Cytoprotective Potential Research Articles

Ethanol-induced gastric ulcer in rats and intervention of tert-butylhydroquinone: Involvement of Nrf2/HO-1 signalling pathway.

Gastric ulcer (GU) is the most common health concern that occurs due to alcohol consumption, smoking and physiological stress. Ethanol-induced GU in animal model resembles the pathophysiology of human ulcer. The present study was designed to investigate the cytoprotective and anti-inflammatory properties of tert-butylhydroquinone (tBHQ), a nuclear factor erythroid 2-related factor 2 (Nrf2) activator, against gastric mucosal damage induced by acute exposure of ethanol (5 ml/kg). The intervention of tBHQ (25 and 50 mg/kg, per os (po)) and omeprazole (20 mg/kg, po) was done for 10 consecutive days. Omeprazole was chosen as a standard drug because it is prescribed for the treatment of GU. Pretreatment of tBHQ decreased gastric mucosal lesion, ulcer index, apoptotic cells and lipid peroxidation level induced by ethanol. Furthermore, the intervention of tBHQ increased gastric mucosa integrity, pH, reduced glutathione, collagen and mucus-producing goblet cells. Intervention of tBHQ increased the expression of antioxidant markers such as Nrf2, haeme oxygenase-1 and catalase and decreased the expressions of inflammatory markers such as nuclear factor kappa-light-chain-enhancer of activated B cells and cyclooxygenase-2. The cytoprotective potential of tBHQ against gastric mucosal damage might be due to its ability to enhance cellular antioxidants and anti-inflammatory responses.

Unravelling the inhibitory and cytoprotective potential of diuretics towards amyloid fibrillation

Protein misfolding and deposition of aggregated proteins inside as well as outside of the cells have been associated with several neurotoxic and neurodegenerative disorders like Alzheimer’s, Parkinson’s and familial amyloid polyneuropathy etc. that could be controlled by anti-aggregation methodologies employing either inhibition or disaggregation of toxic aggregates. Also, the Alzheimer’s disease develops in later life is somehow related to the high mid-life blood pressure. Therefore the present work targets the amyloid inhibiting potential of diuretics (a class of antihypertensive drugs) – Indapamide (INDP) and Hydrochlorothiazide (HCTZ) against human serum albumin (HSA) and human lysozyme (HL) fibrillogenesis. The effect of both INDP and HCTZ on the kinetics of amyloid formation of HSA and HL was illustrated and various biophysical techniques like Thioflavin T (ThT) and 8-Anilinonaphthalene-1-sulfonic acid (ANS) fluorescence measurement, Congo red measurements and circular dichroism (CD) measurements depicted the inhibitory action of both INDP and HCTZ in a dose dependent manner. Transmission Electronic Microscopy (TEM) confirmed the absence of fibrillar structures when HSA and HL were co-incubated with INDP and HCTZ. In addition, molecular docking results revealed that both the drugs interacts with HSA and HL through hydrophobic interactions as well as hydrogen bonding, and also showed non-hemolytic activity on human RBCs demonstrated by the Hemolytic assay. Thus, both INDP and HCTZ could be propitious as a therapeutic agent and aid in the cure of amyloid related diseases.

Protective Effects of Ursolic Acid Against Cytotoxicity Induced by Corticosterone: Role of Protein Kinases.

Neuronal hippocampal death can be induced by exacerbated levels of cortisol, a condition usually observed in patients with Major depressive disorder (MDD). Previous in vitro and in vivo studies showed that ursolic acid (UA) elicits antidepressant and neuroprotective properties. However, the protective effects of UA against glucocorticoid-induced cytotoxicity have never been addressed. Using an in vitro model of hippocampal cellular death induced by elevated levels of corticosterone, we investigated if UA prevents corticosterone-induced cytotoxicity in HT22 mouse hippocampal derived cells. Concentrations lower than 25µM UA did not alter cell viability. Co-incubation with UA for 48h was able to protect HT22 cells from the reduction on cell viability and from the increase in apoptotic cells induced by corticosterone. Inhibition of protein kinase A (PKA), protein kinase C (PKC) and, Ca2+/calmodulin-dependent protein kinase II (CaMKII), but not phosphoinositide 3-kinase(PI3K), by using the pharmacological the inhibitors: H-89, chelerythrine, KN-62, and LY294002, respectively totally abolished the cytoprotective effects of UA. Finally, UA abrogated the reduction in phospho-extracellular signal-regulated kinases 1 and 2 (ERK1/2) but not in phospho-c-Jun kinases induced by corticosterone. These results indicate that the protective effect of UA against the cytotoxicity induced by corticosterone in HT22 cells may involve PKA, PKC, CaMKII, and ERK1/2 activation. The cytoprotective potential of UA against corticosterone-induced cytotoxicity and its ability to modulate intracellular signaling pathways involved in cell proliferation and survival suggest that UA may be a relevant strategy to manage stress-related disorders such as MDD.

C-terminal sequence deletion effect on antioxidative characteristics of VLPVPQK bioactive peptide from buffalo milk casein

In the recent time, demand for nontoxic antioxidative substances such as peptides has boomed among pharmacologists. In the present investigation, peptides, VLPVPQ and VLPVP were generated from parent antioxidative peptide, VLPVPQK. Initially, all these peptides were studied in-silico for biophysical properties like hydrophobicity, structure, Extinction coefficient, isoelectric point, grand average hydropathy value and Wimley White whole residue hydrophobicity. Inspite of this, homology relationship among organisms, taxonomy, digestibility assessment for proteases, solubility, melting temperature index, half-life time in-vitro and in-vivo, instability index and aliphatic index was compared in-silico. Further, based on these properties, VLPVP was compared with parent peptide, VLPVPQK for antioxidative potential. VLPVP exhibited lesser antioxidative potential by chemical method and in-vitro hydrogen peroxide induced oxidative stress conditions generated in fibroblast cells compared to VLPVPQK. The proliferative potential, cell injury marker, nitric oxide production and pro-inflammatory, Tumor Necrosis Factor-α was measured to compare cytoprotective antioxidative potential. The results displayed the cytoprotective potential of VLPVPQK. In addition, the present study suggested that glutamine and lysine are responsible for the c-terminal sequence based response and cytoprotective potential of milk bioactive peptide, VLPVPQK. Other than this, hydrophobic amino acids and positive charge of the VLPVPQK is also responsible for the cytoprotective potential.

Ovatodiolide suppresses inflammatory response in BEAS-2B cells by regulating the CREB/AQP5 pathway, and sensitizes nasopharyngeal carcinoma cells to radiation therapy

Due to the radiosensitivity of the airway epithelium, radiation-induced sinusitis or bronchitis is not uncommon, and makes mitigation of resulting inflammatory airway diseases a principal goal of many investigations. This study examined whether Ovatodiolide (Ova) sensitizes the human metastatic nasopharyngeal cancer (NPC) cell line, NPC-BM2, to irradiation using viability, clonogenicity and Western blot assays. Concurrently, we used varying concentrations of histamine and/or Ova to determine the anti-inflammatory potential of Ovatodiolide on normal bronchus epithelial BEAS-2B cells, as well as on the subcellular distribution of Aquaporin 5 (AQP5) and expression levels of p-CREB, AQP5, p38 MAPK, NF-κB, PI3K, Akt and ERK proteins. We demonstrated that Ova in synergism with irradiation inhibited NPC-BM2 cell viability and suppressed their clonogenicity. Immunofluorescence analysis revealed low-dose (≤ 2.5 μM) Ova reversed histamine-induced suppression of AQP5 expression, and abrogated histamine-enhanced NF-κB nuclear translocation, indicating Ova modulates the p38 MAPK/NF-κB signaling pathway and elicits p-CREB/AQP5-mediated antihistamine effects. Similarly, Ova deregulates the PI3K/Akt/ERK signaling in BEAS-2B cells, suggesting its cytoprotective potential. In conclusion, this study highlights the radio-sensitizing anticancer efficacy of Ova in human metastatic NPC cells, as well as its putative cytoprotective role in normal bronchial cells, for airway surface liquid maintenance and homeostasis during or after radiotherapy.

Hepatoprotective effect of Solanum surattense leaf extract against chemical- induced oxidative and apoptotic injury in rats

BackgroundOf over 35 Saudi plants traditionally used to treat liver disorders, majority still lack scientific validations. We therefore, evaluated the anti-oxidative, anti-apoptotic and hepatoprotective potential of Solanum surattense leaves total ethanol-extract (SSEE).MethodsThe cytoprotective (4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide/ MTT assay) and anti-apoptotic (caspase-3/7) potential of SSEE (25–200 μg/mL) were assessed in cultured HepG2 cells against dichlorofluorescein (DCFH)-induced toxicity. The hepatoprotective salutation of SSEE (100 and 200 mg/kg.bw/day) in carbon tetrachloride (CCl4)-intoxicated rats was evaluated by serum biochemistry and histopathology. The anti-oxidative activity of SSEE (31.25–500 μg/mL) was tested by 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging and linoleic acid bleaching assays. Also, SSEE was subjected to qualitative phytochemical analysis, and standardized by validated high-performance liquid chromatography (HPTLC).ResultsSSEE at doses 50, 100 and 200 μg/mL showed HepG2 cell proliferative and protective potential by about 61.0, 67.2 and 95%, respectively through inhibition of caspase-3/7 against DCFH-toxicity. In CCl4-injured rats, SSEE (200 mg/kg) significantly (P < 0.001) normalized serum transaminases, alkaline phosphatase, bilirubin, cholesterol, triglycerides, and total protein, including tissue malondialdehyde and nonprotein sulfhydryls levels, supported by the liver histopathology. SSEE further showed strong in vitro anti-oxidative and anti-lipid peroxidative activities, evidenced by the presence of alkaloids, flavonoids, tannins, sterols and saponins. Identification of β-sitosterol (3.46 μg/mg) strongly supported the anti-oxidative and hepatoprotective salutation of SSEE.ConclusionOur findings suggest the therapeutic potential of S. surattense against chemical-induced oxidative stress and liver damage. However, isolation of the active principles and elucidation of mechanism of action remain to be addressed.

Proanthocyanidins from the stem bark of Rhus tripartita ameliorate methylgloxal-induced endothelial cell apoptosis

In traditional Arabian medicine, the Rhus tripartita plant (family Anacardiaceae) has been used to treat inflammatory conditions. Although Rhus extracts have been reported for their cardioprotective effects, information regarding their active principle compounds remains insufficient. The present investigation was aimed at determining the antioxidant chemical constituents of the methanolic extract of R. tripartita stem bark and evaluating their ability to ameliorate methylglyoxal-induced endothelial cell apoptosis. Ten flavonoid compounds (1–10) were isolated and identified using DPPH radical scavenging bioassay-guided chromatographic separation. A new proanthocyanidin (rhuspartin) (1) was isolated and identified as 3,5,13,14-flavantetrol-(4β→8)-catechin, using extensive spectroscopic data and high resolution-mass spectrometry. Among the compounds (1, 5, 7–10) tested for toxicity toward cultured endothelial cells (HUVECs), the non-cytotoxic compounds 1 and 7 evinced cytoprotective potential that reversed the methylglyoxal-induced apoptosis (by 62% and 64%, respectively) through downregulation of caspase 3/7.

Human mesenchymal stem cells improve rat islet functionality under cytokine stress with combined upregulation of heme oxygenase-1 and ferritin

BackgroundIslets of Langerhans transplantation is a promising therapy for type 1 diabetes mellitus, but this technique is compromised by transplantation stresses including inflammation. In other tissues, co-transplantation with mesenchymal stem cells has been shown to reduce damage by improving anti-inflammatory and anti-oxidant defences. Therefore, we probed the protection afforded by bone marrow mesenchymal stem cells to islets under pro-inflammatory cytokine stress.MethodsIn order to evaluate the cytoprotective potential of mesenchymal stem cells on rat islets, co-cultures were exposed to the interleukin-1, tumour necrosis factor α and interferon γ cocktail for 24 h. Islet viability and functionality tests were performed. Reactive oxygen species and malondialdehyde were measured. Expression of stress-inducible genes acting as anti-oxidants and detoxifiers, such as superoxide dismutases 1 and 2, NAD(P)H quinone oxidoreductase 1, heme oxygenase-1 and ferritin H, was compared to non-stressed cells, and the corresponding proteins were measured. Data were analysed by a two-way ANOVA followed by a Holm-Sidak post hoc analysis.ResultsExposure of rat islets to cytokines induces a reduction in islet viability and functionality concomitant with an oxidative status shift with an increase of cytosolic ROS production. Mesenchymal stem cells did not significantly increase rat islet viability under exposure to cytokines but protected islets from the loss of insulin secretion. A drastic reduction of the antioxidant factors heme oxygenase-1 and ferritin H protein levels was observed in islets exposed to the cytokine cocktail with a prevention of this effect by the presence of mesenchymal stem cells.ConclusionsOur data evidenced that MSCs are able to preserve islet insulin secretion through a modulation of the oxidative imbalance mediated by heme and iron via heme oxygenase-1 and ferritin in a context of cytokine exposure.

Zawartość związków fenolowych w ekstrakcie z propolisu oraz ocena jego aktywności przeciwutleniającej i cytoochronnej względem erytrocytów ludzkich w warunkach stresu oksydacyjnego in vitro

Introduction. Propolis (bee glue) is a natural product collected by honeybees from buds of various trees, shrubs and other plant species. Extracts of propolis possess numerous biological activities, including antioxidant, antibacterial, antifungal and anticancer. For this reason, propolis is currently used in many applications, such as preparations for cold syndrome, dermatological preparations or as a constituent of nutritional supplements and health food. The chemical composition of this natural material is very complex and depending on many factors, including method of extraction and selection of the solvent for the extraction process. Aim. The aim of the study was to determine concentration of selected phenolic compounds (flavonoids and phenolic acids) in extract of Polish propolis and estimate its antioxidant activity and effect on human red blood cells. Material and methods. In the propolis extract was determined concentration of 14 flavonoids and 9 phenolic acids using ultra-performance liquid chromatography equipped with a photodiode detector and a triple quadrupole mass spectrometer. The antioxidant potential of propolis extract was evaluated applying DPPH˙ free radical scavenging activity assay and Fe3+ reducing power assay. Moreover, the cytotoxicity and cytoprotective potential of propolis extract was estimated using human erythrocytes in vitro. Results. The propolis extract contained high concentration of pinocembrin, galangin, chrysin, apigenin, kaempferol, coumaric acid and cinnamic acid. It exhibited also high antioxidant potential. The antiradical activity of examined propolis extract was equal to 75% approx. activity of both standard antioxidants used in the study, namely Trolox and BHT. The reducing power of extract was equal to 65% approx. of Trolox and 80% of BHT, respectively. The propolis extract had no hemolytic activity, moreover, effectively protected human erythrocytes against free radicals-induced damage in vitro. Conclusions. The results of this study indicate that the propolis extract of national origin is a rich source of flavonoids and phenolic acids. Therefore, the propolis extract possesses a high antioxidant potential and can protect erythrocytes against free radicals-induced oxidative hemolysis.

Cytoprotective effects of Avenathramide C against oxidative and inflammatory stress in normal human dermal fibroblasts

Natural polyphenols are promising anti-aging compounds not only for their antioxidant activity, but also their ability to activate specific cellular pathways mediating the aging process. Avenanthramide C (Avn C), found exclusively in oats, is a natural antioxidant associated with free radical scavenging; however, it is how this compound elicits other protective effects. We investigated the intracellular antioxidant activity of Avn C and other cytoprotective potential in normal human skin fibroblasts exposed to extracellular stress. Avn C reduced H2O2-induced oxidative stress by reducing intracellular free radical levels and antioxidant gene transcripts. Avn C also resulted in decreased levels of gene transcripts encoding pro-inflammatory cytokines in response to H2O2 or tumor necrosis factor-α (TNF-α). This reduction in cytokine gene transcription occurred concomitantly with reduced phosphorylated nuclear factor-κB (NF-κB) p65, and decreased NF-κB DNA binding. Avn C further induced heme oxygense-1 (HO-1) expression through increased Nrf2 DNA binding activity, demonstrating a second mechanism by which Avn C attenuates cellular stress. Collectively, our findings indicate that Avn C protects normal human skin fibroblasts against oxidative stress and inflammatory response through NF-κB inhibition and Nrf2/HO-1 activation.

Design, synthesis and biological evaluation of chalcone analogues with novel dual antioxidant mechanisms as potential anti-ischemic stroke agents

Scavenging reactive oxygen species (ROS) by antioxidants is the important therapy to cerebral ischemia-reperfusion injury (CIRI) in stroke. The antioxidant with novel dual-antioxidant mechanism of directly scavenging ROS and indirectly through antioxidant pathway activation may be a promising CIRI therapeutic strategy. In our study, a series of chalcone analogues were designed and synthesized, and multiple potential chalcone analogues with dual antioxidant mechanisms were screened. Among these compounds, the most active 33 not only conferred cytoprotection of H2O2-induced oxidative damage in PC12 cells through scavenging free radicals directly and activating NRF2/ARE antioxidant pathway at the same time, but also played an important role against ischemia/reperfusion-related brain injury in animals. More importantly, in comparison with mono-antioxidant mechanism compounds, 33 exhibited higher cytoprotective and neuroprotective potential in vitro and in vivo. Overall, our findings showed compound 33 could emerge as a promising anti-ischemic stroke drug candidate and provided novel dual-antioxidant mechanism strategies and concepts for oxidative stress-related diseases treatment.

Assessment of Toxicity, Pro-Inflammatory Cytokines and Cytoprotective Potential of the Phytosaponin in Isolated Rat Pancreatic Islets

The objective of this study was to evaluate the in-depth toxicity assessment of pro-inflammatory and cytoprotective activity of phytosaponin. Saponin was isolated from methanolic extract of fruits of Momordica dioica and purification was achieved through the fractionation method of TLC. Toxicities were done as per OECD guidelines viz. In vivo micronucleus test 474 In vitro micronucleus test 487 In vitro chromosomal aberration test 473 in Neuroblastoma cells NB41A3 lines and Ames test 471. Saponin Momordica dioica was screened for production of pro-inflammatory cytokines viz. IL-1beta IL-6 and TNF-alpha was determined by ELISA against high glucose-induced cytoprotective activity like iNOS determined by western blot of against STZ-induced beta cell destruction in pancreatic isolated islets of rat. It was found that phytosaponin does not possess significant toxicities. Isolated pancreatic islet cells treated with high glucose produced pro-inflammatory cytokines which were reduced upon treatment with phytosaponin as compared to the high glucose control group. In similarly mediator of inflammation like iNOS was assessed and analysis showed SMD inhibited moderately in STZ stimulated pancreatic islet cells. The results concluded that phytosaponin possesses moderate to good cytoprotective nature and proves itself to be a potential candidate against diabetes

Safranal Attenuates Excitotoxin-Induced Oxidative OLN-93 Cells Injury.

Researches have been shown that glutamic acid (GA) or quinolinic acid (QA) can play role in neuroinflammatory and demyelinating diseases including multiple sclerosis (MS), mainly via oligodendrocytes activation and extreme free radicals generation. Recent studies have demonstrated that safranal, an active constituent of Crocus sativus, has several pharmacological effects such as antioxidant, anti-inflammatory and neuroprotective properties. Since there is no data about the impact of safranal on MS, this study was designed to investigate the protective effect of safranal on OLN-93 oligodendrocytes injury induced by GA or QA. At first, the potential toxic effect of safranal on OLN-93 viability was evaluated. Also, the cells were pretreated with safranal (0.1, 1, 10, 50, 100 and 200 μM) for 2 h and then subjected to GA (16 mM) or QA (8 mM) toxicity for 24 h, in which the same treatments were applied. The cell viability and parameters of redox status such as the levels of intracellular reactive oxygen species (ROS) and lipid peroxidation were measured. Safranal at concentration ranges of 1-800 μM had no toxic effect on cell viability (p>0.05). Treatment with safranal significantly increased cell viability following GA or QA insults at concentrations higher than 1 μM (p<0.01). The cytoprotective potential of safranal was also accompanied by decreased ROS accumulation (p<0.001) and malondialdehyde level (p<0.001) following GA or QA insults. The data suggests that safranal exhibits oligoprotection potential by means of inhibiting oxidative stress parameters.

LC-MS characterization and reduction of the phytotoxic effect of aluminium by natural products from Eugenia jambolana Lam.

The objective of this study was to quantify the flavonoids present in the Eugenia jambolana Lam extract and fractions, identify their composition by LC-MS, to determine the cytoprotective potential against aluminium Chloride toxicity in a prokaryotic and eukaryotic model, as well as the mechanism of cytoprotection of the extract and fractions. The ethanolic extract from E. jambolana, as well as its tannic and flavonoid fractions, were tested and the minimum bactericidal and fungicidal concentration of the products associated with aluminum chloride in different concentrations were established. These same products were used in the germination of lettuce seeds (Lactuva sativa). The extract and fractions did not show cytoprotective activity in bacterial and fungal models, since it was not able to interfere with the growth profile of these microorganisms. In relation to the vegetal model, it was possible to observe significant effects on caulis and lettuce radicle growth, as well as on the dry weight of radicles, showing a cytoprotective effect capable of inhibiting the aluminum chloride toxicity at different concentrations. In this way, due to the problems faced with aluminum contamination and the characteristics of the soils the E. jambolana extract may show an alternative to the toxicity of this metal.

Govindasamy Mugesh

Angewandte Chemie International EditionVolume 58, Issue 3 p. 662-662 Author ProfileFree Access Govindasamy Mugesh First published: 30 August 2018 https://doi.org/10.1002/anie.201809460Citations: 2AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract “When I was eighteen I wanted to be a farmer. The natural talent I would like to be gifted with is the ability to learn new languages quickly …” Find out more about Govindasamy Mugesh in his Author Profile. Govindasamy Mugesh The author presented on this page has recently published his 10th article since 2010 in Angewandte Chemie: “Remarkable Effect of Halogen Substitution on the Membrane Transport of Fluorescent Molecules in Living Cells”: H. Ungati, V. Govindaraj, G. Mugesh, Angew. Chem. Int. Ed. 2018, 57, 8989; Angew. Chem. 2018, 130, 9127. The work of G. Mugesh has been featured on the cover of Angewandte Chemie: “Chemistry and Biology in the Biosynthesis and Action of Thyroid Hormones”: S. Mondal, K. Raja, U. Schweizer, G. Mugesh, Angew. Chem. Int. Ed. 2016, 55, 7606; Angew. Chem. 2016, 128, 7734. Date of birth: May 29, 1970 Position: Professor, Indian Institute of Science, Bangalore E-mail: mugesh@iisc.ac.in Homepage: http://ipc.iisc.ac.in/gm.php ORCID: 0000-0002-5389-5309 Education: 1993 MSc, Bharathidasan University, Tiruchirappalli 1998 PhD with Prof. Harkesh B. Singh, Indian Institute of Technology, Bombay 2000–2001 Postdoctoral fellow with Prof. W.-W. du Mont, Technische Universität Braunschweig 2001–2002 Postdoctoral fellow with Prof. K. C. Nicolaou, The Scripps Research Institute, La Jolla Awards: 2011 CRSI Bronze Medal; 2011 AstraZeneca Excellence in Chemistry Award; 2012 Shanti Swarup Bhatnagar Prize; 2015 JC Bose Fellowship, Science and Engineering Research Board; 2017 National Prize for Research on Interfaces of Chemistry and Biology; Current research interests: Artificial enzymes; cellular redox regulation; ferroptosis; fluorescent probes; nitric oxide signaling; thyroid hormones Hobbies: Watching movies, cooking, driving When I was eighteen I wanted to be a farmer. The natural talent I would like to be gifted with is the ability to learn new languages quickly. The biggest challenge facing scientists is too many irrelevant and misleading research problems. My motto is work hard with dedication, serve people, and do not expect anything in return. Looking back over my career, I am satisfied! My favorite saying is “great minds discuss ideas; average minds discuss events; weak minds discuss people”. My favorite time of day is 10.30 am when I take a break and go with my colleagues to the Faculty Club on our beautiful campus for a cup of tea. I advise my students to be honest and help others. My favorite molecule is thyroxine, a simple molecule with amazing functions in the human body. My favorite composer is Isai Gnani Ilaiyaraaja, one of the greatest Indian composers, who wrote music for our every emotion in life. My favorite book is Thirukkural—a 2000-year-old classic Tamil work on ethics, which consists of 1 330 couplets (Kurals), dealing with all aspects of Aram (virtue), Poruḷ (wealth), and Inbam (love). My 5 top papers: 1“An antioxidant nanozyme that uncovers the cytoprotective potential of vanadia nanowires”: A. A. Vernekar, D. Sinha, S. Srivastava, P. U. Paramasivam, P. D'Silva, G. Mugesh, Nature Commun. 2014, 5, 5301. (Turning potentially cytotoxic vanadium into a cytoprotective redox modulator in human cells.) 2“A Chemical Model for the Inner-Ring Deiodination of Thyroxine by Iodothyronine Deiodinase”: D. Manna, G. Mugesh, Angew. Chem. Int. Ed. 2010, 49, 9246– 9249; Angew. Chem. 2010, 122, 9432. (Highlights the importance of two biological trace elements, selenium and iodine, in thyroid hormone activation and metabolism.) 3“Antibiotic Resistance: Mono- and Dinuclear Zinc Complexes as Metallo-β-Lactamase Mimics”: A. Tamilselvi, M. Nethaji, G. Mugesh, Chem. Eur. J. 2006, 12, 7797. (The key role played by metal ions in bacterial drug resistance and inactivation of β-lactam antibiotics.) 4“Biomimetic Studies on Anti-Thyroid Drugs and Thyroid Hormone Synthesis”: G. Roy, M. Nethaji, G. Mugesh, J. Am. Chem. Soc. 2004, 126, 2712. (My first paper as an independent researcher. Selenomethimazole can exert its anti-thyroid action by a mechanism different from that of the sulfur analogue.) 5“Synthesis and Structural Characterization of Monomeric Selenolato Complexes of Zinc, Cadmium, and Mercury”: G. Mugesh, H. B. Singh, R. P. Patel, R. J. Butcher, Inorg. Chem. 1998, 37, 2663. (My first ever publication. An intramolecular coordination strategy to prevent the polymerization that is generally observed for Group 12 metal chalcogenolate complexes.) Citing Literature Volume58, Issue3January 14, 2019Pages 662-662 ReferencesRelatedInformation

Neuroprotective activity of orexin system in ischemic stroke

The protective potential of orexin system is a field of interest in the search of the new methods to diminish brain damage in ischemic stroke. The cytoprotective potential of orexins in hypoxic damage is associated with their antioxidant, anti-inflammatory and anti-apoptotic properties and with their ability to activate proliferation and normalize metabolism. Even though today little is known about the role of orexins in memory and pain in ischemic stroke, the common features of the pathogenesis of these disruptions and the mechanisms of orexin-associated protection could suggest the opportunity to use of orexins for correction of these complications following ischemic stroke. Further studies of the orexin-associated neuroprotection could become the further step on the way to the new therapeutic approaches in ischemic stroke.

Protective potential of dimethyl fumarate in a mouse model of thalamocortical demyelination

Alterations in cortical cellular organization, network functionality, as well as cognitive and locomotor deficits were recently suggested to be pathological hallmarks in multiple sclerosis and corresponding animal models as they might occur following demyelination. To investigate functional changes following demyelination in a well-defined, topographically organized neuronal network, in vitro and in vivo, we focused on the primary auditory cortex (A1) of mice in the cuprizone model of general de- and remyelination. Following myelin loss in this model system, the spatiotemporal propagation of incoming stimuli in A1 was altered and the hierarchical activation of supra- and infragranular cortical layers was lost suggesting a profound effect exerted on neuronal network level. In addition, the response latency in field potential recordings and voltage-sensitive dye imaging was increased following demyelination. These alterations were accompanied by a loss of auditory discrimination abilities in freely behaving animals, a reduction of the nuclear factor-erythroid 2-related factor-2 (Nrf-2) protein in the nucleus in histological staining and persisted during remyelination. To find new strategies to restore demyelination-induced network alteration in addition to the ongoing remyelination, we tested the cytoprotective potential of dimethyl fumarate (DMF). Therapeutic treatment with DMF during remyelination significantly modified spatiotemporal stimulus propagation in the cortex, reduced the cognitive impairment, and prevented the demyelination-induced decrease in nuclear Nrf-2. These results indicate the involvement of anti-oxidative mechanisms in regulating spatiotemporal cortical response pattern following changes in myelination and point to DMF as therapeutic compound for intervention.

Anti-inflammatory, antiproliferative and cytoprotective potential of the Attalea phalerata Mart. ex Spreng. pulp oil.

The anti-inflammatory, antiproliferative and cytoprotective activity of the Attalea phalerata Mart. ex Spreng pulp oil was evaluated by in vitro and in vivo methods. As for the chemical profile, the antioxidant activity was performed by spectrophotometry, and the profile of carotenoids and amino acids by chromatography. Our data demonstrated that A. phalerata oil has high carotenoid content, antioxidant activity and the presence of 5 essential amino acids. In the in vitro models of inflammation, the oil demonstrated the capacity to inhibit COX1 and COX2 enzymes, the production of nitric oxide and also induces macrophages to spreading. In the in vivo models of inflammation, the oil inhibited edema and leukocyte migration in the Wistar rats. In the in vitro model of antiproliferative and cytoprotective activity, the oil was shown inactive against the kidney carcinoma and prostate carcinoma lineage cells and with cytoprotective capacity in murine fibroblast cells, inhibiting the cytotoxic action of doxorubicin. Therefore, it is concluded that A. phalerata pulp oil has anti-inflammatory effects with nutraceutical properties potential due to the rich composition. Moreover, the oil also has cytoprotective activity probably because of its ability to inhibit the action of free radicals.

C‐peptide and Insulin Work in Concert to Mitigate Hyperglycemia‐induced Oxidative Stress and Facilitate Cellular Recovery

The role of C‐peptide in the prevention and resolution of diabetes‐induced vascular injuries is not fully understood. C‐peptide is a 31 amino acid peptide that is co‐produced and co‐secreted with insulin by pancreatic beta islet cells. In insulin‐dependent diabetics C‐peptide levels correlate with the delayed onset of comorbidities that arise as a consequence of vascular compromise. These comorbidities include increased incidence of cardiovascular disease, retinopathies, renal failure, and compromised wound healing. In 2013, G‐protein‐coupled‐receptor 146 was identified by our group as the receptor for C‐peptide. GPR146 is highly expressed on endothelial cells, fibroblasts, red blood cells, and lymphocytes. We hypothesized that C‐peptide and insulin act in concert to regulate and reduce hyperglycemia‐induced oxidative stress and normalize cellular function in hyperglycemia. In this study, primary human dermal microvascular endothelial cells (HDMEC), primary normal human dermal fibroblasts (NHDF), and human microvascular endothelial cells (HMEC), were used to investigate cellular response to incubation in normal glucose(NG) or high glucose (25 mM)(HG) alone or with the addition of C‐peptide (1.5 nM), insulin (0.5 nM), or both C‐peptide and insulin. All cell lines were pre‐screened for the presence of the insulin receptor and GPR 146 by qPCR and the responses to C‐peptide and insulin by relative expression of cFOS mRNA. In cells incubated with 25 mM glucose for 3 days, the ratio of phosphorylated ERK1–2/ERK 1–2 was not significantly increased by C‐peptide or insulin alone but was significantly increased by incubation with both. Cells incubated in HG for 3 days demonstrated phosphorylated AKT/AKT levels which were not altered by C‐peptide alone, but were increased by insulin and markedly enhanced by the presence of both. In wound healing assays cells in HG demonstrated impaired migration relative to those in NG and the greatest improvement in migration was in the presence of paired C‐peptide and insulin. Endothelial cell nitric oxide (NO) production was significantly elevated in HG, and while there was no significant inhibition by C‐peptide or insulin alone, incubation with both resulted in complete restoration to normal levels. NO generated by ECs in response to HG is produced in conditions of mitochondrial oxidative stress and production of radical oxygen species (ROS), in this environment NO complexes with ROS to form peroxynitrites. Peroxynitrites are potent mediators of cellular damage, forming complexes with proteins, enzymes, and lipids. ROS and superoxide (SO) levels were increased in cells exposed to high glucose conditions, and incubation with both C‐peptide and insulin resulted in the reduction of ROS and SO levels. This study demonstrated the cytoprotective potential of C‐peptide when paired with insulin. These results support the hypothesis that co‐administration of C‐peptide with insulin to insulin‐dependent diabetics may reduce the onset of comorbidities.Support or Funding InformationHJ121456This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Identification of the Multifaceted Chemopreventive Activity of Curcumin Against the Carcinogenic Potential of the Food Additive, KBrO3.

Background: Potassium bromate (KBrO3), a food additive, has been used in many bakery products as an oxidizing agent. It has been shown to induce renal cancer in many in-vitro and in-vivo experimental modelsObjectives: This study evaluated the carcinogenic potential of potassium bromate (KBrO3) and the chemopreventive mechanisms of the anti-oxidant and anti-inflammatory phytochemical, curcumin against KBrO3-induced carcinogenicity.Method: Lactate dehydrogenase (LDH) cytotoxicity assay and morphological characteristics were used to assess curcumin's cytoprotective potential against KBrO3 toxicity. To assess the chemopreventive potential of curcumin against KBrO3-induced oxidative insult, intracellular H2O2 and the nuclear concen-tration of the DNA adduct 8-OHdG were measured. PCR array, qRT-PCR, and western blot analysis were used to identify dysregulated genes by KBrO3 exposure. Furthermore, immunofluorescence was used to evaluate the ciliary loss and the disturbance of cellular tight junction induced by KBrO3.Results: Oxidative stress assays showed that KBrO3 increased the levels of intracellular H2O2 and the DNA adduct 8-OHdG. Combination of curcumin with KBrO3 efficiently reduced the level of H2O2 and 8-OHdG while up-regulating the expression of catalase. PCR array, qRT-PCR, and western blot analysis revealed that KBrO3 dysregulated multiple genes involved in inflammation, proliferation, and apoptosis, namely CTGF, IL-1, and TRAF3. Moreover, qRT-PCR and immunofluorescence studies showed that KBrO3 negatively affected the tight junctional protein (ZO-1) and induced a degeneration of primary ciliary proteins. The negative impact of KBrO3 on cilia was markedly repressed by curcumin.Conclusion: Curcumin could potentially be used as a protective agent against carcinogenicity of KBrO3.