Mitochondrial dysfunction and organophosphorus compounds

Organophosphorous (OPs) pesticides are the most widely used pesticides in the agriculture and home. However, many acute or chronic poisoning reports about OPs have been published in the recent years. Mitochondria as a site of cellular oxygen consumption and energy production can be a target for OPs poisoning as a non-cholinergicmechanismof toxicity of OPs. In the present review, we have reviewed and criticized all the evidences about the mitochondrial dysfunctions as a mechanism of toxicity of OPs. For this purpose, all biochemical, molecular, and morphological data were retrieved from various studies. Some toxicities of OPs are arisen from dysfunction of mitochondrial oxidative phosphorylation through alteration of complexes I, II, III, IV and V activities and disruption of mitochondrial membrane. Reductions of adenosine triphosphate (ATP) synthesis or induction of its hydrolysis can impair the cellular energy. The OPs disrupt cellular and mitochondrial antioxidant defense, reactive oxygen species generation, and calcium uptake and promote oxidative and genotoxic damage triggering cell death via cytochrome C released from mitochondria and consequent activation of caspases. The mitochondrial dysfunction induced by OPs can be restored by use of antioxidants such as vitamin E and C, alpha-tocopherol, electron donors, and through increasing the cytosolic ATP level. However, to elucidate many aspect of mitochondrial toxicity of Ops, further studies should be performed

A comprehensive review on experimental and clinical findings in intermediate syndrome caused by organophosphate poisoning

Acute organophosphate (OP) intoxication is important because of its high morbidity and mortality and occurrence ofmuscular paralysis associated by inhibition of acetylcholinesterase (AChE) activity at the neuromuscular junction. Cholinergic crisis, intermediate syndrome (IMS), and OP-induced delayed neuropathy (OPIDN) are the evidences that can be observed in OP intoxication. The main cause of morbidity due to OP poisoning is IMS that occurs 24–96 h after poisoning. Mechanisms underlying the IMS are not fully known. Although the electrophysiological aspects of delayed neuropathy are best characterized, the IMS remain very little studied. The aimof this study was to revisit current knowledge related to OP and the IMS. For this purpose, a systematic review without date limitation was performed. A total of 599 relevant articles were found and reviewed. Data were categorized according to experimental and clinical studies. Occurrences of persistent AChE inhibition, electromyography changes, muscle cell injury, and oxidative stress are the most important pieces of evidence for involvement of IMS in OP toxicity. Delayed AChE inhibition,muscle necrosis, down regulation or desensitization of postsynaptic ACh receptors, failure of postsynaptic ACh release, and oxidative stress-related myopathy are involved in IMS. Toxicokinetic factors, such as a high lipid-solubility, duration of AChE inhibition andmetabolite excretion, evolution of alterations on repetitive nerve stimulation (RNS), type and frequency of muscle lesions can estimate the probability of the IMS. Plasma AChE of less than 200 units is a predictor and the 30 Hz RNS decremental response could be a useful marker for the IMS

Environmental and Population Studies Concerning Exposure to Pesticides in Iran: A Comprehensive Review

Pesticides are widely used in Iranian agriculture and this has made a major toxicological concern among health professionals. The objective of this study is to explore national data about pesticides toxicity. All relevant databases such as Google Scholar, PubMed, and Scopus in a time period of 1960 to 2012 were searched for the keywords “Pesticides, Iran, Environment, and Population studies”. A total of 57 studies were found relevant and then included into study. Almost all non-experimental studies carried out in Iran were classified into two main categories of residue assessment in different samples and toxic effects on human. Depending on the dose and duration of exposure, toxic effects of pesticides have been studied in two classifications including acute toxicity or acute poisoning and chronic toxicity. High extent of pesticides have been used during the past decade in Iran while no enough proper studies were done to explore their possible toxic effects in the environment and the people

Dihidroksiaceton kao definitivni lijek za trovanje aluminijevim fosfidom u štakora

Aluminium phosphide (AlP), a very toxic pesticide also known as the rice tablet, releases phosphine gas upon contact with water, moisture, or gastric acid. Its mortality rate in humans is 70-100 % due to cardiogenic shock and refractory hypotension. Dihydroxyacetone (DHA) is a simple ketonic carbohydrate, mainly used for sunless skin tanning. It also plays a beneficial role in the treatment of hypotension and cardiogenic shock by restoring blood volume and cellular respiration. The aim of this study was to investigate the its effect on the haemodynamics and electrocardiogram (ECG) in male rats poisoned with AlP. The animals were divided into the following groups: control (received 1 mL corn oil, orally), AlP (received 15 mg kg-1 AlP solved in corn oil, orally), AlP plus DHA (treated with 50 mg kg-1 of DHA 30 min after receiving AlP), and AlP plus N-acetyl cysteine (NAC) (treated with 200 mg kg-1 of NAC 30 min after receiving AlP). The animals were then anaesthetised and ECG, blood pressure, and heart rate were recorded for 120 min. Treatment with AlP alone and in combination with NAC was associated with progressive hypotension, tachycardia, and ECG disturbances in rats, resulting in 100 % mortality 3 h after poisoning. However, DHA achieved 100 % survival in the poisoned rats and prevented AlP-induced ECG and haemodynamic abnormalities. The main mechanism of DHA in the treatment of AlP poisoning is unclear, but the findings suggest the promising therapeutic potential of DHA against AlP poisoning.Aluminijev fosfid (AlP) je pesticid koji u dodiru s vodom, vlagom ili želučanom kiselinom oslobađa iznimno toksičan plin fosfin. Smrtnost u ljudi je od 70 do 100 % zbog srčanog šoka i refraktorne hipotenzije. Dihidroksiaceton (DHA) jednostavan je ketonski ugljikovodik koji se mahom rabi kao preparat za tamnjenje kože. Osim toga, rabi se u liječenju niskog krvnog tlaka i srčanog šoka, a djeluje tako što volumen krvi i stanično disanje vraća na normalnu razinu. Cilj je ovoga istraživanja bio ispitati njegov utjecaj na hemodinamiku i elektrokardiogram (EKG) u mužjaka Wistar štakora otrovanih aluminijevim fosfidom. Životinje su podijeljene u sljedeće skupine: kontrolnu (koja je jednokratno primila 1 mL kukuruznog ulja na usta), AlP (koja je jednokratno primila 15 mg kg-1 AlP-a otopljenog u kukuruznom ulju na usta), AlP plus DHA (koja je jednokratno primila 50 mg kg-1 DHA 30 min nakon trovanja AlP-om) te AlP plus N-acetilcistein (NAC) (koja je jednokratno primila 200 mg kg-1 NAC-a 30 min nakon trovanja AlP-om). Životinje su potom anestezirane i u idućih 120 min mjereni su im EKG, sistolički krvni tlak i broj otkucaja srca. Primjena AlP-a samog ili u kombinaciji s NAC-om bila je povezana s progresivnom hipotenzijom, tahikardijom i poremećajima u EKG-u te je dovela do 100-postotne smrtnosti unutar tri sata od trovanja. S druge pak strane, DHA je osigurao 100-postotno preživljenje otrovanih štakora i spriječio poremećaje u EKG-u i hemodinamici izazvane trovanjem AlP-om. Još nije jasan osnovni mehanizam djelovanja DHA, ali naši rezultati upućuju na obećavajući terapeutski potencijal DHA u liječenju otrovanja AlP-om

Štetno djelovanje organofosfornih pesticida na jetra: kratki pregled četrdesetogodišnjeg istraživanja

Organophosphorus pesticides (OPs) are widely used volatile pesticides that have harmful effects on the liver in acute and chronic exposures. This review article summarises and discusses a wide collection of studies published over the last 40 years reporting on the effects of OPs on the liver, in an attempt to propose general mechanisms of OP hepatotoxicity and possible treatment. Several key biological processes have been reported as involved in OP-induced hepatotoxicity such as disturbances in the antioxidant defence system, oxidative stress, apoptosis, and mitochondrial and microsomal metabolism. Most studies show that antioxidants can attenuate oxidative stress and the consequent changes in liver function. However, few studies have examined the relationship between OP structures and the severity and mechanism of their action. We hope that future in vitro, in vivo, and clinical trials will answer the remaining questions about the mechanisms of OP hepatotoxicity and its management.Organofosforni pesticidi (OP) imaju veoma široku primjenu, ali i štetno djeluju na jetru pri akutnoj i kroničnoj izloženosti. Ovaj članak daje pregled 40 godina istraživanja djelovanja OP-ova na jetru s namjerom da predloži neke zajedničke mehanizme njihova toksičnog djelovanja na jetru i liječenje. U istraživanjima se izdvaja nekoliko ključnih bioloških procesa koji sudjeluju u hepatotoksičnosti OP-ova, poput narušavanja antioksidacijskoga obrambenog sustava, oksidacijskoga stresa, apoptoze te mitohondrijskoga i mikrosomalnoga metabolizma. Rezultati većine istraživanja potvrdili su da antioksidansi uspješno ublažavaju posljedice oksidacijskoga stresa u jetri. Međutim, gotovo da i nije istražena povezanost između strukture OP-ova i njihove štetnosti odnosno mehanizama djelovanja. Nadamo se da će buduća in vitro i in vivo istraživanja te klinička ispitivanja odgovoriti na preostala pitanja vezana uz mehanizme hepatotoksičnoga djelovanja OP-ova i njegova uspješnoga liječenja

Losartan enhances the suppressive effect of pirfenidone on the bleomycin-induced epithelial-mesenchymal transition and oxidative stress in A549 cell line

Objective(s): Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease. Despite the promising anti-fibrotic effect, the toleration of pirfenidone (PFD) by the patients in full dose is low. Combination therapy is a method for enhancing the therapeutic efficiency of PFD and decreasing its dose. Therefore, the present study evaluated the effect of a combination of losartan (LOS) and PFD on oxidative stress parameters and the epithelial-mesenchymal transition (EMT) process induced by bleomycin (BLM) in human lung adenocarcinoma A549 cells. Materials and Methods: The non-toxic concentrations of BLM, LOS, and PFD were assessed by the MTT assay. Malondialdehyde (MDA) and anti-oxidant enzyme activity including catalase (CAT) and superoxide dismutase (SOD) were assessed after co-treatment. Migration and western blot assays were used to evaluate EMT in BLM-exposed A549 after single or combined treatments. Results: The combination treatment exhibited a remarkable decrease in cellular migration compared with both single and BLM-exposed groups. Furthermore, the combination treatment significantly improved cellular anti-oxidant markers compared with the BLM-treated group. Moreover, combined therapy markedly increased epithelial markers while decreasing mesenchymal markers. Conclusion: This in vitro study revealed that the combination of PFD with LOS might be more protective in pulmonary fibrosis (PF) than single therapy because of its greater efficacy in regulating the EMT process and oxidative stress. The current results might offer a promising therapeutic strategy for the future clinical therapy of lung fibrosis

Potential Therapeutic Uses of Thalidomide for Pulmonary Fibrosis

Thalidomide was widely used to avoid morning sickness in pregnant women, but was recalled due to its teratogenic effects and malformations in thousands of children. However, potential beneficial effects such as anti-inflammatory, system regulatory activities and the anti-angiogenic effect of thalidomide have been reported. As the studies about thalidomide continued, its new effects and applications made researchers more interested in it and became a promising agent in the treatment of a variety of clinical situations where standard treatments have failed. To make this purpose more achievable, Scopus, Science Direct, Google Scholar, and PubMed were searched. After obtaining and reviewing articles related to thalidomide and its indications, different therapeutic uses of thalidomide for pulmonary diseases are classified on mechanisms. In recent years, thalidomide has been an effective agent in treating cough associated with pulmonary fibrosis and the main suggested mechanism refers to regulation production of inflammatory mediators, including cytokines and chemokines, which trigger Epithelial-Mesenchymal Transition (EMT). The mechanism of EMT is related to the inhibition of Transforming growth factor-beta (TGF-β1)-mediated signaling pathways, Smad2 (Suppressor of Mothers against decapentaplegic homolog 2) / 3, Akt / Glycogen synthase kinase 3 beta (GSK-3β), and Mitogen-activated protein kinase (MAPK). Thalidomide is also involved in paraquat-induced and bleomycin-induced pulmonary fibrosis. Also, Thalidomide gained attention as a suitable agent for the treatment of cough associated with idiopathic pulmonary fibrosis (IPF) and for severe pulmonary damage cause by severe acute respiratory syndrome, coronavirus 2 (SARS-CoV-2), responsible for the global pandemic in 2020, due to its anti-inflammatory-anti-angiogenesis and pro-apoptotic properties

Alterations in juvenile diploid and triploid African catfish skin gelatin yield and amino acid composition: effects of chlorpyrifos and butachlor exposures

Skin is a major by-product of the fisheries and aquaculture industries and is a valuable source of gelatin. This study examined the effect of triploidization on gelatin yield and proximate composition of the skin of African catfish (Clarias gariepinus). We further investigated the effects of two commonly used pesticides , chlorpyrifos (CPF) and butachlor (BUC), on the skin gelatin yield and amino acid composition in juvenile full-sibling diploid and triploid African catfish. In two separate experiments, diploid and triploid C. gariepinus were exposed for 21 days to graded CPF [mean measured: 10, 16, or 31 mg/L] or BUC concentrations [Mean measured: 22, 44, or 60 mg/L]. No differences in skin gelatin yield, amino acid or proximate compositions were observed between diploid and triploid control groups. None of the pesticide treatments affected the measured parameters in diploid fish. In triploids, however, gelatin yield was affected by CPF treatments while amino acid composition remained unchanged. Butachlor treatments did not alter any of the measured variables in triploid fish. To our knowledge, this study is the first to investigate changes in the skin gelatin yield and amino acid composition in any animal as a response to polyploidization and/or contaminant exposure

Mechanisms of muscular electrophysiological and mitochondrial dysfunction following exposure to malathion, an organophosphorus pesticide

Muscle dysfunction in acute organophosphorus (OP) poisoning is a cause of death in human. The present study was conducted to identify the mechanism of action of OP in terms of muscle mitochondrial dysfunction. Electromyography (EMG) was conducted on rats exposed to the acute oral dose of malathion (400 mg/kg) that could inhibit acetylcholinesterase activity up to 70%. The function of mitochondrial respiratory chain and the rate of production of reactive oxygen species (ROS) from intact mitochondria were measured. The bioenergetic pathways were studied by measurement of adenosine triphosphate (ATP), lactate, and glycogen. To identify mitochondrial-dependent apoptotic pathways, the messenger RNA (mRNA) expression of bax and bcl-2, protein expression of caspase-9, mitochondrial cytochrome c release, and DNA damage were measured. The EMG confirmed muscle weakness. The reduction in activity of mitochondrial complexes and muscular glycogen with an elevation of lactate was in association with impairment of cellular respiration. The reduction in mitochondrial proapoptotic stimuli is indicative of autophagic process inducing cytoprotective effects in the early stage of stress. Downregulation of apoptotic signaling may be due to reduction in ATP and ROS, and genotoxic potential of malathion. The maintenance of mitochondrial integrity by means of artificial electron donors and increasing exogenous ATP might prevent toxicity of OPs

Adipose tissue concentrations of persistent organic pollutants and total cancer risk in an adult cohort from Southern Spain: Preliminary data from year 9 of the follow-up

There is an increasing trend in the incidence of cancer worldwide, and it has been accepted that environmental factors account for an important proportion of the global burden. The present paper reports preliminary findings on the influence of the historical exposure to a group of persistent organic pollutants on total cancer risk, at year 9 in the follow-up of a cohort from Southern Spain. A cohort of 368 participants (median age 51 years) was recruited in 2003. Their historical exposure was estimated by analyzing residues of persistent organic pollutants in adipose tissue. Estimation of cancer incidence was based on data from a population-based cancer registry. Statistical analyses were performed using multivariable Cox-regression models. In males, PCB 153 concentrations were positively associated with total cancer risk, with an adjusted hazard ratio (95% confidence interval) of 1.20 (1.01–1.41) for an increment of 100 ng/g lipid. Our preliminary findings suggest a potential relationship between the historical exposure to persistent organic pollutants and the risk of cancer in men. However, these results should be interpreted with caution and require verification during the future follow-up of this cohort.This study was supported in part by research grants from the Spanish Ministry of Health (FIS 02/974, EUS2008-03574), CIBER de Epidemiología; Junta de Andalucía (01/264, P09-CTS-5488 Project of Excellence, PI-0675-2010, and PI-0513-2012), and the Instituto de Salud Carlos III (FIS PI11/0610)