Publications by authors named "Madhavan Nampoothiri"

81 Publications

Oral semaglutide in the management of type 2 DM: Clinical status and comparative analysis.

Curr Drug Targets 2021 Sep 1. Epub 2021 Sep 1.

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India.

Background: In the incretin system, Glucagon-like peptide-1 (GLP-1) is a hormone that inhibits the release of glucagon and regulates glucose-dependent insulin secretion. In type 2 diabetes, correcting the impaired incretin system using GLP-1 agonist is a well-defined therapeutic strategy.

Objectives: This review article aims to discuss the mechanism of action, key regulatory events, clinical trials for glycaemic control and comparative analysis of semaglutide with the second-line antidiabetic drugs.

Description: Semaglutide is a glucagon-like peptide 1 (GLP 1) receptor agonist with enhanced glycaemic control in diabetes patients. In 2019, USFDA approved the first oral GLP-1 receptor agonist, semaglutide to be administered as a once-daily tablet. Further, recent studies highlight the ability of semaglutide to improve the glycaemic control in obese patients with a reduction in body weight. Still, in clinical practice, in type 2 DM treatment paradigm the impact of oral semaglutide remains unidentified. This review article discusses the mechanism of action, pharmacodynamics, key regulatory events, and clinical trials regarding glycaemic control.

Conclusion: The review highlights the comparative analysis of semaglutide with the existing second-line drugs for the management of type 2 diabetes mellitus by stressing on its benefits and adverse events.
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http://dx.doi.org/10.2174/1389450122666210901125420DOI Listing
September 2021

In silico screening of neurokinin receptor antagonists as a therapeutic strategy for neuroinflammation in Alzheimer's disease.

Mol Divers 2021 Jul 31. Epub 2021 Jul 31.

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.

Neuroinflammation is one of the detrimental factors leading to neurodegeneration in Alzheimer's disease (AD) and other neurodegenerative disorders. The activation of microglial neurokinin 1 receptor (NK1R) by substance P (SP) enhances neuroinflammation which is mediated through pro-inflammatory pathways involving NFkB, ERK1/2, and P38 and thus projects the scope and importance of NK1R inhibitors. Emphasizing the inhibitory role of N Acetyl L Tryptophan (L-NAT) on NK1R, this is the first in silico screening of L-NAT mediated NK1R antagonism. In addition, FDA- approved ligands were screened for their potential NK1R antagonism. The L-NAT was docked in XP (Extra Precision) mode while FDA-approved ligands were screened in HTVS (High Throughput Virtual Screening), SP (Standard Precision), and XP mode onto NK1R (PDB:6HLO). The L-NAT and top 3 compounds FDA-approved ligands were subjected to molecular dynamics (MD) studies of 100 ns simulation time. The XP docking of L-NAT, indacaterol, modafinil and alosetron showed good docking scores. Their 100 ns MD showed brief protein-ligand interactions with an acceptable root mean square deviation. The protein-ligand contacts depicted pi-pi stacking, pi-cation, hydrogen bonds, and water bridges with the amino acids necessary for NK1R inhibition. The variable colour band intensities on the protein-ligand contact map indicated their binding strength with amino acids. The molecular mechanics/generalized born surface area (MM-GBSA) scores suggested favourable binding free energy of the complexes. Thus, our study predicted the ability of L-NAT, indacaterol, modafinil, and alosetron as capable NK1R inhibitors that can aid to curb neuroinflammation in conditions of AD which could be further ascertained in subsequent studies.
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http://dx.doi.org/10.1007/s11030-021-10276-6DOI Listing
July 2021

The divergent roles of sortase in the biology of Gram-positive bacteria.

Cell Surf 2021 Dec 13;7:100055. Epub 2021 Jun 13.

Microbial Processes and Technology Division, CSIR - National Institute for Interdisciplinary Science and Technology (NIIST), Trivandrum 695019, Kerala, India.

The bacterial cell wall contains numerous surface-exposed proteins, which are covalently anchored and assembled by a sortase family of transpeptidase enzymes. The sortase are cysteine transpeptidases that catalyzes the covalent attachment of surface protein to the cell wall peptidoglycan. Among the reported six classes of sortases, each distinct class of sortase plays a unique biological role in anchoring a variety of surface proteins to the peptidoglycan of both pathogenic and non-pathogenic Gram-positive bacteria. Sortases not only exhibit virulence and pathogenesis properties to host cells, but also possess a significant role in gut retention and immunomodulation in probiotic microbes. The two main distinct functions are to attach proteins directly to the cell wall or assemble pili on the microbial surface. This review provides a compendium of the distribution of different classes of sortases present in both pathogenic and non-pathogenic Gram-positive bacteria and also the noteworthy role played by them in bacterial cell wall assembly which enables each microbe to effectively interact with its environment.
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http://dx.doi.org/10.1016/j.tcsw.2021.100055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225981PMC
December 2021

An overview of functional genomics and relevance of glycosyltransferases in exopolysaccharide production by lactic acid bacteria.

Int J Biol Macromol 2021 Aug 24;184:1014-1025. Epub 2021 Jun 24.

Microbial Processes and Technology Division (MPTD), CSIR - National Institute for Interdisciplinary Science and Technology (NIIST), Trivandrum, Kerala 695 019, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India. Electronic address:

There are many reports on exopolysaccharides of lactic acid bacteria (LAB EPS) such as isolation, production and applications. The LAB EPS have been proved to exhibit significantly improved texture and rheological properties in order to prevent syneresis of fermented foods. Furthermore, they are known to have many biological properties such as mouthwatering flavors, antioxidant activity, cholesterol lowering and antimicrobial activities. Considering their GRAS status, LAB EPS need to be explored for better titre and improved biological properties, where strain improvement by genetic engineering has a major role for making tailor-made EPS. The genetic overview of the EPS production by LAB is an auxiliary area of interest as the process and the biosynthetic pathway involves numerous genes and their proteins. Among them Glycosyltransferases (gtfs) are the key enzymes involved in EPS biosynthesis. Current knowledge of gtfs of LAB and its manipulation is limited. The present review spotlights the importance of glycosyltransferases and their specific role on the biosynthesis of LAB EPS and addresses the functionality and applicability of these enzymes and their products. It enfold the available literature including some patents in recent past to underline the fact that glycosyltransferases are un-reluctantly the key proteins involved in the EPS biosynthesis.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.06.131DOI Listing
August 2021

Production of Biopolyamide Precursors 5-Amino Valeric Acid and Putrescine From Rice Straw Hydrolysate by Engineered .

Front Bioeng Biotechnol 2021 29;9:635509. Epub 2021 Mar 29.

Microbial Processes and Technology Division (MPTD), CSIR-National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram, India.

The non-proteinogenic amino acid 5-amino valeric acid (5-AVA) and the diamine putrescine are potential building blocks in the bio-polyamide industry. The production of 5-AVA and putrescine using engineered by the co-consumption of biomass-derived sugars is an attractive strategy and an alternative to their petrochemical synthesis. In our previous work, 5-AVA production from pure xylose by C. was shown by heterologously expressing from and from . Apart from this AVA Xyl culture, the heterologous expression of and was also carried out in a putrescine producing to engineer a PUT Xyl strain. Even though, the pure glucose (40 g L) gave the maximum product yield by both the strains, the utilization of varying combinations of pure xylose and glucose by AVA Xyl and PUT Xyl in CGXII synthetic medium was initially validated. A blend of 25 g L of glucose and 15 g L of xylose in CGXII medium yielded 109 ± 2 mg L putrescine and 874 ± 1 mg L 5-AVA after 72 h of fermentation. Subsequently, to demonstrate the utilization of biomass-derived sugars, the alkali (NaOH) pretreated-enzyme hydrolyzed rice straw containing a mixture of glucose (23.7 g L) and xylose (13.6 g L) was fermented by PUT Xyl and AVA Xyl to yield 91 ± 3 mg L putrescine and 260 ± 2 mg L 5-AVA, respectively, after 72 h of fermentation. To the best of our knowledge, this is the first proof of concept report on the production of 5-AVA and putrescine using rice straw hydrolysate (RSH) as the raw material.
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http://dx.doi.org/10.3389/fbioe.2021.635509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044859PMC
March 2021

Remedial effects of caffeine against depressive-like behaviour in mice by modulation of neuroinflammation and BDNF.

Nutr Neurosci 2021 Apr 5:1-9. Epub 2021 Apr 5.

School of Pharmacy and Pharmacology, MHIQ, QUM Network, Griffith University, Gold Coast, Australia.

Caffeine (CAF) is one of the most commonly consumed nutritional stimulant in beverages. Interestingly, CAF produces varied effects in a dose-dependent manner, and that makes it one of the most controversial nutritional ingredients. Various studies have linked CAF consumption and reduced risk of depressive disorders. The aim of this study was to investigate the effect of CAF on lipopolysaccharide (LPS)-induced neuroinflammation and depressive-like behaviour. C57BL/6J male mice were divided into four groups consisting of saline (SAL), LPS, CAF and Imipramine (IMI). Animals were pretreated orally with CAF (10 mg/kg) and IMI (10 mg/kg) for 14 days once daily and all groups except SAL were challenged with LPS (0.83 mg/kg) intraperitoneally on day 14. LPS produced a biphasic behavioural response with a significantly high immobility time and weight loss after 24 h. The brain cytokines (TNF-α, IL-6, IL-1β, and IFN-γ) levels were remarkably high, along with increased lipid peroxidation and reduced Brain Derived Neurotrophic Factor (BDNF). These biochemical and behavioural changes were significantly alleviated by CAF and IMI chronic treatment. The results of this study implicate that mild-moderate consumption of CAF could impart anti-inflammatory properties under neuroinflammatory conditions by modulating the cytokine and neurotrophic mechanisms.
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http://dx.doi.org/10.1080/1028415X.2021.1906393DOI Listing
April 2021

Melittin, a honeybee venom derived peptide for the treatment of chemotherapy-induced peripheral neuropathy.

Med Oncol 2021 Apr 2;38(5):52. Epub 2021 Apr 2.

Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.

Chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent neurological complication of cancer treatment which involves sensory and motor nerve dysfunction. Severe CIPN has been reported in around 5% of patients treated with single and up to 38% of patients treated with multiple chemotherapeutic agents. Present medications available for CIPN are the use of opioids, nonsteroidal anti-inflammatory agents, and tricyclic antidepressants, which are only marginally effective in treating neuropathic symptoms. In reality, symptom reappears after these drugs are discontinued. The pathogenesis of CIPN has not been sufficiently recognized and methods for the prevention and treatment of CIPN remain vulnerable to therapeutic problems. It has witnessed that the present medicines available for the disease offer only symptomatic relief for the short term and have severe adverse side effects. There is no standard treatment protocol for preventing, reducing, and treating CIPN. Therefore, there is a need to develop curative therapy that can be used to treat this complication. Melittin is the main pharmacological active constituent of honeybee venom and has therapeutic values including in chemotherapeutic-induced peripheral neuropathy. It has been shown that melittin and whole honey bee venom are effective in treating paclitaxel and oxaliplatin-induced peripheral neuropathy. The use of melittin against peripheral neuropathy caused by chemotherapy has been limited despite having strong therapeutic efficacy against the disease. Melittin mediated haemolysis is the key reason to restrict its use. In our study, it is found that α-Crystallin (an eye lens protein) is capable of inhibiting melittin-induced haemolysis which gives hope of using an appropriate combination of melittin and α-Crystallin in the treatment of CIPN. The review summarizes the efforts made by different research groups to address the concern with melittin in the treatment of chemotherapeutic-induced neuropathy. It also focuses on the possible approaches to overcome melittin-induced haemolysis.
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http://dx.doi.org/10.1007/s12032-021-01496-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016801PMC
April 2021

Sirtuins, a potential target in Traumatic Brain Injury and relevant experimental models.

Brain Res Bull 2021 Jun 26;171:135-141. Epub 2021 Mar 26.

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India. Electronic address:

Traumatic brain injury (TBI) can simply be defined as a violent external injury to the head causing brain dysfunction. The primary injury occurs immediately on impact whereas the secondary injury begins minutes to months after impact. TBI affects a vast majority of population worldwide yet, there isn't any therapeutic intervention available. Sirtuins (SIRTs) are important regulator proteins found in humans. In several neurodegenerative diseases, SIRTs have proven its neuroprotective actions. Owing to the pathophysiological similarities in these diseases and TBI, SIRTs may serve as a potential target for therapeutic intervention in TBI. This review aims to describe the relevance of SIRTs as a potential pharmacological target in TBI. Also, the experimental animal model of TBI explored to understand the role of SIRTs in TBI have been discussed.
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http://dx.doi.org/10.1016/j.brainresbull.2021.03.016DOI Listing
June 2021

JAK-STAT Pathway Inhibition and their Implications in COVID-19 Therapy.

Postgrad Med 2021 Jun 16;133(5):489-507. Epub 2020 Dec 16.

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India.

As the incidence of COVID-19 increases with time, more and more efforts are made to pave a way out for the therapeutic strategies to deal with the disease progression. Inflammation being a significant influencer in COVID-19 patients, it drives our focus onto the signaling cascades of the JAK/STAT pathway. JAK phosphorylation mediated by cytokine receptor activation leads to phosphorylation of STATs that translocate into the nucleus to translate for inflammatory mediators. The SARS-CoV-2 structural proteins like spike, nucleocapsid, membrane and envelope proteins along with the non- structural proteins 1-16 including proteases like 3CL  and PL promote its entry and survival in hosts. The SARS-CoV-2 infection triggers inflammation via the JAK/STAT pathway leading to recruitment of pneumocytes, endothelial cells, macrophages, monocytes, lymphocytes, natural killer cells and dendritic cells progressing towards cytokine storm. This produces various inflammatory markers in the host that determine the disease severity. The JAK/STAT signaling also mediates immune responses via B cell and T cell differentiation.With an attempt to reduce excessive inflammation, JAK/STAT inhibitors like Ruxolitinib, Baricitinib, Tofacitinib have been employed that mediate its actions via suppressors of cytokine signaling, cytokine inducible SH2 containing protein, Protein inhibitor of activated STAT and protein tyrosine phosphatases. Even though they are implicated with multiple adverse effects, the regulatory authorities have supported its use, and numerous clinical trials are in progress to prove their safety and efficacy. On the contrary, the exact mechanism of JAK/STAT inhibition at molecular levels remains speculative for which further investigations are required.
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http://dx.doi.org/10.1080/00325481.2020.1855921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784782PMC
June 2021

Inhibition of NLRP3-inflammasome mediated IL-1β release by phenylpropanoic acid derivatives: in-silico and in-vitro approach.

Eur J Pharm Sci 2021 Feb 7;157:105637. Epub 2020 Nov 7.

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, India. Electronic address:

NLRP3 inflammasome activation and subsequent release of IL-1β are being explored as a causal pathology for inflammatory and autoimmune disorders. Modulation of this pathway by the compounds from natural sources may provide a better targeted approach with improved therapeutic outcome. The study was carried out to test the ability of phenylpropanoic acid derivatives to inhibit the NLRP3 inflammasome pathway and IL-1β release. The main purpose of the study was to test the active derivatives with respect to the possible molecular interactions in-silico, effect on mRNA expression of molecular markers and, effect on released cytokine. Autodock along with SwissADME was used to carry out the in-silico studies including the prediction studies as well as molecular docking studies. The effect of test compounds on mRNA expression of important proteins was evaluated against U87MG cells using RT-qPCR. The changes in released cytokine levels was evaluated using ELISA. The tested phenylpropanoic acid derivatives had a comparable molecular docking profile to that of selected standards. The prediction studies indicated that these compounds have suitable properties to be a drug candidate. mRNA expression studies showed that the derivatives can downregulate the proteins responsible for inflammasome activation and same was reflected in ELISA when the concentration of released cytokine was evaluated. Based on the above results, phenylpropanoic acid derivatives have potential to be developed as specific NLRP3-inflammasome inhibitors.
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http://dx.doi.org/10.1016/j.ejps.2020.105637DOI Listing
February 2021

Involvement of the nervous system in COVID-19: The bell should toll in the brain.

Life Sci 2020 Dec 6;262:118568. Epub 2020 Oct 6.

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, India. Electronic address:

The world is fuming at SARS-CoV-2 for being the culprit for causing the devastating COVID-19, claiming millions of lives across the globe in the form of respiratory disorders. But lesser known are its effects on the CNS that are slowly surfacing in the worldwide population. Our review illustrates findings that claim SARS-CoV-2's arrival onto the ACE2 receptors of neuronal and glial cells mainly via CSF, olfactory nerve, trigeminal nerve, neuronal dissemination, and hematogenous pathways. The role of SARS-CoV-2 structural proteins in its smooth viral infectivity of the host cannot be ignored, especially the spike proteins that mediate spike attachment and host membrane fusion. Worth mentioning the nucleocapsid, envelope, and membrane proteins make the proliferation of SARS-CoV-2 much simpler than expected in spreading infection. This has led to catastrophic conditions like seizures, Guillain-Barré syndrome, viral encephalitis, meningoencephalitis, acute cerebrovascular disease, and respiratory failures. Placing a magnifying lens on the lesser-explored CNS consequences of COVID-19, we attempt to shift the focus of our readers onto the new supporting threats to which further studies are needed.
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http://dx.doi.org/10.1016/j.lfs.2020.118568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537730PMC
December 2020

Zinc as a plausible epigenetic modulator of glioblastoma multiforme.

Eur J Pharmacol 2020 Nov 12;887:173549. Epub 2020 Sep 12.

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, India. Electronic address:

Glioblastoma Multiforme (GBM) is an aggressive brain tumor (WHO grade 4 astrocytoma) with unknown causes and is associated with a reduced life expectancy. The available treatment options namely radiotherapy, surgery and chemotherapy have failed to improve life expectancy. Out of the various therapeutic approaches, epigenetic therapy is one of the most studied. Epigenetic therapy is involved in the effective treatment of GBM by inhibiting DNA methyltransferase, histone deacetylation and non-coding RNA. It also promotes the expression of the tumor suppressor gene and is involved in the suppression of the oncogene. Various targets are being studied to implement proper epigenetic regulation to control GBM effectively. Zinc is one of the micronutrients which is considered to maintain epigenetic regulation by promoting the proper DNA folding, protecting genetic material from the oxidative damage and controlling the enzyme activation involved in the epigenetic regulation. Here, we are discussing the importance of zinc in regulating the epigenetic modifications and assessing its role in glioblastoma research. The discussion also highlights the importance of artificial intelligence using epigenetics for envisaging the glioma progression, diagnosis and its management.
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http://dx.doi.org/10.1016/j.ejphar.2020.173549DOI Listing
November 2020

Spermidine, an autophagy inducer, as a therapeutic strategy in neurological disorders.

Neuropeptides 2020 Oct 24;83:102083. Epub 2020 Aug 24.

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, India. Electronic address:

Spermidine is a naturally occurring endogenous polyamine synthesized from diamine putrescine. It is a well-known autophagy inducer that maintains cellular and neuronal homeostasis. Healthy brain development and function are dependent on brain polyamine concentration. Polyamines interact with the opioid system, glutamatergic signaling and neuroinflammation in the neuronal and glial compartments. Among the polyamines, spermidine is found highest in the human brain. Age-linked fluctuations in the spermidine levels may possibly contribute to the impairments in neural network and neurogenesis. Exogenously administered spermidine helps in the treatment of brain diseases. Further, current studies highlight the ability of spermidine to promote longevity by inducing autophagy. Still, the causal neuroprotective mechanism of spermidine in neuronal dysfunction remains unidentified. This review aims to summarize various neuroprotective effects of spermidine related to anti-aging/ anti-inflammatory properties and the prevention of neurotoxicity that helps in achieving beneficial effects in age-related neurological disorder. We also expose the signaling cascades modulated by spermidine which might result in therapeutic action. The present review highlights clinical studies along with in-vivo and in-vitro preclinical studies to provide a new dimension for the therapeutic potential of spermidine in neurological disorders.
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http://dx.doi.org/10.1016/j.npep.2020.102083DOI Listing
October 2020

Hydroxychloroquine in COVID-19: Potential Mechanism of Action Against SARS-CoV-2.

Curr Pharmacol Rep 2020 Aug 24:1-9. Epub 2020 Aug 24.

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104 India.

Purpose Of Review: The rapid spread of virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has turned out to be a global emergency. Symptoms of this viral infection, coronavirus disease 2019 (COVID-19), include mild infections of the upper respiratory tract, viral pneumonia, respiratory failure, multiple organ failure and death. Till date, no drugs have been discovered to treat COVID-19 patients, and therefore, a considerable amount of interest has been shown in repurposing the existing drugs.

Recent Findings: Out of these drugs, chloroquine (CQ) and hydroxychloroquine (HCQ) have demonstrated positive results indicating a potential antiviral role against SARS-CoV-2. Its mechanism of action (MOA) includes the interference in the endocytic pathway, blockade of sialic acid receptors, restriction of pH mediated spike (S) protein cleavage at the angiotensin-converting enzyme 2 (ACE2) binding site and prevention of cytokine storm. Unfortunately, its adverse effects like gastrointestinal complications, retinopathy and QT interval prolongation are evident in treated COVID-19 patients. Yet, multiple clinical trials have been employed in several countries to evaluate its ability in turning into a needed drug in this pandemic.

Summary: This review attempts to summarize the MOA of CQ/HCQ and its side effects. The existing literature hints that till date, the role of CQ/HCQ in COVID-19 may be sceptical, and further studies are warranted for obtaining a therapeutic option that could be effectively used across the world to rise out from this pandemic.
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http://dx.doi.org/10.1007/s40495-020-00231-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443392PMC
August 2020

Structural Proteins in Severe Acute Respiratory Syndrome Coronavirus-2.

Arch Med Res 2020 08 25;51(6):482-491. Epub 2020 May 25.

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India. Electronic address:

What began with a sign of pneumonia-related respiratory disorders in China has now become a pandemic named by WHO as Covid-19 known to be caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). The SARS-CoV-2 are newly emerged β coronaviruses belonging to the Coronaviridae family. SARS-CoV-2 has a positive viral RNA genome expressing open reading frames that code for structural and non-structural proteins. The structural proteins include spike (S), nucleocapsid (N), membrane (M), and envelope (E) proteins. The S1 subunit of S protein facilitates ACE2 mediated virus attachment while S2 subunit promotes membrane fusion. The presence of glutamine, asparagine, leucine, phenylalanine and serine amino acids in SARS-CoV-2 enhances ACE2 binding. The N protein is composed of a serine-rich linker region sandwiched between N Terminal Domain (NTD) and C Terminal Domain (CTD). These terminals play a role in viral entry and its processing post entry. The NTD forms orthorhombic crystals and binds to the viral genome. The linker region contains phosphorylation sites that regulate its functioning. The CTD promotes nucleocapsid formation. The E protein contains a NTD, hydrophobic domain and CTD which form viroporins needed for viral assembly. The M protein possesses hydrophilic C terminal and amphipathic N terminal. Its long-form promotes spike incorporations and the interaction with E facilitates virion production. As each protein is essential in viral functioning, this review describes the insights of SARS-CoV-2 structural proteins that would help in developing therapeutic strategies by targeting each protein to curb the rapidly growing pandemic.
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http://dx.doi.org/10.1016/j.arcmed.2020.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247499PMC
August 2020

Heterologous expression of genes for bioconversion of xylose to xylonic acid in Corynebacterium glutamicum and optimization of the bioprocess.

AMB Express 2020 Apr 15;10(1):68. Epub 2020 Apr 15.

Microbial Processes and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (NIIST), Thiruvananthapuram, 695019, Kerala, India.

In bacterial system, direct conversion of xylose to xylonic acid is mediated through NAD-dependent xylose dehydrogenase (xylB) and xylonolactonase (xylC) genes. Heterologous expression of these genes from Caulobacter crescentus into recombinant Corynebacterium glutamicum ATCC 13032 and C. glutamicum ATCC 31831 (with an innate pentose transporter, araE) resulted in an efficient bioconversion process to produce xylonic acid from xylose. Process parameters including the design of production medium was optimized using a statistical tool, Response Surface Methodology (RSM). Maximum xylonic acid of 56.32 g/L from 60 g/L xylose, i.e. about 76.67% of the maximum theoretical yield was obtained after 120 h fermentation from pure xylose with recombinant C. glutamicum ATCC 31831 containing the plasmid pVWEx1 xylB. Under the same condition, the production with recombinant C. glutamicum ATCC 13032 (with pVWEx1 xylB) was 50.66 g/L, i.e. 69% of the theoretical yield. There was no significant improvement in production with the simultaneous expression of xylB and xylC genes together indicating xylose dehydrogenase activity as one of the rate limiting factor in the bioconversion. Finally, proof of concept experiment in utilizing biomass derived pentose sugar, xylose, for xylonic acid production was also carried out and obtained 42.94 g/L xylonic acid from 60 g/L xylose. These results promise a significant value addition for the future bio refinery programs.
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http://dx.doi.org/10.1186/s13568-020-01003-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158973PMC
April 2020

Engineering bio-mimicking functional vesicles with multiple compartments for quantifying molecular transport.

Chem Sci 2020 Apr 6;11(18):4669-4679. Epub 2020 Apr 6.

Microbial Processes and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (NIIST) Trivandrum 695019 Kerala India

Controlled design of giant unilamellar vesicles under defined conditions has vast applications in the field of membrane and synthetic biology. Here, we bio-engineer bacterial-membrane mimicking models of controlled size under defined salt conditions over a range of pH. A complex bacterial lipid extract is used for construction of physiologically relevant Gram-negative membrane mimicking vesicles whereas a ternary mixture of charged lipids (DOPG, cardiolipin and lysyl-PG) is used for building Gram-positive bacterial-membrane vesicles. Furthermore, we construct stable multi-compartment biomimicking vesicles using the gel-assisted swelling method. Importantly, we validate the bio-application of the bacterial vesicle models by quantifying diffusion of chemically synthetic amphoteric antibiotics. The transport rate is pH-responsive and depends on the lipid composition, based on which a permeation model is proposed. The permeability properties of antimicrobial peptides reveal pH dependent pore-forming activity in the model vesicles. Finally, we demonstrate the functionality of the vesicles by quantifying the uptake of membrane-impermeable molecules facilitated by embedded pore-forming proteins. We suggest that the bacterial vesicle models developed here can be used to understand fundamental biological processes like the peptide assembly mechanism or bacterial cell division and will have a multitude of applications in the bottom-up assembly of a protocell.
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http://dx.doi.org/10.1039/d0sc00084aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159255PMC
April 2020

Production of low-calorie structured lipids from spent coffee grounds or olive pomace crude oils catalyzed by immobilized lipase in magnetic nanoparticles.

Bioresour Technol 2020 Jul 19;307:123223. Epub 2020 Mar 19.

Instituto Superior de Agronomia, Universidade de Lisboa, LEAF, Linking Landscape, Environment, Agriculture and Food, Lisbon, Portugal. Electronic address:

In this study, crude oils extracted from spent coffee grounds (SCG) and olive pomace (OP) were used as raw-material to synthesize low-calorie triacylglycerols, either by acidolysis with capric acid, or by interesterification with ethyl caprate, in solvent-free media, catalyzed by sn-1,3 regioselective lipases. The Rhizopus oryzae lipase (ROL) was immobilized in magnetite nanoparticles (MNP-ROL) and tested as novel biocatalyst. MNP-ROL performance was compared with that of the commercial immobilized Thermomyces lanuginosus lipase (Lipozyme TL IM). For both oils, Lipozyme TL IM preferred interesterification over acidolysis. MNP-ROL catalyzed reactions were faster and acidolysis was preferred with yields of c.a. 50% new triacylglycerols after 3 h acidolysis of OP or SCG oils. MNP-ROL was very stable following the Sadana deactivation model with half-lives of 163 h and 220 h when reused in batch acidolysis and interesterification of OP oil, respectively.
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http://dx.doi.org/10.1016/j.biortech.2020.123223DOI Listing
July 2020

An Appraisal of Current Pharmacological Perspectives of Sesamol: A Review.

Mini Rev Med Chem 2020 ;20(11):988-1000

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India.

Sesame (Sesamum indicum L.) seeds have been authenticated for its medicinal value in both Chinese and Indian systems of medicine. Its numerous potential nutritional benefits are attributed to its main bioactive constituents, sesamol. As a result of those studies, several molecular mechanisms are emerging describing the pleiotropic biological effects of sesamol. This review summarized the most interesting in vitro and in vivo studies on the biological effects of sesamol. The present work summarises data available from Pubmed and Scopus database. Several molecular mechanisms have been elucidated describing the pleiotropic biological effects of sesamol. Its major therapeutic effects have been elicited in managing oxidative and inflammatory conditions, metabolic syndrome and mood disorders. Further, compelling evidence reflected the ability of sesamol in inhibiting proliferation of the inflammatory cell, prevention of invasion and angiogenesis via affecting multiple molecular targets and downstream mechanisms. Sesamol is a safe, non-toxic chemical that mediates anti-inflammatory effects by down-regulating the transcription of inflammatory markers such as cytokines, redox status, protein kinases, and enzymes that promote inflammation. In addition, sesamol also induces apoptosis in cancer cells via mitochondrial and receptor-mediated pathways, as well as activation of caspase cascades. In the present review, several pharmacological effects of sesamol are summarised namely, antioxidant, anti-cancer, neuroprotective, cardioprotective, anti-inflammatory, hypolipidemic, radioprotective, anti-aging, anti-ulcer, anti-dementia, anti-depressant, antiplatelet, anticonvulsant, anti-anxiolytic, wound healing, cosmetic (skin whitening), anti-microbial, matrix metalloproteinase (MMPs) inhibition, hepatoprotective activity and other biological effects. Here we have summarized the proposed mechanism behind these pharmacological effects.
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http://dx.doi.org/10.2174/1389557520666200313120419DOI Listing
February 2021

An Overview on Chemotherapy-induced Cognitive Impairment and Potential Role of Antidepressants.

Curr Neuropharmacol 2020 ;18(9):838-851

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India.

Background: Cognitive impairment is an adverse reaction of cancer chemotherapy and is likely to affect up to 75% of patients during the treatment and 35% of patients experience it for several months after the chemotherapy. Patients manifest symptoms like alteration in working ability, awareness, concentration, visual-verbal memory, attention, executive functions, processing speed, fatigue and behavioural dysfunctions. Post-chemotherapy, cancer survivors have a reduced quality of life due to the symptoms of chemobrain. Apart from this, there are clinical reports which also associate mood disorders, vascular complications, and seizures in some cases. Therefore, the quality of lifestyle of cancer patients/ survivors is severely affected and only worsens due to the absence of any efficacious treatments. With the increase in survivorship, it's vital to identify effective strategies, until then only symptomatic relief for chemobrain can be provided. The depressive symptoms were causally linked to the pathophysiological imbalance between the pro and antiinflammatory cytokines.

Conclusion: The common causative factor, cytokines can be targeted for the amelioration of an associated symptom of both depression and chemotherapy. Thus, antidepressants can have a beneficial effect on chemotherapy-induced inflammation and cognitive dysfunction via cytokine balance. Also, neurogenesis property of certain antidepressant drugs rationalises their evaluation against CICI. This review briefly glances upon chemotherapy-induced cognitive impairment (CICI), and the modulatory effect of antidepressants on CICI pathomechanisms.
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http://dx.doi.org/10.2174/1570159X18666200221113842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569321PMC
July 2021

Lipase of Pseudomonas guariconesis as an additive in laundry detergents and transesterification biocatalysts.

J Basic Microbiol 2020 Feb 30;60(2):112-125. Epub 2019 Oct 30.

Microbial Processes and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Thiruvananthapuram, Kerala, India.

A newly isolated culture, Pseudomonas guariconesis, is reported for the first time for lipase production. Various process parameters affecting enzyme production were optimized through statistical design experiments. The Plackett-Burman experimental design was used for screening 10 parameters for lipase production, which was further optimized using the central composite design of response surface methodology. Maximum lipase activity of 220 U/ml was obtained after 24 h of incubation in shake-flask cultures with an inoculum concentration of 0.6% v/v, incubation temperature of 30°C, and medium pH 9.0. Castor oil (0.5% v/v) was used as the inducer for lipase production. The enzyme was found to be compatible with five different commercial detergents, indicating its potential to be used in detergent formulations. It also acted as a biocatalyst in a transesterification process. The alkaline enzyme was found to be stable in the presence of bleaching agents, metal ions, and organic solvents as well.
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http://dx.doi.org/10.1002/jobm.201900326DOI Listing
February 2020

Fermentative Production of -Alkylated Glycine Derivatives by Recombinant Using a Mutant of Imine Reductase DpkA From .

Front Bioeng Biotechnol 2019 26;7:232. Epub 2019 Sep 26.

Genetics of Prokaryotes, Faculty of Biology and CeBiTec, Bielefeld University, Bielefeld, Germany.

Sarcosine, an -methylated amino acid, shows potential as antipsychotic, and serves as building block for peptide-based drugs, and acts as detergent when acetylated. -methylated amino acids are mainly produced chemically or by biocatalysis, with either low yields or high costs for co-factor regeneration. , which is used for the industrial production of amino acids for decades, has recently been engineered for production of -methyl-L-alanine and sarcosine. Heterologous expression of in a strain engineered for glyoxylate overproduction enabled fermentative production of sarcosine from sugars and monomethylamine. Here, mutation of an amino acyl residue in the substrate binding site of DpkA (DpkA) led to an increased specific activity for reductive alkylamination of glyoxylate using monomethylamine and monoethylamine as substrates. Introduction of DpkA into the production strain accelerated the production of sarcosine and a volumetric productivity of 0.16 g L h could be attained. Using monoethylamine as substrate, we demonstrated -ethylglycine production with a volumetric productivity of 0.11 g L h, which to the best of our knowledge is the first report of its fermentative production. Subsequently, the feasibility of using rice straw hydrolysate as alternative carbon source was tested and production of -ethylglycine to a titer of 1.6 g L after 60 h of fed-batch bioreactor cultivation could be attained.
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http://dx.doi.org/10.3389/fbioe.2019.00232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775277PMC
September 2019

Neprilysin, the kidney brush border neutral proteinase: a possible potential target for ischemic renal injury.

Toxicol Mech Methods 2020 Feb 10;30(2):88-99. Epub 2019 Oct 10.

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India.

Neprilysin (NEP) is an endogenously induced peptidase for modulating production and degradation of various peptides in humans. It is most abundantly present in kidney and regulates the intrinsic renal homeostatic mechanism. Recently, drugs inhibiting NEP have been approved for the use in heart failure. In the context of increased prevalence of ischemia associated renal failure, NEP could be an attractive target for treating kidney failure. In the kidney, targeting NEP may possess potential benefits as well as adverse consequences. The unfavorable outcomes of NEP are mainly attributed to the degradation of the natriuretic peptides (NPs). NPs are involved in the inhibition of the renin-angiotensin-aldosterone system (RAAS) and activation of the sympathetic system contributing to the tubular and glomerular injury. In contrary, NEP exerts the beneficial effect by converting angiotensin-1 (Ang I) to angiotensin-(1-7) (Ang-(1-7)), thus activating MAS-related G-protein coupled receptor. MAS receptor antagonizes angiotensin type I receptor (AT-1R), reduces reactive oxygen species (ROS) and inflammation, thus ameliorating renal injury. However, the association of NEP with complex cascades of renal ischemia remains vague. Therefore, there is a need to evaluate the putative mechanism of NEP and its overlap with other signaling cascades in conditions of renal ischemia.
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http://dx.doi.org/10.1080/15376516.2019.1669246DOI Listing
February 2020

Possible involvement of metformin in downregulation of neuroinflammation and associated behavioural changes in mice.

Inflammopharmacology 2019 Oct 3;27(5):941-948. Epub 2019 Sep 3.

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, India.

Metformin (MET), a biguanide oral hypoglycaemic agent, recently has been shown to be effective in various conditions other than type-2 diabetes including cancer, stroke, weight reduction, and polycystic ovarian syndrome, to name a few. MET has also possessed antioxidant and antiinflammatory properties by activation of AMPK . This study was aimed at evaluating the effects of MET on lipopolysaccharide (LPS)-induced systemic and neuroinflammation, oxidative stress, and behavioural changes. The study consisted of six groups, where three selected doses of MET (100, 200, and 300 mg/kg) were employed in male Swiss albino mice, with one group of imipramine (IMI), saline, and LPS each. Systemic inflammation was induced by injecting LPS (1.5 mg/kg) by intraperitoneal route. A battery of behavioural tests including open field, forced swim, and tail suspension tests were employed to assess the impact of systemic inflammation on exploratory behaviour and learned helplessness. LPS induced significant immobility with profound symptoms of sickness behaviour. Furthermore, LPS led to significant increase in serum and brain proinflammatory cytokines TNF-α and IL-6; and also increased lipid peroxidation with reduced glutathione levels. Pretreatment of the animals with 100 and 200 mg/kg of MET significantly reduced both systemic and central inflammatory markers along with protecting against LPS-induced oxidative stress. The higher dose, 300 mg/kg of MET was not effective against most of LPS-induced biochemical changes. Our preliminary results from this study suggest the antiinflammatory and neuroprotective effects of MET in LPS-induced model of sickness behaviour and neuroinflammation.
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http://dx.doi.org/10.1007/s10787-019-00638-wDOI Listing
October 2019

Detecting the structural assembly pathway of human antimicrobial peptide pores at single-channel level.

Biomater Sci 2019 Aug 5;7(8):3226-3237. Epub 2019 Jun 5.

Membrane Biology Laboratory, Interdisciplinary Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, India.

The pore-forming structures of an anionic human antimicrobial peptide dermcidin (DCD) in a membrane environment has not been demonstrated previously. Using single-channel electrical recordings, we characterized the structural and functional properties of the DCD peptide channel in lipid membranes. We show that a 48-residue, 8 nm long anionic DCD-1L peptide is folded in the right conformation in sodium dodecyl sulfate (SDS) that spontaneously inserts into lipid bilayers to form well-defined channels. However, the DCD-1L peptides are not properly folded in n-dodecyl-β-d-maltoside (DDM), resulting in unstable channels suggesting the significance of specific detergent in stable channel formation. Furthermore, a 25-residue cationic DCD SSL-25 peptide formed channels both in SDS and DDM micelles as the length of the peptide matches with the thickness of the membrane. Finally, we quantified the permeation of small molecules through the DCD channels in liposome assays. Accordingly, we propose a molecular model demonstrating the structural self-assembly of the DCD channels in the membrane. We suggest that an understanding of the mechanism of action of DCD peptides at single-channel resolution will lead to developing peptide-based therapeutics.
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http://dx.doi.org/10.1039/c9bm00181fDOI Listing
August 2019

Effect of Caffeic Acid on Ischemia-Reperfusion-Induced Acute Renal Failure in Rats.

Pharmacology 2019 14;103(5-6):315-319. Epub 2019 Mar 14.

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India,

Background: Cyclooxygenase (COX)-lipooxygenase (LOX) pathway plays a key role in the pathogenesis of renal ischemia/reperfusion (IR).

Objective: This study was aimed to evaluate the role of dietary phenol caffeic acid (CA), alone and in combination with selective COX-2 inhibitor celecoxib (CEL) in IR-induced acute renal failure (ARF) in rats.

Materials And Methods: Renal IR was induced by bilateral occlusion of renal pedicels for 90 min followed by reperfusion for 24 h. Rats were randomized into 4 groups: Sham, IR, CA + IR, and CA + CEL + IR, with 7 day treatment before IR. Serum creatinine (SCr), blood urea nitrogen (BUN), antioxidant enzymes, tumor necrosis factor alpha (TNF-α), and histopathological changes were evaluated in the kidney after IR.

Results: Renal IR caused significant derangement in renal function and histology. In the IR group, an increase in lipid peroxidation and decreased antioxidant defense enzyme activity were observed. Pretreatment with CA and CA + CEL showed a significant decrease in the BUN, SCr, TNF-α, oxidative stress markers and corrected the histological changes in the kidney.

Conclusion: This study demonstrated the renoprotective potential of CA and combination of CA + CEL in IR-induced ARF in rats. The plausible mechanisms for the efficacy of CA could be attributed to its ability to modulate the -COX-LOX system in renal IR.
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http://dx.doi.org/10.1159/000497474DOI Listing
April 2019

Bark Ameliorates Inflammation and Arthritis in Carrageenan Induced Inflammatory Model and Freund's Adjuvant-Induced Arthritis Model in Rats.

J Toxicol 2019 17;2019:7898914. Epub 2019 Jan 17.

Department of Pharmacognosy, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India.

bark belongs to the family Combretaceae. The plant bark is astringent and useful in the treatment of ulcers, vata, fractures, hemorrhages, bronchitis, and diarrhea. Phytochemical investigation of bark confirms the presence of flavonoids, polyphenols, and tannins. The plant has not been investigated for its anti-inflammatory and antiarthritic activity. The present study was undertaken to explore its possible anti-inflammatory and antiarthritic activity. Anti-inflammatory activity of alcoholic and aqueous extracts of the bark was assessed by methods. antiarthritic potential of the extracts was evaluated by Complete Freund's Adjuvant (CFA) induced arthritis in Wistar rats. Our findings showed that the alcoholic and aqueous extracts exhibited anti-inflammatory activity at 500 mg/kg oral dose in carrageenan-induced hind paw edema and carrageenan-induced air pouch inflammation models. We also found alcoholic as well as aqueous extracts of the bark restored the altered blood and serum parameters caused by the Complete Freund's Adjuvant-induced arthritis in Wistar rats. This study shows that the bark extracts possess anti-inflammatory activity and have pronounced effects on adjuvant arthritis also. Future studies are necessary to provide deeper insight into the exact mechanism of the action of anti-inflammatory and antiarthritic activity of .
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http://dx.doi.org/10.1155/2019/7898914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354132PMC
January 2019

Cannabinoid receptor 2 activation mitigates lipopolysaccharide-induced neuroinflammation and sickness behavior in mice.

Psychopharmacology (Berl) 2019 Jun 22;236(6):1829-1838. Epub 2019 Jan 22.

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.

Rationale And Objectives: Cannabinoid receptor 2 (CB2R) signaling in the brain is associated with the pathophysiology of depression. Sickness behavior, characterized by lessened mobility, social interaction, and depressive behavior, is linked with neuroinflammation, oxidative stress, and immune system. The present study was aimed at evaluating 1-phenylisatin (PI), a CB2R agonist, in sickness behavior.

Methods: Influence of acute and 7-day activation of CB2R using PI in lipopolysaccharide (LPS)-induced sickness behavior was assessed in mice. An acute injection of LPS (1.5 mg/kg) produced a fully developed sickness behavior in animals within 1 h of administration. The behavioral paradigm was assessed by open field test, forced swim test, and tail suspension test. Further, tumor necrosis factor-α (TNF-α), antioxidant enzymes, and lipid peroxidation were measured in the brain to correlate neuroinflammation and oxidative stress with sickness behavior. Both treatments, PI (20 mg/kg) and imipramine (15 mg/kg), were administered orally (once for acute and once daily for 7-day protocols).

Results: LPS elevated the brain TNF-α level, augmented oxidative stress, and induced the sickness behavior in mice. Acute and 7-day treatment of mice with PI significantly reduced the LPS-induced sickness behavior. In addition, PI inhibited the neuroinflammation evidenced by a reduction in brain TNF-α and oxidative stress.

Conclusion: Our data propose that acute and long-term activation of CB2R might prevent neuroinflammation and oxidative stress-associated sickness behavior.
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http://dx.doi.org/10.1007/s00213-019-5166-yDOI Listing
June 2019

Neuromodulatory potential of phenylpropanoids; para-methoxycinnamic acid and ethyl-p-methoxycinnamate on aluminum-induced memory deficit in rats.

Toxicol Mech Methods 2019 Jun 4;29(5):334-343. Epub 2019 Feb 4.

a Department of Pharmacology, Manipal College of Pharmaceutical Sciences , Manipal Academy of Higher Education , Manipal , India.

Para-methoxycinnamic acid (PMCA) and Ethyl-p-methoxycinnamate (EPMC) are reported to possess neuroprotective effect in reversing an acute memory deficit. However, there is a dearth of evidence for their therapeutic effect in chronic memory deficit. Thus, there is a scope to study these derivatives against the chronic model of cognitive dysfunction. The present study was aimed to determine the cognitive enhancing activity of PMCA and EPMC in aluminum-induced chronic dementia. Cognitive enhancing property of PMCA and EPMC was assessed using Morris water maze by analyzing spatial memory parameters such as escape latency, D-quadrant latency, and island entries. To find a possible mechanism, the effect of test compounds on altered acetylcholinesterase (AChE) activity and oxidative stress was determined in the hippocampus and frontal cortex of rats. Docking interaction of these derivatives with acetylcholinesterase enzyme and glutamate receptors was also studied. Treatment with PMCA and EPMC showed a significant improvement in spatial memory markers and altered hippocampal AChE activity in rats with cognitive dysfunction. The implication of hippocampal and cortical oxidative stress in memory impairment was confirmed with decreased catalase/increased thiobarbituric acid reactive substances (TBARS) in rats. PMCA and EPMC reversed the oxidative stress in the brain by negatively affecting TBARS levels. Against depleted catalase levels, PMCA was more effective than EPMC in raising the depleted catalase levels. In silico analysis revealed poor affinity of EPMC and PMCA with AChE enzyme and glutamate receptor. To conclude, PMCA and EPMC exerted cognitive enhancing property independent of direct AChE and glutamate receptor inhibition.
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http://dx.doi.org/10.1080/15376516.2018.1561779DOI Listing
June 2019

Crosstalk between neurokinin receptor signaling and neuroinflammation in neurological disorders.

Rev Neurosci 2019 04;30(3):233-243

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India.

The neurokinin 1 receptor with the natural substrate substance P is one of the intensely studied receptors among the neurokinin receptors. The intracellular signaling mechanism uses G protein-coupled transduction regulating various physiological processes from nausea to Alzheimer's disease. The neurokinin 1 receptor plays a significant role in neuroinflammation-mediated alterations in neural circuitry. Neurokinin 1 receptor antagonists are selective, potent and exhibited efficacy in animal models of nervous system disorders. Evolving data now strengthen the viewpoint of brain substance P/neurokinin 1 receptor axis-mediated action in neural circuit dysfunction. Thus, a deep-rooted analysis of disease mechanism in which the neurokinin 1 receptor is involved is necessary for augmenting disease models which encourage the pharmaceutical industry to intensify the research pipeline. This review is an attempt to outline the concept of neurokinin 1 receptor signaling interlinked to the brain innate immune system. We also uncover the mechanisms of the neurokinin 1 receptor involved in neurological disorder and various methods of modulating the neurokinin 1 receptor, which may result in therapeutic action.
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http://dx.doi.org/10.1515/revneuro-2018-0021DOI Listing
April 2019
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