Browsing by Author "Surendra Kumar Trigun"

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Activation of oxidative stress and inflammatory factors could account for histopathological progression of aflatoxin-B1 induced hepatocarcinogenesis in rat
(Kluwer Academic Publishers, 2015) Krishna Beer Singh; Brajesh Kumar Maurya; Surendra Kumar Trigun
Aflatoxin-B1 (AFB1) intoxication is known to develop hepatocellular carcinoma (HCC). However, pathogenesis and diagnosis of AFB1-induced HCC remain undefined. This article describes histopathological progression versus kinetics of the placental glutathione S-transferase (GST-pi) expression and profiles of the antioxidant enzymes, pro-inflammatory cytokines, and proliferative cell nuclear antigen (PCNA) in the liver from the rats administered with two doses of 1 mg AFB1/kg b.w. Histopathologically, hepatocytes necrosis could be observed after 4 weeks of the AFB1 treatment, which subsequently developed into the well-defined foci of altered hepatocytes (FAH) at 10 weeks post-treatment stage. This was consistent with an increasing trend of GST-pi immunostaining especially in the liver foci as a function of FAH progression and thus, suggesting that GST-pi over expression may serve as a marker for AFB1-induced hepatocarcinogenesis. The liver from AFB1-treated rats showed significantly enhanced level of reactive oxygen species coinciding with the declined immunostaining for superoxide dismutase-1, a committed enzyme of the antioxidant pathway, in the FAH regions and also with declined activity of the other antioxidant enzymes. Concordantly, the liver from the AFB1-treated rats showed over expression of pro-inflammatory cytokines; TNF-α & IL-1α and a cell proliferative marker PCNA. These findings present histological characterization of AFB1-induced HCC development and provide evidence for activation of oxidative stress–pro-inflammatory pathway during hepatocarcinogenesis induced by AFB1 toxicity. © 2014, Springer Science+Business Media New York.
Activation of p53 mediated glycolytic inhibition-oxidative stress-apoptosis pathway in Dalton's lymphoma by a ruthenium (II)-complex containing 4-carboxy N-ethylbenzamide
(Elsevier, 2015) Raj Kumar Koiri; Surendra Kumar Trigun; Lallan Mishra
There is a general agreement that most of the cancer cells switch over to aerobic glycolysis (Warburg effect) and upregulate antioxidant enzymes to prevent oxidative stress induced apoptosis. Thus, there is an evolving view to target these metabolic alterations by novel anticancer agents to restrict tumor progression in vivo. Previously we have reported that when a non toxic dose (10 mg/kg bw i.p.) of a novel anticancer ruthenium(II)-complex containing 4-carboxy N-ethylbenzamide; Ru(II)-CNEB, was administered to the Dalton's lymphoma (DL) bearing mice, it regressed DL growth by inducing apoptosis in the DL cells. It also inactivated M4-LDH (M4-lactate dehydrogenase), an enzyme that drives anaerobic glycolysis in the tumor cells. In the present study we have investigated whether this compound is able to modulate regulation of glycolytic inhibition-apoptosis pathway in the DL cells in vivo. We observed that Ru(II)-CNEB could decline expression of the inducible form of 6-phosphofructo-2-kinase (iPFK2: PFKFB3), the master regulator of glycolysis in the DL cells. The complex also activated superoxide dismutase (the H2O2 producing enzyme) but declined the levels of catalase and glutathione peroxidase (the two H2O2 degrading enzymes) to impose oxidative stress in the DL cells. This was consistent with the enhanced p53 level, decline in Bcl2/Bax ratio and activation of caspase 9 in those DL cells. The findings suggest that Ru(II)-CNEB is able to activate oxidative stress-apoptosis pathway via p53 (a tumor supressor protein) mediated repression of iPFK2, a key glycolytic regulator, in the DL cells in vivo. © 2015 Elsevier B.V. and Société franc¸aise de biochimie et biologie Moléculaire (SFBBM). All rights reserved.
Acute and chronic hyperammonemia modulate antioxidant enzymes differently in cerebral cortex and cerebellum
(2008) Santosh Singh; Raj K. Koiri; Surendra Kumar Trigun
Studies on acute hyperammonemic models suggest a role of oxidative stress in neuropathology of ammonia toxicity. Mostly, a low grade chronic type hyperammonemia (HA) prevails in patients with liver diseases and causes derangements mainly in cerebellum associated functions. To understand whether cerebellum responds differently than other brain regions to chronic type HA with respect to oxidative stress, this article compares active levels of all the antioxidant enzymes vis a vis extent of oxidative damage in cerebral cortex and cerebellum of rats with acute and chronic HA induced by intra-peritoneal injection of ammonium acetate (successive doses of 10 × 103 & 8 × 103 μmol/kg b.w. at 30 min interval for acute and 8 × 103 μmol/kg b.w. daily up to 3 days for chronic HA). As compared to the respective control sets, cerebral cortex of acute HA rats showed significant decline (P < 0.01-0.001) in the levels of superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) but with no change in glutathione reductase (GR). In cerebellum of acute HA rats, SOD, catalase and GR though declined significantly, GPx level was found to be stable. Contrary to this, during chronic HA, levels of SOD, catalase and GPx increased significantly in cerebral cortex, however, with a significant decline in the levels of SOD and GPx in cerebellum. The results suggest that most of the antioxidant enzymes decline during acute HA in both the brain regions. However, chronic HA induces adaptive changes, with respect to the critical antioxidant enzymes, in cerebral cortex and renders cerebellum susceptible to the oxidative stress. This is supported by ∼ 2- and 3-times increases in the level of lipid peroxidation in cerebellum during chronic and acute HA respectively, however, with no change in the cortex due to chronic HA. © 2007 Springer Science+Business Media, LLC.
Ambroxol modulates 6-Hydroxydopamine-induced temporal reduction in Glucocerebrosidase (GCase) enzymatic activity and Parkinson's disease symptoms
(Elsevier Inc., 2018) Akanksha Mishra; Lalit Pratap Chandravanshi; Surendra Kumar Trigun; Sairam Krishnamurthy
Reduced glucocerebrosidase (GCase) enzymatic activity is found in sporadic cases of Parkinson's disease making GCase a serious risk factor for PD. GCase gene mutations constitute a major risk factor in early-onset PD but only account for 5–10% cases. Having enough evidence for construct and face validity, 6-OHDA-induced hemiparkinson's model may be useful to assess the GCase-targeting drugs in order to have new leads for treatment of PD. Ambroxol (AMB) is reported to increase GCase activity in different brain-regions. Therefore, we investigated anti-PD like effects of AMB as well as GCase activity in striatal and nigral tissues of rats in hemiparkinson's model. AMB was given a dose of 400 mg/kg per oral twice daily and SEL used as positive control was given in the dose of 10 mg/kg per oral daily from D-4 to D-27 after 6-OHDA administration. 6-OHDA reduced GCase activity in striatal and in a progressive manner in nigral tissues. AMB and SEL attenuated 6-OHDA-induced motor impairments, dopamine (DA) depletion and GCase deficiency. AMB and SEL also ameliorated 6-OHDA-induced mitochondrial dysfunction in terms of MTT reduction, α-synuclein pathology, loss of nigral cells, and intrinsic pathway of apoptosis by modulating cytochrome-C, caspase-9, and caspase-3 expressions. The results suggest that AMB attenuated 6-OHDA-induced GCase deficiency and PD symptoms. Therefore, the regenerative effects of AMB in dopamine toxicity may be due to its effects on GCase activity and mitochondrial function. Results indicate that SEL also has regenerative effect in the 6-OHDA model. Thus, GCase enzymatic activity is likely to be involved in the development of PD symptoms, and 6-OHDA-induced hemiparkinson's model may be used to evaluate compounds targeting GCase activity for management of PD symptoms. © 2018 Elsevier Inc.
Apoptosis of Dalton's lymphoma due to in vivo treatment with emodin is associated with modulations of hydrogen peroxide metabolizing antioxidant enzymes
(Humana Press Inc., 2013) Krishna Beer Singh; Surendra Kumar Trigun
The evolving concept of pro-oxidative mechanism-based antitumor activity of emodin (1,3,8-trihydroxy-6-methyl anthraquinone), derived mainly from in vitro studies, needs to be defined for in vivo tumor models. The present article describes apoptosis and regression of Dalton's lymphoma (DL) in mice by emodin vis a vis modulations of hydrogen peroxide (H2O2) metabolizing antioxidant enzymes in the tumor cells in vivo. A non-toxic dose (40 mg/kg bw) of emodin, given intraperitoneally to the DL bearing mice daily up to 12th post DL transplantation day, caused a significant decline (P < 0.05) in the number of viable DL cells and could significantly increase life span of the DL mice (P < 0.01). A significant decline in Bcl2/Bax ratio consistent with the release of mitochondrial cytochrome c release in DL cells from emodin-treated DL mice suggested that emodin could induce mitochondrial pathway of apoptosis in the DL cells in vivo. Apoptosis of DL cells by emodin was further confirmed by the appearance of smaller DNA fragments on DNA ladder analysis. Over activation of both, the Cu-Zn-superoxide dismutases (SOD1) and Mn-SOD (SOD2), has been found correlated with the tumor suppression. Emodin caused significant increases in the expression and activity of SOD1 and SOD2 in the DL cells. H2O2 produced by SODs is degraded by catalase and glutathione peroxidase in the cells. Both these enzymes were observed to be declined significantly with a concomitant increment in H2O2 concentration (P < 0.01) in the DL cells from emodin-treated DL mice. It is concluded that emodin is able to induce mitochondrial pathway of apoptosis in the DL cells in vivo via reciprocal modulations of H2O2 producing and degrading antioxidant enzymes. © 2011 Springer Science+Business Media, LLC.
Bacopa monnieri Extract (CDRI-08) Modulates the NMDA Receptor Subunits and nNOS-Apoptosis Axis in Cerebellum of Hepatic Encephalopathy Rats
(Hindawi Limited, 2015) Papia Mondal; Surendra Kumar Trigun
Hepatic encephalopathy (HE), characterized by impaired cerebellar functions during chronic liver failure (CLF), involves N-methyl-D-aspartate receptor (NMDAR) overactivation in the brain cells. Bacopa monnieri (BM) extract is a known neuroprotectant. The present paper evaluates whether BM extract is able to modulate the two NMDAR subunits (NR2A and NR2B) and its downstream mediators in cerebellum of rats with chronic liver failure (CLF), induced by administration of 50 mg/kg bw thioacetamide (TAA) i.p. for 14 days, and in the TAA group rats orally treated with 200 mg/kg bw BM extract from days 8 to 14. NR2A is known to impart neuroprotection and that of NR2B induces neuronal death during NMDAR activation. Neuronal nitric oxide synthase- (nNOS-) apoptosis pathway is known to mediate NMDAR led excitotoxicity. The level of NR2A was found to be significantly reduced with a concomitant increase of NR2B in cerebellum of the CLF rats. This was consistent with significantly enhanced nNOS expression, nitric oxide level, and reduced Bcl2/Bax ratio. Moreover, treatment with BM extract reversed the NR2A/NR2B ratio and also normalized the levels of nNOS-apoptotic factors in cerebellum of those rats. The findings suggest modulation of NR2A and NR2B expression by BM extract to prevent neurochemical alterations associated with HE. © 2015 Papia Mondal and Surendra Kumar Trigun.
Biological significance and pathophysiological role of Matrix Metalloproteinases in the Central Nervous System
(Elsevier B.V., 2024) Krishnendu Ganguly; Krishnendu Adhikary; Arup Acharjee; Papia Acharjee; Surendra Kumar Trigun; Alaa Saeed Mutlaq; Sumel Ashique; Sabina Yasmin; Asma M. Alshahrani; Mohammad Yousuf Ansari
Matrix Metalloproteinases (MMPs), which are endopeptidase reliant on zinc, are low in embryonic tissues but increases in response to a variety of physiological stimulus and pathological stresses. Neuro-glial cells, endothelial cells, fibroblasts, and leucocytes secrete MMPs, which cleave extracellular matrix proteins in a time-dependent manner. MMPs affect synaptic plasticity and the development of short-term memory by controlling the size, shape, and excitatory synapses' function through the lateral diffusion of receptors. In addition, MMPs influence the Extracellular Matrix proteins in the Peri-Neuronal Net at the Neuro-glial interface, which aids in the establishment of long-term memory. Through modulating neuronal, and glial cells migration, differentiation, Neurogenesis, and survival, MMPs impact brain development in mammals. In adult brains, MMPs play a beneficial role in physiological plasticity, which includes learning, memory consolidation, social interaction, and complex behaviors, by proteolytically altering a wide variety of factors, including growth factors, cytokines, receptors, DNA repair enzymes, and matrix proteins. Additionally, stress, depression, addiction, hepatic encephalopathy, and stroke may all have negative effects on MMPs. In addition to their role in glioblastoma development, MMPs influence neurological diseases such as epilepsy, schizophrenia, autism spectrum disorder, brain damage, pain, neurodegeneration, and Alzheimer's and Parkinson's. To help shed light on the potential of MMPs as a therapeutic target for neurodegenerative diseases, this review summarizes their regulation, mode of action, and participation in brain physiological plasticity and pathological damage. Finally, by employing different MMP-based nanotools and inhibitors, MMPs may also be utilized to map the anatomical and functional connectome of the brain, analyze its secretome, and treat neurodegenerative illnesses. © 2024 Elsevier B.V.
Cationic Ru(II), Rh(III) and Ir(III) complexes containing cyclic π-perimeter and 2-aminophenyl benzimidazole ligands: Synthesis, molecular structure, DNA and protein binding, cytotoxicity and anticancer activity
(Elsevier, 2016) Amit Kumar; Ashish Kumar; Rakesh Kumar Gupta; Rajendra Prasad Paitandi; Krishna Beer Singh; Surendra Kumar Trigun; Maninder Singh Hundal; Daya Shankar Pandey
Synthesis, characterization, DNA and protein binding as well as anticancer activity of the organometallic complexes [(η6-C6H6)RuCl(APBI)]Cl (1), [(η6-p-MeC6H4Pri)RuCl(APBI)]Cl (2), [(η6-C6Me6)RuCl(APBI)]Cl (3), [(η5-C5Me5)RhCl(APBI)]Cl·H2O (4) and [(η5-C5Me5)IrCl(APBI)]Cl·H2O (5) containing 2-aminophenyl benzimidazole (APBI) have been described. The complexes 1-5 exhibited strong DNA, protein binding and anticancer activity against cervical cancer (SiHa) cell line. Their binding with calf thymus DNA (CT-DNA) and bovine serum albumin (BSA) have been examined by absorption and emission spectral studies. Strong interactions between complexes and CT-DNA have been affirmed by absorption spectral and EthBr displacement studies, while interaction with BSA via static quenching explored by fluorescence titration, synchronous and 3D fluorescence spectroscopy. The interactions between 1-5 and DNA has also been scrutinized by 1H NMR spectral studies using guanosine as a model for DNA. These results have been supported by DFT calculations and molecular docking studies. Cytotoxicity, apoptosis and in vitro anticancer activity of 1-5 toward SiHa cell line have been investigated by MTT assay and acridine (AO)/ethidium bromide (EthBr) fluorescence staining. Overall results revealed that DNA and protein binding, as well as anticancer activity of 1-5 follows the order as 5 > 3 > 2 > 1 > 4. © 2015 Elsevier B.V. All rights reserved.
Cilostamide, a phosphodiesterase 3A inhibitor, sustains meiotic arrest of rat oocytes by modulating cyclic adenosine monophosphate level and the key regulators of maturation promoting factor
(John Wiley and Sons Inc, 2022) Anumegha Gupta; Surendra Kumar Trigun
Cilostamide, a phosphodiesterase 3A (Pde3A) inhibitor, is known to increase intraoocyte cyclic adenosine monophosphate (cAMP) level which is involved in sustaining meiotic arrest of the oocytes. To explore the mechanisms involved in the cilostamide-mediated meiotic arrest of the oocytes, the present study describes the effects of cilostamide on cAMP level and related factors involved in maturation of the oocytes at its different meiotic stages; diplotene, metaphase I (MI) and metaphase II (MII). The oocytes from these three stages were collected from rat ovary and incubated with 10 µM cilostamide for 3 h in CO2 incubator. The levels of cAMP, cyclic guanosine monophosphate (cGMP) and the key players of maintaining meiotic arrest during oocyte maturation; Emi2, Apc, Cyclin B1, and Cdk1, were analyzed in diplotene, MI and MII stages. Pde3A was found to be expressed at all three stages but with the lowest level in MI oocyte. As compared to the control sets, the cAMP concentration was found to be highest in MII whereas cGMP was highest in the diplotene stage of cilostamide-treated group. The treated group showed declined reactive oxygen species level as compared with the control counterparts. Relatively increased levels of the Emi2, Cyclin B1, and phosphorylated thr161 of Cdk1 versus declined levels of phosphorylated thr14/tyr15 of Cdk1 in diplotene and MII stage oocytes are known to be involved in maintaining meiotic arrest and all these factors were found to undergo similar pattern of change due to the treatment with cilostamide. The findings thus suggest that cilostamide treatment promotes meiotic arrest by Pde3A inhibition led increase of both cAMP and cGMP level vis-a-vis modulation of the related regulatory factors such as Emi2, CyclinB1, and phosphorylated status of Cdk1 in diplotene and MII stage oocytes. Such a mechanism of meiotic arrest could allow the oocyte to prepare itself for meiotic maturation and thereby to improve oocyte quality. © 2022 Wiley Periodicals LLC.
Cytotoxic activity, cell imaging and photocleavage of DNA induced by a Pt(ii) cyclophane bearing 1,2 diamino ethane as a terminal ligand
(2011) Niraj Kumari; Brajesh Kumar Maurya; Raj Kumar Koiri; Surendra Kumar Trigun; Srikrishna Saripella; Michael P. Coogan; Lallan Mishra
A Pt II complex [{Pt(en)L} 2]·4PF 6 (Ptcyp) (LH 2 = N,N′-bis(salicylidene)-p-phenylenediamine, en = 1,2-diamino ethane) shows high cytotoxicity against HeLa cells (IC 50 - 11.5 μM) and against Dalton's lymphoma (DL) cells (IC 50 - 0.65 nM); UV-vis titration of Ptcyp with calf thymus DNA (CT-DNA) demonstrated its DNA binding, which could be further quantified by competitive fluorescence titration of DNA, Ptcyp and ethidium bromide. Circular dichroism studies suggest that Ptcyp interacts with CT-DNA by intercalation in an aqueous medium containing a minimum amount of DMSO. Agarose gel electrophoresis showed that Ptcyp is able to convert a supercoiled pBR322 plasmid DNA into a nicked circular DNA in DMSO, but to a much lower extent in an aqueous medium. However, with UV irradiation, Ptcyp is able to cause concentration-dependent nicking of supercoiled DNA in an aqueous medium. These findings indicate the DNA binding and UV exposure-dependent DNA cleavage properties of Ptcyp. Cell imaging studies using the HeLa cell line carried out in the presence of Ptcyp represent one of the first examples of Pt complexes applied as fluorophores in cell imaging and strongly support its interaction with DNA. © 2011 The Royal Society of Chemistry.
Design and development of benzyl piperazine linked 5-phenyl-1,2,4-triazole-3-thione conjugates as potential agents to combat Alzheimer's disease
(Academic Press Inc., 2023) Pidugu Venkata Ravi Kiran; Digambar Kumar Waiker; Akash Verma; Poorvi Saraf; Bhagwati Bhardwaj; Hansal Kumar; Abhinav Singh; Pradeep Kumar; Namrata Singh; Saripella Srikrishna; Surendra Kumar Trigun; Sushant Kumar Shrivastava
Our present work demonstrates the molecular hybridization-assisted design, synthesis, and biological evaluation of 22 benzylpiperazine-linked 1,2,4-triazole compounds (PD1-22) as AD modifying agents. All the compounds were tested for their in vitro hChEs, hBACE-1, and Aβ-aggregation inhibition properties. Among them, compound PD-08 and PD-22 demonstrated good hChE and hBACE-1 inhibition as compared to standards donepezil and rivastigmine. Both compounds displaced PI from PAS at 50 µM concentration which was comparable to donepezil and also demonstrated anti-Aβ aggregation properties in self- and AChE-induced thioflavin T assay. Both compounds have shown excellent BBB permeation via PAMPA-BBB assay and were found to be non-neurotoxic at 80 µM concentration against differentiated SH-SY5Y cell lines. Compound PD-22 demonstrated an increase in rescued eye phenotype in Aβ-phenotypic drosophila AD model and amelioration of behavioral deficits in the Aβ-induced rat model of AD. The in-silico docking studies of compound PD-22 revealed a good binding profile towards CAS and PAS residues of AChE and the catalytic dyad of the BACE-1. The 100 ns molecular dynamics simulation studies of compound PD-22 complexed with AChE and BACE-1 enzymes suggested stable ligand-protein complex throughout the simulation run. Based on our findings compound PD-22 could further be utilized as a lead to design a promising candidate for AD therapy © 2023 Elsevier Inc.
Design, Synthesis, and Biological Evaluation of Piperazine and N-Benzylpiperidine Hybrids of 5-Phenyl-1,3,4-oxadiazol-2-thiol as Potential Multitargeted Ligands for Alzheimer’s Disease Therapy
(American Chemical Society, 2023) Digambar Kumar Waiker; Akash Verma; None Akhilesh; T.A. Gajendra; Namrata Singh; Anima Roy; Hagera Dilnashin; Vinod Tiwari; Surendra Kumar Trigun; Surya P. Singh; Sairam Krishnamurthy; Prem Lama; Vincent Jo Davisson; Sushant Kumar Shrivastava
Our present work demonstrates the successful design and synthesis of a new class of compounds based upon a multitargeted directed ligand design approach to discover new agents for use in Alzheimer’s disease (AD). All the compounds were tested for their in vitro inhibitory potential against human acetylcholinesterase (hAChE), human butylcholinesterase (hBChE), β-secretase-1 (hBACE-1), and amyloid β (Aβ) aggregation. Compounds 5d and 5f have shown hAChE and hBACE-1 inhibition comparable to donepezil, while hBChE inhibition was comparable to rivastigmine. Compounds 5d and 5f also demonstrated a significant reduction in the formation of Aβ aggregates through the thioflavin T assay and confocal, atomic force, and scanning electron microscopy studies and significantly displaced the total propidium iodide, that is, 54 and 51% at 50 μM concentrations, respectively. Compounds 5d and 5f were devoid of neurotoxic liabilities against RA/BDNF (RA = retinoic acid; BDNF = brain-derived neurotrophic factor)-differentiated SH-SY5Y neuroblastoma cell lines at 10-80 μM concentrations. In both the scopolamine- and Aβ-induced mouse models for AD, compounds 5d and 5f demonstrated significant restoration of learning and memory behaviors. A series of ex vivo studies of hippocampal and cortex brain homogenates showed that 5d and 5f elicit decreases in AChE, malondialdehyde, and nitric oxide levels, an increase in glutathione level, and reduced levels of pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) mRNA. The histopathological examination of mice revealed normal neuronal appearance in the hippocampal and cortex regions of the brain. Western blot analysis of the same tissue indicated a reduction in Aβ, amyloid precursor protein (APP)/Aβ, BACE-1, and tau protein levels, which were non-significant compared to the sham group. The immunohistochemical analysis also showed significantly lower expression of BACE-1 and Aβ levels, which was comparable to donepezil-treated group. Compounds 5d and 5f represent new lead candidates for developing AD therapeutics. © 2023 American Chemical Society.
Design, synthesis, and biological evaluation of some 2-(3-oxo-5,6-diphenyl-1,2,4-triazin-2(3H)-yl)-N-phenylacetamide hybrids as MTDLs for Alzheimer's disease therapy
(Elsevier Masson s.r.l., 2024) Digambar Kumar Waiker; Akash Verma; T.A. Gajendra; Namrata; Anima Roy; Pradeep Kumar; Surendra Kumar Trigun; Saripella Srikrishna; Sairam Krishnamurthy; Vincent Jo Davisson; Sushant Kumar Shrivastava
Inspite of established symptomatic relief drug targets, a multi targeting approach is highly in demand to cure Alzheimer's disease (AD). Simultaneous inhibition of cholinesterase (ChE), β secretase-1 (BACE-1) and Dyrk1A could be promising in complete cure of AD. A series of 18 diaryl triazine based molecular hybrids were successfully designed, synthesized, and tested for their hChE, hBACE-1, Dyrk1A and Aβ aggregation inhibitory potentials. Compounds S-11 and S-12 were the representative molecules amongst the series with multi-targeted inhibitory effects. Compound S-12 showed hAChE inhibition (IC50 value = 0.486 ± 0.047 μM), BACE-1 inhibition (IC50 value = 0.542 ± 0.099 μM) along with good anti-Aβ aggregation effects in thioflavin-T assay. Only compound S-02 of the series has shown Dyrk1A inhibition (IC50 value = 2.000 ± 0.360 μM). Compound S-12 has also demonstrated no neurotoxic liabilities against SH-SY5Y as compared to donepezil. The in vivo behavioral studies of the compound S-12 in the scopolamine- and Aβ-induced animal models also demonstrated attanuation of learning and memory functions in rats models having AD-like characteristics. The ex vivo studies, on the rat hippocampal brain demonstrated reduction in certain biochemical markers of the AD brain with a significant increase in ACh level. The Western blot and Immunohistochemistry further revealed lower tau, APP and BACE-1 molecular levels. The drosophilla AD model also revealed improved eyephenotype after treatment with compound S-12. The molecular docking studies of the compounds suggested that compound S-12 was interacting with the ChE-PAS & CAS residues and catalytic dyad residues of the BACE-1 enzymes. The 100 ns molecular dynamics simulation studies of the ligand-protein complexed with hAChE and hBACE-1 also suggested stable ligand–protein confirmation throughout the simulation run. © 2024 Elsevier Masson SAS
Design, Synthesis, and Biological Investigation of Quinazoline Derivatives as Multitargeting Therapeutics in Alzheimer’s Disease Therapy
(American Chemical Society, 2024) Akash Verma; Digambar Kumar Waiker; Neha Singh; Anima Roy; Namrata Singh; Poorvi Saraf; Bhagwati Bhardwaj; Sairam Krishnamurthy; Surendra Kumar Trigun; Sushant Kumar Shrivastava
An efficient and promising method of treating complex neurodegenerative diseases like Alzheimer’s disease (AD) is the multitarget-directed approach. Here in this work, a series of quinazoline derivatives (AV-1 to AV-21) were rationally designed, synthesized, and biologically evaluated as multitargeted directed ligands against human cholinesterase (hChE) and human β-secretase (hBACE-1) that exhibit moderate to good inhibitory effects. Compounds AV-1, AV-2, and AV-3 from the series demonstrated balanced and significant inhibition against these targets. These compounds also displayed excellent blood−brain barrier permeability via the PAMPA-BBB assay. Compound AV-2 significantly displaced propidium iodide (PI) from the acetylcholinesterase-peripheral anionic site (AChE-PAS) and was found to be non-neurotoxic at the maximum tested concentration (80 μM) against differentiated SH-SY5Y cell lines. Compound AV-2 also prevented AChE- and self-induced Aβ aggregation in the thioflavin T assay. Additionally, compound AV-2 significantly ameliorated scopolamine and Aβ-induced cognitive impairments in the in vivo behavioral Y-maze and Morris water maze studies, respectively. The ex vivo and biochemical analysis further revealed good hippocampal AChE inhibition and the antioxidant potential of the compound AV-2. Western blot and immunohistochemical (IHC) analysis of hippocampal brain revealed reduced Aβ, BACE-1, APP/Aβ, and Tau molecular protein expressions levels. The pharmacokinetic analysis of compound AV-2 demonstrated significant oral absorption with good bioavailability. The in silico molecular modeling studies of lead compound AV-2 moreover demonstrated a reasonable binding profile with AChE and BACE-1 enzymes and stable ligand−protein complexes throughout the 100 ns run. Compound AV-2 can be regarded as the lead candidate and could be explored more for AD therapy. © 2024 American Chemical Society.
Epigenetic role of sirtuins in neurodegenerative brain disorders
(Elsevier, 2021) Archita Khanna; Anamika; Surendra Kumar Trigun
Sirtuins, a family of NAD+-dependent class III histone deacetylases (HDACs), are known to deacetylate some histone and nonhistone proteins including various transcription and cell signaling factors, thereby helping to regulate expression of many genes under a variety of stress challenges, and therefore they are referred to as important epigenetic regulators of the cell functions. This is in line with the classical Zn2+-dependent class I and class II HDACs, first recognized as protein level epigenetic regulators, which by modulating chromatin dynamics could affect DNA functions. All together, seven cell organelle-specific mammalian sirtuin homologues are known with distinct metabolic roles. SIRT 1, 6, and 7 are predominantly localized in the nucleus; SIRT 3, 4, and 5 are mitochondrial; while SIRT2 is found in the cytoplasm. The research during the past decade could characterize a good number of protein targets like histone H3 (H3K9), PGC1α, FOX03a, p53, and NF-κB type transcription factors for SIRT1 and SOD2, IDH2, LCAD, AceCS2, FOX03a etc. for mitochondrial SIRT3, which are now argued to be critically associated with the cell survival versus cell death mechanisms. As dysregulation of gene expression and mitochondrial dysfunction constitutes the base line of pathogenesis of many neurodegenerative brain disorders, like Alzheimer’s disease, Parkinson’s disease, Huntington’s, stroke etc., it is argued that SIRT1 and SIRT3 are likely to be the logical hot spots for exploring pathogenesis and therapeutic options against these brain disorders. Indeed some findings describe that SIRT1 and/or SIRT3 overexpression/activation could impart neuroprotection, whereas their inactivation/suppression could correlate with the neuronal derangements associated with aging and excitotoxic brain disorders. Thus sirtuin biochemistry seems to be an evolving concept in discerning the neuropathology of brain disorders. © 2021 Elsevier Inc. All rights reserved.
Fisetin induces apoptosis in colorectal cancer cells by suppressing autophagy and down-regulating nuclear factor erythroid 2-related factor 2 (Nrf2)
(John Wiley and Sons Inc, 2023) Akanksha Pandey; Surendra Kumar Trigun
Modulation of autophagy is evolving as a relevant strategy in cancer pathogenesis and therapeutic intervention and hence, needs to be examined as a target for the promising anticancer agents. Fisetin, a dietary flavanol, is emerging as a potent anticancer agent, however, its tumour-specific pharmacological targets remain largely unexplored. This article describes correlative profiles of autophagy and apoptotic markers versus nuclear factor erythroid 2-related factor 2 (Nrf2) and reactive oxygen species (ROS) in the colorectal cancer (CRC) cell line SW-480. As compared to the untreated cells, significantly less number of fluorescent detected autophagic vacuoles (AVOs) in the fisetin-treated cells coincided with a similar decline of the autophagy flux markers, Beclin 1 and microtubule-associated protein-1 light chain-3 and accumulation of p62 in those cells. The significantly increased number of annexin-V/propidium iodide (+/+) positive and acridine orange/ethidium bromide-stained apoptotic cells coincided with the enhanced signals for the cleaved caspase 3 and nuclear PARP-1 in those fisetin-treated cells. This was consistent with the collapse of mitochondrial membrane potential and release of cytochrome c. The fisetin-treated cells showed increased ROS level and a significant decline in nuclear Nrf2 immunosignal versus recovery in nuclear Nrf2 due to the treatment with curcumin and resveratrol (Nrf2 activators) and thus, suggesting a role of Nrf2 suppression in fisetin-mediated apoptosis in SW-480 cells. The effect of chloroquine, an autophagy inhibitor, resulted into declined number of AVOs and enhanced apoptosis, similar to that of the fisetin effect. Also, regaining of AVOs number and reduced apoptosis of CRC cells due to the treatment with rapamycin, an autophagy inducer, could be observed. These loss and gain of functions experiments thus suggested a correlation between fisetin-mediated autophagy suppression and apoptotic induction in a colorectal cell line. © 2023 Wiley Periodicals LLC.
Fisetin Modulates Antioxidant Enzymes and Inflammatory Factors to Inhibit Aflatoxin-B1 Induced Hepatocellular Carcinoma in Rats
(Hindawi Publishing Corporation, 2016) Brajesh Kumar Maurya; Surendra Kumar Trigun
Fisetin, a known antioxidant, has been found to be cytotoxic against certain cell lines. However, the mechanism by which it inhibits tumor growth in vivo remains unexplored. Recently, we have demonstrated that Aflatoxin-B1 (AFB1) induced hepatocarcinogenesis is associated with activation of oxidative stress-inflammatory pathway in rat liver. The present paper describes the effect of in vivo treatment with 20 mg/kg b.w. Fisetin on antioxidant enzymes vis-a-vis oxidative stress level and on the profile of certain proinflammatory cytokines in the hepatocellular carcinoma (HCC) induced by two doses of 1 mg/kg b.w. AFB1 i.p. in rats. The reduced levels of most of the antioxidant enzymes, coinciding with the enhanced level of reactive oxygen species in the HCC liver, were observed to regain their normal profiles due to Fisetin treatment. Also, Fisetin treatment could normalize the enhanced expression of TNFα and IL1α, the two proinflammatory cytokines, reported to be involved in HCC pathogenesis. These observations were consistent with the regression of neoplastic lesion and declined GST-pi (placental type glutathione-S-transferase) level, a HCC marker, in the liver of the Fisetin treated HCC rats. The findings suggest that Fisetin attenuates oxidative stress-inflammatory pathway of AFB1 induced hepatocarcinogenesis. © 2016 Brajesh Kumar Maurya and Surendra Kumar Trigun.
Gender-specific association of oxidative stress and immune response in septic shock mortality using NMR-based metabolomics
(Royal Society of Chemistry, 2022) Swarnima Pandey; Mohd. Adnan Siddiqui; Surendra Kumar Trigun; Afzal Azim; Neeraj Sinha
Background: Sepsis and septic shock are still associated with a high mortality rate. The early-stage prediction of septic shock outcomes would be helpful to clinicians for designing their treatment protocol. In addition, it would aid clinicians in patient management by understanding gender disparity in terms of clinical outcomes of septic shock by identifying whether there are sex-based differences in sepsis-associated mortality. Objective: This study aimed to test the hypothesis that gender-based metabolic heterogeneity is associated with sepsis survival and identify the biomarkers of mortality for septic shock in an Indian cohort. Method: The study was performed in an Indian population cohort diagnosed with sepsis/septic shock within 24 hours of admission. The study group was 50 patients admitted to intensive care, comprising 23 females and 27 males. Univariate and multivariate analysis were performed to identify the biomarkers for septic shock mortality and the gender-specific metabolic fingerprint in septic shock-associated mortality. Results: The energy-related metabolites, ketone bodies, choline, and NAG were found to be primarily responsible for differentiating survivors and non-survivors. The gender-based mortality stratification identified a female-specific association of the anti-inflammatory response, innate immune response, and β oxidation, and a male-specific association of the pro-inflammatory response to septic shock. Conclusion: The identified mortality biomarkers may help clinicians estimate the severity of a case, as well as predict the outcome and treatment efficacy. The study underlines that gender is one of the most significant biological factors influencing septic shock metabolomic profiles. This understanding can be utilized to identify novel gender-specific biomarkers and innovative targets relevant for gender medicine. © The Royal Society of Chemistry.
Hyperglycolysis-Inflammation Connect as a Mechanistic Hot Spot in Oxidatively Compromised Cancer
(Springer Nature, 2022) Brajesh Kumar Maurya; Akanksha Pandey; Surendra Kumar Trigun
Hyperglycolysis, as a major bioenergetics shift in the growing tumor cells, ensures adequate amount of ATP synthesis by avoiding mitochondrial oxidative mechanism and thereby protects tumor cells from reactive oxygen species (ROS)-induced cellular damage. Such an oxidatively compromised state of the tumor cells is considered crucial for making them immortal. The generation of pro-inflammatory factors around the tumor cells is advocated as another important event, and that, together with the hyperglycolysis, it constitutes a pro-tumorigenic tumor microenvironment (TME) and facilitates in vivo tumorigenesis. Herein, the enhanced lactate secretion, due to upregulated aerobic glycolysis, by the tumor stem cells (TSCs), acts as a key integrator of hyperglycolysis-inflammation connect. Consequently, dynamic interaction takes place between the TSC, the tumor-associated macrophages (TAMs), and the tumor matrix around the TSC niche. The TAMs play a central role in orchestrating neoplastic growth around the TSCs. The lactate-dependent transition from M1 (tumoricidal) macrophages to M2 (immunosuppressive and pro-tumorigenic) phenotype is considered the most critical event of this mechanism. In this chapter, we have attempted to summarize the recent advances in the area of tumor growth associated with hyperglycolysis-inflammation connect in general and on the TAM-mediated endothelial-mesenchymal transition (EMT), required for angiogenesis and metastasis in the growing in vivo tumors in particular. The key hyperglycolytic players focused are hexokinase II, inducible phosphofructokinase 2, pyruvate kinase M2, and M4-lactate dehydrogenase, and those of inflammation are colony-stimulating factor 1 (CSF1) and several other cytokines. The TAM, the programmed cell death-1 ligand (PD-L1), and PD-1-mediated suppression of T cell response against cancer cells have been given special focus. Similarly, the role of REDD1 (regulated in development and DNA damage responses 1), a potent stress response factor, in TAM-mediated metastasis and neovascularization, has been advocated as an evolving concept of TAM-mediated tumorigenesis. In view of the above, we have tried to summarize the current status about whether these key players of hyperglycolysis-inflammation axis could be exploited as targets for restricting tumor growth in vivo. © Springer Nature Singapore Pte Ltd. 2022.
Impairments of Spatial Memory and N-methyl-d-aspartate Receptors and Their Postsynaptic Signaling Molecules in the Hippocampus of Developing Rats Induced by As, Pb, and Mn Mixture Exposure
(Multidisciplinary Digital Publishing Institute (MDPI), 2023) Lalit P. Chandravanshi; Prashant Agrawal; Hany W. Darwish; Surendra Kumar Trigun
Exposure to metal mixtures is recognized as a real-life scenario, needing novel studies that can assess their complex effects on brain development. There is still a significant public health concern associated with chronic low levels of metal exposure. In contrast to other metals, these three metals (As, Pb, and Mn) are commonly found in various environmental and industrial contexts. In addition to additive or synergistic interactions, concurrent exposure to this metal mixture may also have neurotoxic effects that differ from those caused by exposure to single components. The NMDA receptor and several important signaling proteins are involved in learning, memory, and synaptic plasticity in the hippocampus, including CaMKII, postsynaptic density protein-95 (PSD-95), synaptic Ras GTPase activating protein (SynGAP), a negative regulator of Ras-MAPK activity, and CREB. We hypothesized that alterations in the above molecular players may contribute to metal mixture developmental neurotoxicity. Thus, the aim of this study was to investigate the effect of these metals and their mixture at low doses (As 4 mg, Pb 4 mg, and Mn 10 mg/kg bw/p.o) on NMDA receptors and their postsynaptic signaling proteins during developing periods (GD6 to PD59) of the rat brain. Rats exposed to As, Pb, and Mn individually or at the same doses in a triple-metal mixture (MM) showed impairments in learning and memory functions in comparison to the control group rats. Declined protein expressions of NR2A, PSD-95, p- CaMKII, and pCREB were observed in the metal mix-exposed rats, while the expression of SynGAP was found to be enhanced in the hippocampus as compared to the controls on PD60. Thereby, our data suggest that alterations in the NMDA receptor complex and postsynaptic signaling proteins could explain the cognitive dysfunctions caused by metal-mixture-induced developmental neurotoxicity in rats. These outcomes indicate that incessant metal mixture exposure may have detrimental consequences on brain development. © 2023 by the authors.