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.

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.

Unleashing new MTDL AChE and BuChE inhibitors as potential anti-AD therapeutic agents: In vitro, in vivo and in silico studies.

Alzheimer's disease (AD) is challenging due to its irreversible declining cognitive symptoms and multifactorial nature. This work tackles targeting both acetylcholinesterase (AChE) and BuChE with a multitarget-directed ligand (MTDL) through design, synthesis, and biological and in silico evaluation of a series of twenty eight new 5-substituted-2-anilino-1,3,4-oxadiazole derivatives 4a-g, 5a-g, 9a-g and 13a-g dual inhibitors of the target biomolecules. In vitro cholinesterases inhibition and selectivity assay of the synthesized derivatives showed excellent nanomolar level inhibitory activities. Compound 5a, the most potent inhibitor, elicited IC50s of 46.9 and 3.5 nM against AChE and BuChE, respectively (SI = 0.07), 5 folds better than the known dual inhibitor Rivastagmine. In vivo and ex vivo investigation showed that 5a significantly inhibited MDA levels and increased GSH contents, thus, attenuating the brain tissue oxidative stress. Additionally, 5a significantly decreased AChE and BuChE levels and inhibited self-mediated ß-amyloid aggregation in brains of treated rats. Histopathological and immunohistochemical evaluation demonstrated lessened damage and decreased caspase-3 and VEGF expression levels. In silico prediction of 5a's pharmacokinetics and toxicity profiles reflected promising results. Finally, 5a demonstrated tight binding interactions with the two target biomolecules upon docking along with stable complex formation with its bio-targets throughout the 100 ns MD trajectories.

Maca roots: A potential therapeutic in the management of metabolic disorders through the modulation of metabolic biochemical markers in rats fed high-fat high-carbohydrate diet.

ETHNOPHARMACOLOGICAL RELEVANCE: Maca root (Lepidium meyenii Walp.) is a Peruvian plant of the Brassicaceae family. Maca roots are popular food supplements used to treat a variety of ailments described traditionally as enhancing metabolic and health conditions. AIM OF THE STUDY: Metabolic syndrome (MetS) has been the real scourge globally, affecting more than one-fourth of the global population. MetS causes the development of multi-organ illnesses, including altered blood cholesterol and sugar levels, oxidative stress, and hypertension. This study evaluated maca root total methanolic extract (MTE) as a potential nutraceutical to manage the complications of MetS. MATERIALS AND METHODS: After the first 4 weeks of a high-fat high-carbohydrate diet (HFCD), streptozotocin (STZ) was injected in Wistar rats to induce the MetS model. Animals were treated orally with MTE at 100 mg/kg and 300 mg/kg for 4 weeks compared to metformin at 200 mg/kg after confirmation of diabetes. RESULTS: One month of MTE supplementation in HFCD-fed rats remarkably decreased the elevation of blood glucose and lipids, improved liver function and insulin resistance, additionally it successfully restored the state of inflammatory and oxidative stress. The extract was standardized to contain total phenolics equal to 24.45 ± 0.96 µg Gallic acid/mg extract. CONCLUSIONS: Our findings suggest that MTE improves MetS by reducing hyperglycemia, hyperlipidemia, inflammation, and oxidative stress. While also improving beta cell secretory functions, implying that MTE could be used as a balancing drug in the prevention and treatment of metabolic abnormalities linked to type 2 diabetes.

Efficacy of Quercetin and Quercetin Loaded Chitosan Nanoparticles Against Cisplatin-Induced Renal and Testicular Toxicity via Attenuation of Oxidative Stress, Inflammation, and Apoptosis.

BACKGROUND/OBJECTIVES: Flavonoids, including quercetin, have attracted much attention due to their potential health-promoting effects. METHODS: The current experiment aims to see whether quercetin (QUE) in nanoparticle form could mitigate testicular and renal toxicity caused by cisplatin (CIS) more effectively than normally formulated QUE. Rats were randomly treated with CIS alone or in combination with QUE or QUE.NPs (Quercetin-loaded chitosan nanoparticles) for 4 weeks. QUE and QUE.NPs were given orally (10 mg/kg, three times a week), while CIS was given intraperitoneally (2 mg/kg, twice a week). RESULTS: Compared to QUE- and CIS + QUE.NP-treated rats, CIS exposure induced anxiety and emotional stress as well as promoted oxidative stress in both testicular and renal tissues. Moreover, CIS reduced serum testosterone levels and diminished testicular IL-10, as well as CIS-induced renal failure, as indicated by hypokalemia, and increased levels of creatinine, urea, sodium, IL-18, and KIM-1. Further, severe histological changes were observed in the testis and kidney of CIS-intoxicated rats. Regarding immunohistochemical staining, CIS significantly upregulated Bax, downregulated Bcl-2, and moderately enhanced PCNA expression. CONCLUSIONS: Our findings suggest that both QUE and QUE.NPs modulated emotional disturbance and improved testicular and renal functions via modulation of oxidation, inflammation, and apoptosis. However, QUE.NPs performed better than QUE-treated rats.

Soluble Dietary Fibers as Antihyperlipidemic Agents: A Comprehensive Review to Maximize Their Health Benefits.

The number of hypercholesterolemic people is increasing rapidly worldwide, with elevated lipid profiles representing a major risk factor of coronary heart diseases. Dietary intervention was shown to improve the lipid profile, thus enhancing the quality of life. Dietary fiber is a nondigestible form of carbohydrates, due to the lack of the digestive enzyme in humans required to digest fiber, and is classified according to its water solubility properties as either soluble (SDF) or insoluble dietary fiber (IDF). Consumption of SDF is associated with several health benefits such as reduced lipid levels, lower blood pressure, improved blood glucose control, improved immune function, and reduced inflammation. SDF has been shown to lower blood cholesterol by several action mechanisms including directly due to the gelling, mucilaginous, and viscous fiber nature, and indirectly due to its fermented products and modulation of the gut microbiome. This review aims to provide a holistic overview on how SDF impacts the lipid profile. We start by providing an overview of the chemical structure of the major SDFs including mucilage, gums (gum arabic and guar gum), pectin, and inulin.

Fortified anti-proliferative activity of niclosamide for breast cancer treatment: In-vitro and in-vivo assessment.

Breast cancer represents one of the top lethal cancer types among the females worldwide. Several factors manipulate the clinical outcome of the treatment as the stage of the cancer upon detection, genetic and hormonal factors, drug resistance and metastasis. Accordingly, drug's repositioning, enhancing the bioavailability and encapsulation into nanoparticles (NPs) are among the predilected pathways for enhanced therapeutic outcome. Niclosamide (NIC) is an anthelmintic drug and has been repositioned as anticancer agent after revealing its anti-neoplastic activity. Piperine (PIP) was used as food spice until its anticancer activity was discovered. However, their hydrophobicity constrains their therapeutic efficiency. The cytotoxicity of both drugs in the free form was tested on MCF-7 cells, and the results indicated a NIC cytotoxicity enhancement by PIP. Then, NIC and PIP were encapsulated successfully into F127-NPs with entrapment efficiency of 97 % and 82 %, respectively. Particle size, zeta potential, TEM and FTIR confirmed the micellization process and drug encapsulation. The developed NIC-NPs and PIP-NPs exerted potent anticancer effect as compared to the free forms. Accordingly, the mixture; NIC-NPs/PIP-NPs was tested and its cytotoxicity exceeded the individually encapsulated drugs. Flowcytometry assessment was performed and demonstrated an induced cell death through the apoptotic stage. Additionally, in-vivo therapeutic efficiency of NIC-NPs/PIP-NPs was assessed through Ehrlich ascites tumor and the nanocombination therapy exerted superior additive anticancer effect when compared to NIC-NPs which is attributed to the PIP-NPs induced bioavailability. The study can be considered the first one investigating the PIP role in bioenhancing the anti-proliferative activity of NIC to combat breast cancer.

Layer-by-layer development of chitosan/alginate-based platelet-mimicking nanocapsules for augmenting doxorubicin cytotoxicity against breast cancer.

Breast carcinoma is considered one of the most invasive and life-threatening malignancies in females. Mastectomy, radiation therapy, hormone therapy and chemotherapy are the most common treatment choices for breast cancer. Doxorubicin (DOX) is one of the most regularly utilized medications in breast cancer protocols. However, DOX has showed numerous side effects including lethal cardiotoxicity. This study aims to fortify DOX cytotoxicity and lowering its side effects via its combining with the antidiabetic metformin (MET) as an adjuvant therapy, along with its effective delivery using natural platelet-rich plasma (PRP), and newly-developed PRP-mimicking nanocapsules (NCs). The PRP-mimicking NCs were fabricated via layer-by-layer (LBL) deposition of oppositely charged biodegradable and biocompatible chitosan (CS) and alginate (ALG) on a core of synthesized polystyrene nanoparticles (PS NPs) followed by removal of the PS core. Both natural PRP and PRP-mimicking NCs were loaded with DOX and MET adjuvant therapy, followed by their physicochemical characterizations including DLS, FTIR, DSC, and morphological evaluation using TEM. In-vitro drug release studies, cytotoxicity, apoptosis/necrosis, and cell cycle analysis were conducted using MCF-7 breast cancer cells. Also, an in-vivo assessment was carried out using EAC-bearing balb/c mice animal model to evaluate the effect of DOX/MET-loaded natural PRP and PRP-mimicked NCs on tumor weight, volume and growth biomarkers in addition to analyzing the immunohistopathology of the treated tissues. Results confirmed the development of CS/ALG-based PRP-mimicking NCs with a higher loading capacity of both drugs (DOX and MET) and smaller size (259.7 ± 19.3 nm) than natural PRP (489 ± 20.827 nm). Both in-vitro and in-vivo studies were in agreement and confirmed that MET synergized the anticancer activity of DOX against breast cancer. Besides, the developed LBL NCs successfully mimicked the PRP in improving the loaded drugs biological efficiency more than free drugs.

Correction: Mansour et al. Dual-Enhanced Pluronic Nanoformulated Methotrexate-Based Treatment Approach for Breast Cancer: Development and Evaluation of In Vitro and In Vivo Efficiency. Pharmaceutics 2022, 14, 2668.

In the original publication [...].

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.

Recent advances in glycyrrhizin metabolism, health benefits, clinical effects and drug delivery systems for efficacy improvement; a comprehensive review.

BACKGROUND: Glycyrrhizin (GL) is a major active constituent of licorice root (Glycyrrhiza glabra) that is considered one of the oldest and most frequently employed botanicals in Chinese medicine and worldwide, with most effects attributed to its rich GL content. Structurally, GL a triterpene saponin that is widely used as a flavoring agent in foodstuffs and cosmetics, and also proposed for various clinical applications with a myriad of health benefits. Pharmacological and biological activities of GL include antiviral, anti-inflammatory, antioxidant, and anticancer activities (in vitro and in vivo). Currently, there is no comprehensive review on GL biological effects and its action mechanisms. PURPOSE: This review summarizes GL pharmacological actions from a molecular biology perception, presented on its metabolism and side effects based on in vitro, in vitro and clinical studies. Moreover, the potential of GL as a nanomedicine delivery system is also summarized. The progress in drug delivery research using GL presented herein is expected to provide a theoretical basis for developing other novel drugs formulations. METHODS: A systematic review was carried out in several electronic databases (Science Direct, SpringerLink, CNKI, PubMed, Web of Science, Elsevier, and Scopus), using the following key words: glycyrrhizin "AND" bioactivity "OR" clinic "OR" therapeutic "OR" drug delivery. This search included manuscripts published between 1989 and 2021. RESULTS: 126 researches were selected and summarized in this review. The analysis of these studies indicated that GL has antiviral activity against different viruses. Further, GL efficiently suppressed the respiratory manifestations associated with COVID-19 by reducing the expression of angiotensin converting enzyme 2 (ACE2) that employed by the virus as an entry point. Otherwise, GL was found to induce antioxidant, anti-inflammatory, immune-modulatory, and anticancer activity. Besides, diminution the particle size of GL to nanometer size significantly augments their action and biodistribution. CONCLUSION: This article summarizes the pharmacological actions of GL. The potential of GL as a nanomedicine delivery system is also presented. Nevertheless, most studies reported provide no deep insight of GL health effects warranting for more future studies to elucidate its action mechanism and potential therapeutic benefits through preclinical and clinical trials.

Anti-arthritic activity of the flavonoids fraction of ivy leaves (Hedera helix L.) standardized extract in adjuvant induced arthritis model in rats in relation to its metabolite profile using LC/MS.

Ivy leaves (Hedera helix) is a traditional plant used for common cold, cough, and bronchial disorders and can be used for rheumatoid arthritis (RA) as an attempt in alternative medicine. RA is a chronic autoimmune disease characterized by its increasing frequency and adverse consequences. There is an urgent need for a long-term therapy that has favorable biological effects and is less expensive than the already authorized synthetic medicines. This study aimed to determine the anti-arthritic potentials of Hedera helix with determination of the bioactive fraction and discovery of its second-generation metabolites by means of LC/MS. The total ivy ethanolic extract (TIE-E), saponins fraction (Sap-F) and flavonoids fraction (Flav-F) were investigated for their in-vitro anti-arthritic effects and in-vivo by Adjuvant-induced arthritis (AIA) using Complete Freund's Adjuvant (0.1 mL, CFA) intradermal relative to the usual dose of ibuprofen (5 mg/kg). We examined the physical alterations, rheumatoid biomarkers, cytokines that cause and inhibit inflammation, markers of oxidative stress, hyaluronidase and ß-glucuronidase enzyme activity. Each paw's histopathology was also evaluated. The chemical profiles of TIE-E were studied using LC/MS in both positive and negative ionization modes. TIE-E (200 mg/kg) and Flav-F (100 mg/kg) significantly (P < 0.05) lowered the edema of the paws, serum immunological indicators, inflammatory cytokines, degenerative enzymes, and indicators of reactive oxygen species with increasing in the anti-inflammatory cytokines. Our findings suggest that extracts of ivy leaves might be used effectively to treat rheumatoid arthritis, where its flavonoid content is responsible for that, and it is able to repress biochemical, oxidative, and pathological changes associated with (AIA) Adjuvant-induced arthritis.

Switching indication of PEGylated lipid nanocapsules-loaded with rolapitant and deferasirox against breast cancer: Enhanced in-vitro and in-vivo cytotoxicity.

Breast cancer (BC) is considered the leading cause of mortality and morbidity among adult women worldwide, and it is associated with many genetic or hormonal factors. Despite the advanced therapeutic and theranostic strategies for BC treatment, cancer metastasis and relapse are often observed among patients which lead to therapeutic failure. Accordingly, among the repositioned medication against BC proliferation is neurokinin receptor antagonists and iron chelating agents especially rolapitant HCl (RP) and deferasirox (DFO), respectively. However, RP and DFO are classified as class II with low aqueous solubility. Both drugs were nanoformulated into PEGylated lipid nanocapsules (LNCs) for enhancing their aqueous solubility and augmenting their efficacy. RP-LNCs, DFO-LNCs and their combinations were evaluated according to particle size (PS), zeta potential, polydispersity index (PDI) and surface morphology. Importantly, the antitumor effect of these novel molecules and their nanoforms was evaluated against the suppression of Ehrlich Ascites tumor model using female mice. Results revealed that RP-LNCs, DFO-LNCs and RP/DFO-LNCs exerted PS from 45.23 ± 3.54 to 60.1 ± 3.32 nm with PDI around 0.20 which indicates homogenous particles distribution. Also, RP-LNCs, DFO-LNCs and RP/DFO-LNCs displayed surface charges of +16.6 ± 6.9, -13.3 ± 5.82 and - 20.2 ± 5.40 mV, respectively. The obtained LNCs conferred a high potent cytotoxic effect against MCF7 cancer cells as compared to parent drugs, with IC50 of 10.86 ± 0.89, 3.34 ± 0.99 and 2.24 ± 0.97 µg/mL for RP-LNCs, DFO-LNCs and RP/DFO-LNCs, respectively. The in-vivo pharmacodynamics effect of the developed nano-formulations showed superior antitumor effect for the individual drugs rather than their combinations as compared to the control group. The current study confirmed the potential of RP and DFO nanoforms as promising therapeutic agents for BC treatment.

Bioactive phenolics fraction of Hedera helix L. (Common Ivy Leaf) standardized extract ameliorates LPS-induced acute lung injury in the mouse model through the inhibition of proinflammatory cytokines and oxidative stress.

Hedera helix L. (family Araliaceae) is classified as a conventional plant used as a medicinal product in the cure and prevention of upper respiratory tract inflammation and infection due to its secretolytic and broncholytic effects. Our research was conducted to authenticate the anti-inflammatory effect of ivy leaves extract in the prevention of acute lung injury (ALI) caused by intranasal administration of lipopolysaccharides (LPS). In-vitro antimicrobial, anti-inflammatory, and anti-oxidant were evaluated, in addition to the in-vivo acute lung inflammation model induced by LPS in mice. The animals were divided into seven groups randomly (each group containing 10 mice): control negative (saline only), control positive (LPS group), standard (Dexamethasone 2 mg/kg), ethanolic ivy leaves extract (EIE, 100 mg/kg), ethanolic ivy leaves extract (EIE, 200 mg/kg), saponin rich fraction (SRF, 100 mg/kg) and phenolic rich fraction (PRF, 100 mg/kg). Right lungs were homogenized to determine the levels of SOD, MDA, catalase, IL-10, TNF-α, NO, IL-1ß, IL-6, PGE2, and MPO. Left lungs were excised for histopathology and histomorphometry. Immunohistochemistry of Cox-2 and TNF-α levels were measured. Additionally, Western blotting was used to determine the levels of phosphorylated MAPK. Also, the ethanolic extract was also standardized through HPLC analysis for its content of rutin.The data showed that the oral supplementation with EIE, 200 mg/kg significantly (P < 0.05) decreased the pro-inflammatory mediators, and oxidative stress biomarkers induced by LPS. Interestingly, the phenolics showed promising activity, therefore they are responsible for the action. In conclusion, the standardized ivy leaf extract could be advised for acute lung injury for its antimicrobial, anti-oxidant, and anti-inflammatory activities.

Dual-Enhanced Pluronic Nanoformulated Methotrexate-Based Treatment Approach for Breast Cancer: Development and Evaluation of In Vitro and In Vivo Efficiency.

Breast cancer is a prevalent tumor and causes deadly metastatic complications. Myriad cancer types, including breast cancer, are effectively treated by methotrexate (MTX). However, MTX hydrophobicity, adverse effects and the development of resistance have inspired a search for new effective strategies to overcome these challenges. These may include the addition of a bioenhancer and/or encapsulation into appropriate nano-based carriers. In the present study, the anticancer effect of MTX was fortified through dual approaches. First, the concomitant use of piperine (PIP) as a bioenhancer with MTX, which was investigated in the MCF-7 cell line. The results depicted significantly lower IC50 values for the combination (PIP/MTX) than for MTX. Second, PIP and MTX were individually nanoformulated into F-127 pluronic nanomicelles (PIP-NMs) and F-127/P-105 mixed pluronic nanomicelles (MTX-MNMs), respectively, validated by several characterization techniques, and the re-investigated cytotoxicity of PIP-NMs and MTX-MNMs was fortified. Besides, the PIP-NMs/MTX-MNMs demonstrated further cytotoxicity enhancement. The PIP-NMs/MTX-MNMs combination was analyzed by flow cytometry to understand the cell death mechanism. Moreover, the in vivo assessment of PIP-NMs/MTX-MNMs was adopted through the Ehrlich ascites model, which revealed a significant reduction of the tumor weight. However, some results of the tumor markers showed that the addition of PIP-NMs to MTX-MNMs did not significantly enhance the antitumor effect.

Discovery of New 1,3,4-Oxadiazoles with Dual Activity Targeting the Cholinergic Pathway as Effective Anti-Alzheimer Agents.

Finding an effective anti-Alzheimer agent is quite challenging due to its multifactorial nature. As such, multitarget directed ligands (MTDLs) could be a promising paradigm for finding potential therapeutically effective new small-molecule bioactive agents against Alzheimer's disease (AD). We herein present the design, synthesis, and biological evaluation of a new series of compounds based on a 5-pyrid-3-yl-1,3,4-oxadiazole scaffold. Our synthesized compounds displayed excellent in vitro enzyme inhibitory activity at nanomolar (nM) concentrations against two major AD disease-modifying targets, i.e., acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among our compounds, 5e was considered the best dual inhibitor of both AChE (IC50 = 50.87 nM) and BuChE (IC50 = 4.77 nM), where these values surpassed those of rivastagmine (the only FDA-approved dual AChE and BuChE inhibitor) in our study. Furthermore, in vivo and ex vivo testing of the hit compound 5e highlighted its significant AD-biotargeting effects including reducing the elevated levels of lipid peroxidation and glutathione (GSH), normalizing levels of 8-OHdG, and, most importantly, decreasing the levels of the well-known AD hallmark ß-amyloid protein. Finally, the binding ability of 5e to each of our targets, AChE and BuChE, was confirmed through additional molecular docking and molecular dynamics (MD) simulations that reflected good interactions of 5e to the active site of both targets. Hence, we herein present a series of new 1,3,4-oxadiazoles that are promising leads for the development of dual-acting AChE and BuChE inhibitors for the management of AD.

The dual gastro- and neuroprotective effects of curcumin loaded chitosan nanoparticles against cold restraint stress in rats.

Stress is a condition affecting different body systems. Curcumin (CUR) is a natural compound that has various pharmacological benefits. However, its poor oral bioavailability limits its therapeutic value. This study aimed to formulating curcumin loaded chitosan nanoparticles (CS.CUR.NPs) and investigate its gastroprotective and neuroprotective effects in rats subjected to cold restraint stress (CRS), in reference to conventional oral CUR preparation, and explore its underlying mechanism. Treated groups received either CUR or CS.CUR.NPs (100 mg∕kg) orally for 14 days before exposure to CRS. CRS elicited marked behavioral changes and gastric ulcer accompanied by histopathological abnormalities of the brain and stomach along with elevation of pain score. CUR and CS.CUR.NPs improved stress-induced gastric ulcer, cognitive performance, and pain sensation. Mechanistically, CRS disrupts oxidative and inflammatory status of the brain as manifested by high malondialdehyde and IL-6 and low total antioxidant capacity and IL-10, along with high C-reactive protein level. CRS decreased nuclear factor erythroid 2-related factor2 (Nrf2) and increased nuclear factor-kappa B (NF-κB) expressions. Furthermore, brain levels of unphosphorylated signal transducer and activator of transcription3 (U-STAT3) and glial fibrillary acidic protein (GFAP) were upregulated with stress. CUR and CS.CUR.NPs provided beneficial effects against harmful consequences resulting from stress with superior beneficial effects reported with CS.CUR.NPs. In conclusion, these findings shed light on the neuroprotective effect of CUR and CS.CUR.NPs against stress-induced neurobehavioral and neurochemical deficits and protection against stress-associated gastric ulcer. Moreover, we explored a potential crosslink between neuroinflammation, U-STAT3, NF-κB, and GFAP in brain dysfunction resulted from CRS.

Metabolome-based profiling of African baobab fruit (Adansonia digitata L.) using a multiplex approach of MS and NMR techniques in relation to its biological activity.

Adansonia digitata L. also known as African baobab is one of the most important fruit-producing trees, widely distributed in the African continent. Baobab fruits are known to possess potential health benefits and nutritional value. This study aimed to holistically dissect the metabolome of A. digitata fruits using a novel comparative protocol using three different analytical platforms. Ultra high performance liquid chromatography coupled to high-resolution tandem mass spectrometry (UHPLC-HRMS/MS), and headspace solid-phase microextraction/gas chromatography coupled to mass spectrometry (HS-SPME/GC-MS) were respectively employed for phytonutrients and aroma profiling, whereas GC-MS post silylation provided an overview of nutrients i.e., sugars. UHPLC-HRMS/MS analysis allowed for the assignment of 77 metabolites, among which 50% are reported for the first time in the fruit. While GC-MS of silylated and aroma compounds led to the identification of 74 and 16 compounds, respectively. Finally, NMR-based metabolite fingerprinting permitted the quantification of the major metabolites for future standardization. In parallel, in vivo antidiabetic potential of the baobab fruit using a streptozotocin (STZ) induced diabetic rat model was assessed. Histopathological and immune-histochemical investigations revealed hepatoprotective and renoprotective effects of A. digitata fruit along with mitigation against diabetes complications. Moreover, the administration of A. digitata fruits (150 mg kg-1) twice a week lowered fasting blood glucose levels.

Acetylator Genotype-Dependent Dyslipidemia in Rats Congenic for N-Acetyltransferase 2.

Recent reports suggest that arylamine N-acetyltransferases (NAT1 and/or NAT2) serve important roles in regulation of energy utility and insulin sensitivity. We investigated the interaction between diet (control vs. high-fat diet) and acetylator phenotype (rapid vs. slow) using previously established congenic rat lines (in F344 background) that exhibit rapid or slow Nat2 (orthologous to human NAT1) acetylator genotypes. Male and female rats of each genotype were fed control or high-fat (Western-style) diet for 26 weeks. We then examined diet- and acetylator genotype-dependent changes in body and liver weights, systemic glucose tolerance, insulin sensitivity, and plasma lipid profile. Male and female rats on the high fat diet weighed approximately 10% more than rats on the control diet and the percentage liver to body weight was consistently higher in rapid than slow acetylator rats. Rapid acetylator rats were more prone to develop dyslipidemia overall (i.e., higher triglyceride; higher LDL; and lower HDL), compared to slow acetylator rats. Total cholesterol (TC)-to-HDL ratios were significantly higher and HDL-to-LDL ratios were significantly lower in rapid acetylator rats. Our data suggest that rats with rapid systemic Nat2 (NAT1 in humans) genotype exhibited higher dyslipidemia conferring risk for metabolic syndrome and cardiovascular dysfunction.