Publications by authors named "Mohd Akhtar"

148 Publications

Facile Synthesis of Zn-Doped BiO Nanoparticles and Their Selective Cytotoxicity toward Cancer Cells.

ACS Omega 2021 Jul 29;6(27):17353-17361. Epub 2021 Jun 29.

King Abdullah Institute for Nanotechnology, King Saud University, Riyadh 11451, Saudi Arabia.

Bismuth (III) oxide nanoparticles (BiO NPs) have shown great potential for biomedical applications because of their tunable physicochemical properties. In this work, pure and Zn-doped (1 and 3 mol %) BiO NPs were synthesized by a facile chemical route and their cytotoxicity was examined in cancer cells and normal cells. The X-ray diffraction results show that the tetragonal phase of β-BiO remains unchanged after Zn-doping. Transmission electron microscopy and scanning electron microscopy images depicted that prepared particles were spherical with smooth surfaces and the homogeneous distribution of Zn in BiO with high-quality lattice fringes without distortion. Photoluminescence spectra revealed that intensity of BiO NPs decreases with increasing level of Zn-doping. Biological data showed that Zn-doped BiO NPs induce higher cytotoxicity to human lung (A549) and liver (HepG2) cancer cells as compared to pure BiO NPs, and cytotoxic intensity increases with increasing concentration of Zn-doping. Mechanistic data indicated that Zn-doped BiO NPs induce cytotoxicity in both types of cancer cells through the generation of reactive oxygen species and caspase-3 activation. On the other hand, biocompatibility of Zn-doped BiO NPs in normal cells (primary rat hepatocytes) was greater than that of pure BiO NPs and biocompatibility improves with increasing level of Zn-doping. Altogether, this is the first report highlighting the role of Zn-doping in the anticancer activity of BiO NPs. This study warrants further research on the antitumor activity of Zn-doped BiO NPs in suitable models.
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http://dx.doi.org/10.1021/acsomega.1c01467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280700PMC
July 2021

Efficient Data Communication Using Distributed Ledger Technology and IOTA-Enabled Internet of Things for a Future Machine-to-Machine Economy.

Sensors (Basel) 2021 Jun 25;21(13). Epub 2021 Jun 25.

Department of Electrical and Information Engineering, Polytechnic University of Bari, 70126 Bari, Italy.

A potential rise in interest in the Internet of Things in the upcoming years is expected in the fields of healthcare, supply chain, logistics, industries, smart cities, smart homes, cyber physical systems, etc. This paper discloses the fusion of the Internet of Things (IoT) with the so-called "distributed ledger technology" (DLT). IoT sensors like temperature sensors, motion sensors, GPS or connected devices convey the activity of the environment. Sensor information acquired by such IoT devices are then stored in a blockchain. Data on a blockchain remains immutable however its scalability still remains a challenging issue and thus represents a hindrance for its mass adoption in the IoT. Here a communication system based on IOTA and DLT is discussed with a systematic architecture for IoT devices and a future machine-to-machine (M2M) economy. The data communication between IoT devices is analyzed using multiple use cases such as sending DHT-11 sensor data to the IOTA tangle. The value communication is analyzed using a novel "micro-payment enabled over the top" (MP-OTT) streaming platform that is based on the "pay-as-you-go" and "consumption based" models to showcase IOTA value transactions. In this paper, we propose an enhancement to the classical "masked authenticated message" (MAM) communication protocol and two architectures called dual signature masked authenticated message (DSMAM) and index-based address value transaction (IBAVT). Further, we provided an empirical analysis and discussion of the proposed techniques. The implemented solution provides better address management with secured sharing and communication of IoT data, complete access control over the ownership of data and high scalability in terms of number of transactions that can be handled.
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http://dx.doi.org/10.3390/s21134354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271827PMC
June 2021

Pt-Coated Au Nanoparticle Toxicity Is Preferentially Triggered Via Mitochondrial Nitric Oxide/Reactive Oxygen Species in Human Liver Cancer (HepG2) Cells.

ACS Omega 2021 Jun 28;6(23):15431-15441. Epub 2021 May 28.

Department of Biochemistry, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.

Reactive nitrogen species (RNS) that are formed from the reaction of versatile nitric oxide (NO) with reactive oxygen species (ROS) have been less explored in potential cancer therapy. This may be partly due to the fewer available agents that could induce NO in cells. Here, we report platinum-coated gold nanoparticles (Pt-coated Au NPs; 27 ± 20 nm) as a strong inducer of NO (assessed by live-cell imaging under NO-specific DAR-1 probe labeling and indirectly using a Griess reagent) in human liver carcinoma (HepG2) cells. In addition to NO, this study found a critical role of ROS from mitochondrial sources in the mechanism of toxicity caused by Pt-coated Au NPs. Cotreatment with a thiol-replenishing general antioxidant NAC (-acetyl cysteine) led to significant amelioration of oxidative stress against NP-induced toxicity. However, NAC did not exhibit as much ameliorative potential against NP-induced oxidative stress as the superoxide radical (O)-scavenging mitochondrial specific antioxidant mito-TEMPO did. The higher protective potential of mito-TEMPO in comparison to NAC reveals mitochondrial ROS as an active mediator of NP-induced toxicity in HepG2 cells. Moreover, the relatively unaltered NP-induced NO concentration under cotreatment of GSH modulators NAC and buthionine sulfoximine (BSO) suggested that NO production due to NP treatment is rather independent of the cellular thiols at least in HepG2 cells. Moreover, toxicity potentiation by exogenous HO again suggested a more direct involvement of ROS/RNS in comparison to the less potentiation of toxicity due to GSH-exhausting BSO. A steeper amelioration in NP-induced NO and ROS and, consequently, cytotoxicity by mito-TEMPO in comparison to NAC reveal a pronounced role of NO and ROS via the mitochondrial pathway in the toxicity of Pt-coated Au NPs in HepG2 cells.
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http://dx.doi.org/10.1021/acsomega.1c01882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210405PMC
June 2021

Distributed ledger technology based robust access control and real-time synchronization for consumer electronics.

PeerJ Comput Sci 2021 1;7:e566. Epub 2021 Jun 1.

Department of Electronics and Communication Engineering, Birla Institute of Technology, Ranchi, Jharkhand, India.

Background: Consumer electronics or daily use home appliances are the basic necessity of every household. With the adoption of IoT in consumer electronics, this industry is set to rise exponentially. In recent times, the demand for consumer electronics rises amidst the pandemic due to a paradigm shift from in-office culture to work from home. Despite intelligent IoT devices, smart home configuration, and appliances at our disposal, the rudimentary client-server architecture fails to provide facilities like full access control of data and devices, transparency, secured communication, and synchronization between multiple devices, etc. to the users.

Methods: To overcome these limitations, Blockchain technology has been adopted in recent years, however, it has its own set of limitations in its widespread implementation. Hence, we propose a methodology using the IOTA platform, a distributed ledger technology (DLT) for secured communication between consumer electronics devices and appliances.

Results: The implementation provides access control, interoperability, data storage, and management with an exploratory insight towards a decentralized micro-payment use-case between Electric cars and charging stations.
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http://dx.doi.org/10.7717/peerj-cs.566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176550PMC
June 2021

Linagliptin, a DPP-4 inhibitor, ameliorates Aβ (1-42) peptides induced neurodegeneration and brain insulin resistance (BIR) via insulin receptor substrate-1 (IRS-1) in rat model of Alzheimer's disease.

Neuropharmacology 2021 Jun 11;195:108662. Epub 2021 Jun 11.

Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India. Electronic address:

Alzheimer's disease (AD) is the most devastating neurodegenerative disorder, accounting over 46 million cases of dementia globally. Evidence supports that Brain Insulin Resistance (BIR) due to serine phosphorylation of Insulin Receptor Substrate-1 (IRS-1) has an association with AD. GLP-1 an incretin hormone, rapidly degraded by Dipeptidyl Peptidase-4 (DPP-4) has also confirmed its efficacious role in AD. Linagliptin, a DPP-4 inhibitor is hypothesized to increase GLP-1 level, which then crosses Blood Brain Barrier (BBB), decreases Amyloid-beta (Aβ) and insulin resistance in hippocampus. Thus, the present study was designed to evaluate Linagliptin in Aβ (1-42) peptides induced rat model of AD. Following 1 week of induction, rats were administered with Linagliptin (0.513 mg/kg, 3 mg/kg, and 5 mg/kg) orally for 8 weeks and donepezil (5 mg/kg) as a reference standard. At the end of scheduled treatment neurobehavioral parameters were assessed. After this, rats were sacrificed, hippocampus was isolated from the whole brain for histopathological analysis and biochemical parameters estimation. Linagliptin dose-dependently and significantly reversed motor and cognitive impairment, assessed through locomotor activity (LA) and Morris water maze (MWM) test respectively. Moreover, Linagliptin augmented GLP-1 level and attenuated soluble Aβ (1-42), IRS-1 (s307), GSK-3β, TNF-α, IL-1β, IL-6, AchE and oxidative/nitrosative stress level in hippocampus. H&E and Congo red staining also exhibited neuroprotective and anti-amylodogenic effect respectively. Our study findings implies the significant effect of Linagliptin in reversing the behavioural and biochemical deficits by altering Aβ (1-42) and BIR via IRS-1 confirming one of the mechanism underlying the pathophysiology of AD.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108662DOI Listing
June 2021

Roflumilast and tadalafil improve learning and memory deficits in intracerebroventricular Aβ1-42 rat model of Alzheimer's disease through modulations of hippocampal cAMP/cGMP/BDNF signaling pathway.

Pharmacol Rep 2021 Apr 15. Epub 2021 Apr 15.

Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard (Hamdard University), New Delhi, 110062, India.

Background: Alzheimer's disease (AD) is the most prevalent age-dependent neurodegenerative disease characterized by progressive impairment of memory and cognitive functions. Cyclic nucleotides like cAMP and cGMP are well-known to play an important role in learning and memory functions. Enhancement of cAMP and cGMP levels in the hippocampus by phosphodiesterase (PDE) inhibitors might be a novel therapeutic approach for AD. Thus, the present study was planned to explore the therapeutic potential of roflumilast (RFM) and tadalafil (TDF) phosphodiesterase inhibitors in intracerebroventricular (ICV) Aβ1-42 induced AD in rats.

Methods: ICV Aβ1-42 was administered in rats followed by treatment with RFM (0.05 mg/kg) and TDF (0.51 mg/kg) for 15 days. Novel object recognition (NOR), and Morris water maze (MWM) test were performed during the drug treatment schedule. On the day, 22 rats were sacrificed, and hippocampus was separated for biochemical, neuroinflammation, and histopathological analysis.

Results: Aβ1-42 infused rats were induce behavioral impairment and increased AChE, BACE-1, Aβ1-42, GSK-3β, phosphorylated tau (p-Tau), pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) levels, oxidative stress (increased MDA, Nitrite and decreased GSH), histopathological changes, and reduced cAMP, cGMP, and BDNF levels. RFM and TDF significantly attenuated Aβ1-42 induced memory deficits and neuropathological alterations in the hippocampus.

Conclusion: The outcomes of the current study indicate that RFM and TDF lead to memory enhancement through upregulation of cAMP/cGMP/BDNF pathway, thus they may have a therapeutic potential in cognitive deficits associated with AD.
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http://dx.doi.org/10.1007/s43440-021-00264-wDOI Listing
April 2021

Evaluation of Antinociceptive Profile of Chalcone Derivative (3-(2,5-dimethoxyphenyl)-1-(5-methylfuran-2-yl) prop-2-en-1-one (DMPF-1) .

J Pharm Bioallied Sci 2020 Nov 5;12(Suppl 2):S711-S717. Epub 2020 Nov 5.

Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia.

Introduction: Pain is a major global health issue, where its pharmacotherapy prompts unwanted side effects; hence, the development of effective alternative compounds from natural derivatives with lesser side effects is clinically needed. Chalcone; the precursors of flavonoid, and its derivatives have been widely investigated due to its pharmacological properties.

Objective: This study addressed the therapeutic effect of 3-(2,5-dimethoxyphenyl)-1-(5-methyl furan-2-yl) prop-2-en-1-one (DMPF-1); synthetic chalcone derivative, on antinociceptive activity .

Materials And Methods: The antinociceptive profile was evaluated using acetic-acid-induced abdominal writhing, hot plate, and formalin-induced paw licking test. Capsaicin, phorbol 12-myristate 12 acetate (PMA), and glutamate-induced paw licking test were carried out to evaluate their potential effects toward different targets.

Results: It was shown that the doses of 0.1, 0.5, 1, and 5 mg/kg of DMPF-1 given via intraperitoneal injection showed significant reduction in writhing responses and increased the latency time in hot-plate test where reduced time spent on licking the injected paw in formalin and dose contingency inhibition was observed. The similar results were observed in capsaicin, PMA, and glutamate-induced paw licking test. In addition, the challenge with nonselective opioid receptor antagonist (naloxone) aimed to evaluate the involvement of the opioidergic system, which showed no reversion in analgesic profile in formalin and hot-plate test.

Conclusion: Collectively, this study showed that DMPF-1 markedly inhibits both peripheral and central nociception through the mechanism involving an interaction with vanilloid and glutamatergic system regardless of the activation of the opioidergic system.
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http://dx.doi.org/10.4103/jpbs.JPBS_344_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021043PMC
November 2020

Alendronate reduces the cognitive and neurological disturbances induced by combined doses of d-galactose and aluminum chloride in mice.

J Appl Toxicol 2021 Mar 10. Epub 2021 Mar 10.

Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India.

Neurological disturbances including cholinergic dysfunction, oxidative stress, neuroinflammation, and cognitive impairments are the well-reported consequences of old age-related disorders like Alzheimer's disease (AD) or dementia. Bisphosphonates were shown to ameliorate dementia in osteoporotic patients, neuroinflammation, and cholinesterase activity in rodents. Thus, the present study has been designed to examine the role of alendronate against cognitive and neurological disturbances in mice induced by a combined oral dose of d-galactose and aluminum chloride (AlCl ) for 6 weeks. d-galactose acts as a senescence agent, whereas AlCl is a neurotoxin and in combination generates neuropathologies and cognitive depletion resembling aging and AD. It was found that memory was markedly impaired in d-galactose + AlCl -treated mice as assessed in different behavioral paradigms. Additionally, d-galactose + AlCl led to neurotoxicity assessed on the basis of neuroinflammation, oxidative stress, glial cell activation, neuronal damage, and augmented GSK-3β level in mice hippocampus. Consequently, alendronate administration orally for 15 days in d-galactose + AlCl -exposed mice prominently reversed all these behavioral and neuropathological changes. These findings show that alendronate can be a potential therapeutic molecule with multiple targets for the management of age-related neurological disorders such as AD.
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http://dx.doi.org/10.1002/jat.4160DOI Listing
March 2021

α-Synuclein Oligomers Induce Glutamate Release from Astrocytes and Excessive Extrasynaptic NMDAR Activity in Neurons, Thus Contributing to Synapse Loss.

J Neurosci 2021 03 22;41(10):2264-2273. Epub 2021 Jan 22.

Neuroscience Translational Center and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92037

Synaptic and neuronal loss are major neuropathological characteristics of Parkinson's disease. Misfolded protein aggregates in the form of Lewy bodies, comprised mainly of α-synuclein (αSyn), are associated with disease progression, and have also been linked to other neurodegenerative diseases, including Lewy body dementia, Alzheimer's disease, and frontotemporal dementia. However, the effects of αSyn and its mechanism of synaptic damage remain incompletely understood. Here, we show that αSyn oligomers induce Ca-dependent release of glutamate from astrocytes obtained from male and female mice, and that mice overexpressing αSyn manifest increased tonic release of glutamate In turn, this extracellular glutamate activates glutamate receptors, including extrasynaptic NMDARs (eNMDARs), on neurons both in culture and in hippocampal slices of αSyn-overexpressing mice. Additionally, in patch-clamp recording from outside-out patches, we found that oligomerized αSyn can directly activate eNMDARs. In organotypic slices, oligomeric αSyn induces eNMDAR-mediated synaptic loss, which can be reversed by the drug NitroSynapsin. When we expose human induced pluripotent stem cell-derived cerebrocortical neurons to αSyn, we find similar effects. Importantly, the improved NMDAR antagonist NitroSynapsin, which selectively inhibits extrasynaptic over physiological synaptic NMDAR activity, protects synapses from oligomeric αSyn-induced damage in our model systems, thus meriting further study for its therapeutic potential. Loss of synaptic function and ensuing neuronal loss are associated with disease progression in Parkinson's disease (PD), Lewy body dementia (LBD), and other neurodegenerative diseases. However, the mechanism of synaptic damage remains incompletely understood. α-Synuclein (αSyn) misfolds in PD/LBD, forming Lewy bodies and contributing to disease pathogenesis. Here, we found that misfolded/oligomeric αSyn releases excessive astrocytic glutamate, in turn activating neuronal extrasynaptic NMDA receptors (eNMDARs), thereby contributing to synaptic damage. Additionally, αSyn oligomers directly activate eNMDARs, further contributing to damage. While the FDA-approved drug memantine has been reported to offer some benefit in PD/LBD (Hershey and Coleman-Jackson, 2019), we find that the improved eNMDAR antagonist NitroSynapsin ameliorates αSyn-induced synaptic spine loss, providing potential disease-modifying intervention in PD/LBD.
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http://dx.doi.org/10.1523/JNEUROSCI.1871-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018774PMC
March 2021

SnO-Doped ZnO/Reduced Graphene Oxide Nanocomposites: Synthesis, Characterization, and Improved Anticancer Activity via Oxidative Stress Pathway.

Int J Nanomedicine 2021 8;16:89-104. Epub 2021 Jan 8.

King Abdullah Institute for Nanotechnology, King Saud University, Riyadh 11451, Saudi Arabia.

Background: Therapeutic selectivity and drug resistance are critical issues in cancer therapy. Currently, zinc oxide nanoparticles (ZnO NPs) hold considerable promise to tackle this problem due to their tunable physicochemical properties. This work was designed to prepare SnO-doped ZnO NPs/reduced graphene oxide nanocomposites (SnO-ZnO/rGO NCs) with enhanced anticancer activity and better biocompatibility than those of pure ZnO NPs.

Materials And Methods: Pure ZnO NPs, SnO-doped ZnO (SnO-ZnO) NPs, and SnO-ZnO/rGO NCs were prepared via a facile hydrothermal method. Prepared samples were characterized by field emission transmission electron microscopy (FETEM), energy dispersive spectroscopy (EDS), field emission scanning electron microscopy (FESEM), X-ray diffraction (XRD), ultraviolet-visible (UV-VIS) spectrometer, and dynamic light scattering (DLS) techniques. Selectivity and anticancer activity of prepared samples were assessed in human breast cancer (MCF-7) and human normal breast epithelial (MCF10A) cells. Possible mechanisms of anticancer activity of prepared samples were explored through oxidative stress pathway.

Results: XRD spectra of SnO-ZnO/rGO NCs confirmed the formation of single-phase of hexagonal wurtzite ZnO. High resolution TEM and SEM mapping showed homogenous distribution of SnO and rGO in ZnO NPs with high quality lattice fringes without any distortion. Band gap energy of SnO-ZnO/rGO NCs was lower compared to SnO-ZnO NPs and pure ZnO NPs. The SnO-ZnO/rGO NCs exhibited significantly higher anticancer activity against MCF-7 cancer cells than those of SnO-ZnO NPs and ZnO NPs. The SnO-ZnO/rGO NCs induced apoptotic response through the upregulation of caspase-3 gene and depletion of mitochondrial membrane potential. Mechanistic study indicated that SnO-ZnO/rGO NCs kill cancer cells through oxidative stress pathway. Moreover, biocompatibility of SnO-ZnO/rGO NCs was also higher against normal breast epithelial (MCF10A cells) in comparison to SnO-ZnO NPs and ZnO NPs.

Conclusion: SnO-ZnO/rGO NCs showed enhanced anticancer activity and better biocompatibility than SnO-ZnO NPs and pure ZnO NPs. This work suggested a new approach to improve the selectivity and anticancer activity of ZnO NPs. Studies on antitumor activity of SnO-ZnO/rGO NCs in animal models are further warranted.
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http://dx.doi.org/10.2147/IJN.S285392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802795PMC
January 2021

Co-exposure of BiO nanoparticles and bezo[a]pyrene-enhanced in vitro cytotoxicity of mouse spermatogonia cells.

Environ Sci Pollut Res Int 2021 Apr 4;28(14):17109-17118. Epub 2021 Jan 4.

King Abdullah Institute for Nanotechnology, King Saud University, Riyadh, 11451, Saudi Arabia.

Recent attention has been focused on reproductive toxicity of nanoscale materials in combination with pre-existing environmental pollutants. Due to its unique characteristics, bismuth (III) oxide (BiO) nanoparticles (BONPs) are being used in diverse fields including cosmetics and biomedicine. Benzo[a]pyrene (BaP) is a known endocrine disruptor that most common sources of BaP exposure to humans are cigarette smoke and well-cooked barbecued meat. Hence, joint exposure of BONPs and BaP in humans is common. There is scarcity of information on toxicity of BONPs in combination with BaP in human reproductive system. In this work, combined effects of BONPs and BaP in mouse spermatogonia (GC-1 spg) cells were assessed. Results showed that combined exposure of BONPs and BaP synergistically induced cell viability reduction, lactate dehydrogenase leakage, induction of caspases (-3 and -9) and mitochondrial membrane potential loss in GC-1 spg cells. Co-exposure of BONPs and BaP also synergistically induced production of pro-oxidants (reactive oxygen species and hydrogen peroxide) and reduction of antioxidants (glutathione and several antioxidant enzymes). Experiments with N-acetyl-cysteine (NAC, a reactive oxygen species scavenger) indicated that oxidative stress was a plausible mechanism of synergistic toxicity of BONPs and BaP in GC-1 spg cells. Present data could be helpful for future in vivo research and risk assessment of human reproductive system co-exposed to BONPs and BaP.
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http://dx.doi.org/10.1007/s11356-020-12128-6DOI Listing
April 2021

Barium Titanate (BaTiO) Nanoparticles Exert Cytotoxicity through Oxidative Stress in Human Lung Carcinoma (A549) Cells.

Nanomaterials (Basel) 2020 Nov 22;10(11). Epub 2020 Nov 22.

Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.

Barium titanate (BaTiO) nanoparticles (BT NPs) have shown exceptional characteristics such as high dielectric constant and suitable ferro-, piezo-, and pyro-electric properties. Thus, BT NPs have shown potential to be applied in various fields including electro-optical devices and biomedicine. However, very limited knowledge is available on the interaction of BT NPs with human cells. This work was planned to study the interaction of BT NPs with human lung carcinoma (A549) cells. Results showed that BT NPs decreased cell viability in a dose- and time-dependent manner. Depletion of mitochondrial membrane potential and induction of caspase-3 and -9 enzyme activity were also observed following BT NP exposure. BT NPs further induced oxidative stress indicated by induction of pro-oxidants (reactive oxygen species and hydrogen peroxide) and reduction of antioxidants (glutathione and several antioxidant enzymes). Moreover, BT NP-induced cytotoxicity and oxidative stress were effectively abrogated by N-acetyl-cysteine (an ROS scavenger), suggesting that BT NP-induced cytotoxicity was mediated through oxidative stress. Intriguingly, the underlying mechanism of cytotoxicity of BT NPs was similar to the mode of action of ZnO NPs. At the end, we found that BT NPs did not affect the non-cancerous human lung fibroblasts (IMR-90). Altogether, BT NPs selectively induced cytotoxicity in A549 cells via oxidative stress. This work warrants further research on selective cytotoxicity mechanisms of BT NPs in different types of cancer cells and their normal counterparts.
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http://dx.doi.org/10.3390/nano10112309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700150PMC
November 2020

Elucidating the Neuroprotective Role of Formulated Camel α-Lactalbumin-Oleic Acid Complex by Curating the SIRT1 Pathway in Parkinson's Disease Model.

ACS Chem Neurosci 2020 12 30;11(24):4416-4425. Epub 2020 Nov 30.

Department of Biochemistry, King George's Medical University (KGMU), Lucknow, 226003 U.P., India.

Parkinson's Disease (PD) is characterized by increased oxidative stress and decreased level of dopamine. At present, the therapeutic interventions of PD are associated with undesirable adverse effects. To overcome these side effects, a new candidate bioinspired molecule is needed for the management of PD. Camel α-lactalbumin (α-LA) is the most abundant protein in camel's milk and has a potential to act as a nutraceutical supplement for neurological functions. Oleic acid, a monounsaturated fatty acid, has been widely associated with a reduced risk of PD. The present study aimed to formulate the camel α-LA and oleic acid (CLOA) complex under specific conditions and to evaluate its efficacy as a neuroprotective in rotenone induced PC12 cell model of PD. Our results demonstrated that removal of Ca++ ions from camel α-LA by EDTA enhances its binding efficiency with oleic acid, and the complex was characterized by UV-CD, ANS fluorescence spectroscopy, and NMR spectroscopy. Moreover, CLOA complex treatment reduced the oxidative stress and increased the cell viability by enhancing the level of dopamine and the expression of SIRT1, FOXO3a, HIF-1α, and HSF-1. We also validated the neuroprotective role of the complex by incubating the cells with CLOA complex prior to rotenone treatment. We inferred from the outcome of the results that the individual entity, i.e., α-LA or OA, is not as effective as the complex. Taken together, our study indicates that CLOA complex might be a potential candidate for the development of future therapeutic drugs for PD.
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http://dx.doi.org/10.1021/acschemneuro.0c00639DOI Listing
December 2020

Nicotinamide Therapy in Dialysis Patients: A Systematic Review of Randomized Controlled Trials.

Saudi J Kidney Dis Transpl 2020 Sep-Oct;31(5):883-897

Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India.

Randomized controlled trials (RCTs) have presented variable findings concerning the reduction of phosphorous level by nicotinamide. This systematic review is aimed to explore the safety and efficacy of nicotinamide in hemodialysis patients and was conducted by adhering to the PRISMA guidelines. Studies for inclusion were identified by running the suitable keywords in PubMed, Embase, and Cochrane Central till June 13, 2018. Cochrane risk of bias tool was used to judge the quality of the included RCTs. The primary outcome was change in serum phosphorus, calcium, and calcium-phosphorus product levels. Change in other biochemical parameters including serum calcium, parathormone, platelets, lipid profile parameters, and the safety profile was considered under secondary outcomes. Review Manager (RevMan v5.3) was used for the risk of bias estimate. A total of 12 articles were qualified for inclusion in this study. All the included RCTs showed a statistically significant reduction in mean serum phosphorous and calcium-phosphorus product levels in the treatment arm as compared to the placebo group. Among several biochemical parameters analyzed, only high-density lipoprotein (HDL) was found to be significantly increased from baseline to the endpoint of the study in the nicotinamide group, while the placebo group showed no significant difference. Flushing and diarrhea, followed by thrombocytopenia, were the most commonly reported adverse events in the treatment group. Nicotinamide was found to be effective in reducing the phosphorous level and calcium-phosphorus product level and increasing the HDL cholesterol level in dialysis patients. The safety profile was found to be satisfactory.
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http://dx.doi.org/10.4103/1319-2442.301195DOI Listing
November 2020

Collagen Nanoparticle-Mediated Brain Silymarin Delivery: An Approach for Treating Cerebral Ischemia and Reperfusion-Induced Brain Injury.

Front Neurosci 2020 26;14:538404. Epub 2020 Oct 26.

Department of Chemistry, School of Chemical & Life Sciences, Jamia Hamdard, New Delhi, India.

Silymarin is a bioactive constituent isolated from milk thistle (). Since its discovery, silymarin has been considered a gold standard drug in treating ailments related to the liver, resulting from alcohol consumption and viral hepatitis. This hepatoprotective nature of silymarin arises out of antioxidative and tissue-regenerating properties of silymarin. However, several recent studies have established the neuroprotective link of silymarin, too. Thus, the current investigation was aimed at exploring the neuroprotective effect of nanosilymarin (silymarin encapsulated inside collagen-based polymeric nanoparticulate drug delivery system). The study aimed at bringing out the role of nanoparticles in enhancing the therapeutic effect of silymarin against neuronal injury, originating out of oxidative-stress-related brain damages in focal cerebral ischemia. Collagen-based micellar nanoparticles were prepared and stabilized using 3-ethyl carbodiimide-hydrochloride (EDC-Hcl) and malondialdehyde (MDA) as crosslinkers. Nanoparticles were characterized using dynamic light scattering (DLS), transmission electron microscopy (TEM), and Fourier transform infrared (FT-IR) spectroscopy techniques, and the size of nanoparticles was found to be around 48 nm. Male albino Wistar rats were pretreated with three different doses of nanosilymarin of 10, 100, and 1,000 μg/kg b.wt and a dose of free silymarin of 100 mg/kg b.wt intraperitoneally (i.p.) for 7 days. Focal cerebral ischemia was induced using the middle cerebral artery occlusion (MCAO) model on the eighth day for 1 h followed by 24 h reperfusion. The animals were then evaluated for neurobehavioral, infarct analysis, biochemical, histopathological, and immunohistochemical studies. All the above parameters showed remarkable improvement in nanosilymarin-treated groups in comparison to the silymarin-treated group. Nanoparticle encapsulation of drug enhanced neuroprotection by increasing drug bioavailability and targeting. Thus, the present study concluded with satisfactory results, showing the critical role played by nanoparticles in improving the neuroprotection at very low drug doses.
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http://dx.doi.org/10.3389/fnins.2020.538404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649428PMC
October 2020

Single-Walled Carbon Nanotubes Attenuate Cytotoxic and Oxidative Stress Response of Pb in Human Lung Epithelial (A549) Cells.

Int J Environ Res Public Health 2020 11 6;17(21). Epub 2020 Nov 6.

King Abdullah Institute for Nanotechnology, King Saud University, Riyadh 11451, Saudi Arabia.

Combined exposure of single-walled carbon nanotubes (SWCNTs) and trace metal lead (Pb) in ambient air is unavoidable. Most of the previous studies on the toxicity of SWCNTs and Pb have been conducted individually. There is a scarcity of information on the combined toxicity of SWCNTs and Pb in human cells. This work was designed to explore the combined effects of SWCNTs and Pb in human lung epithelial (A549) cells. SWCNTs were prepared through the plasma-enhanced vapor deposition technique. Prepared SWCNTs were characterized by x-ray diffraction, x-ray photoelectron spectroscopy, scanning electron microscopy, and dynamic light scattering. We observed that SWCNTs up to a concentration of 100 µg/mL was safe, while Pb induced dose-dependent (5-100 µg/mL) cytotoxicity in A549 cells. Importantly, cytotoxicity, cell cycle arrest, mitochondrial membrane potential depletion, lipid peroxidation, and induction of caspase-3 and -9 enzymes following Pb exposure (50 µg/mL for 24 h) were efficiently attenuated by the co-exposure of SWCNTs (10 µg/mL for 24 h). Furthermore, generation of Pb-induced pro-oxidants (reactive oxygen species and hydrogen peroxide) and the reduction of antioxidants (antioxidant enzymes and glutathione) were also mitigated by the co-exposure of SWCNTs. Inductively coupled plasma-mass spectrometry results suggest that the adsorption of Pb on the surface of SWCNTs could attenuate the bioavailability and toxicity of Pb in A549 cells. Our data warrant further research on the combined effects of SWCNTs and Pb in animal models.
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http://dx.doi.org/10.3390/ijerph17218221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664418PMC
November 2020

Effect of statins on amyloidosis in the rodent models of Alzheimer's disease: Evidence from the preclinical meta-analysis.

Brain Res 2020 12 10;1749:147115. Epub 2020 Sep 10.

Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India. Electronic address:

Introduction: Previous studies have shown contrasting results in determining efficacy of statins against amyloid beta accumulation. The aim of this study was to assess the impact of statin in AD.

Method: We searched PubMed and Embase for relevant preclinical studies. A meta-analysis of the statin's efficacy on amyloidosis and cognitive impairment was performed. Also, stratified analysis was performed on several covariates including the type of statin used, gender and age of rodents and duration of statin therapy, to account for the reported heterogeneity in the results obtained. The study protocol was registered in PROSPERO (CRD42018102557).

Result: 17 studies including 22 comparisons, containing a sample size of 446 rodents, participated in the meta-analysis of statin's effect on overall Aβ deposition. Although the effect of statin on overall Aβ deposition was found to be protective (p < 0.00001) but as we categorized the efficacy of statin on different Aβ species (soluble and insoluble Aβ40/42) and Aβ plaque load, we found that significance in the protection decreased. A stratified meta-analysis demonstrated a significant role in the duration of statin supplements and rodent's age on the heterogeneity of the results. Statin administered to rodents for the longest duration (>6 months) and younger rodents (<6 months of age) demonstrated significant efficacy of statin on Aβ deposition.

Conclusion: Statin showed reduction in Aβ level but stratified analysis revealed that this effect of statin was dependent on rodent's age and duration of the treatment.
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http://dx.doi.org/10.1016/j.brainres.2020.147115DOI Listing
December 2020

Development, optimisation and evaluation of chitosan nanoparticles of alendronate against Alzheimer's disease in intracerebroventricular streptozotocin model for brain delivery.

J Drug Target 2021 02 10;29(2):199-216. Epub 2020 Sep 10.

Department of Pharmacology, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, India.

The current study aimed to develop alendronate (ALN)-loaded chitosan nanoparticles (CS-ALN-NPs) for brain delivery intranasal route. These CS-ALN-NPs reduced the peripheral side effects and released ALN directly to brain. These NPs were formulated through ionic gelation technique by mixing sodium tripolyphosphate (1.5mg/ml) in ALN-CS (1.75mg/ml) solution. CS-ALN-NPs attained 135.75±5.80nm, 0.21±0.013, 23.8±3.69mV, 72.46±0.879% and 30.92±0.375% mean particle size, PDI, zeta potential, entrapment efficiency and loading capacity, respectively. Furthermore, the TEM and SEM analysis of CS-ALN-NPs, respectively, revealed the particle size in 200nm range and spherical shape. The and release profile revealed a sustained drug release through CS-ALN-NPs as compared to pure drug solution. Also these NPs acquired a high concentration in mice brain and better pharmacokinetic profile than ALN solution (intranasal) CS-ALN-NPs were then evaluated against intracerebroventricular-streptozotocin (ICV-STZ) induced Alzheimer's disease (AD)-like pathologies in mice. The intranasal CS-ALN-NP altered the ICV-STZ induced neurobehavioral, neurochemical and histopathological changes in mice. These effects were significant to those of ALN solution (intranasal). The neuroprotective potential of CS-ALN-NPs observed in ICV-STZ mice model of AD may be a promising brain-targeted delivery system for AD treatment along with further extensive exploration at both pre-clinical and clinical edge. HIGHLIGHTS CS-ALN-NPs were developed and optimised to overcome the poor pharmacokinetic profile and associated side effects of ALN CS-ALN-NPs showed particle size within 200 nm range as well as controlled and sustained release in in vitro release study These optimised NPs of ALN attained higher brain:blood ratio and better pharmacokinetic profile (Cmax, tmax, AUC) CS-ALN-NPs markedly altered ICV STZ induced impairment in cognitive functions of mice and changes in APP processing, neuroinflammatory cytokines and other biochemical parameters in mice hippocampus.
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http://dx.doi.org/10.1080/1061186X.2020.1817041DOI Listing
February 2021

Alogliptin reversed hippocampal insulin resistance in an amyloid-beta fibrils induced animal model of Alzheimer's disease.

Eur J Pharmacol 2020 Dec 29;889:173522. Epub 2020 Aug 29.

Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India. Electronic address:

The complications of Alzheimer's disease (AD) have made the development of its treatment a challenging task. Several studies have indicated the disruption of insulin receptor substrate-1 (IRS-1) signaling during the development and progression of AD. The role of a dipeptidyl peptidase-4 (DPP-4) inhibitor on hippocampal IRS-1 signaling has not been investigated before. In this study, we evaluated the efficacy of alogliptin (DPP-4 inhibitor) on hippocampal insulin resistance and associated AD complications. In the present study, amyloid-β (1-42) fibrils were produced and administered intrahippocampally for inducing AD in Wistar rats. After 7 days of surgery, rats were treated with 10 and 20 mg/kg of alogliptin for 28 days. Morris water maze (MWM) test was performed in the last week of our experimental study. Post 24 h of final treatment, rats were euthanized and hippocampi were separated for biochemical and histopathological investigations. In-silico analysis revealed that alogliptin has a good binding affinity with Aβ and beta-secretase-1 (BACE-1). Alogliptin significantly restored cognitive functions in Aβ (1-42) fibrils injected rats during the MWM test. Alogliptin also significantly attenuated insulin level, IRS-1pS307 expression, Aβ (1-42) level, GSK-3β activity, TNF-α level and oxidative stress in the hippocampus. The histopathological analysis supported alogliptin mediated neuroprotective and anti-amyloidogenic effect. Immunohistochemical analysis also revealed a reduction in IRS-1pS307 expression after alogliptin treatment. The in-silico, behavioral, biochemical and histopathological analysis supports the protective effect of alogliptin against hippocampal insulin resistance and AD.
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http://dx.doi.org/10.1016/j.ejphar.2020.173522DOI Listing
December 2020

Gadolinium Oxide Nanoparticles Induce Toxicity in Human Endothelial HUVECs via Lipid Peroxidation, Mitochondrial Dysfunction and Autophagy Modulation.

Nanomaterials (Basel) 2020 Aug 26;10(9). Epub 2020 Aug 26.

Department of Physics and Astronomy, College of Sciences, King Saud University, Riyadh 11451, Saudi Arabia.

In spite of the potential preclinical advantage of GdO nanoparticles (designated here as GO NPs) over gadolinium-based compounds in MRI, recent concerns of gadolinium deposits in various tissues undergoing MRI demands a mechanistic investigation. Hence, we chose human to measure umbilical vein endothelial cells (HUVECs) that line the vasculature and relevant biomarkers due to GO NPs exposure in parallel with the NPs of ZnO as a positive control of toxicity. GO NPs, as measured by TEM, had an average length of 54.8 ± 29 nm and a diameter of 13.7 ± 6 nm suggesting a fiber-like appearance. With not as pronounced toxicity associated with a 24-h exposure, GO NPs induced a concentration-dependent cytotoxicity (IC = 304 ± 17 µg/mL) in HUVECs when exposed for 48 h. GO NPs emerged as significant inducer of lipid peroxidation (LPO), reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and autophagic vesicles in comparison to that caused by ZnO NPs at its IC for the same exposure time (48 h). While ZnO NPs clearly appeared to induce apoptosis, GO NPs revealed both apoptotic as well as necrotic potentials in HUVECs. Intriguingly, the exogenous antioxidant NAC (N-acetylcysteine) co-treatment significantly attenuated the oxidative imbalance due to NPs preventing cytotoxicity significantly.
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http://dx.doi.org/10.3390/nano10091675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559735PMC
August 2020

Reduced graphene oxide mitigates cadmium-induced cytotoxicity and oxidative stress in HepG2 cells.

Food Chem Toxicol 2020 Sep 4;143:111515. Epub 2020 Jul 4.

King Abdullah Institute for Nanotechnology, King Saud University, Riyadh, 11451, Saudi Arabia; Department of Physics and Astronomy, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia.

Numerous applications of reduced graphene oxide (RGO) and pervasive cadmium (Cd) have led concern about their co-exposure to the environment and human. We studied the combined effects of RGO and Cd in human liver (HepG2) cells. Initially, we found that RGO (up to 50 μg/ml) did not harm to HepG2 cells while Cd induced dose-dependent (1-10 μg/ml) cytotoxicity. Exciting observations were that a non-cytotoxic concentration of RGO (25 μg/ml) effectively mitigates the toxic effects of Cd (2 μg/ml) such as cell viability reduction, lactate dehydrogenase release, and irregular cell morphology. Cd-induced cell cycle arrest, induction of caspases (3 and 9) enzymes activity, and loss of mitochondrial membrane potential were also significantly alleviated by RGO co-exposure. Moreover, generation of pro-oxidants (reactive oxygen species and hydrogen peroxide levels) and depletion of antioxidants (glutathione level and superoxide dismutase activity) due to Cd exposure was effectively attenuated by RGO co-exposure. Mitigating effect of RGO could be due to strong adsorption of Cd on the large surface area of RGO sheets, which decrease the cellular uptake and bioavailability of Cd for HepG2 cells. This study warrants future research on potential mechanisms of mitigating effects of RGO against Cd-induced toxicity in animal models.
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http://dx.doi.org/10.1016/j.fct.2020.111515DOI Listing
September 2020

Neuroprotective role of alendronate against APP processing and neuroinflammation in mice fed a high fat diet.

Brain Res Bull 2020 08 8;161:197-212. Epub 2020 May 8.

Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India. Electronic address:

Obesity and consumption of diet rich in fat are known to contribute to the development of Alzheimer's disease (AD) which is a complex and multifactorial neurodegenerative disease and a leading cause of mortality with unmet medical needs. Hypercholesterolemia was discovered to increase neuropathological changes along with cognitive decline in AD mouse models but still the underlying mechanism is elusive. Furthermore, isoprenoids, the crucial products of Mevalonate-pathway produced by the action of farnesyl pyrophosphate synthase (FPPS) enzyme, are also demonstrated to play a key role in AD. Nevertheless, bisphosphonates target this enzyme in order to treat osteoporosis and also found to alleviate dementia in such patients. As per the cited inhibitory action of alendronate, against acetylcholinesterase and cholesterol level, we hypothesized to explore the potential of alendronate against high fat diet (HFD) induced neuropathologies and cognitive disabilities in AD mouse model. Here we noticed that in mice provided with HFD for 14 weeks, spatial memory was compromised as interpreted in different behavioral paradigms. Together with cognitive depletion, there was observed a provoking effect on amyloid precursor protein (APP)-processing via amyloidogenic pathway due to enhanced β-site APP cleaving enzyme-1 (BACE-1) level which in turn leads to augmented release of amyloid beta (Aβ) in hippocampus of HFD mice. Relevant to these, significant elevation in hippocampal level of neuroinflammatory cytokines, oxidative stress markers and isoprenoids and serum cholesterol were also found after HFD exposure. Marked reversal of cognitive impairment, enhanced APP-processing, neuroinflammation along with other neuropathological alterations in hippocampus was demonstrated following oral administration of alendronate (1.76 mg/kg) for 15 days despite of HFD treatment. These changes were noted to be due to modulation of isoprenoids and cholesterol level by alendronate. Supporting these, histopathological analysis done by congo red revealed the reduced Aβ deposition in hippocampus of drug treated HFD mice The current outcomes provide important implications for the contribution of Mevalonate-pathway and HFD for the onset of AD and also support alendronate as a prominent intervention for amelioration of AD-like pathologies.
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http://dx.doi.org/10.1016/j.brainresbull.2020.04.010DOI Listing
August 2020

Trigonelline Demonstrated Ameliorative Effects in Dexamethasone Induced Osteoporotic Rats.

Drug Res (Stuttg) 2020 Jun 14;70(6):257-264. Epub 2020 Apr 14.

Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India.

Aim: Trigonelline is a potent phytochemical present in fenugreek, which has strong anti-oxidant and phytoestrogenic activities. This study was carried out to investigate this estrogenic activity as a possible mechanisms involved in preventing the symptoms of osteoporosis in dexamethasone induced osteoporosis in rats.

Materials And Methods: Wistar rats were randomly divided into eight groups, six animals in each group. Osteoporosis was induced using dexamethasone 0.1mg/kg subcutaneously in rats for three times per week for 8 consecutive weeks and treatment with drugs up to 12 weeks as per the treatment schedule described. After 12 weeks, rats were sacrificed; blood samples were collected from each rat and the clear, non hemolysed supernatant sera was used for biochemical examinations. Femurs were used for Bone Mineral Density (BMD), microcomputed tomography (Micro CT), histology and biochemical examinations.

Results: BMD, bone micro structure, serum calcium, phosphorus level and serum estradiol levels were decreased while serum PTH levels, SAP and acid phosphatase (ACP) were elevated in dexamethasone treated rats as compared to control (p<0.01). Dexmethasone treated animals showed loss of marrow at multifocal area, cartilage and trabeculae and thinning of trabeculae (bone resorption), zone of cartilage was poorly seen and fat cells in marrow. Trigonelline showed significant improvement and prevent the progression of osteoporosis by enhancing the BMD, restoring bone physiology.

Conclusion: Our results confirm the estrogenic activity of triogonelline, which is responsible for its effects; still, it needs further evaluation in other animal models to provide a more conclusive view for its therapeutic usefulness in osteoporosis.
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http://dx.doi.org/10.1055/a-1147-5724DOI Listing
June 2020

Alleviating effects of reduced graphene oxide against lead-induced cytotoxicity and oxidative stress in human alveolar epithelial (A549) cells.

J Appl Toxicol 2020 09 27;40(9):1228-1238. Epub 2020 Mar 27.

King Abdullah Institute for Nanotechnology, King Saud University, Riyadh, Saudi Arabia.

Broad application of reduced graphene oxide (rGO) and ubiquitous lead (Pb) pollution may increase the possibility of combined exposure of humans. Information on the combined effects of rGO and Pb in human cells is scarce. This work was designed to explore the potential effects of rGO on Pb-induced toxicity in human alveolar epithelial (A549) cells. Prepared rGO was polycrystalline in nature. The formation of a few layers of visible creases and silky morphology due to high aspect ratio was confirmed. Low level (25 μg/mL) of rGO was not toxic to A549 cells. However, Pb exposure (25 μg/mL) induced cell viability reduction, lactate dehydrogenase enzyme leakage with rounded morphology in A549 cells. Remarkably, Pb-induced cytotoxicity was significantly mitigated by rGO co-exposure. Pb-induced mitochondrial membrane potential loss, cell cycle arrest and higher activity of caspase-3 and -9 enzymes were also alleviated by rGO co-exposure. Moreover, we observed that Pb exposure causes generation of pro-oxidants (e.g., reactive oxygen species, hydrogen peroxide and lipid peroxidation) and antioxidant depletion (e.g., glutathione and antioxidant enzymes). In addition, the effects of Pb on pro-oxidant and antioxidant markers were significantly reverted by GO co-exposure. Inductively coupled plasma-mass spectrometry suggested that due to the adsorption of Pb on rGO sheets, accessibility of Pb ions for A549 cells was limited. Hence, rGO reduced the toxicity of Pb in A549 cells. This research warrants further study to work on detailed underlying mechanisms of the mitigating effects of rGO against Pb-induced toxicity on a molecular level.
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http://dx.doi.org/10.1002/jat.3980DOI Listing
September 2020

Thymoquinone Loaded Solid Lipid Nanoparticles Demonstrated Antidepressant-Like Activity in Rats via Indoleamine 2, 3- Dioxygenase Pathway.

Drug Res (Stuttg) 2020 May 20;70(5):206-213. Epub 2020 Mar 20.

Department of Pharmacology, School of Pharmaceutical Education and Research (Formerly: Faculty of Pharmacy), Jamia Hamdard, New Delhi, INDIA.

The World Health Organization (WHO) has ranked depression the 4 leading cause of disability worldwide. Thymoquinone (TQ), is an active constituent of having various medicinal properties but has poor solubility and bioavailability. This problem was overcome by developing nanoformulation of TQ. Previously TQ reported good antioxidant and anti-inflammatory effects. Recently TQ's anti-depressant effect was demonstrated. However, the mechanisms underlying the antidepressant effect of TQ still needs evaluation. Activation of Indoleamine-2,3-dioxygenase (IDO), (an enzyme that participates in the tryptophan metabolism), leads to a decrease of serotonin (5-HT) levels. The expression of this enzyme is associated with immune system activation, which has been proposed as a common mechanism that links depression. The present study was performed in stressed animals where hippocampal levels of pro-inflammatory cytokines (IL-6 and TNF α levels), brain derived neurotropic factor (BDNF) and hippocampal kynurenine (KYN), tryptophan (TRP) and serotonin (5-HT) levels were estimated. Treatment with TQ solid lipid nanoparticles (TQSLN 20 mg/kg p.o) and TQ suspension (20 mg/kg p.o) demonstrated antidepressant-like activity in chronic forced-swim stress model. Further, it reduced the elevated hippocampal IL-6 & TNFα and reversed the increased activity of IDO as measured by ratio of hippocampal KYN/TRP and 5HT/TRP in stressed rats. The results of the present study confirm anti-inflammatory and neuroprotective effects of TQ which may be associated with 5-HT pathway. Thus, the present study offers a newer approach to reduce symptoms of depression using TQSLN. Our results are preliminary, further research is needed for more conclusive view.
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http://dx.doi.org/10.1055/a-1131-7793DOI Listing
May 2020

High Surface Reactivity and Biocompatibility of YO NPs in Human MCF-7 Epithelial and HT-1080 FibroBlast Cells.

Molecules 2020 Mar 3;25(5). Epub 2020 Mar 3.

Department of Physics and Astronomy, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.

This study aimed to generate a comparative data on biological response of yttrium oxide nanoparticles (YO NPs) with the antioxidant CeO NPs and pro-oxidant ZnO NPs. Sizes of YO NPs were found to be in the range of 35±10 nm as measured by TEM and were larger from its hydrodynamic sizes in water (1004 ± 134 nm), PBS (3373 ± 249 nm), serum free culture media (1735 ± 305 nm) and complete culture media (542 ± 108 nm). Surface reactivity of YO NPs with bovine serum albumin (BSA) was found significantly higher than for CeO and ZnO NPs. The displacement studies clearly suggested that adsorption to either BSA, filtered serum or serum free media was quite stable, and was dependent on whichever component interacted first with the YO NPs. Enzyme mimetic activity, like that of CeO NPs, was not detected for the NPs of YO or ZnO. Cell viability measured by MTT and neutral red uptake (NRU) assays suggested YO NPs were not toxic in human breast carcinoma MCF-7 and fibroblast HT-1080 cells up to the concentration of 200 μg/mL for a 24 h treatment period. Oxidative stress markers suggested YO NPs to be tolerably non-oxidative and biocompatible. Moreover, mitochondrial potential determined by JC-1 as well as lysosomal activity determined by lysotracker (LTR) remained un-affected and intact due to YO and CeO NPs whereas, as expected, were significantly induced by ZnO NPs. Hoechst-PI dual staining clearly suggested apoptotic potential of only ZnO NPs. With high surface reactivity and biocompatibility, NPs of YO could be a promising agent in the field of nanomedicine.
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http://dx.doi.org/10.3390/molecules25051137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179248PMC
March 2020

Guggulipid: A Promising Multi-Purpose Herbal Medicinal Agent.

Drug Res (Stuttg) 2020 Apr 28;70(4):123-130. Epub 2020 Feb 28.

Department of Pharmacognosy, HIMT College of Pharmacy, Noida, India.

Herbal medicines therapy is appreciated by many research works because herbal drugs have relatively high therapeutic window, lower side effects and more cost effective. Guggulipid is an ethyl acetate extract of resin known as guggul from the tree . Chemical analysis revealed that the compounds responsible for the major activities of gum guggul are the isomers E- and Z-guggulsterone. Guggul has been used for thousands of years in the treatment of arthritis, inflammation, obesity, cardiac protection, anti-ulcer, anti-epileptic and disorders of lipid metabolism. This review is an assortment of available information reported on its chemical, pharmacological and toxicological properties in various research studies. The available therapeutic properties of guggulipid make it suitable natural product for the treatment of various disorders like inflammation, pain, wounds, liver disorder and Acne etc. Graphical Abstract Graphical Abstract.
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http://dx.doi.org/10.1055/a-1115-4669DOI Listing
April 2020

Investigation of Cytotoxicity, Apoptosis, and Oxidative Stress Response of FeO-RGO Nanocomposites in Human Liver HepG2 cells.

Materials (Basel) 2020 Feb 2;13(3). Epub 2020 Feb 2.

King Abdullah Institute for Nanotechnology, King Saud University, Riyadh 11451, Saudi Arabia.

Iron oxide-reduced graphene oxide (FeO-RGO) nanocomposites have attracted enormous interest in the biomedical field. However, studies on biological response of FeO-RGO nanocomposites at the cellular and molecular level are scarce. This study was designed to synthesize, characterize, and explore the cytotoxicity of FeO-RGO nanocomposites in human liver (HepG2) cells. Potential mechanisms of cytotoxicity of FeO-RGO nanocomposites were further explored through oxidative stress. Prepared samples were characterized by UV-visible spectrophotometer, X-ray diffraction, scanning electron microscopy, transmission electron microscopy, and energy dispersive spectroscopy. The results demonstrated that RGO induce dose-dependent cytotoxicity in HepG2 cells. However, FeO-RGO nanocomposites were not toxic. We further noted that RGO induce apoptosis in HepG2 cells, as evidenced by mitochondrial membrane potential loss, higher caspase-3 enzyme activity, and cell cycle arrest. On the other hand, FeO-RGO nanocomposites did not alter these apoptotic parameters. Moreover, we observed that RGO increases intracellular reactive oxygen species and hydrogen peroxide while decrease antioxidant glutathione. Again, FeO-RGO nanocomposites did not exert oxidative stress. Altogether, we found that RGO significantly induced cytotoxicity, apoptosis and oxidative stress. However, FeO-RGO nanocomposites showed good biocompatibility to HepG2 cells. This study warrants further research to investigate the biological response of FeO-RGO nanocomposites at the gene and molecular level.
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http://dx.doi.org/10.3390/ma13030660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040707PMC
February 2020

TiO nanoparticles potentiated the cytotoxicity, oxidative stress and apoptosis response of cadmium in two different human cells.

Environ Sci Pollut Res Int 2020 Apr 15;27(10):10425-10435. Epub 2020 Jan 15.

King Abdullah Institute for Nanotechnology, King Saud University, Riyadh, 11451, Saudi Arabia.

Widespread application of titanium dioxide nanoparticles (nTiO) and ubiquitous cadmium (Cd) pollution may increase their chance of co-existence in the natural environment. Toxicological information on co-exposure of nTiO and Cd in mammalian models is largely lacking. Hence, we studied the combined effects of nTiO and Cd in human liver (HepG2) and breast cancer (MCF-7) cells. We observed that nTiO did not produce toxicity to HepG2 and MCF-7 cells. However, moderate concentration of Cd exposure caused cytotoxicity to both cells. Interestingly, non-cytotoxic concentration of nTiO effectively enhanced the oxidative stress response of Cd indicated by pro-oxidants generation (reactive oxygen species, hydrogen peroxide, and lipid peroxidation) and antioxidants depletion (glutathione level and glutathione reductase, superoxide dismutase, and catalase enzymes). Moreover, nTiO potentiated the Cd-induced apoptosis in both cells suggested by altered expression of p53, bax, and bcl-2 genes along with low mitochondrial membrane potential. Cellular uptake results demonstrated that nTiO facilitates the internalization of Cd into the cells. Overall, this study demonstrated that non-cytotoxic concentration of nTiO enhanced the toxicological potential of Cd in human cells. Therefore, more attention should be paid on the combine effects of nTiO and Cd on human health.
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http://dx.doi.org/10.1007/s11356-019-07130-6DOI Listing
April 2020

Influence of silica nanoparticles on cadmium-induced cytotoxicity, oxidative stress, and apoptosis in human liver HepG2 cells.

Environ Toxicol 2020 May 6;35(5):599-608. Epub 2020 Jan 6.

King Abdullah Institute for Nanotechnology, King Saud University, Riyadh, Saudi Arabia.

Extensive application of amorphous silica nanoparticles (Si NPs) and ubiquitous cadmium (Cd) may increase their chances of coexposure to humans. Studies on combined effects of Si NPs and Cd in human cells are very limited. We investigated the potential mechanism of toxicity caused by coexposure of amorphous Si NPs and Cd in human liver (HepG2) cells. Results showed that Si NPs were not toxic to HepG2. However, Cd induced significant toxicity in HepG2 cells. Interestingly, we observed that a noncytotoxic concentration of Si NPs potentiated the cytotoxicity of Cd in HepG2 cells. We further noticed that coexposure of Si NPs and Cd augmented oxidative stress evidenced by the generation of oxidants (reactive oxygen species, hydrogen peroxide, and lipid peroxidation) and depletion of antioxidants (glutathione level and antioxidant enzyme activity). Coexposure of Si NPs and Cd also augmented mitochondria-mediated apoptosis in HepG2 cells indicated by altered regulation of apoptotic genes (p53, bax, bcl-2, caspase-3, and caspase-9) along with reduced mitochondrial membrane potential. Interaction data indicated that Si NPs facilitate the cellular uptake of Cd due to its strong adsorption on the surface of Si NPs. Hence, Si NPs increased the bioaccumulation and toxicity of Cd in HepG2 cells. This study warrants further research to explore the potential mechanisms of combined toxicity of Si NPs and Cd in animal models.
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http://dx.doi.org/10.1002/tox.22895DOI Listing
May 2020
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