Phospholipase A2: A Potential Therapeutic Target in Inflammation and Cancer (In silico, In vitro, In vivo and Clinical Approach)

Yarla, Nagendra Sastry; Satyakumar, Koduri; Srinivasu, Duppalapudi; Kaladhar, Dsvgk

doi:10.4172/1948-5956.1000357

Cited by 10 publications

(9 citation statements)

References 21 publications

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“…It is not clear if the anti-inflammatory effect of gabapentin is related to calcium modulation rather than other mechanisms such as stimulation of endogenous anti-oxidants like GSH, inhibition of NF-kB, block of NMDA receptor or activation of adenosine A1 receptor (Abdel-Salam and Sleem, 2009; Kim et al, 2009; Yang et al, 2012; Dias et al, 2014; Wang et al, 2014; Martins et al, 2015; Xu et al, 2017). Phosphorylation and calcium concentrations are the effectors modulating the activity of cPLA 2 and recent studies have highlighted the role of PLAs 2 as potential therapeutic target in inflammation and in other serious disorders, and the increase of PLA 2 has been linked with the severity of the disease (Yarla et al, 2015). AA is released from phospholipids by the action of different isoforms of phospholipase A 2 s (PLA 2 s) and converted to PGs or leukotrienes (LTs) by the action of COXs and 5-lipoxygenase, respectively.…”

Section: Discussionmentioning

confidence: 99%

Gabapentin Attenuates Ocular Inflammation: In vitro and In vivo Studies

et al. 2017

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To investigate the effects of gabapentin, a structural analog of γ-amino butyric acid (GABA), on the inflammatory response of lipopolysaccharide (LPS)-stimulated rabbit corneal cells (SIRC) and on endotoxin-induced uveitis (EIU) in rabbits. We investigated the LPS-induced expression of several inflammatory mediators, such as TNF-α, IL-1β, cPLA2, COX-2, and PGE2 in the SIRC cells with or without gabapentin treatment. Gabapentin treatment significantly (p < 0.05) attenuated cytokines production, cPLA2 activation, COX-2 expression, and PGE2 levels in SIRC. EIU was induced by an intraocular injection of 0.1 μg of LPS in albino rabbit eye. After 7 and 24 h from LPS injection clinical signs of ocular inflammation were examined by slit lamp with or without topical treatment of 0.5% gabapentin. Tears, aqueous, cornea, conjunctiva, and iris-ciliary body were collected and inflammatory biomarkers assessed. Topical treatment with gabapentin significantly (p < 0.05) reduced clinical signs and biomarkers of inflammation compared with the LPS group both at 7 and 24 h. In conclusion, the results generated in the present study suggest that ophthalmic formulation based on gabapentin may be useful in the treatment of inflammatory conditions associated to ocular pain such as uveitis, and that clinical studies to evaluate this possibility may be warranted.

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Section: Discussionmentioning

confidence: 99%

Gabapentin Attenuates Ocular Inflammation: In vitro and In vivo Studies

et al. 2017

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“…Considering the results of this study, calcium induces atomistic movements and conformational changes in snake venom PLA2 which leads to formation of wider cleft at the active site of calcium bound PLA2 when compared with free PLA2. The results of this work have shed more light into the mechanism of action of calcium in snake venom toxicity and could be helpful to design small molecules which could function as novel inhibitors of PLA2 as none is available as drug in the market [23]. Such molecules would likely act by inhibiting the formation of loops or its flexibility and/or stabilization of the generated helical structures which would prevent the widening of the cleft at the active site of PLA2.…”

Section: Resultsmentioning

confidence: 95%

The Role of Calcium on the Active Site of Snake Venom Phospholipase A2: Molecular Dynamics Simulations

I.¹

2016

CBB

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Snake venoms are rich in phospholipase A2 (PLA2) and their hydrolysis of cell membrane phospholipids explains the role of the enzyme in venom toxicity. Calcium is known to plays important role at the active site of PLA2 during catalysis. In this study, molecular dynamics simulations of free PLA2 and calcium bound PLA2 were carried out using GROMACS 4.5.5 to evaluate the role of calcium in PLA2 catalysis. The results showed that calcium induced formation of helical structures between Arg62-Lys66, Asn107-Tyr111 and Asp114-Cys119 in PLA2 which with time disappeared through the formation and opening of loops. Calcium induced atomistic movements and conformational changes in snake venom PLA2 which led to the formation of a widened cleft at the active site of calcium bound PLA2 when compared with free PLA2. This could lead to a better binding and accommodation of substrate, thus enhancing catalysis. This study confirms the role of calcium towards the action of PLA2 in snake venom toxicity and could provide useful information for the design of small molecules that can function as PLA2 inhibitors.

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“…They also play a significant role in various cellular processes such as biotransformation and digestion of phospholipids, signal transduction and host defense (Dennis et al, 2011). PLA 2 s are connected to human pathophysiological events and associated with certain types of cancers, arthritis, and inflammatory disorders, and therefore have been studied extensively (Brglez et al, 2014;Murakami et al, 2014;Yarla et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Development of high-throughput screening assays for profiling snake venom phospholipase A2 activity after chromatographic fractionation

Still

Slagboom

Kidwai

et al. 2020

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Phospholipase A2: A Potential Therapeutic Target in Inflammation and Cancer (In silico, In vitro, In vivo and Clinical Approach)

Cited by 10 publications

References 21 publications

Gabapentin Attenuates Ocular Inflammation: In vitro and In vivo Studies

Gabapentin Attenuates Ocular Inflammation: In vitro and In vivo Studies

The Role of Calcium on the Active Site of Snake Venom Phospholipase A2: Molecular Dynamics Simulations

Development of high-throughput screening assays for profiling snake venom phospholipase A2 activity after chromatographic fractionation

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