Colloidal Stability and Cytotoxicity of Polydopamine-Conjugated Gold Nanorods against Prostate Cancer Cell Lines.

Prostate cancer is one of the most common cancers in men. Cell invasion is an important step in the process of cancer metastasis. Herein, gold nanorods (GNRs) and polyethylene glycol (PEG)-coated GNRs were conjugated with polydopamine (PDA). The PDA-nanoconjugates demonstrated excellent colloidal stability upon lyophilization and dispersion in cell culture media with or without the addition of fetal bovine albumin (FBS), compared to unconjugated GNRs. PDA-nanoconjugates exhibited a considerable cytotoxicity against DU-145 and PC3 prostate cancer cell lines over a concentration range of 48 µg/mL-12 µg/mL, while they were biocompatible over a concentration range of 3.0 µg/mL-0.185 µg/mL. Furthermore, PDA-nanoconjugates demonstrated possible anti-invasion activity towards prostate cancer cell lines, particularly DU-145 cell line, by reducing cell migration and cell adhesion properties. The PDA-nanoconjugates could be considered a promising nano-platform toward cancer treatment by reducing the invasion activity; it could also be considered a drug delivery system for chemotherapeutic agents.

Hypolipidemic effect of novel 2,5-bis(4-hydroxybenzylidenamino)-1,3,4-thiadiazole as potential peroxisome proliferation-activated receptor-α agonist in acute hyperlipidemic rat model.

The development of new antihyperlipidemic agents with higher potency and lower side effects is of high priority. In this study, 1,3,4 thiadiazole Schiff base derivatives were synthesized as potential peroxisome proliferation-activated receptor-α (PPARα) agonists and characterized using elemental analysis, FTIR, 1H-NMR, 13C-NMR and mass spectroscopy and then tested for their hypolipidemic activity in Triton WR-1339-induced acute hyperlipidemic rat model in comparison with bezafibrate. The compounds showed significant hypolipidemic activity. Induced fit docking showed that the compounds are potential activators of PPARα with binding scores - 8.00 Kcal/mol for 2,5-bis(4-hydroxybenzylidenamino)-1,3,4-thiadiazole. PCR array analysis showed an increase in the expression of several genes involved in lipid metabolism through mitochondrial fatty acid ß oxidation and are part of PPARα signaling pathway including Acsm3, Fabp4 and Hmgcs1. Gene expression of Lrp12 and Lrp1b involved in LDL uptake by liver cells and Cyp7a1 involved in cholesterol catabolism were also found to be upregulated.

N-(3-Benzoylphenyl)-1H-Indole-2-Carboxamide decreases triglyceride levels by downregulation of Apoc3 gene expression in acute hyperlipidemic rat model.

Hyperlipidemia is a known cause of coronary vascular diseases, which is a major cause of death in many parts of the world. Targeting several pathways that lead to increase in lipid profiles is of great potential to control diseases. 1H-indole-2-carboxamide derivatives were tested for their hypolipidemic activity at the molecular level in comparison with bezafibrate. The gene expression profiles of lipoprotein signaling and cholesterol metabolism and fatty acid metabolism PCR arrays were determined in rats with acute hyperlipidemia induced by Triton WR1339. Lipid profiles of serum from treated rats showed significant hypolipidemic effect by the compounds. Several genes of potential interest were reported to be overexpressed by Triton WR1339 including Apoc3, Apob, Hmgcs2, Apoa1, Apoe, Apof, acsl1, and Decr1. Most of the overexpressed genes were downregulated by N-(3-Benzoylphenyl)-1H-Indole-2-Carboxamide with significant decreases in Apoc3, Apob, Acaa2, Acsl1, and Slc247a5 gene expression levels. N-(4-Benzoylphenyl)-1H-Indole-2-Carboxamide and bezafibrate did not significantly affect the gene expression levels which were increased with acute hyperlipidemia induced by Triton WR1339. In conclusion, gene expression profiling identified the possible mechanism in which Triton WR1339 induces its acute hyperlipidemic effect which was reversed by the use of N-(3-Benzoylphenyl)-1H-Indole-2-Carboxamide.

The pharmacological effects of novel 5-fluoro-N-(9,10-dihydro-9,10-dioxoanthracen-8-yl)-1H-indole-2-carboxamide derivatives on plasma lipid profile of Triton-WR-1339-induced Wistar rats.

A novel series of 5-fluoro-N-(9,10-dihydro-9,10-dioxoanthracen-8-yl)-1H-indole-2-carboxamides (3c-3g) were synthesized. The present study was undertaken to investigate the possible antihyperlipidemic effect of these novel compounds on hyperlipidemic rats. Hyperlipidemia was induced by a single intraperitoneal injection of Triton WR-1339 (300 mg/kg). The tested animals were divided into normal control (NCG), hyperlipidemic control (HCG), compounds 3c-, 3d-, 3e-, 3f-, 3g- and bezafibrate (BF)-treated groups. At a dose of 15 mg/kg, compounds 3c-3g and BF (100 mg/kg) significantly (p < 0.0001) reduced elevated plasma triglycerides levels after 12 and 24 h compared to the hyperlipidemic control group. However, only compounds 3e and 3g obviously showed a significant (p < 0.0001) reduction in plasma total cholesterol levels after 12 and 24 h. Moreover, high-density lipoprotein cholesterol levels were significantly increased in all treated groups. The current study demonstrates that 5-fluoro-N-(9,10-dihydro-9,10-dioxoanthracen-8-yl)-1H-indole-2-carboxamides (3c-3g) have a definite antihyperlipidemic potential and these beneficial activities may contribute to their cardioprotective and antiatherosclerotic role.

The Role of Vitamin E in Protecting against Oxidative Stress, Inflammation, and the Neurotoxic Effects of Acute Paracetamol in Pregnant Female Rats.

Paracetamol (acetaminophen, APAP) is the most common non-prescription analgesic drug used during pregnancy. The aim of this study was to investigate the effect of vitamin E on acute APAP toxicity in pregnant rats. Toxicity in the liver, kidney, and brain (hippocampus, cerebellum, and olfactory bulb) was examined. Twenty pregnant female Wistar rats at gestational day 18 were used. Pregnant rats were divided into four groups: Control, APAP, E + APAP, and APAP + E. The Control group was treated with 0.5 mL p.o. corn oil. The APAP group received 3000 mg/kg p.o. APAP. The E + APAP group received 300 mg/kg p.o. vitamin E one hour before 3000 mg/kg APAP. The APAP + E group received 3000 mg/kg paracetamol one hour before 300 mg/kg p.o. vitamin E. Twenty-four hours after the last treatment administration, rats were euthanized and blood, brain, liver, and kidney samples were collected. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine levels, uric acid (UA), and superoxide dismutase (SOD) levels, as well as the relative mRNA expression of Cyp1a4, Cyp2d6, and Nat2, were determined. Acute APAP treatment upregulated ALT, AST, BUN, and creatinine levels. APAP treatment downregulated UA and SOD levels. APAP treatment upregulated the relative mRNA expression of Cyp1a4 and Cyp2d6, but downregulated Nat2 expression. Vitamin E treatment, either before or after APAP administration, attenuated the toxic effects of APAP. In conclusion, the results showed that an acute toxic APAP dose in late pregnancy can cause oxidative stress and dysregulation in Cyp isoform expression, and that vitamin E treatment attenuates these effects.

In vivo antihyperlipidemic activity of a new series of N-(benzoylphenyl) and N-(acetylphenyl)-1-benzofuran-2-carboxamides in rats.

A new series of N-(benzoylphenyl) and N-(acetylphenyl)-1-benzofuran-2-carboxamides (3a-3d and 4a'-4c') were synthesized. Compounds (3a, 3b, and 4a'-4c') were tested in vivo using Triton-WR-1339-induced hyperlipidemic rats as an experimental model for their hypolipidemic activity. The tested animals were divided into eight groups: control, hyperlipidemic, 3a, 3b, 4a', 4b', 4c', and bezafibrate. At a dose of 15 mg/kg, the elevated plasma triglyceride (TG) levels were significantly reduced in compounds 3b (p <0.0001) and 4c' (p <0.05) after 12 and 24 h compared to the normal control group. Furthermore, high-density lipoprotein-cholesterol levels were remarkably increased in compounds 3b (p <0.001) and 4c' (p <0.05). Meanwhile, compound 4b' slightly reduced the TG levels after 12 and 24 h. The present study demonstrated new properties of the novel series of benzofuran-2-carboxamides 3b and 4c' as potent lipid-lowering agents. It is, therefore, reasonable to assume that compounds 3b and 4c' may have a promising potential in the treatment of hyperlipidemia and coronary heart diseases.

Effects of waterpipe tobacco smoke and ceftriaxone treatment on the expression of endocannabinoid receptors in mesocorticolimbic brain regions.

Chronic tobacco exposure can alter the endocannabinoid (eCB) system, consequently leading to an anxiety state. In this study, we investigated the effects of waterpipe tobacco smoke (WTS) on cannabinoid receptor 1 and 2 (CBR1 and CBR2) gene and protein expression in mesocorticolimbic brain regions. Using elevated plus maze (EPM) and open field (OF) tests, the effects of WTS exposure on withdrawal-induced anxiety-like behavior were examined. The effect of ceftriaxone (CEF), a ß-lactam known to upregulate glutamate transporter 1 (GLT-1), on anxiety and the expression of cannabinoid receptors was also determined. Male Sprague-Dawley rats were randomly assigned to four groups: 1) the Control group was exposed only to standard room air; 2) the WTS group was exposed to tobacco smoke and treated with saline vehicle; 3) the WTS-CEF group was exposed to WTS and treated with ceftriaxone; and 4) the CEF group was exposed only to standard room air and treated with ceftriaxone. Rats were exposed to WTS (or room air) for two hours per day, five days per week for a period of four weeks. Behavioral tests (EPM and OF) were conducted weekly during acute withdrawal, 24 h following WTS exposure. Rats were given either saline or ceftriaxone (200 mg/kg i.p.) for five days during Week 4, 30 min prior to WTS exposure. Withdrawal-induced anxiety was induced by WTS exposure but was reduced by ceftriaxone treatment. WTS exposure decreased CBR1 mRNA and protein expression in the NAc and VTA, but not PFC, and ceftriaxone treatment attenuated these effects. WTS exposure did not change CBR2 mRNA expression in the NAc, VTA, or PFC. These findings demonstrate that WTS exposure dysregulated the endocannabinoid system and increased anxiety-like behavior, and these effects were reversed by ceftriaxone treatment, which suggest the involvement of glutamate transporter 1 in these effects.

Antihyperlipidemic properties of novel N-(benzoylphenyl)-5-substituted-1H-indole-2-carboxamides in Triton WR-1339-induced hyperlipidemic rats.

In the search for new potential antihyperlipidemic agents, the present study focuses on the synthesis of novel N-(benzoylphenyl)-5-substituted-1H-indole-2-carboxamides (compounds 8-12, 15, 16, 18) and investigating their antihyperlipidemic activity using Triton WR-1339-induced hyperlipidemic rats as an experimental model. Hyperlipidemia was developed by intraperitoneal injection of Triton WR-1339 (250 mg/kg body weight). The tested animals were divided into normal control (NCG), hyperlipidemic (HG), compound 8, 9, 15, 16, 18- and bezafibrate treated groups. At a dose of 15 mg/kg body weight, compounds 9, 16, 18 and bezafibrate (100 mg/kg) significantly (p < 0.0001) reduced elevated plasma triglycerides levels after 12 h compared to the hyperlipidemic control group. However, only the group treated with compounds 9, 16 and 18 showed an obviously significant (p < 0.001) reduction in plasma total cholesterol levels after 12 h compared to the hyperlipidemic control group. Moreover, high density lipoprotein-cholesterol levels were significantly (p < 0.0001) increased in all treated groups after 12 h compared to the hyperlipidemic control group, except for compounds 8 and 15 which revealed inactive. It is therefore reasonable to assume that compounds 9, 16 and 18 may have potential in the treatment of hyperlipidemia.

PI3K/AKT and MAPK1 molecular changes preceding matrix metallopeptidases overexpression during tamoxifen-resistance development are correlated to poor prognosis in breast cancer patients.

BACKGROUND: Metastasis and drug resistance remain a persistent key clinical obstacle to the success of breast cancer treatments. Recent years have seen an increased focus on understanding the factors that influence metastasis and drug resistance. METHODS: In this study, the changes in MMPs gene expression were investigated together with their regulatory pathways-PI3K, MAPK and NFKß pathways-during the process of developing tamoxifen resistance in MCF7 cell line. Gene correlation maps and Kaplan-Meier survival plots among all breast cancer patients and patients treated with tamoxifen were evaluated. RESULTS: MMPs gene expression was found to be up regulated in MCF7 cell line treated with tamoxifen during the development of tamoxifen resistance using two approaches. Up-regulation of gene expression of AKT1 and MAPK1 started in cells treated with 10 µM tamoxifen that was followed with up-regulation of other genes in these pathways and MMPs in cells treated with 35 µM tamoxifen. MMPs and genes from PI3K, MAPK and NFKß pathways showed highly significant increase of expression at 50 µM or when cells were treated sequentially six times with 35 µM. Furthermore, increased genes expression was associated with aggressive pattern, clear morphological changes, higher growth rate, increased migration and adhesion potential and tamoxifen insensitivity. Breast cancer distant metastasis-free survival, and survival among tamoxifen treated patients had high expression levels of MAPK1, AKT1, TIMP2, MMP1, and MMP9 showed poor prognosis. CONCLUSION: Early changes of MAPK1, AKT1 gene expression upon tamoxifen treatment could possibly be used as an early marker of resistance and future poor prognosis.

Ceftriaxone Reduces Waterpipe Tobacco Smoke Withdrawal-induced Anxiety in rats via Modulating the Expression of TNF-α/NFĸB, Nrf2, and GLT-1.

Tobacco exposure has been linked to neuroinflammation and adaptive/maladaptive changes in neurotransmitter systems, including in glutamatergic systems. We examined the effects of waterpipe tobacco smoke (WTS) on inflammatory mediators and astroglial glutamate transporters in mesocorticolimbic brain regions including the prefrontal cortex (PFC), nucleus accumbens (NAc) and ventral tegmental area (VTA). The behavioral consequences of WTS exposure on withdrawal-induced anxiety-like behavior were assessed using elevated plus maze (EPM) and open field (OF) tests. Male Sprague-Dawley rats were randomly assigned to 3 experimental groups: a control group exposed only to standard room air, a WTS exposed group treated with saline vehicle, and a WTS exposed group treated with ceftriaxone. WTS exposure was performed for 2 h/day, 5 days/week, for 4 weeks. Behavioral tests (EPM and OF) were conducted weekly 24 h after WTS exposure, during acute withdrawal. During week 4, rats were given either saline or ceftriaxone (200 mg/kg i.p.) 30 min before WTS exposure. WTS increased withdrawal-induced anxiety, and ceftriaxone attenuated this effect. WTS exposure increased the relative mRNA levels for nuclear factor ĸB (NFĸB), tumor necrosis factor-α (TNF-α), and brain-derived neurotrophic factor (BDNF) in the PFC, NAc and VTA, and ceftriaxone treatment reversed these effects. In addition, WTS decreased the relative mRNA of nuclear factor erythroid 2 related factor 2 (Nrf2), glutamate transporter 1 (GLT-1) and cystine-glutamate transporter (xCT) in PFC, NAc and VTA, and ceftriaxone treatment normalized their expression. WTS caused neuroinflammation, alteration in relative mRNA glutamate transport expression, and increased anxiety-like behavior, and these effects were attenuated by ceftriaxone treatment.

Cytotoxicity and Cellular Death Modality of Surface-Decorated Gold Nanorods against a Panel of Breast Cancer Cell Lines.

Herein, the antiproliferative effect of surface-decorated gold nanorods (GNRs) was investigated against three different breast cancer cell lines. The results indicate that the cell lines exhibited different biological responses and death modalities toward the treatment. The cell lines exhibited similar cellular uptake of the nanoparticles; however, MDA-MB-231 demonstrated the highest cytotoxicity compared to other cell lines upon treatment with GNRs. The expression of the CDH1 gene, which is involved in cell adhesion and metastasis, was dramatically increased in treated MDA-MB-231 cells compared to other cell lines. Early apoptosis and late apoptosis are the dominant cellular death modalities of MDA-MB-231 cells upon treatment with GNRs.

Correction: Nanoparticle size and chemical modification play a crucial role in the interaction of nano gold with the brain: extent of accumulation and toxicity.

Correction for 'Nanoparticle size and chemical modification play a crucial role in the interaction of nano gold with the brain: extent of accumulation and toxicity' by Nouf N. Mahmoud et al., Biomater. Sci., 2020, DOI: 10.1039/c9bm02072a.

Nanoparticle size and chemical modification play a crucial role in the interaction of nano gold with the brain: extent of accumulation and toxicity.

The blood brain barrier (BBB) is a very selective barrier that protects the brain and the central nervous system (CNS) from the entry of harmful substances and helps regulate the exchange of different molecules and nutrients from and into the brain and the CNS. This selectivity makes delivering therapeutic and diagnostic materials across the BBB very challenging. In this study, different shapes and sizes of gold nanoparticles (GNP) were synthesized and functionalized with five different thiolated ligands to obtain GNP with various surface chemistries. The potential of GNP of different properties to be accumulated into the brain through the BBB and into other organs was investigated in a mouse model using qualitative and quantitative approaches. Gold nanorods (GNR) functionalized with 4-mercaptophenol (Mph) showed the highest penetration ability across the BBB into the brain with no significant deposition in other organs. Interestingly, increasing the size of GNR retarded their delivery into the brain, while enhancing their accumulation in other organs. On the other hand, gold nanospheres (GNS) demonstrated high deposition percentages in the brain and other organs with possible toxic effects. The properties of GNP play a crucial role in their interaction with the BBB and accumulation in the brain and other organs. Thus, GNP can be considered a promising nano-platform for drug delivery into the brain and as a photothermal-inducing agent against brain cancer.

Gold nanoparticles loaded into polymeric hydrogel for wound healing in rats: Effect of nanoparticles' shape and surface modification.

Nanotechnology-based platforms have gained a growing interest in skin wound healing. Herein, gold nanoparticles (AuNPs) of different shapes (rods and spheres) and surface modifications (neutral, cationic and anionic charged polymers) were synthesized, characterized and loaded into a thermosensitive hydrogel (poloxamer 407). AuNPs-hydrogels exhibited excellent colloidal stability and demonstrated slow and prolonged release behavior over a 48-h of exposure using in vitro model. Hydrogels of poly ethylene glycol (PEG)-gold nanorods (AuNRs) and cationic poly allyl amine hydrochloride (PAH)-AuNRs demonstrated remarkable wound healing properties upon topical application on wounds using an animal model. PEGylated and cationic charged-AuNRs hydrogels have enhanced skin re-epithelization and collagen deposition after 14 days of daily wound treatment compared to controls, and they affected the gene expression of several inflammatory and anti-inflammatory mediators. Hydrogels of PEG-AuNRs and PAH-AuNRs exhibited potent in vitro antibacterial activity against staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa). Furthermore, AuNPs of different shapes and surface modifications demonstrated low percentages of deposition into the main body organs after 21 days of daily wound treatment. Hydrogels of AuNRs could be a promising nano-platform for wound healing.

Second exposure to acetaminophen overdose is associated with liver fibrosis in mice.

Repeated administration of hepatotoxicants is usually accompanied by liver fibrosis. However, the difference in response as a result of repeated exposures of acetaminophen (APAP) compared to a single dose is not well-studied. Therefore, in the current study, the liver response after a second dose of APAP was investigated. Adult fasted Balb/C mice were exposed to two toxic doses of 300 mg/kg APAP, which were administered 72 h apart from each other. Subsequently, blood and liver from the treated mice were collected 24 h and 72 h after both APAP administrations. Liver transaminase, i.e. alanine amino transferase (ALT) and aspartate amino transferase (AST) levels revealed that the fulminant liver damage was reduced after the second APAP administration compared to that observed at the same time point after the first treatment. These results correlated with the necrotic areas as indicated by histological analyses. Surprisingly, Picro Sirius Red (PSR) staining showed that the accumulation of extracellular matrix after the second dose coincides with the upregulation of some fibrogenic signatures, e.g., alpha smooth muscle actin. Non-targeted liver tissue metabolic profiling indicates that most alterations occur 24 h after the first dose of APAP. However, the levels of most metabolites recover to basal values over time. This organ adaptation process is also confirmed by the upregulation of antioxidative systems like e.g. superoxide dismutase and catalase. From the results, it can be concluded that there is a different response of the liver to APAP toxic doses, if the liver has already been exposed to APAP. A necroinflammatory process followed by a liver regeneration was observed after the first APAP exposure. However, fibrogenesis through the accumulation of extracellular matrix is observed after a second challenge. Therefore, further studies are required to mechanistically understand the so called "liver memory".