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Alpha-Linolenic acid (ALA), an omega-3 polyunsaturated fatty acid, is extracted from plant sources and has been shown to be one of the anti-inflammatory and antioxidant agents. Herein, we revealed the molecular mechanism underlying the anti-inflammatory and antioxidant potential of (ALA), against cadmium in the adult mouse brain. We evaluated the neuroprotective effect of ALA (60 mg/kg per oral for 6 weeks) against CdCl 2 (5 mg/kg)-induced oxidative stress, neuroinflammation, and neuronal apoptosis. According to our findings, ALA markedly reduced ROS production and nitric oxide synthase 2 (NOS2) and enhanced the expression of nuclear factor-2 erythroid-2 (Nrf-2) and heme oxygenase-1 (HO-1) in mice treated with CdCl 2 . Most importantly, the molecular docking study revealed that ALA allosterically decreases the overexpression of c-Jun N-terminal kinase (JNK) activity and inhibited the detrimental effect against CdCl 2 . Moreover, ALA suppressed CdCl 2 -induced glial fibrillary acidic protein (GFAP), nuclear factor-kappa b (NF-κB), and interleukin-1β (IL-1β) in the mouse brain. Further, we also checked the pro- and anti-apoptotic proteins markers such as Bax, Bcl-2, and caspase-3, which were regulated in the cortex of ALA co-treated mouse brain. Overall, our study suggests that oral administration of ALA can impede oxidative stress, neuroinflammation, and increase neuronal apoptosis in the cortex of Cd-injected mouse brain.

Fine tuning of the metabolic, physiological and immunological cues along with interplay between the biomolecules of the host and the parasite could be responsible for the successful establishment of parasitic infections. The present investigation was aimed at evaluating the oxidative status and the level of adenosine deaminase (ADA) in the serum and liver of rabbits experimentally infected with Fasciola gigantica. A significant increase in level of ROS, MDA and 4-HNE along with a decline in the SOD, CAT, GR and GST activity was evident in rabbits experimentally infected with Fasciola gigantica. However, there was an increase in the GPX activity in the sera of infected rabbits. The increased GPX activity and decreased GR activity would have resulted in the depletion of GSH, a key non-enzymatic antioxidant, in the infected animals. The level of GSSG was also found to be higher in the sera and liver tissues of the infected rabbits along with a decline in the GSH/GSSG ratio, indicating a high level of oxidative stress in the infected animals, which also showed a significant increase in the activity of the marker enzymes of liver pathology, AST and ALT. Further, a significant inhibition of the adenosine deaminase (ADA) activity in the infected rabbits was accompanied with the reduction in the level of pro-inflammatory cytokine, IL-6 while the anti-inflammatory cytokine, IL-4 level was significantly elevated. In conclusion, the F. gigantica induced significant oxidative stress as evident from the increased levels of ROS and lipid peroxidation along with the disruption of antioxidant and detoxification cascade ultimately lead to pathogenic and inflammatory responses in the experimental host. Whereas, the altered ADA activity could modulate the host's immune responses toward Th-2 type and would facilitate the successful establishment of flukes within their host, thus indicating that ADA could be exploited as a target for the development of novel anthelmintic drugs against fasciolosis., (Copyright © 2020. Published by Elsevier B.V.)

Alzheimer's disease (AD) is a progressive neurodegenerative disorder typified by several neuropathological features including amyloid-beta (A β ) plaque and neurofibrillary tangles (NFTs). Cholesterol retention and oxidative stress (OS) are the major contributors of elevated β - and γ -secretase activities, leading to excessive A β deposition, signifying the importance of altered cholesterol homeostasis and OS in the progression of A β -mediated neurodegeneration and cognitive deficit. However, the effect of A β on cholesterol metabolism is lesser-known. In this study, we evaluated the effect of quinovic acid (QA; 50 mg/kg body weight, i.p.) against the intracerebroventricular (i.c.v.) injection of A β (1-42)-induced cholesterol dyshomeostasis, oxidative stress, and neurodegeneration in the cortex and hippocampal brain regions of wild-type male C57BL/6J mice. Our results indicated that A β (1-42)-treated mice have increased A β oligomer formation along with increased β -secretase expression. The enhanced amyloidogenic pathway in A β (1-42)-treated mice intensified brain cholesterol accumulation due to increased expressions of p53 and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) enzyme. Importantly, we further confirmed the p53-mediated HMGCR axis activation by using pifithrin- α (PFT) in SH-SY5Y cells. Furthermore, the augmented brain cholesterol levels were also associated with increased OS. However, the QA administration to A β (1-42)-injected mice significantly ameliorated the A β burden, p53 expression, and cholesterol accumulation by deterring the oxidative stress through upregulating the Nrf2/HO-1 pathway. Moreover, the QA downregulated gliosis, neuroinflammatory mediators (p-NF- κ B and IL-1 β ), and the expression of mitochondrial apoptotic markers (Bax, cleaved caspase-3, and cytochrome c). QA treatment also reversed the deregulated synaptic markers (PSD-95 and synaptophysin) and improved spatial learning and memory behaviors in the A β -treated mouse brains. These results suggest that A β (1-42) induces its acute detrimental effects on cognitive functions probably by increasing brain cholesterol levels through a possible activation of the p53/HMGCR axis. However, QA treatment reduces the cholesterol-induced oxidative stress, neuroinflammation, and neurodegeneration, leading to the restoration of cognitive deficit after A β (1-42) i.c.v. injection in mice., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Kamran Saeed et al.)

Fasciolosis is a neglected tropical disease caused by the liver fluke Fasciola gigantica. The absence of successful vaccine and emerging resistance in flukes against the drug of choice, triclabendazole, has necessitated the search for alternatives including phyto-therapeutic approaches. Curcumin and thymoquinone, the active ingredients of Curcuma longa and Nigella sativa plants respectively, were first screened for their binding affinity with Glutathione-S-transferase (GST) molecule through in silico molecular docking followed by in vitro treatment of worms with varying concentrations of the test compounds. The in silico molecular docking of curcumin and thymoquinone with sigma GST revealed strong hydrogen bonding as well as hydrophobic interactions with high fitness scores but showing inter-specific differences. The in vitro treatment of F. gigantica worms with both curcumin and thymoquinone resulted in a significant increase in the generation of reactive oxygen species (ROS) whereas the level of reduced glutathione, a primary redox regulator, was found to be significantly decreased (p < 0.05). The two compounds not only inhibited the GST activity, which is an important detoxification enzyme and also a key drug/vaccine target for the control of fasciolosis but also significantly inhibited the activity of antioxidant enzymes glutathione peroxidase and glutathione reductase that are vital in maintenance of redox homeostasis. The immunohistochemistry performed using anti sigma GST polyclonal antibodies revealed that both the compounds used in the present study significantly reduced immunofluorescence in the vitellaria, developing eggs present in the ovary and the intestinal caecae indicating inhibition of GST enzyme in these regions of the worms. Further, following treatment with curcumin and thymoquinone, chromatin condensation and DNA fragmentation was also observed in F. gigantica worms. In conclusion, both curcumin and thymoquinone generated oxidative stress in the worms by production of ROS and significantly inhibiting their antioxidant and detoxification ability. The oxidative stress along with induction of apoptotic like events would compromise the survival ability of worms within the host. However, further studies are required to establish their anthelmintic potential alone and in combination with the commonly used anthelmintic drugs under in vivo conditions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Ω-3 fatty acids perform several therapeutic functions in the body, however, their applications are limited due to the inferior oxidative stability. To improve the oxidative stability and release properties of Ω-3 fatty acids, microencapsulation is performed. Butter is a good source of fat-soluble vitamins and antioxidant systems however, it is not a good source of Ω-3 fatty acids. Supplementation of butter with microcapsules of vegetable oils rich in Ω-3 fatty acids is not reported in literature., Methods: Microcapsules of chia oil (MCO) were prepared using chitosan as encapsulating material by spray drying at lower temperature. Unsalted butter prepared from cultured cream using Lactococcus lactis ssp. Lactis at 21 °C for 16 Hrs. Cream was churned at 12 °C and microcapsules of chia oil were added to the butter during the working stage at four different concentrations i.e. 2, 4, 6 and 8% (T 1 , T 2 , T 3 and T 4 , respectively). Butter without supplementation of MCO were kept as control. Butter samples were stored for 90 days at -10 °C. Butter composition, antioxidant capacity, fatty acid profile, induction period, free fatty acids, peroxide value and sensory evaluation were performed at 0, 45 and 90 days of storage., Results: Addition of MCO in butter did not have any effect on standards of identity of butter. Microencapsulation had no effect on fatty acid profile of microcapsules of chia oil. Concentration of alpha-linolenic acid (ALA) in control, T 1 , T 2 , T 3 and T 4 were 0.49, 4.29, 8.41, 13.21 and 17.44%, respectively. Concentration of ALA in fresh and 90 days stored butter samples were 17.44 and 17.11%, respectively. After 90 days of storage, loss of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) were 0.07%, 0.05 and 0.03%, respectively. At 0, 45 and 90 days of storage, 2, 2-Diphenyl-1-picrylhydrazyle (DPPH) free radical scavenging activity of free chia oil was 39.81, 71.22 and 62.18%, respectively. However, microcapsules of chia oil had superior antioxidant activity. DPPH free radical scavenging activity of microcapsules at 0, 45 and 90 days of storage was 36.51, 36.43 and 35.96%, respectively (p > 0.05). Total antioxidant capacity of microcapsules at 0, 45 and 90 days of storage was 70.53, 69.88 and 68.52%, respectively (p > 0.05). It was recorded that induction period of free chia oil and microcapsules was only 2.86 h and 8.55 h. Among the butter samples, control revealed the lowest induction period. While, induction period of experimental samples was not different from each other. Peroxide value and free fatty acids of the butter samples at the end of storage period (90 days) was less than the European Union standards limit (10MeqO 2 /kg and 0.2%). Sensory characteristics of experimental samples were similar to the control. MCO can be added in butter to improve its functional value., Conclusion: Concentration of Ω-3 fatty acids in butter up to 8% can be increased through microcapsules of chia oil with reasonable oxidative stability and no effect on sensory characteristics.

All over the world, metabolic syndrome constitutes severe health problems. Multiple factors have been reported in the pathogenesis of metabolic syndrome. Metabolic disorders result in reactive oxygen species (ROS) induced oxidative stress, playing a vital role in the development and pathogenesis of major health issues, including neurological disorders Alzheimer's disease (AD) Parkinson's disease (PD). Considerable increasing evidence indicates the substantial contribution of ROS-induced oxidative stress in neurodegenerative diseases. An imbalanced metabolism results in a defective antioxidant defense system, free radicals causing inflammation, cellular apoptosis, and tissue damage. Due to the annual increase in financial and social burdens, in addition to the adverse effects associated with available synthetic agents, treatment diversion from synthetic to natural approaches has occurred. Antioxidants are now being considered as convincing therapeutic agents against various neurodegenerative disorders. Therefore, medicinal herbs and fruits currently receive substantially more attention as commercial sources of antioxidants. In this review, we argue that ROS-targeted therapeutic interventions with naturally occurring antioxidant flavonoid, anthocyanin, and anthocyanin-loaded nanoparticles might be the ultimate treatment against devastating illnesses. Furthermore, we elucidate the hidden potential of the neuroprotective role of anthocyanins and anthocyanin-loaded nanoparticles in AD and PD neuropathies, which lack sufficient attention compared with other polyphenols, despite their strong antioxidant potential. Moreover, we address the need for future research studies of native anthocyanins and nano-based-anthocyanins, which will be helpful in developing anthocyanin treatments as therapeutic mitochondrial antioxidant drug-like regimens to delay or prevent the progression of neurodegenerative diseases, such as AD and PD., Competing Interests: The authors declared no competing financial interests.

Dawood Shah,1 Arshad Iqbal,1 Fahad S Alshehri,2 Aman Ullah,3 Gowhar Ali,4 Tahir Muhammad,5,6 Rahim Ullah,4,7 Robert D E Sewell,8 Yusuf S Althobaiti9,10 1Department of Botany, Islamia College Peshawar, Peshawar, Pakistan; 2Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia; 3College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University, Islamabad, Pakistan; 4Department of Pharmacy, University of Peshawar, Peshawar, Pakistan; 5Molecular Neuropsychiatry and Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; 6Institute of Medical Science, University of Toronto, Toronto, ON, Canada; 7Department of Pharmacy, Faculty of Life Sciences, Sarhad University of Science and Information Technology, Peshawar, Khyber Pakhtunkhwa, Pakistan; 8Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, CF10 3NB, UK; 9Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, Taif, Saudi Arabia; 10Addiction and Neuroscience Research Unit, Taif University, Taif, Saudi ArabiaCorrespondence: Gowhar Ali, Department of Pharmacy, University of Peshawar, Peshawar, 25120, Pakistan, Tel +92-919216750, Fax +92-91921813, Email gowhar_ali@uop.edu.pk; gohar.pharmacist@gmail.com Yusuf S Althobaiti, Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia, Email ys.althobaiti@tu.edu.saBackground: Alzheimer’s disease (AD) is a neurodegenerative disorder that is more prevalent in the elderly. There is extensive literature on using Acacia species against central nervous system disorders, although Acacia stenophylla has not been investigated for any neuroprotective potential. The purpose of the study was to elucidate the ameliorative effect of ethyl acetate (ASEE) and butanol (ASB) extracts from the bark of A. stenophylla on memory deficits and cognitive dysfunction in scopolamine- or diazepam-induced amnesia in mice.Methods: The phytochemical constituents of the extracts of A. stenophylla were determined by GC-MS and the in vitro anticholinesterase plus antioxidant activities were also evaluated. Anti-amnesic effects were determined employing the open field test, elevated plus maze (EPM), Morris water maze (MWM), and Y-maze paradigms.Results: The in vitro cholinesterase assays disclosed a concentration-dependent inhibition of both AChE and BuChE with IC50 values of 28.48 and 44.86 μg/mL for the ASEE extract and 32.04 and 50.26 μg/mL for the ASB extract against AChE and BuChE respectively. DPPH and H2O2 antioxidant assays revealed respective IC50 values for the ASEE extract of 28.04 and 59.84 μg/mL, plus 32.77 and 64.65 μg/mL for ASB extract. The findings revealed that both extracts possessed substantial antioxidant properties. Furthermore, these fractions restored scopolamine- and diazepam-induced memory deficits in a dose-dependent manner, as observed by a significant decrease in the transfer latency in EPM, reduction in escape latency, added time spent in the target quadrant in the MWM, and elevated spontaneous alternation behavior (SAB) in the Y-maze test.Conclusion: The ameliorative effect of A. stenophylla on scopolamine- and diazepam-induced amnesia can be attributed to antioxidant and anticholinesterase activity. Consequently, the use of A. stenophylla might be exploited in the alleviation of oxidative stress and the management of AD.Keywords: Acacia stenophylla, amnesia, oxidative stress, cognitive deficits, acetylcholinesterase

Ashfaq Ahmad,1,2 Farhat Ullah,2 Abdul Sadiq,2 Muhammad Ayaz,2 Muhammad Saeed Jan,2 Muhammad Shahid,2 Abdul Wadood,3 Fawad Mahmood,2 Umer Rashid,4 Riaz Ullah,5 Muhammad Umar Khayam Sahibzada,1 Ali S Alqahtani,5 Hafiz Majid Mahmood6 1Department of Pharmacy, Sarhad University of Science & Technology, Peshawar, KPK, Pakistan; 2Department of Pharmacy, Faculty of Biological Sciences, University of Malakand, Chakdara, 18000, KP, Pakistan; 3Department of Biochemistry, UCS, Shankar Abdul Wali Khan University, Mardan 23200, Pakistan; 4Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan; 5Department of Pharmacognosy, Medicinal, Aromatic and Poisonous Plants Research Center (MAPRC), College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia; 6Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaCorrespondence: Abdul SadiqDepartment of Pharmacy,Faculty of Biological Sciences, University of Malakand, Chakdara 18000, KP, PakistanTel +92 301-2297-102Email sadiquom@yahoo.comAshfaq AhmadDepartment of Pharmacy, Sarhad University of Information Technology, Peshawar, PakistanEmail ashfaqpharma123@gmail.comIntroduction: The current study was designed to synthesize derivatives of succinimide and compare their biological potency in anticholinesterase, alpha-glucosidase inhibition, and antioxidant assays.Methods: In this research, two succinimide derivatives including (S)-1-(2,5-dioxo-1-phenylpyrrolidin-3-yl) cyclohexanecarbaldehyde (Compound 1) and (R)-2-((S)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-2-phenylpropanal (Compound 2) were synthesized using Michael addition. Both the compounds, ie, 1 and 2 were evaluated for in-vitro acetylcholinesterase (AChE), butyrylctcholinesterase (BChE), antioxidant, and α-glucosidase inhibitory potentials. Furthermore, molecular docking was performed using Molecular Operating Environment (MOE) to explore the binding mode of both the compounds against different enzymes. Lineweaver–Burk plots of enzyme inhibitions representing the reciprocal of initial enzyme velocity versus the reciprocal of substrate concentration in the presence of synthesized compounds and standard drugs were constructed using Michaelis–Menten kinetics.Results: In AChE inhibitory assay, compounds 1 and 2 exhibited IC50 of 343.45 and 422.98 μM, respectively, against AChE enzyme. Similarly, both the compounds showed IC50 of 276.86 and 357.91 μM, respectively, against BChE enzyme. Compounds 1 and 2 displayed IC50 of 157.71 and 471.79 μM against α-glucosidase enzyme, respectively. In a similar pattern, compound 1 exhibited to be more potent as compared to compound 2 in all the three antioxidant assays. Compound 1 exhibited IC50 values of 297.98, 332.94, and 825.92 μM against DPPH, ABTS, and H2O2 free radicals, respectively. Molecular docking showed a triple fold in the AChE and BChE activity for compound 1 compared with compound 2. The compound 1 revealed good interaction against both the AChE and BChE enzymes which revealed the high potency of this compound compared to compound 2.Conclusion: Both succinimide derivatives exhibited considerable inhibitory activities against cholinesterases and α-glucosidase enzymes. Of these two, compound 1 revealed to be more potent against all the in-vitro targets which was supported by molecular docking with the lowest binding energies. Moreover, compound 1 also proved to have antiradical properties.Keywords: succinimides, Alzheimer’s disease, cholinesterase, antioxidant, glucosidase, molecular docking

Ashfaq Ahmad,1 Farhat Ullah,1 Abdul Sadiq,1 Muhammad Ayaz,1 Haroon Rahim,2 Umer Rashid,3 Sajjad Ahmad,1 Muhammad Saeed Jan,1 Riaz Ullah,4 Abdelaat A Shahat,4,5 Hafiz Majid Mahmood6 1Department of Pharmacy, University of Malakand, Chakdara, Dir (L), KP (Khyber Pakhtunkhwa) 18000, Pakistan; 2Department of Pharmacy, Sarhad University of Science & Information Technology, Peshawar, KP (Khyber Pakhtunkhwa), Pakistan; 3Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, KP (Khyber Pakhtunkhwa), Pakistan; 4Department of Pharmacognosy (MAPPRC), College of Pharmacy, King Saud University Riyadh, Riyadh, Saudi Arabia; 5Phytochemistry Department, National Research Centre, Giza, Egypt; 6Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaCorrespondence: Haroon Rahim; Abdul SadiqDepartment of Pharmacy, Sarhad University of Science and Information Technology Peshawar, Peshawar, Khyber Pakhtunkhwa, Pakistan; Department of Pharmacy, University of Malakand Khyber Pakhtunkhwa, Chakdara 18800, PakistanTel +92-3329461642; +92-301-2297102Email hrahimpk@gmail.com, sadiquom@yahoo.comPurpose: The current work was designed to synthesize a bioactive derivative of succinimide and evaluate it for anti-Alzheimer, anticancer and anti-diabetic potentials.Methods: The compound was synthesized by Michael addition of butyraldehyde with N-phenylmaleimide. The synthesized compound was screened for biological potentials including anti-cholinesterase, in-vitro anti-diabetic, antioxidant and anthelmintic potentials. The anti-cholinesterase potential was evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), anti-diabetic potential against α-glucosidase, antioxidant potential against ABTS, DPPH and H2O2 and anthelmintic potential against Perethima posthuma and Ascaridia galli respectively.Results: The compound demonstrated significant AChE and BChE inhibition i.e., 71.34±1.92 and 73.42 ±1.92 at the concentration of 1000 μg/mL respectively. Other dilutions exhibited concentration-dependent inhibitory activity against both enzymes. In the MTT assay, the newly synthesized compound was found active against all of the cell lines viz, HCT-116, MDA-MB231, NIH/3T3 and MCF-7 and the highest cytotoxicity potential was observed against the colon cancer cell line (HCT-116) with an IC50 value of 78 μg/mL exhibiting its highest potential. Moreover, the compound exhibited prominent α-glucosidase inhibitory potentials (79.86±2.54% at 1000 μg/mL) with IC50 value of 156.23 μg/mL. Further, our test compound exhibited considerable scavenging activity against DPPH, ABTS and H2O2 free radicals with percent inhibitions of 75.84±1.58, 72.85±1.17 and 54.82±1.82 and IC50 values of 84.36, 139.74 and 752.21 μg/mL respectively. Our test sample exhibited significant anthelmintic potentials. It demonstrated significant paralysis and death of the test worms in an unbelievably short time in comparison with albendazole.Conclusion: Going into the detail of all observations, it may be deduced that the newly synthesized succinimide derivative could be an important drug candidate against neurodegenerative disorders like Alzheimer’s disease, cancer, diabetes mellitus and worms. Further detailed studies in animal models are required for in-vivo analysis of the compound.Keywords: Succinimide, Alzheimer’s disease, MTT, oxidative stress, diabetes, helminthiasis