An Update on Inhibitors of Human 14 kDa Type II s-PLA2 in Development&gt;

Springer, Dane M.

doi:10.2174/1381612013398275

Cited by 18 publications

(4 citation statements)

References 36 publications

(41 reference statements)

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“…Further, considering the limitations of antiserum therapy (Dhananjaya et al, 2011, Girish and Kemparaju, 2011), it is justified that research has to focus on developing alternatives and in this regard finding inhibitors of the multi-toxic svPLA 2 s from medicinal plants have gained much interest in the recent past (Carvalho et al, 2013, Gomes et al, 2012). Although many sPLA 2 inhibitors have been isolated from various medicinal plants (Springer, 2001, Nanda et al, 2007, Narendra Sharath Chandra et al, 2007), however, still effective and specific inhibitors of sPLA 2 are not available. In these line of studies, the aqueous steam bark extract of M. indica is evaluated for its potential to inhibit phospholipase A 2 (PLA 2 ) belonging to group IA i.e.…”

Section: Resultsmentioning

confidence: 99%

“…Further, considering the limitations of antiserum therapy (Dhananjaya et al, 2011, Girish and Kemparaju, 2011), researches are focusing on the development of alternative treatments and in this regard finding inhibitors of the multi-toxic svPLA 2 s from medicinal plants have gained much interest (Carvalho et al, 2013, Gomes et al, 2012). In this context, although many sPLA 2 inhibitors have been isolated from various medicinal plants (Springer, 2001, Nanda et al, 2007, Narendra Sharath Chandra et al, 2007) that have been demonstrated to bring down the toxic and lethal effects of several venoms (Girish and Kemparaju, 2011), however, still effective and specific inhibitors of sPLA 2 are not available.…”

Section: Introductionmentioning

confidence: 99%

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The standard aqueous stem bark extract of Mangifera indica L. inhibits toxic PLA 2 – NN-XIb-PLA 2 of Indian cobra venom

Dhananjaya

Sudarshan

Dongol

et al. 2016

Saudi Pharmaceutical Journal

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The aqueous extract of Mangifera indica is known to possess diverse medicinal properties, which also includes anti-snake venom activities. However, its inhibitory potency and mechanism of action on multi-toxic snake venom phospholipases A2s are still unknown. Therefore, the objective of this study was to evaluate the modulatory effect of standard aqueous bark extract of M. indica on NN-XIb-PLA2 of Indian cobra venom. The in vitro sPLA2, in situ hemolytic and in vivo edema inhibition effect were carried out as described. Also the effect of substrate and calcium concentration was carried out. M. indica extract dose dependently inhibited the GIA sPLA2 (NN-XIb-PLA2) activity with an IC50 value of 7.6 μg/ml. M. indica extract effectively inhibited the indirect hemolytic activity up to 98% at ∼40 μg/ml concentration. Further, M. indica extract (0-50 μg/ml) inhibited the edema formed in a dose dependent manner. When examined as a function of increased substrate and calcium concentration, there was no relieve of inhibitory effect of M. indica extract on the NN-XIb-PLA2. Further, the inhibition was irreversible as evident from binding studies. The in vitro inhibition is well correlated with in situ and in vivo edema inhibiting activities of M. indica. As the inhibition is independent of substrate and calcium and was irreversible, it can be concluded that M. indica extract mode of inhibition could be due to direct interaction of components present in the extract with the PLA2 enzyme. The aqueous extract of M. indica effectively inhibits svPLA2 enzymatic and its associated toxic activities, which substantiate their anti-snake venom properties. Further in-depth studies on the role and mechanism of the principal constituents present in the extract, responsible for the anti-PLA2 activity will be interesting to develop them into potent antisnake component and also as an anti-inflammatory agent.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The standard aqueous stem bark extract of Mangifera indica L. inhibits toxic PLA 2 – NN-XIb-PLA 2 of Indian cobra venom

Dhananjaya

Sudarshan

Dongol

et al. 2016

Saudi Pharmaceutical Journal

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“…BMS‐181162 progressed to Phase II clinical trials for the topical treatment of psoriasis. However, this compound failed to demonstrate efficacy and development was discontinued (Springer, 2001). Modification of the BMS‐181162 structure led to the development of a series of biaryl dicarboxylic acids (Springer et al., 2000).…”

Section: Examples Of Inhibitors and Inhibitor Classes Of The Spla2smentioning

confidence: 99%

Interactions of small molecule inhibitors with secreted phospholipase A₂: A review of the structural data

Crous,

Petzer,

Petzer

2024

Chem Biol Drug Des

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The secreted phospholipase A2 (sPLA2) family of enzymes hydrolyzes glycerophospholipid substrates at the sn‐2 position of the acyl ester bond. Besides their roles in the degradation of phospholipids, these enzymes also play an important role in the immune response by promoting inflammation. The products of sPLA2‐catalysis (lysophospholipids and free fatty acids such as arachidonic acid) as well as secondary metabolites produced by the arachidonic acid cascade are mediators of inflammation and subsequent tissue injury. Based on their physiological functions, the sPLA2 enzymes are pharmacological targets for the treatment of diseases with an inflammatory component such as atherosclerosis and rheumatoid arthritis. Interestingly, sPLA2s may also have roles in various types of cancer such as malignant prostate cancer. While a number of sPLA2 inhibitors have been described, compounds which have been co‐crystallized with human sPLA2 enzymes are of much importance as such three‐dimensional structures provide valuable information regarding the structural requirements of good potency inhibitors as well as the molecular interactions between the enzyme and inhibitor. This review selected four structures of human sPLA2s complexed with inhibitors from the Protein Data Bank to illustrate the important molecular interactions of inhibitor compounds with the enzymes and to highlight the structural features important for interaction with the sPLA2 active site. In addition, the complex of the sPLA2 inhibitor, varespladib, with a Lys49‐PLA2‐like snake venom toxin is also discussed. Knowledge of the molecular interactions acquired from such structures would greatly aid the discovery of small molecule inhibitors of sPLA2s for the treatment of snakebite envenoming. The three‐dimensional structures presented in this review have been published by various research groups and have been deposited in the Protein Data Bank.

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“…[ 1 4 5 ] Due to the central role of sPLA 2 s in the inflammatory process and considering the drawbacks and severe side effects exhibited by present anti-inflammatory therapeutic agents, which includes the nonsteroidal anti-inflammatory drugs that inhibit either lipoxygenase or cyclooxygenase (COX)-½ enzymes,[ 6 ] there is renewed pharmacological interest in search of potent and specific sPLA 2 inhibitors from diverse sources. [ 1 5 ] In this context, many plant extracts and its constituents are reported for their anti-inflammatory activity through the inhibition of sPLA 2 s.[ 1 5 7 ] However, effective and specific inhibitors of sPLA 2 are still not available to date.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of group IIA secretory phospholipase A₂and its inflammatory reactions in mice by ethanolic extract of Andrographis paniculata, a well-known medicinal food

et al. 2016

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Andrographis paniculata Nees is an important medicinal plant found in the tropical regions of the world, which has been traditionally used in Indian and Chinese medicinal systems. It is also used as medicinal food. A. paniculata is found to exhibit anti-inflammatory activities; however, its inhibitory potential on inflammatory Group IIA phospholipases A2 (PLA2) and its associated inflammatory reactions are not clearly understood. The aim of the present study is to evaluate the inhibitory/neutralizing potential of ethanolic extract of A. paniculata on the isolated inflammatory PLA2 (VRV-PL-VIIIa) from Daboii rusellii pulchella (belonging to Group IIA inflammatory secretory PLA2 [sPLA2]) and its associated edema-induced activities in Swiss albino mice. A. paniculata extract dose dependently inhibited the Group IIA sPLA2 enzymatic activity with an IC50 value of 10.3 ± 0.5 μg/ml. Further, the extract dose dependently inhibited the edema formation, when co-injected with enzyme indicating that a strong correlation exists between lipolytic and pro-inflammatory activities of the enzyme. In conclusion, results of this study shows that the ethanolic extract of A. paniculata effectively inhibits Group IIA sPLA2 and its associated inflammatory activities, which substantiate its anti-inflammatory properties. The results of the present study warranted further studies to develop bioactive compound (s) in ethanolic extract of A. paniculata as potent therapeutic agent (s) for inflammatory diseases.SUMMARY This study emphasis the anti-inflammatory effect of A. paniculata by inhibiting the inflammatory Group IIA sPLA2 and its associated inflammatory activities such as edema. It was found that there is a strong correlation between lipolytic activity and pro-inflammatory activity inhibition. Therefore, the study suggests that the extract processes potent anti-inflammatory agents, which could be developed as a potential therapeutic agent against inflammatory and related diseases.

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An Update on Inhibitors of Human 14 kDa Type II s-PLA2 in Development>

Cited by 18 publications

References 36 publications

The standard aqueous stem bark extract of Mangifera indica L. inhibits toxic PLA 2 – NN-XIb-PLA 2 of Indian cobra venom

The standard aqueous stem bark extract of Mangifera indica L. inhibits toxic PLA 2 – NN-XIb-PLA 2 of Indian cobra venom

Interactions of small molecule inhibitors with secreted phospholipase A₂: A review of the structural data

Inhibition of group IIA secretory phospholipase A₂and its inflammatory reactions in mice by ethanolic extract of Andrographis paniculata, a well-known medicinal food

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An Update on Inhibitors of Human 14 kDa Type II s-PLA2 in Development>

Cited by 18 publications

References 36 publications

The standard aqueous stem bark extract of Mangifera indica L. inhibits toxic PLA 2 – NN-XIb-PLA 2 of Indian cobra venom

The standard aqueous stem bark extract of Mangifera indica L. inhibits toxic PLA 2 – NN-XIb-PLA 2 of Indian cobra venom

Interactions of small molecule inhibitors with secreted phospholipase A2: A review of the structural data

Inhibition of group IIA secretory phospholipase A2and its inflammatory reactions in mice by ethanolic extract of Andrographis paniculata, a well-known medicinal food

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Product

Resources

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Interactions of small molecule inhibitors with secreted phospholipase A₂: A review of the structural data

Inhibition of group IIA secretory phospholipase A₂and its inflammatory reactions in mice by ethanolic extract of Andrographis paniculata, a well-known medicinal food