PMID: 

Naunyn Schmiedebergs Arch Pharmacol. 2019 Nov ;392(11):1383-1391. Epub 2019 Jun 24. PMID: 31236657

Abstract Title: 

Effect of oleuropein on morphine-induced hippocampus neurotoxicity and memory impairments in rats.

Abstract: 

Oleuropein, as an olive leaf extract antioxidant polyphenol, has been reported to be a free radical scavenger. This study was done to investigate the effects of oleuropein, against morphine-induced hippocampus neurotoxicity and memory impairment in rats. The Morris water maze (MWM) test was used to assess the effect of oleuropein (5, 15, and 30 mg/kg, i.p., co-administrated with morphine) on spatial learning and memory of male Wistar rats which were treated with morphine sulfate (45 mg/kg, s.c., 4 weeks). In order to evaluate the cleaved caspase-3, Bax, and Bcl2 protein expression (as biochemical markers of apoptosis) in CA1 area of hippocampus tissue, the western blot test was used. Also, to evaluate the oxidative stress status of hippocampus CA1 area tissue, the malondialdehyde (MDA) level, superoxide dismutase (SOD) activity, and glutathione peroxidase (GPx) activity were assessed. The data showed that oleuropein treatment (15and 30 mg/kg) improves the spatial learning and memory impairments in morphine-treated animals. Also, oleuropein treatment decreased the apoptosis and oxidative stress levels in the hippocampus CA1 area of morphine-treated rats. Oleuropein can prevent the spatial learning and memory impairments inmorphine-treated rats. Molecular mechanisms underlying the observed effects could be at least partially related to the inhibition of neuronal apoptosis and oxidative stress in the hippocampus CA1 area of morphine-treated rats.

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PMID: 

Anticancer Agents Med Chem. 2019 Jul 21. Epub 2019 Jul 21. PMID: 31333142

Abstract Title: 

Hydroxytyrosol and Oleuropein Inhibit Migration and Invasion of MDA-MB-231 Triple-Negative Breast Cancer Cell via Induction of Autophagy.

Abstract: 

BACKGROUND: Breast Cancer (BC) is the leading cause of cancer-related deaths among women. As such, novel chemotherapeutic agents are urgently needed, especially for Triple-Negative Breast Cancer (TNBC). Hydroxytyrosol (HT) and Oleuropein (OL) are rich in olive oil, which is associated with a low occurrence of BC. However, the effects and mechanisms of action of HT and OL in BC cells is still unclear. This study aimed to explore the molecular mechanisms underlying the antitumor effect of HT and OL in TNBC.METHODS: TNBC MDA-MB-231 cells were treated with HT and OL in combination with Hepatocyte Growth Factor (HGF), rapamycin (Rapa, an inducer of autophagy) or 3-methyladenine (3-MA, an inhibitor of autophagy). Cell viability, migration, invasion, and autophagy signaling were analyzed by scratch assays, transwell migration assays, and Western blot analysis.RESULTS: Treatment with HT or OL reduced MDA-MB-231 cell viability in a dose-dependent manner. MDA-MB-231 cells were more sensitive to HT treatment than OL treatment. Rapa treatment could significantly block HGF-induced MDA-MB-231 cell migration and invasion, suggesting that inhibition of autophagy could promote migration and invasion. Moreover, HT or OL treatment significantly suppressed HGF or 3-MA induced cell migration and invasion by reversing LC3 II/I and Beclin-1 downregulation and reversing p62 upregulation.CONCLUSION: These data indicated that HT and OL may inhibit migration and invasion of TNBC cells by activating autophagy. These findings provide potential therapeutic strategies that target autophagy to limit the pathogenesis and progression of BC.

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PMID: 

Int J Mol Med. 2019 Oct ;44(4):1531-1540. Epub 2019 Aug 5. PMID: 31432093

Abstract Title: 

Hydroxytyrosol promotes autophagy by regulating SIRT1 against advanced oxidation protein product‑induced NADPH oxidase and inflammatory response.

Abstract: 

Advanced oxidation protein products (AOPPs) can trigger NADPH oxidase (NOX) and lead to the production of reactive oxygen species (ROS) in the pathophysiology of rheumatoid arthritis (RA). Hydroxytyrosol (HT) is a phenolic composite in olive oil that has antioxidant and anti‑inflammatory effects and enhances autophagy. Early research has revealed that HT can activate the silent information regulator 1 (SIRT1) pathway to induce autophagy and alleviate the cartilage inflammatory response caused by H2O2. However, whether HT can attenuate AOPP‑induced NOX and inflammatory responses remains to be elucidated. The present study aimed to investigate how HT can alleviate the damage caused by AOPPs. In cell experiments, chondrocytes were pre‑stimulated with HT and then exposed to AOPPs. First, it was found that HT promoted autophagy through the SIRT1 pathway, increased the expression of autophagy‑related proteins including microtubule‑associated protein 1 light chain 3, autophagy related (ATG)5 and ATG7, and decreased the expression of P62. Furthermore, HT reduced the expression of NOX, which was affected by AOPPs in chondrocytes through the SIRT1 pathway.Finally, the expression of inflammatory cytokines caused by AOPPs was downregulated following HT treatment. In conclusion, it was found that HT reduced the expression of NOX and inhibited the inflammatory response caused by AOPPs in chondrocytes through the SIRT1 pathway.

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PMID: 

Biofactors. 2019 Aug 27. Epub 2019 Aug 27. PMID: 31454114

Abstract Title: 

Docosahexaenoic acid and hydroxytyrosol co-administration fully prevents liver steatosis and related parameters in mice subjected to high-fat diet: A molecular approach.

Abstract: 

Attenuation of high-fat diet (HFD)-induced liver steatosis is accomplished by different nutritional interventions. Considering that the n-3 PUFA docosahexaenoic acid (DHA) modulates lipid metabolism and the antioxidant hydroxytyrosol (HT) diminishes oxidative stress underlying fatty liver, it is hypothesized that HFD-induced steatosis is suppressed by DHA and HT co-administration. Male C57BL/6J mice were fed a control diet (CD; 10% fat, 20% protein, 70% carbohydrates) or a HFD (60% fat, 20% protein, 20% carbohydrates) for 12 weeks, without and with supplementation of DHA (50 mg/kg/day), HT (5 mg/kg/day) or both. The combined DHA + HT protocol fully prevented liver steatosis and the concomitant pro-inflammatory state induced by HFD, with suppression of lipogenic and oxidative stress signaling, recovery of fattyacid oxidation capacity and enhancement in resolvin availability affording higher inflammation resolution capability. Abrogation of HFD-induced hepatic steatosis by DHA and HT co-administration represents a crucial therapeutic strategy eluding disease progression into stages lacking efficacious handling at present time.

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PMID: 

Nutrients. 2019 Oct 11 ;11(10). Epub 2019 Oct 11. PMID: 31614692

Abstract Title: 

Hydroxytyrosol, the Major Phenolic Compound of Olive Oil, as an Acute Therapeutic Strategy after Ischemic Stroke.

Abstract: 

Stroke is one of the leading causes of adult disability worldwide. After ischemic stroke, damaged tissue surrounding the irreversibly damaged core of the infarct, the penumbra, is still salvageable and is therefore a target for acute therapeutic strategies. The Mediterranean diet (MD) has been shown to lower stroke risk. MD is characterized by increased intake of extra-virgin olive oil, of which hydroxytyrosol (HT) is the foremost phenolic component. This study investigates the effect of an HT-enriched diet directly after stroke on regaining motor and cognitive functioning, MRI parameters, neuroinflammation, and neurogenesis. Stroke mice on an HT diet showed increased strength in the forepaws, as well as improved short-term recognition memory probably due to improvement in functional connectivity (FC). Moreover, mice on an HT diet showed increased cerebral blood flow (CBF) and also heightened expression of brain derived neurotrophic factor (Bdnf), indicating a novel neurogenic potential of HT. This result was additionally accompanied by an enhanced transcription of the postsynaptic marker postsynaptic density protein 95 (Psd-95) and by a decreased ionized calcium-binding adapter molecule 1 (IBA-1) level indicative of lower neuroinflammation. These results suggest that an HT-enriched diet could serve as a beneficial therapeutic approach to attenuate ischemic stroke-associated damage.

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PMID: 

Nutrients. 2019 Oct 17 ;11(10). Epub 2019 Oct 17. PMID: 31627295

Abstract Title: 

Hydroxytyrosol Modulates Adipocyte Gene and miRNA Expression Under Inflammatory Condition.

Abstract: 

Chronic inflammation of the adipose tissue (AT) is a major contributor to obesity-associated cardiometabolic complications. The olive oil polyphenol hydroxytyrosol (HT) contributes to Mediterranean diet cardiometabolic benefits through mechanisms still partially unknown. We investigated HT (1 and 10μmol/L) effects on gene expression (mRNA and microRNA) related to inflammation induced by 10 ng/mL tumor necrosis factor (TNF)-α in human Simpson-Golabi-Behmel Syndrome (SGBS) adipocytes. At real-time PCR, HT significantly inhibited TNF-α-induced mRNA levels, of monocyte chemoattractant protein-1, C-X-C Motif Ligand-10, interleukin (IL)-1β, IL-6, vascular endothelial growth factor, plasminogen activator inhibitor-1, cyclooxygenase-2, macrophage colony-stimulating factor, matrix metalloproteinase-2, Cu/Zn superoxide dismutase-1, and glutathione peroxidase, as well as surface expression of intercellular adhesion molecule-1, and reverted the TNF-α-mediated inhibition of endothelial nitric oxide synthase, peroxisome proliferator-activated receptor coactivator-1α, and glucose transporter-4. We found similar effects in adipocytes stimulated by macrophage-conditioned media. Accordingly, HT significantly counteracted miR-155-5p, miR-34a-5p, and let-7c-5p expression in both cells and exosomes, and prevented NF-κB activation and production of reactive oxygen species. HT can therefore modulate adipocyte gene expression profile through mechanisms involving a reduction of oxidative stress and NF-κB inhibition. By such mechanisms, HT may blunt macrophage recruitment and improve AT inflammation, preventing the deregulation of pathways involved in obesity-related diseases.

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PMID: 

Drug Chem Toxicol. 2019 Oct 23:1-12. Epub 2019 Oct 23. PMID: 31645146

Abstract Title: 

Chemical composition, antioxidant activities, in an allergic asthma model, ofL. leaf extracts from Collo (Skikda, Algeria).

Abstract: 

This study is an attempt to characterize the chemical composition and antioxidant activity of olive leaves variety (namely Bouricha variety) that is very widespread in the East of Algeria. The aqueous extract (AE) of leaves was initially analyzed for its phenolic profile. Using the liquid chromatography coupled to tandem mass spectrometry analysis, it was possible to identify the predominant components in the AE of the leaves. This extract was hydrolyzed with acid and gave hydroxytyrosol (HT). AE and HT were evaluated for their 1,1-diphenyl-2-picrylhydrazyl radical scavenging capacity, ferric reducing antioxidant power and total antioxidant activity by phosphomolybdenum method. The antioxidant and anti-asthmatic activities of these extracts were examined in a model of experimental asthma in Wistar rats. For measuring the intensity of the airway inflammation, oxidative stress parameters were analyzed in lungs and a histological study of this tissue was performed. The obtained results showed that the sensitization of the ovalbumin (OVA) group induced lung inflammation and severe lipid peroxidation (LPO) revealed by a significant increase in malondialdehyde (MDA) levels and a decrease in the non-enzymatic and enzymatic antioxidant systems. However, the administration of AE and HT extracts significantly improved the antioxidant state in asthma disease and provided evidence for the relation between phenolic compounds and the high antioxidant activity of olive leaves extracts, especially HT more than AE.

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PMID: 

Drug Deliv Transl Res. 2019 Oct 21. Epub 2019 Oct 21. PMID: 31637677

Abstract Title: 

Gold nanoparticles attenuate albuminuria by inhibiting podocyte injury in a rat model of diabetic nephropathy.

Abstract: 

Several recent studies have reported that gold nanoparticles (AuNPs) attenuate hyperglycemia in diabetic animal models without any observed side effects. The present study was intended to provide insight into the effects of 50-nm AuNPs on diabetic kidney disease. Adult male rats were divided into three groups (n = 7/group): control (non-diabetic, ND), diabetic (D), and diabetic treated intraperitoneally with 50-nm AuNPs (AuNPs + D; 2.5 mg/kg/day) for 7 weeks. Diabetes was induced by a single-dose injection of 55 mg/kg streptozotocin. The result showed that AuNP treatment prevented diabetes-associated increases in the blood glucose level. Reduction in 24-h urinary albumin excretion rate, glomerular basement membrane thickness, foot process width, and renal oxidative stress markers was also demonstrated in the AuNP-treated group. In addition, the results showed downregulation effect of AuNPs inrenal mRNA or protein expression of transforming growth factor β1 (TGF-β), fibronectin, collagen IV, tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor-A (VEGF-A). Moreover, the protein expression of nephrin and podocin, podocyte markers, in glomeruli was increased in the AuNPs + D group compared with the D group. These results provide evidence that 50-nm AuNPs can ameliorate renal damage in experimental models of diabetic nephropathy through improving the renal function and downregulating extracellular matrix protein accumulation, along with inhibiting renal oxidative stress and amelioration of podocyte injury.

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PMID: 

J Drug Target. 2019 Oct 17:1-9. Epub 2019 Oct 17. PMID: 31594390

Abstract Title: 

Gold nanoparticles potentiates N-acetylcysteine effects on neurochemicals alterations in rats after polymicrobial sepsis.

Abstract: 

Herein, we report the effect of gold nanoparticles (AuNP) and n-acetylcysteine (NAC) isolated or in association as important anti-inflammatory and antioxidant compounds on brain dysfunction in septic rats. Male Wistar rats after sham operation or caecal ligation and perforation (CLP) were treated with subcutaneously injection of AuNP (50 mg/kg) and/or NAC (20 mg/kg) or saline immediately and 12 h after surgery. Twenty-four hours after CLP, hippocampus and prefrontal cortex were obtained and assayed for myeloperoxidase (MPO) activity, cytokines, lipid peroxidation, protein carbonyls formation, mitochondrial respiratory chain,and CK activity. AuNP + NAC association decreased MPO activity and pro-inflammatory cytokines production, being more effective than NAC or AuNP isolated treatment. AuNP + NAC association and NAC isolated treatment decreased oxidative stress to lipids in both brain structures, while protein oxidation decreased only in the hippocampus of AuNP + NAC association-treated animals. Complex I activity was increased with AuNP + NAC association and NAC isolated in the hippocampus. Regarding CK activity, AuNP and AuNP + NAC association increased this marker in both brain structures after CLP. Our data provide the first experimental demonstration that AuNP and NAC association was able to reduce sepsis-induced brain dysfunction in rats by decreasing neuroinflammation, oxidative stress parameters, mitochondrial dysfunction and CK activity.

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PMID: 

Adv Ther. 2019 Oct 9. Epub 2019 Oct 9. PMID: 31598901

Abstract Title: 

Effect of Orally Administered N-Acetylcysteine on Chronic Bronchitis: A Meta-analysis.

Abstract: 

INTRODUCTION: The effect of N-acetylcysteine (NAC) treatment for patients with chronic bronchitis (CB) is controversial. To better understand the role of NAC in CB treatment, we performed a meta-analysis to provide a more accurate estimation of the importance of NAC treatment.METHODS: PubMed, Embase, and CNKI were systematically searched. The pooled relative risk (RR) and 95% confidence intervals (CI) were calculated using either fixed-effect model or random-effect model based on heterogeneity examination. Statistical analyses were performed using the STATA 12.0 and RevMan 5.2.RESULTS: A total of 11 publications with 775 patients who were taking NAC and 789 controls who were taking placebo were judged eligible regarding inclusion criteria. The pooled analysis demonstrated significant evidence that NAC reduced the frequency of CB exacerbations (RR = 0.81, 95% CI 0.69-0.93, P = 0.004). Patients treated with NAC had significant symptom improvement compared with controls (RR = 1.68, 95% CI 1.13-2.52, P = 0.01). NAC did not significantly increase the risk of adverse effects compared with placebo (RR 0.86, 95% CI 0.67-1.09, P = 0.22). Subgroup analysis was carried out to assess the stability of results. No publication bias was detected during analyses.CONCLUSION: There is a role for NAC treatment in the management of CB by reducing symptoms and exacerbations compared with placebo, without increasing the risk of adverse effects. A regular treatment of low dosage (

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