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Pseudomonas aeruginosa ( P. aeruginosa ) is an aerobic gram-negative, non-spore forming, rod-shaped bacterium. It accelerates the decline in lung function and ultimately leads to increased mortality and morbidity rate. Survival and virulence of P. aeruginosa is due to its biofilm formation ability. The main aim of this study was to test the synergistic effect of silver nanoparticles (AgNPs) in combination with Polymyxin B against biofilms of P. aeruginosa . A total of 500 pus aspirations were collected and bacterial pathogens were identified. Biofilm formation was attained using a glass tube method and microtiter plate assay. The minimum inhibitory concentration of Polymyxin B was determined using agar well diffusion method. Silver nanoparticles were synthesized by chemical reduction method followed by determination of their anti-pseudomonal ability separately and in combination with Polymyxin B using microtiter plate assay. Our results showed that 120 out of 500 samples were Pseudomonas positive. The ratio of multidrug-resistant (MDR) in our collected Pseudomonas samples was 83% (25/30). Generally, the minimum inhibitory concentration (MIC) of Polymyxin B was 16 µg/mL and that of AgNPs was null. However, AgNPs showed great synergistic effect in combination with Polymyxin B. Synergistically, the efficacy of Polymyxin B was enhanced four times as compared to unaided Polymyxin B.

Background: Obstructive jaundice due to malignancies of the biliary tree, gall bladder and pancreas account for a significant number of patients managed by tertiary centres. Management options are curative or palliative, depending on disease stage. This study was performed to see the effectiveness of treatment modalities for these patients and eventual outcome., Methods: This cross-sectional analytical study was conducted at the Department of Gastroenterology and Hepatology, Shaikh Zayed Hospital Lahore, from January 2015 to June 2016. All adult patients aged 18 and above of either sex presenting with obstructive jaundice secondary to malignant disease originating from the gallbladder, biliary-tree or pancreas were included in the study. The disease was staged after admission. The patients then underwent endoscopic, surgical or percutaneous drainage and were followed up for a period of one year., Results: Two hundred & sixty-two patients presenting with jaundice due to malignancy arising from the biliary tree, gall bladder or pancreas were enrolled between January 2015 and June 2016, 141 (53.8%) males and 121 (46.2%) females. Eighty (30.5%) had cholangiocarcinoma, 70 (26.7%), had gall bladder tumours, 61 (23.3%) pancreatic cancer and 51(19.5%) had ampullary tumours. 31 (11.8%) patients had disease qualifying curative surgical resection. One hundred & eighty-five (70.6%) patients underwent palliative therapy in the form of percutaneous in 86 (32.9%) and endoscopic drainage in 126 (48.1%). Twenty-eight (10.7%) patients refused all treatment. Eighteen (6.9%) patients died before undergoing any therapeutic intervention. Thirty-three (12.6%) died during hospital stay. Survival at 3, 6 and 12 months was 49.2% (129 patients), 28.2% (74 patients) and 8.4% (22 patients), respectively. These 22 included all patients who had undergone curative resection. We attributed the largest number of deaths, 197 (75.2%) patients, to metastatic/advanced disease and associated complications., Conclusions: The results showed that patients with advanced disease who were only eligible for palliative therapy, at first presentation, constituted the majority of patients. These patients require skilled endoscopy and interventional radiology teams for successful biliary drainage.

Well-established studies have shown an elevated level of reactive oxygen species (ROS) that induces oxidative stress in the Alzheimer's disease (AD) patient's brain and an animal model of AD. Herein, we investigated the underlying anti-oxidant neuroprotective mechanism of natural dietary supplementation of anthocyanins extracted from Korean black beans in the amyloid precursor protein/presenilin-1 (APP/PS1) mouse model of AD. Both in vivo (APP/PS1 mice) and in vitro (mouse hippocampal HT22 cells) results demonstrated that anthocyanins regulate the phosphorylated-phosphatidylinositol 3-kinase-Akt-glycogen synthase kinase 3 beta (p-PI3K/Akt/GSK3β) pathways and consequently attenuate amyloid beta oligomer (AβO)-induced elevations in ROS level and oxidative stress via stimulating the master endogenous anti-oxidant system of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (Nrf2/HO-1) pathways and prevent apoptosis and neurodegeneration by suppressing the apoptotic and neurodegenerative markers such as activation of caspase-3 and PARP-1 expression as well as the TUNEL and Fluoro-Jade B-positive neuronal cells in the APP/PS1 mice. In vitro ApoTox-Glo™ Triplex assay results also showed that anthocyanins act as a potent anti-oxidant neuroprotective agent and reduce AβO-induced neurotoxicity in the HT22 cells via PI3K/Akt/Nrf2 signaling. Importantly, anthocyanins improve memory-related pre- and postsynaptic protein markers and memory functions in the APP/PS1 mice. In conclusion, our data suggested that consumption and supplementation of natural-derived anti-oxidant neuroprotective agent such as anthocyanins may be beneficial and suggest new dietary-supplement strategies for intervention in and prevention of progressive neurodegenerative diseases, such as AD.

The blood-brain barrier (BBB) hinders drug delivery to the brain. Despite various efforts to develop preprogramed actuation schemes for magnetic drug delivery, the unmodeled aggregation phenomenon limits drug delivery performance. This paper proposes a novel scheme with an aggregation model for a feed-forward magnetic actuation design. A simulation platform for aggregated particle delivery is developed and an actuation scheme is proposed to deliver aggregated magnetic nanoparticles (MNPs) using a discontinuous asymmetrical magnetic actuation. The experimental results with a Y-shaped channel indicated the success of the proposed scheme in steering and disaggregation. The delivery performance of the developed scheme was examined using a realistic, three-dimensional (3D) vessel simulation. Furthermore, the proposed scheme enhanced the transport and uptake of MNPs across the BBB in mice. The scheme presented here facilitates the passage of particles across the BBB to the brain using an electromagnetic actuation scheme., Competing Interests: The authors declare no conflict of interest.

Amyloid-beta (Aβ 1-42 ) plaques and neurofibrillary tangles (NFTs) are the main hallmarks considered to be associated with neuroinflammation in Alzheimer's disease (AD). Recently, nanoparticle-based targeted drug delivery approaches have been found to be a useful tool in the neurotherapeutics field. Therefore, we examined and compared the neuroprotective effect of anthocyanins alone and anthocyanin-loaded poly (ethylene glycol)-gold nanoparticles (PEG-AuNPs) in Aβ 1-42 -injected mouse and in vitro models of AD. We determined that anthocyanins alone or conjugated with PEG-AuNPs (AnPEG-AuNPs) reduced Aβ 1-42 -induced neuroinflammatory and neuroapoptotic markers via inhibiting the p-JNK/NF-κB/p-GSK3β pathway in both in vivo and in vitro AD models. However, anthocyanins loaded with PEG-AuNPs were more effective compared to anthocyanins alone. Taken together, these results demonstrate that PEG-coated gold anthocyanins nanoparticles could be a new therapeutic agent in the field of nanomedicine to prevent neurodegenerative diseases such as AD., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disease, pathologically characterized by the accumulation of aggregated amyloid beta (Aβ) in the brain. Here, we describe for the first time the development of a new, pioneering nanotechnology-based drug delivery approach for potential therapies for neurodegenerative diseases, particularly AD. We demonstrated the delivery of fluorescent carboxyl magnetic Nile Red particles (FMNPs) to the brains of normal mice using a functionalized magnetic field (FMF) composed of positive- and negative-pulsed magnetic fields generated by electromagnetic coils. The FMNPs successfully reached the brain in a few minutes and showed evidence of blood-brain barrier (BBB) crossing. Moreover, the best FMF conditions were found for inducing the FMNPs to reach the cortex and hippocampus regions. Under the same FMF conditions, dextran-coated Fe 3 O 4 magnetic nanoparticles (MNPs) loaded with osmotin (OMNP) were transported to the brains of Aβ 1-42 -treated mice. Compared with native osmotin, the OMNP potently attenuates Aβ 1-42 -induced synaptic deficits, Aβ accumulation, BACE-1 expression and tau hyperphosphorylation. This magnetic drug delivery approach can be extended to preclinical and clinical use and may advance the chances of success in the treatment of neurological disorders like AD in the future.

Despite the promising results in magnetic nanoparticles (MNPs) based targeted drug delivery (TDD), the aggregation of the magnetic nanoparticles deteriorates targeting performance. This paper aims to introduce a magnetic actuation function for aggregated nanoparticles steering in vascular network. To improve the drug delivery performance, first the governing dynamics has been introduced, next the modified field function (MFF) concept has been proposed and finally a computational platform for a Y-shape channel has been used to simulate the particles steering performance. The results showed an acceptable agreement with the experimental results. The proposed actuation method enables us to more accurately steer aggregated nanoparticles and improves targeting performance.

Background: In order to increase the bioavailability of hydrophilic unstable drugs like anthocyanins, we employed a polymer-based nanoparticles approach due to its unique properties such as high stability, improved bioavailability and high water-soluble drug loading efficiency. Anthocyanins constitute a subfamily of flavonoids that possess anti-oxidative, anti-inflammatory and neuroprotective properties. However, anthocyanins are unstable because their phenolic hydroxyl groups are easily oxidized into quinones, causing a reduced biological activity. To overcome this drawback and improve the free radical scavenging capabilities of anthocyanins, in the current study we for the first time encapsulated the anthocyanins in biodegradable nanoparticle formulation based on poly (lactide-co-glycolide) (PLGA) and a stabilizer polyethylene glycol (PEG)-2000. The biological activity and neuroprotective effect of anthocyanin loaded nanoparticles (An-NPs) were investigated in SH-SY5Y cell lines., Results: Morphological examination under transmission electron microscopy (TEM) showed the formation of smooth spherically shaped nanoparticles. The average particle size and zeta potential of An-NPs were in the range of 120-165 nm and -12 mV respectively, with a low polydispersity index (0.4) and displayed a biphasic release profile in vitro. Anthocyanins encapsulation in PLGA@PEG nanoparticles (NPs) did not destroy its inherent properties and exhibit more potent neuroprotective properties. An-NPs were nontoxic to SH-SY5Y cells and increased their cell viability against Aβ 1-42 by its free radical scavenging characteristics and abrogated ROS generation via the p38-MAPK/JNK pathways accompanied by induction of endogenous nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1). Comparative to native bulk anthocyanins, An-NPs effectively attenuated Alzheimer's markers like APP (amyloid precursor protein), BACE-1 (beta-site amyloid precursor protein cleaving enzyme 1), neuroinflammatory markers such as p-NF-kB (phospho-nuclear factor kappa B), TNF-α (tumor necrosis factor) and iNOS (inducible nitric oxide synthase) and neuroapoptotic markers including Bax, Bcl 2 , and Caspase-3 protein expressions accompanied by neurodegeneration against Aβ 1-42 in SH-SY5Y cell lines., Conclusions: Overall, this data not only confirmed the therapeutic potential of anthocyanins in reducing AD pathology but also offer an effective way to improve the efficiency of anthocyanins through the use of nanodrug delivery systems.

Increasing evidence demonstrates that β-amyloid (Aβ) elicits oxidative stress, which contributes to the pathogenesis and disease progression of Alzheimer's disease (AD). The aims of the present study were to determine and explore the antioxidant nature and potential mechanism of vanillic acid (VA) in Aβ 1-42 -induced oxidative stress and neuroinflammation mediated cognitive impairment in mice. An intracerebroventricular (i.c.v.) injection of Aβ 1-42 into the mouse brain triggered increased reactive oxygen species (ROS) levels, neuroinflammation, synaptic deficits, memory impairment, and neurodegeneration. In contrast, the i.p. (intraperitoneal) administration of VA (30 mg/kg, for 3 weeks) after Aβ 1-42 -injection enhanced glutathione levels (GSH) and abrogated ROS generation accompanied by an induction of the endogenous nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) via the activation of Akt and glycogen synthase kinase 3β (GSK-3β) in the brain mice. Additionally, VA treatment decreased Aβ 1-42 -induced neuronal apoptosis and neuroinflammation and improved synaptic and cognitive deficits. Moreover, VA was nontoxic to HT22 cells and increased cell viability after Aβ 1-42 exposure. To our knowledge, this study is the first to reveal the neuroprotective effect of VA against Aβ 1-42 -induced neurotoxicity. Our findings demonstrate that VA could potentially serve as a novel, promising, and accessible neuroprotective agent against progressive neurodegenerative diseases such as AD.

Aims: Lipopolysaccharide (LPS) induces oxidative stress and neuroinflammation both in vivo and in vitro. Here, we provided the first detailed description of the mechanism of melatonin neuroprotection against LPS-induced oxidative stress, acute neuroinflammation, and neurodegeneration in the hippocampal dentate gyrus (DG) region of the postnatal day 7 (PND7) rat brain., Methods: The neuroprotective effects of melatonin against LPS-induced neurotoxicity were analyzed using multiple research techniques, including Western blotting, immunofluorescence, and enzyme-linked immunosorbent assays (ELISAs) in PND7 rat brain homogenates and BV2 cell lysates in vitro. We also used EX527 to inhibit silent information regulator transcript-1 (SIRT1)., Results: A single intraperitoneal (i.p) injection of LPS to PND7 rats significantly induced glial cell activation, acute neuroinflammation, reactive oxygen species (ROS) production and apoptotic neurodegeneration in hippocampal DG region after 4 h. However, the coadministration of melatonin significantly inhibited both LPS-induced acute neuroinflammation and apoptotic neurodegeneration and improved synaptic dysfunction in the hippocampal DG region of PND7 rats. Most importantly, melatonin stimulated the SIRT1/Nrf2 (nuclear factor-erythroid 2-related factor 2) signaling pathway to reduce LPS-induced ROS generation. The beneficial effects of melatonin were further confirmed in LPS-stimulated BV2 microglia cell lines in vitro using EX527 as an inhibitor of SIRT1. LPS-induced oxidative stress, Nrf2 inhibition, and neuroinflammation are SIRT1-dependent in BV2 microglia cell lines., Conclusion: These results demonstrated that melatonin treatment rescued the hippocampal DG region of PND7 rat brains against LPS-induced oxidative stress damage, acute neuroinflammation, and apoptotic neurodegeneration via SIRT1/Nrf2 signaling pathway activation., (© 2016 John Wiley & Sons Ltd.)

Background: Glutamate-induced excitotoxicity, oxidative damage, and neuroinflammation are believed to play an important role in the development of a number of CNS disorders. We recently reported that a high dose of glutamate could induce AMPK-mediated neurodegeneration in the postnatal day 7 (PND7) rat brain. Yet, the mechanism of glutamate-induced oxidative stress and neuroinflammation in the postnatal brain is not well understood. Here, we report for the first time the mechanism of glutamate-induced oxidative damage, neuroinflammation, and neuroprotection by polyphenolic anthocyanins in PND7., Methods: PND7 rat brains, SH-SY5Y, and BV2 cells treated either alone with glutamate or in combination with anthocyanins and compound C were examined with Western blot and immunofluorescence techniques. Additionally, reactive oxygen species (ROS) assay and other ELISA kit assays were employed to know the therapeutic efficacy of anthocyanins against glutamate., Results: A single injection of glutamate to developing rats significantly increased brain glutamate levels, activated and phosphorylated AMPK induction, and inhibited nuclear factor-E2-related factor 2 (Nrf2) after 2, 3, and 4 h in a time-dependent manner. In contrast, anthocyanin co-treatment significantly reduced glutamate-induced AMPK induction, ROS production, neuroinflammation, and neurodegeneration in the developing rat brain. Most importantly, anthocyanins increased glutathione (GSH and GSSG) levels and stimulated the endogenous antioxidant system, including Nrf2 and heme oxygenase-1 (HO-1), against glutamate-induced oxidative stress. Interestingly, blocking AMPK with compound C in young rats abolished glutamate-induced neurotoxicity. Similarly, all these experiments were replicated in SH-SY5Y cells by silencing AMPK with siRNA, which suggests that AMPK is the key mediator in glutamate-induced neurotoxicity., Conclusions: Here, we report for the first time that anthocyanins can potentially decrease glutamate-induced neurotoxicity in young rats. Our work demonstrates that glutamate is toxic to the developing rat brain and that anthocyanins can minimize the severity of glutamate-induced neurotoxicity in an AMPK-dependent manner.

Here we investigated for the first time the inhibitory potential of Glycine (Gly) against ethanol-induced oxidative stress, neuroinflammation and apoptotic neurodegeneration in human neuroblastoma SH-SY5Y cells and in the developing rat brain. The Gly co-treatment significantly increased the cell viability, inhibited the expression of phospho-Nuclear Factor kappa B (p-NF-kB) and caspase-3 and reduced the oxidative stress in ethanol-treated SH-SY5Y cells in a PI3K-dependent manner. Seven days old male rat pups were injected with ethanol (5 g/kg subcutaneously, prepared in a 20% saline solution) and Gly (1 g/kg). Gly co-treatment stimulated the PI3K/Akt signaling pathway to limit the ethanol induced reactive oxygen species (ROS) production in the developing rat brain. It lowered the ethanol-elevated levels of phospho-c Jun N terminal kinase (p-JNK) and its various downstream apoptotic markers, including Bax, cytochrome C, caspase-3 and PARP-1. Additionally, the Gly treatment upregulated antiapoptotic Bcl-2 proteins and prevented ethanol-induced neurodegeneration as assessed by Fluoro-Jade-B (FJB) and Nissl staining. Furthermore, the Gly administration caused significant reduction in the ethanol-induced neuroinflammation by inhibiting the expression of inflammatory markers such as p-NF-kB, cyclooxygenase 2 (COX2) and tumor necrosis factor-α (TNF-α) and reversed the ethanol-induced synaptic protein markers expression. The results suggest that acute Gly treatment reduces ethanol-induced oxidative stress and neuronal cell loss in SH-SY5Y cells and in the developing rat brain. Therefore, Gly may be considered as potential treatment in ethanol-intoxicated newborns and infants., (Copyright © 2016 Elsevier Ltd. All rights reserved.)