The role of NF-κB and AhR transcription factors in lead-induced lung toxicity in human lung cancer A549 cells.

Lead (Pb) is recognized as the first heavy metal of the top six toxic air pollutants threatening human health and the second hazardous substance. Pb exposure is associated with lung impairment and high incidences of lung cancer. Nuclear factor kappa B (NF-κB) and aryl hydrocarbon receptor (AhR) signaling pathways are known to be expressed and play an important role in the lung. However, the link between Pb lung toxicity and NF-κB and/or AhR pathways remains unclear. This study was established to explore the role of NF-κB and AhR modulation in Pb-induced lung toxicity in human lung cancer A549 cells. In the current study, treatment of A549 cells with Pb significantly induced cell apoptosis as evidenced by increasing a) the percentage of cells underwent apoptosis determined by flow cytometry and b) p53 mRNA level. Pb treatment induced oxidative stress by a) increasing the formation of reactive oxygen species and b) decreasing GSTA1 mRNA levels. The toxic effects of Pb on the lung was associated with significant increases in NF-κB and AhR levels which was accompanied with increases in downstream targets genes, iNOS and CYP1A1, respectively. Inhibition of NF-κB or AhR either chemically using resveratrol or genetically using small interfering RNA (siRNA) significantly rescued A549 cells from Pb-mediated lung toxicity. The results clearly indicate that Pb-mediated lung toxicities are NF-κB and AhR-dependent mechanism.King Abdulaziz City for Science and Technology KACST Qatar National Library QN

Analysis of fatalities involving amphetamine in Jazan, Saudi Arabia

Amphetamine use is associated with high tendence of homicidal or suicidal deaths and fatalities making amphetamine a persistent area of concern. This study analyzed fatalities associated with amphetamine use in Jazan city, Saudi Aarabia from 2018 to 2020 and investigated the postmortem tissue distribution of amphetamine. The fatalities associated with the use of amphetamine and other drugs were increased from 18% in 2018to 52% in 2019 and to 80% in 2020 compared to all fatalities associated with amphetamine alone. Suicidal people had the highest average amphetamine blood concentrations with a 90th percentile concentration of 7.6 mg/L. In those who use amphetamine in combination with other drugs, suicidal and homicidal deaths are more common than those who use amphetamine alone. The results demonstrate the need to raise the awareness of the increasing number of deaths associated with amphetamine use in combination with other drugs in health care providers

Postmortem Tissue Distribution of Citalopram in a Case of Carbon Monoxide Poisoning

Citalopram abuse may impair judgment and increase the risk of suicidal thoughts. This case report aims to study the postmortem tissue distribution of citalopram in a case of carbon monoxide poisoning. Initial analysis was done by both immunoassay and non-targeted GC-MS screening methods. Carbon monoxide was identified and quantified by measuring the carboxyhemoglobin levels in spleen secretion (black bile) and spleen blood using a UV-visible spectrophotometer, while citalopram was identified and quantified by using an LC-MS-MS system. Initial analysis showed that citalopram was present in all samples determined by immunoassay. The results of carboxyhemoglobin analysis were 85% in the spleen secretion and spleen blood, which are generally fatal levels. The results of LC-MS-MS showed that citalopram concentrations were 0.58 mg/L, 0.37 mg/L, 0.29 mg/L, 0.13 mg/L, 0.10 mg/L, and 0.01 mg/L, in the spleen blood, brain, spleen, kidney, liver and stomach, respectively. The highest concentrations of citalopram, 0.58 mg/L and 0.37 mg/L, were detected in spleen blood and brain tissue, respectively, which could be used as an alternative specimen to blood

Postmortem Distribution of Cathinone and Cathine in Human Biological Specimens in a Case of Death Associated with Khat Chewing

Chewing khat leaves has been associated with several adverse health effects, and there are very few case reports of cardiotoxicity, stroke and death resulting from this. In addition, postmortem distribution of cathine and cathinone, active components of khat, are not yet fully clear. This postmortem case report aimed to identify and determine the concentration of cathine and cathinone in different body organs and green chewed plants found in the mouth of the deceased. Immunoassay and non-targeted GC-MS analysis showed that samples were only positive for amphetamine type stimulants. LC-MS/MS quantitative analysis confirmed that samples were positive for cathinone and cathine. The results showed that cathinone concentration was 0.03, 0.03, 0.06, 0.07, 1.85 and 31 μg/ml in brain, liver, blood, vitreous humor, stomach and chewed green plant, respectively. Whereas, the concentration of cathine was 0.31, 3.28, and 141 μg/ml in kidney, stomach and chewed green plant, respectively. Cathine and cathinone concentrations were found to be changed with respect to site of sampling. The results suggest that stomach and chewed green plants are considered as good samples to show the concentration for both cathine and cathinone at the time of death of the khat chewer

Author’s Response

This letter is a response to Letter to the Editor (Corkery J, Schifano F, Guirguis A. Commentary on: Attafi IM, Albeishy MY, Oraiby ME, Khardali IA, Shaikhain GA, Fageeh MM. Postmortem Distribution of Cathinone and Cathine in Human Biological Specimens in a Case of Death Associated with Khat Chewing. Arab J Forensic Sci Forensic Med. 2018 Jun 7;1(7). Arab Journal of Forensic Sciences & Forensic Medicine. 2019 Dec 31;1(10):1473-1475)

Toxicological Findings in a Possible Drug-drug Interaction Death: A Case Report

Synergistic effects are the most encountered types of drug-drug interaction in post-mortem toxicology. Concomitant use of fentanyl, tramadol and carbamazepine may increase the risk of severe serotonin toxicity. The decedent was a 32-year-old black man, with a history of severe migraine headaches. He died after being administered several drugs to treat the migraine. For fentanyl identification and quantification, samples were extracted using solid phase extraction and analyzed by GC-MS. For carbamazepine and tramadol identification and quantification, samples were extracted by liquid-liquid extraction and analyzed by LC-QTOF. Toxicology showed post-mortem concentrations of fentanyl 0.033, 0.025, 0.005, 0.0127, and 0.005 mg/L; tramadol 0.143, 0.093, 0.043, 0.09, and 0.08 mg/L; carbamazepine 1.6, 1.04, 0.3, 0.83, and 0.18 mg/L in the blood, brain, liver, kidney and stomach, respectively. In this case report, the combination of serotonergic drugs can contribute to synergistic serotonergic effects. Therefore, drug-drug interaction is expected, and the cause of death may be attributed to toxic synergistic drug-drug interaction including fentanyl, tramadol and carbamazepin

Post-Mortem Analysis of Diazinon and its major Metabolite, 2-isopropyl-4- methyl-6-hydroxypyrimidine, in a Case of Fatal Diazinon Ingestion

This case report describes a detection and quantitation method for diazinon and its major metabolite, 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP), in postmortem blood and tissue samples from a fatal case of diazinon ingestion. Diazinon and IMHP were extracted from postmortem samples with a liquid/liquid method and analyzed by gas chromatography mass spectrometry (GC/MS). By comparing to diazinon standard and matching the retention time, diazinon was detected in two visceral organs, the stomach (0.89 μg/g) and the small intestine (8.80 μg/g). The highest level of diazinon was detected in the small intestine (8.80 μg/g), whereas the highest amount of IMHP was noted in the kidney (0.84 Area %) and bladder (0.75 Area %). In conclusion, determination of IMHP in postmortem samples could be used as an indicator for diazinon exposure, especially in the case of delayed death; whereas, the small intestine could be the best source of sample in diazinon assessment in cases of fatal diazinon ingestion

Cathine and cathinone disposition kinetics and neurotransmitter profile in several organs of rats exposed to a single dose of Catha edulis (Vahl) Forssk. ex Endl. extract

Catha edulis (Vahl) Forssk. ex Endl. (Khat) is a stimulant plant that contains cathine and cathinone, which its abuses induce euphoria, alertness, and motor activity. Since the toxicokinetics of these substances remain unclear, this study was carried out to investigate the disposition kinetics of cathine and cathinone, the neurotransmitter profile, following a single dose of C. edulis extract in rats. Twenty-four adult male Wistar albino rats (250-300 g) were randomly selected and divided into six groups of four rats each. All groups received a single oral dose of 2,000 mg/kg body weight, and blood and tissue samples from the brain, lung, heart, liver, and kidney were obtained at intervals of 0.5, 1, 2.5, 5, 12, and 24 h. The cathine and cathinone concentrations were identified and quantified using ion trap ultra-high performance liquid chromatography (HPLC-IT/MS). The neurotransmitter profile was detected using the quadrupole time of flight UPLC-QTOF/MS method. The lung, liver, and heart tissues attained the highest levels of cathine, while the highest level of cathinone was determined in the heart. Cathine and cathinone concentrations in the blood and heart peaked at 0.5 h. The concentrations peaked in the brain 2.5 h later, indicating that the heart had an immediate effect, whereas the brain had a longer-lasting one. They have longer half-lives (2.68 and 5.07 h, respectively) and may remain in the brain for longer durations (3.31 and 2.31 h, respectively). The neurotransmitters epinephrine, dopamine, norepinephrine, and serotonin were detected in a delayed, prolonged and organ-specific manner. Cathine and cathinone were deposited in considerable concentrations in all tissues analyzed, with the highest Cmax in the lung and Tmax in the heart tissues but not in the brain. In addition, neurotransmitters such as adrenaline, dopamine, norepinephrine, and serotonin were differentially detected in all tested samples in a organ-specific fashion. More study is needed to identify cathine and cathinone's effects on neurotransmitter profiles. Nevertheless, these findings provided a further basis for experimental, clinical, and forensic investigations

Correction to: Lead nitrate induces inflammation and apoptosis in rat lungs through the activation of NF‑κB and AhR signaling pathways (Environmental Science and Pollution Research, (2022), 29, 43, (64959-64970), 10.1007/s11356-022-19980-8)

The sizing of images Figs. 3 and 4 is modified in the original published proof. The Original article has been corrected

Lead Nitrate Induces Inflammation and Apoptosis in Rat Lungs Through the Activation of NF-κB and AhR Signaling Pathways

Lead (Pb) is one of the most frequent hazardous air contaminants, where the lungs are particularly vulnerable to its toxicity. However, the Pb distribution and its impact on lung inflammation/apoptosis and particularly the involvement of nuclear factor kappa B (NF-κB) and aryl hydrocarbon receptor (AhR) signaling pathways in Pb-induced lung toxicity have not yet been fully investigated. Adult male Wistar albino rats were exposed to Pb nitrate 25, 50, and 100 mg/kg b.w. orally for 3 days. The histopathological changes of several rat organs were analyzed using hematoxylin and eosin staining. The concentrations of Pb ion in different organ tissues were quantified using inductive coupled plasma mass spectrometry, while gas chromatography-mass spectrometry was used to identify organic compounds. The changes in the mRNA and protein expression levels of inflammatory and apoptotic genes in response to Pb exposure were quantified by using RT-PCR and Western blot analyses, respectively. Treatment of rats with Pb for three consecutive days significantly increased the accumulation of Pb in lung tissues causing severe interstitial inflammation. Pb treatment also increased the percentage of lung apoptotic cells and modulated apoptotic genes (Bc2, p53, and TGF-α), inflammatory markers (IL-4, IL-10, TNF-α), and oxidative stress biomarkers (iNOS, CYP1A1, EphX) in rat lung tissues. These effects were associated with a significant increase in organic compounds, such as 3-nitrotyrosine and myeloperoxidase, and some inorganic elements, such as selenium. Importantly, the Pb-induced lung inflammation and apoptosis were associated with a proportional increase in the expression of NF-κB and AhR mRNAs and proteins. These findings clearly show that Pb induces severe inflammation and apoptosis in rat lungs and suggest that NF-κB and AhR may play a role in Pb-induced lung toxicity.Open Access funding is provided by the Qatar National Library. This project was funded by the King Abdulaziz City for Science and Technology (KACST) grant no. (1-18-03-001-0007) Saudi Arabia and the Qatar University research grant no. (QUCG-CPH-20/21-1), Qatar