Paraoxonases: metabolic role and pharmacological projection

Moya, Carlos J.; Máñez, Salvador

doi:10.1007/s00210-018-1473-9

Cited by 38 publications

(36 citation statements)

References 98 publications

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“…One hypothesis could be the short exposure time, while another factor could be related to oxidative stress, since the enzyme is inactivated under these conditions, as demonstrated by Gunay et al 66 In addition, the activity of PON-1 in hydrolysing OP compounds may vary according to OP type 67 ; thus, it is not possible to attribute to this enzyme activity as a biomarker of susceptibility against OP intoxication only. 65 In conclusion, the present study revealed the potential protective effect of oximes and isatins against the toxicity induced by the malathion in A salina. Our findings demonstrated that Cℓ-HIN is the most promising molecule tested, probably due to the combination of isatin and oxime functional groups into its structure.…”

Section: Discussionsupporting

confidence: 51%

“…PON-1 is a high-density enzyme that belongs to one of the classes of paraoxonases (aryldialkylphosphatases, EC 3.1.8.1), which includes the ability to hydrolyse OPs where their action is dependent on the enzyme structure and substrates among its many functions. [63][64][65] The exact mechanism of PON-1 activity is still not well understood, although it plays an important role in the detoxification of metabolites of OPs. 65 Our results showed no change in PON-1 activity of plasma rats exposed to malathion.…”

Section: Discussionmentioning

confidence: 99%

“…[63][64][65] The exact mechanism of PON-1 activity is still not well understood, although it plays an important role in the detoxification of metabolites of OPs. 65 Our results showed no change in PON-1 activity of plasma rats exposed to malathion. One hypothesis could be the short exposure time, while another factor could be related to oxidative stress, since the enzyme is inactivated under these conditions, as demonstrated by Gunay et al 66 In addition, the activity of PON-1 in hydrolysing OP compounds may vary according to OP type 67 ; thus, it is not possible to attribute to this enzyme activity as a biomarker of susceptibility against OP intoxication only.…”

Section: Discussionmentioning

confidence: 99%

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Pre‐clinical evidence of safety and protective effect of isatin and oxime derivatives against malathion‐induced toxicity

Savall

Fidélis

Gutierrez

et al. 2019

Basic Clin Pharma Tox

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The inhibition of acetylcholinesterase (AChE) is a common outcome caused by organophosphorus (OPs) intoxication. Although inconsistent, the standard treatment consists of a muscarinic receptor antagonist (atropine) and AChE‐reactivating molecules such as oximes. This study proposes to test unpublished compounds which contain the moieties of isatin and/or oxime have protective effects against the toxicity induced by malathion in two animal models: Artemia salina and Rattus norvegicus (Wistar rats). The lethality was assessed in A salina, and the calculated LD50 to (3Z)‐5‐chloro‐3‐(hydroxyimino) indolin‐2‐one oxime (Cℓ‐HIN) and 2‐(5‐chloro‐2‐oxoindolin‐3‐ylidene)‐hydrazinecarbothioamide (Cℓ‐OXHS) was higher than 1000 µM while to 3‐(phenylhydrazono) butan‐2‐one oxime (PHBO) was 38 µM. Our screening showed that Cℓ‐HIN seems to be the most promising molecule, with low toxicity to A salina, protection against mortality (with or without atropine) and AChE inhibition induced by malathion. Similarly, the oral administration of 300 mg/kg of Cℓ‐HIN induced low or no toxicity in rats. The plasma butyrylcholinesterase (BChE) and cortical AChE activities were reactivated by Cℓ‐HIN (50 mg/kg, p.o.) in rats exposed to malathion (250 mg/kg, i.p). No difference was observed in paraoxonase‐1 (PON‐1) activity among groups treated. In conclusion, Cℓ‐HIN restored the cholinesterase activities inhibited by malathion in A salina and rats with low toxicity in both. Thus, the data provide evidence that Cℓ‐HIN, a compound that combines isatin and oxime functional groups, is safe and has important properties to reactivate the cholinesterases inhibited by malathion. In addition, we demonstrate the importance of a preliminary assessment in an alternative model in order to reduce the use of mammalians in drug discovery.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Pre‐clinical evidence of safety and protective effect of isatin and oxime derivatives against malathion‐induced toxicity

Savall

Fidélis

Gutierrez

et al. 2019

Basic Clin Pharma Tox

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“…RSV has protective effects in terms of CVD risk due to its capacity to improve PON1 activity. Experiments performed in vitro and in vivo evidenced the positive effects of quercetin/RSV on PON1 activity [95,[114][115][116]. The mechanisms responsible for this effect might be the activation of SIRT-1, which is known as activator of LXR, important regulator of PON1 gene [117].…”

Section: Stilbenesmentioning

confidence: 99%

“…No formulations of caffeic acid to be used for CVD treatment have been developed at present. CAPE has been reported to have antioxidant and anti-inflammatory properties [95]. It was demonstrated that CAPE induces the expression of redox-sensitive HO-1 [96] through activation of the Kelch-like ECH-associated protein 1 (Keap1)/Nrf2/antioxidant response element (ARE) pathway [97], and consequently generates the transcription and translation of detoxifying and antioxidant phase II cytoprotective enzymes.…”

Section: Introductionmentioning

confidence: 99%

Phenolic Compounds Exerting Lipid-Regulatory, Anti-Inflammatory and Epigenetic Effects as Complementary Treatments in Cardiovascular Diseases

et al. 2020

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Atherosclerosis is the main process behind cardiovascular diseases (CVD), maladies which continue to be responsible for up to 70% of death worldwide. Despite the ongoing development of new and potent drugs, their incomplete efficacy, partial intolerance and numerous side effects make the search for new alternatives worthwhile. The focus of the scientific world turned to the potential of natural active compounds to prevent and treat CVD. Essential for effective prevention or treatment based on phytochemicals is to know their mechanisms of action according to their bioavailability and dosage. The present review is focused on the latest data about phenolic compounds and aims to collect and correlate the reliable existing knowledge concerning their molecular mechanisms of action to counteract important risk factors that contribute to the initiation and development of atherosclerosis: dyslipidemia, and oxidative and inflammatory-stress. The selection of phenolic compounds was made to prove their multiple benefic effects and endorse them as CVD remedies, complementary to allopathic drugs. The review also highlights some aspects that still need clear scientific explanations and draws up some new molecular approaches to validate phenolic compounds for CVD complementary therapy in the near future.In the last decade the scientific researchers turned their attention to phytochemicals, as effective, safe and low-cost natural bioactive compounds for CVD treatment.Dyslipidemia consists of increased blood concentrations of total cholesterol (TC), low density lipoproteins-cholesterol (LDL-C) and/or triglycerides (TG), and decreased high density lipoproteins-cholesterol (HDL-C) [6]. The lipid metabolism is complex and the candidate mechanisms that could generate dyslipidemia include: (i) excessive dietary lipid absorption in the small intestine; (ii) packing of exogenous lipids with cholesterol and fatty acids produced de novo in the liver and their secretion as very low density lipoproteins (VLDL); (iii) hydrolysis of TG from VLDL by lipases and their conversion into LDL, which are taken up by the peripheral tissues through LDL receptor (LDL-R) and scavenger receptors; (iv) diminished production of HDL by the liver and small intestine, thereby decreasing reverse cholesterol transport (RCT) from the peripheral tissues to the liver; (v) lowered excess cholesterol excretion from the liver into gallbladder or to the intestinal lumen through the ATP-binding cassette G5 and G8 transporters (ABCG5/G8) that facilitate trans-intestinal cholesterol efflux (TICE). Dyslipidemia is associated with the accumulation of LDL in the sub-endothelium of the artery wall. At this site, LDL undergoes oxidative modifications (oxLDL) that trigger inflammatory responses, and is taken up by the monocyte-derived macrophages infiltrated in the sub-endothelium which thus become lipid-loaded foam cells, the hallmark of atheroma development [7]. Until now, the most effective lipid-lowering treatment for hyperlipidemic patients was the statin therapy. But recen...

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Retinoic acid reduces kidney injury by regulating oxidative stress, NRF‐2, and apoptosis in hyperoxic mice

Kayalar,

Bayrak,

Yildirim

et al. 2024

Cell Biochemistry & Function

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Nuclear factor‐erythroid‐2‐related factor‐2 (NRF‐2) is a cellular resistance protein to oxidants. We investigated the effect of exogenous all‐trans retinoic acid (ATRA) on the antioxidant system and NRF‐2 in mice kidneys under hyperoxia‐induced oxidative stress. Mice were divided into four groups. Daily, two groups were given either peanut‐oil/dimethyl sulfoxide (PoDMSO) mixture or 50 mg/kg ATRA. Oxidative stress was induced by hyperoxia in the remaining groups. They were treated with PoDMSO or ATRA as described above, following hyperoxia (100% oxygen) for 72 h. NRF‐2 and active‐caspase‐3 levels, lipid peroxidation (LPO), activities of antioxidant enzymes, xanthine oxidase (XO), paraoxonase1 (PON1), lactate dehydrogenase (LDH), tissue factor (TF), and prolidase were assayed in kidneys. Hyperoxia causes kidney damage induced by oxidative stress and apoptosis. Increased LPO, LDH, TF, and XO activities and decreased PON1 and prolidase activities contributed to kidney damage in hyperoxic mice. After hyperoxia, increases in the activities of antioxidant enzymes and NRF‐2 level could not prevent this damage. ATRA attenuated damage via its oxidative stress‐lowering effect. The decreased LDH and TF activities increased PON1 and prolidase activities, and normalized antioxidant statuses are indicators of the positive effects of ATRA. We recommend that ATRA can be used as a renoprotective agent against oxidative stress induced‐kidney damage.

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Paraoxonases: metabolic role and pharmacological projection

Cited by 38 publications

References 98 publications

Pre‐clinical evidence of safety and protective effect of isatin and oxime derivatives against malathion‐induced toxicity

Pre‐clinical evidence of safety and protective effect of isatin and oxime derivatives against malathion‐induced toxicity

Phenolic Compounds Exerting Lipid-Regulatory, Anti-Inflammatory and Epigenetic Effects as Complementary Treatments in Cardiovascular Diseases

Retinoic acid reduces kidney injury by regulating oxidative stress, NRF‐2, and apoptosis in hyperoxic mice

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