characteristics, oxidative status, sexual behavior, and the histological structure of the testes and epididymis in male rats. Thirty-two male Wister rats were divided into four groups according to treatment received orally by gavage 3 times/week for 60 days; control, DLM (0.6 mg/kg bwt), SeNPs (0.5 mg/kg bwt), and DLM-SeNPs groups. DLM caused a significant reduction in sperm count, motility, and viability percent, as well as in body weight and serum testosterone level, blood total antioxidant capacity (TAC), and glutathione peroxidase (GPx) activity. The DLM-treated group showed a significant increase in blood malondialdehyde (MDA) concentration and sperm abnormalities (%), as well as a significant reduction in sexual activity, manifested as an increase in mount, intromission, or ejaculation latency and a reduction in mount or intromission frequency. These toxic effects were confirmed by histological alterations, represented by a significant reduction in the diameter of the seminiferous tubules and spermatogenesis. Conversely, treatment with SeNPs improved DLM-induced negative effects on sperm characteristics, testosterone, and antioxidant biomarkers, as well as behavioral and histopathological alterations. The SeNPs treated group showed improved semen parameters, antioxidant status, and sexual performance. In conclusion, SeNPs may represent an effective treatment for reducing the detrimental effects of DLM on male fertility, and lead to enhanced male reproductive performance.

Phytochemical characterization and anti-inflammatory potential of Egyptian Murcott mandarin cultivar waste (stem, leaves and peel).

The stem (S), leaf (L) and fruit peel (P) of Murcott mandarins were separately extracted using 80% ethanol and then fractionated into dichloromethane (DCM) and ethyl acetate (ET). Their metabolic profiles were studied via HPLC-PDA-ESI-MS/MS and afforded a tentative characterization of 98 compounds, including free organic acids, phenolic acid derivatives, flavonoid aglycones, flavonoid glycosides, flavonoids containing 3-hydroxyl-3-methylglutaroyl (HMG) units, coumarin derivatives and limonoids. Column chromatography resulted in isolation of six metabolites for the first time that were identified as nobiletin (C1), isosinensetin (C2), limonin (C3), 4'-demethylnobiletin (C4), stigmasterol-O-glucoside (C5) and hesperidin (C6). In vitro studies of the anti-inflammatory activity of DCM-L against cyclooxygenases (COXs) and 5-lipoxygenase (5-LOX) enzymes revealed that DCM-L showed higher activity than the other tested fractions. The in vivo gastroprotective effects of that fraction were evaluated using alcohol-induced gastric ulcers in rats. The obtained findings validated the gastroprotective and anti-ulcerogenic activities of DCM-L through its anxiolytic, anti-inflammatory, antioxidant and anti-apoptotic effects. Therefore, we recommend the use of Murcott mandarin leaves as a part of a protection strategy for gastric ulcer.