Poisoning cases and their management in Amhara National Regional State, Ethiopia: Hospital-based prospective study.

BACKGROUND: Poisoning is a significant public health problem globally. Ethiopia is a low-income country undergoing technological and social change that may increase access to drugs and chemicals, potentially increasing the incidence of poisoning. This study describes the epidemiology of hospital admissions due to poisoning in a region of Ethiopia. METHODS: An institution based prospective observational study was employed, as a study design, in selected hospitals of the region from January to December 2018. RESULTS: Of 442 poisoning cases, 78 (17.6%) died. Almost all poisoning cases were intentional self-poisonings. The most frequent poisonings were organophosphate compounds, 145 (32.8%), and metal phosphides (majorly aluminum phosphide), 115 (26.0%). The ingested poison was most frequently accessed from the patients' homes, 243 (55.0%), followed by purchases from local shops, 159 (36%). The median duration of admission was 24 hours. Of all the cases, 23 (5.2%) were admitted to intensive care units (ICU) requiring mechanical ventilation. Most of the cases admitted to the ICU were aluminum phosphide-poisoned patients. The majority of deaths (43 of 78) were due to metal phosphides. From the multivariate logistic regression analysis, altered level of consciousness on hospital arrival, metal phosphide poisoning, and no laboratory result as a part of the diagnosis process or investigation of the extent of toxicity were found to be significantly associated with the likelihood of poor treatment outcome. CONCLUSION: The majority of the poisoning cases were females. The most common reasons for the intent of self-poisoning were dispute-related, mainly family disharmonies, followed by psychiatric conditions. The poisoning agents were mostly obtained from households. Organophosphate compounds and metal phosphides were the first and the second most frequently encountered poisoning agents, respectively, and it was noted that the later ones were responsible for most of the fatal cases. Of the pharmacologic interventions, atropine was the only agent regarded as an antidote. The most commonly employed agent for supportive treatment was cimetidine followed by maintenance fluids, while gastric lavage was the only GI decontamination method used among others. The fatality rate of poisoning in this study was found to be much higher than in other similar studies. Impaired consciousness upon hospital arrival, metal phosphide poisoning, and no involvement of laboratory investigation were found to significantly associate with the likelihood of death. Generally, the results dictate the need for the design and implementation of strategies to create awareness, prevent, and manage poisoning incidences in the community.

Evaluation of the protective effect of coenzyme Q10 on hepatotoxicity caused by acute phosphine poisoning.

Background: Aluminum phosphide (AlP) poisoning is prevalent in numerous countries, resulting in high mortality rates. Phosphine gas, the primary agent responsible for AlP poisoning, exerts detrimental effects on various organs, notably the heart, liver and kidneys. Numerous studies have documented the advantageous impact of Coenzyme Q10 (CoQ10) in mitigating hepatic injuries. The objective of this investigation is to explore the potential protective efficacy of CoQ10 against hepatic toxicity arising from AlP poisoning. Method: The study encompassed distinct groups receiving almond oil, normal saline, exclusive CoQ10 (at a dosage of 100 mg/kg), AlP at 12 mg/kg; LD50 (lethal dose for 50%), and four groups subjected to AlP along with CoQ10 administration (post-AlP gavage). CoQ10 was administered at 10, 50, and 100 mg/kg doses via Intraparietal (ip) injections. After 24 h, liver tissue specimens were scrutinized for mitochondrial complex activities, oxidative stress parameters, and apoptosis as well as biomarkers such as aspartate transaminase (AST) and alanine transaminase (ALT). Results: AlP induced a significant decrease in the activity of mitochondrial complexes I and IV, as well as a reduction in catalase activity, Ferric Reducing Antioxidant Power (FRAP), and Thiol levels. Additionally, AlP significantly elevated oxidative stress levels, indicated by elevated reactive oxygen species (ROS) production, and resulted in the increment of hepatic biomarkers such as AST and ALT. Administration of CoQ10 led to a substantial improvement in the aforementioned biochemical markers. Furthermore, phosphine exposure resulted in a significant reduction in viable hepatocytes and an increase in apoptosis. Co-treatment with CoQ10 exhibited a dose-dependent reversal of these observed alterations. Conclusion: CoQ10 preserved mitochondrial function, consequently mitigating oxidative damage. This preventive action impeded the progression of heart cells toward apoptosis.

Characteristics and mechanisms of phosphine production in sulfur-based constructed wetlands.

Phosphine (PH3) is an important contributor to the phosphorus cycle and is widespread in various environments. However, there are few studies on PH3 in constructed wetlands (CWs). In this study, lab-scale CWs and batch experiments were conducted to explore the characteristics and mechanisms of PH3 production in sulfur-based CWs. The results showed that the PH3 release flux of sulfur-based CWs varied from 0.86±0.04 ng·m-2·h-1 to 1.88±0.09 ng·m-2·h-1. The dissolved PH3 was the main PH3 form in CWs and varied from 2.73 µg·L-1 to 4.08 µg·L-1. The matrix-bound PH3 was a staging reservoir for PH3 and increased with substrate depth. In addition, the sulfur-based substrates had a significant improvement on PH3 production. Elemental sulfur is more conducive to PH3 production than pyrite. Moreover, there was a significant positive correlation between PH3 production, the dsrB gene, and nicotinamide adenine dinucleotide (NADH). NADH might catalyze the phosphate reduction process. And the final stage of the dissimilatory sulfate reduction pathway driven by the dsrB gene might also provide energy for phosphate reduction. The migration and transformation of PH3 increased the available P (Resin-P and NaHCO3-P) from 35 % to 56 % in sulfur-based CW, and the P adsorption capacity was improved by 12 %. The higher proportion of available P increased the plant uptake rate of P by 17 %. This study improves the understanding of the phosphorus cycle in sulfur-based CW and provides new insight into the long-term stable operation of CWs.

A Novel Abiotic Pathway for Phosphine Synthesis over Acidic Dust in Venus' Atmosphere.

Recent ground-based observations of Venus have detected a single spectral feature consistent with phosphine (PH3) in the middle atmosphere, a gas which has been suggested as a biosignature on rocky planets. The presence of PH3 in the oxidized atmosphere of Venus has not yet been explained by any abiotic process. However, state-of-the-art experimental and theoretical research published in previous works demonstrated a photochemical origin of another potential biosignature-the hydride methane-from carbon dioxide over acidic mineral surfaces on Mars. The production of methane includes formation of the HC · O radical. Our density functional theory (DFT) calculations predict an energetically plausible reaction network leading to PH3, involving either HC · O or H· radicals. We suggest that, similarly to the photochemical formation of methane over acidic minerals already discussed for Mars, the origin of PH3 in Venus' atmosphere could be explained by radical chemistry starting with the reaction of ·PO with HC·O, the latter being produced by reduction of CO2 over acidic dust in upper atmospheric layers of Venus by ultraviolet radiation. HPO, H2P·O, and H3P·OH have been identified as key intermediate species in our model pathway for phosphine synthesis.

Gastrointestinal decontamination using oil-based solutions in patients with acute aluminum phosphide poisoning: a systematic review and meta-analysis.

Some studies suggested that gastrointestinal (GIT) decontamination with oil may improve the prognosis of patients who ingested aluminum phosphide (AlP). The aim of this study is to compare the efficacy and safety of gastric lavage with oil-based solutions to any method of gastric decontamination not using oils in patients presenting with acute AlP poisoning. The literature was searched for English-published randomized controlled trials (RCTs) from inception to 16 September 2023. The searched electronic databases included MEDLINE/PubMed, Cochrane Library, Web of Science, Egyptian Knowledge Bank, Scopus, and Google Scholar. Data were extracted and pooled by calculating the risk ratio (RR) for categorical outcomes and standardized mean difference (SMD) for numerical outcomes, with 95% confidence intervals (CI). Seven RCTs were included. Paraffin oil was significantly associated with a lower risk of mortality (RR = 0.59 [95% CI: 0.45, 0.76], p < .001), intubation (RR = 0.59 [95% CI: 0.46, 0.76], p < .001) and vasopressor need (RR = 0.71 [95% CI: 0.56, 0.91], p = .006). Survival time was significantly prolonged with paraffin oil (SMD = 0.72 [95% CI: 0.32, 1.13], p < .001). Coconut oil was significantly associated with prolonged survival time (SMD = 0.83 [95% CI: 0.06, 1.59], p = .03) as well as decreased risk of requiring intubation (RR = 0.78 [95% CI: 0.62, 0.99], p = .04). Oil-based GIT decontamination using paraffin oil showed benefits over conventional lavage regarding the incidence of in-hospital mortality and endotracheal intubation, and survival time. Coconut oil showed some benefits in terms of the intubation incidence and survival time. Decontamination using paraffin oil is recommended. Future clinical trials are warranted with larger sample sizes and focusing on cost-benefit and safety.

Synergistic Manganese Cobalt Phosphide core-shell for the Electrochemical Detection of Methyl Parathion in Food Sample.

The development of a robust electrocatalyst for the electrochemical sensor for hazardous pesticides will reduce its effects on the ecosystem. Herein, we synthesized the robust manganese cobalt phosphide (MnCoP) - Core-shell as an electrochemical sensor for the determination of hazardous pesticide methyl parathion (MP). The MnCoP- Core-shell was prepared with the sustainable self-template route can help with the larger surface area. The Core-shell structure of MnCoP possesses a higher active surface area which increases the electrocatalytic performance and is utilized to improve the electrochemical MP reduction with the synergism of the core and shell structure. Remarkably, it realizes the higher sensitivity (0.014 µA µM-1 cm-2) of MnCoP- Core-shell/GCE achieves towards MP with lower limit of detection (LoD 50 nM) and exceptional recovery rate of MP in vegetable samples are achieved with the differential pulse voltammetry (DPV) technique. The MnCoP- Core-shell electrode reserved their superior electrochemical performances with high reproducibility and repeatability. This prominent activity of the MnCoP core-shell towards the MP in real sample analysis, makes it a promising electrochemical sensor for the detection of MP.

Unveiling the promising anticancer activity of palladium(II)-aryl complexes bearing diphosphine ligands: a structure-activity relationship analysis.

In continuation of our previous works on the cytotoxic properties of organopalladium compounds, in this contribution we describe the first systematic study of the anticancer activity of Pd(II)-aryl complexes. To this end, we have prepared and thoroughly characterized a wide range of palladium derivatives bearing different diphosphine, aryl and halide ligands, developing, when necessary, specific synthetic protocols. Most of the synthesized compounds showed remarkable cytotoxicity towards ovarian and breast cancer cell lines, with IC50 values often comparable to or lower than that of cisplatin. The most promising complexes ([PdI(Ph)(dppe)] and [PdI(p-CH3-Ph)(dppe)]), characterized by a diphosphine ligand with a low bite angle, exhibited, in addition to excellent cytotoxicity towards cancer cells, low activity on normal cells (MRC5 human lung fibroblasts). Specific immunofluorescence tests (cytochrome c and H2AX assays), performed to clarify the possible mechanism of action of this class of organopalladium derivatives, seemed to indicate DNA as the primary cellular target, whereas caspase 3/7 assays proved that the complex [PdI(Ph)(dppe)] was able to promote intrinsic apoptotic cell death. A detailed molecular docking analysis confirmed the importance of a diphosphine ligand with a reduced bite angle to ensure a strong DNA-complex interaction. Finally, one of the most promising complexes was tested towards patient-derived organoids, showing promising ex vivo cytotoxicity.

A Study on the Biological Activity of Optically Pure Aziridine Phosphines and Phosphine Oxides.

A series of optically pure aziridine phosphines and their corresponding phosphine oxides were synthesized through established chemical methodologies. The compounds were systematically investigated for their biological properties. Notably, all synthesized compounds demonstrated moderate antibacterial activity only against the reference strain of Staphylococcus aureus. However, compounds 5 and 7 exhibited noteworthy cell viability inhibition of human cervical epithelioid carcinoma HeLa cells and endometrial adenocarcinoma Ishikawa cells. Further studies of these compounds revealed additional biological effects, including disruption of the cell membrane in high concentrations, cell cycle arrest in the S phase, and the induction of reactive oxygen species (ROS). Comparative analysis of the two classes of chiral organophosphorus derivatives of aziridines indicated that chiral phosphine oxides displayed significantly higher biological activity. Consequently, these findings suggest that chiral phosphine oxides may be potential candidates for the development of anticancer drugs. In light of the significant interest in preparations whose structure is based on a three-membered aziridine ring in terms of potential anticancer therapy, this research fits into the current research trend and should constitute a valuable addition to the current state of knowledge and the existing library of aziridine derivatives with anticancer properties.

Design, Synthesis, and Evaluation of B-(Trifluoromethyl)phenyl Phosphine-Borane Derivatives as Novel Progesterone Receptor Antagonists.

We previously revealed that phosphine-boranes can function as molecular frameworks for biofunctional molecules. In the present study, we exploited the diversity of available phosphines to design and synthesize a series of B-(trifluoromethyl)phenyl phosphine-borane derivatives as novel progesterone receptor (PR) antagonists. We revealed that the synthesized phosphine-borane derivatives exhibited LogP values in a predictable manner and that the P-H group in the phosphine-borane was almost nonpolar. Among the synthesized phosphine-boranes, which exhibited PR antagonistic activity, B-(4-trifluoromethyl)phenyl tricyclopropylphosphine-borane was the most potent with an IC50 value of 0.54 µM. A docking simulation indicated that the tricyclopropylphosphine moiety plays an important role in ligand-receptor interactions. These results support the idea that phosphine-boranes are versatile structural options in drug discovery, and the developed compounds are promising lead compounds for further structural development of next-generation PR antagonists.

Platinum(0)-η2-1,2-(E)ditosylethene Complexes Bearing Phosphine, Isocyanide and N-Heterocyclic Carbene Ligands: Synthesis and Cytotoxicity towards Ovarian and Breast Cancer Cells.

A wide range of platinum(0)-η2-(E)-1,2-ditosylethene complexes bearing isocyanide, phosphine and N-heterocyclic carbene ancillary ligands have been prepared with high yields and selectivity. All the novel products underwent thorough characterization using spectroscopic techniques, including NMR and FT-IR analyses. Additionally, for some compounds, the solid-state structures were elucidated through X-ray diffractometry. The synthesized complexes were successively evaluated for their potential as anticancer agents against two ovarian cancer cell lines (A2780 and A2780cis) and one breast cancer cell line (MDA-MB-231). The majority of the compounds displayed promising cytotoxicity within the micromolar range against A2780 and MDA-MB-231 cells, with IC50 values comparable to or even surpassing those of cisplatin. However, only a subset of compounds was cytotoxic against cisplatin-resistant cancer cells (A2780cis). Furthermore, the assessment of antiproliferative activity on MRC-5 normal cells revealed certain compounds to exhibit in vitro selectivity. Notably, complexes 3d, 6a and 6b showed low cytotoxicity towards normal cells (IC50 > 100 µM) while concurrently displaying potent cytotoxicity against cancer cells.

Direct Synthesis of α- and ß-2'-Deoxynucleosides with Stereodirecting Phosphine Oxide via Remote Participation.

2'-Deoxynucleosides and analogues play a vital role in drug development, but their preparation remains a significant challenge. Previous studies have focused on ß-2'-deoxynucleosides with the natural ß-configuration. In fact, their isomeric α-2'-deoxynucleosides also exhibit diverse bioactivities and even better metabolic stability. Herein, we report that both α- and ß-2'-deoxynucleosides can be prepared with high yields and stereoselectivity using a remote directing diphenylphosphinoyl (DPP) group. It is particularly efficient to prepare α-2'-deoxynucleosides with an easily accessible 3,5-di-ODPP donor. Instead of acting as a H-bond acceptor on a 2-(diphenylphosphinoyl)acetyl (DPPA) group in our previous studies for syn-facial O-glycosylation, the phosphine oxide moiety here acts as a remote participating group to enable highly antifacial N-glycosylation. This proposed remote participation mechanism is supported by our first characterization of an important 1,5-briged P-heterobicyclic intermediate via variable-temperature NMR spectroscopy. Interestingly, antiproliferative assays led to a α-2'-deoxynucleoside with IC50 values in the low micromole range against central nervous system tumor cell lines SH-SY5Y and LN229, whereas its ß-anomer exhibited no inhibition at 100 µM. Furthermore, the DPP group significantly enhanced the antitumor activities by 10 times.

Preparation of thiol-free amino acid plasma matrix for quantification of thiol amino acids and their oxidized forms in human plasma by UPLC-MS/MS.

Thiol amino acids, with great physiological significance, are unstable, and have small molecular weights, as well as very low endogenous concentrations. Therefore, to quantitatively and directly analyze them using liquid chromatography-tandem mass spectrometry is difficult. To overcome these problems, we aimed to prepare a thiol-free amino acid plasm matrix as blank sample to reduce the background for the first time. Using compounds with maleimide group that react with classical thiols to generate water-insoluble products. Reducing agents Tris(2-carboxyethyl)phosphine (TCEP) was applied to cooperate with bismaleimide (DM) for elimination of thiol amino acids from plasma 10 min at room temperature and pH 7. Further, the residual TCEP from plasma were removed using an anion exchange resin within 10 min. Methodological validation analysis revealed good performance in linearity, precision, extraction recovery (≥ 82 %), and stability (except oxidized glutathione). This quantitative analysis was successfully applied to blood samples of 9 people in good health. This study provides a foundation for the development of accurate and rigorous quantitative analysis methods targeting thiol amino acids in different body fluids or tissues. Moreover, it paves the way toward realizing several clinical applications.

Recent Advances in the Application of P(III)-Nucleophiles to Create New P-C Bonds through Michaelis-Arbuzov-Type Rearrangement.

Organophosphorus compounds have long been considered valuable in both organic synthesis and life science. P(III)-nucleophiles, such as phosphites, phosphonites, and diaryl/alkyl phosphines, are particularly noteworthy as phosphorylation reagents for their ability to form new P-C bonds, producing more stable, ecofriendly, and cost-effective organophosphorus compounds. These nucleophiles follow similar phosphorylation routes as in the functionalization of P-H bonds and P-OH bonds. Activation can occur through photocatalytic, electrocatalytic, or thermo-driven reactions, often in coordination with a Michaelis-Arbuzov-trpe rearrangement process, to produce the desired products. As such, this review offers a thorough overview of the phosphorylated transformation and potential mechanisms of P(III)-nucleophiles, specifically focusing on developments since 2010. Notably, this review may provide researchers with valuable insights into designing and synthesizing functionalized organophosphorus compounds from P(III)-nucleophiles, guiding future advancements in both research and practical applications.

Synthesis, anticancer activity, and molecular docking of half-sandwich iron(II) cyclopentadienyl complexes with maleimide and phosphine or phosphite ligands.

In these studies, we designed and investigated the potential anticancer activity of five iron(II) cyclopentadienyl complexes bearing different phosphine and phosphite ligands. All complexes were characterized with spectroscopic analysis viz. NMR, FT-IR, ESI-MS, UV-Vis, fluorescence, XRD (for four complexes) and elemental analyses. For biological studies, we used three types of cells-normal peripheral blood mononuclear (PBM) cells, leukemic HL-60 cells and non-small-cell lung cancer A549 cells. We evaluated cell viability and DNA damage after cell incubation with these complexes. We observed that all iron(II) complexes were more cytotoxic for HL-60 cells than for A549 cells. The complex CpFe(CO)(P(OPh)3)(η1-N-maleimidato) 3b was the most cytotoxic with IC50 = 9.09 µM in HL-60 cells, IC50 = 19.16 µM in A549 and IC50 = 5.80 µM in PBM cells. The complex CpFe(CO)(P(Fu)3)(η1-N-maleimidato) 2b was cytotoxic only for both cancer cell lines, with IC50 = 10.03 µM in HL-60 cells and IC50 = 73.54 µM in A549 cells. We also found the genotoxic potential of the complex 2b in both types of cancer cells. However, the complex CpFe(CO)2(η1-N-maleimidato) 1 which we studied previously, was much more genotoxic than complex 2b, especially for A549 cells. The plasmid relaxation assay showed that iron(II) complexes do not induce strand breaks in fully paired ds-DNA. The DNA titration experiment showed no intercalation of complex 2b into DNA. Molecular docking revealed however that complexes CpFe(CO)(PPh3) (η1-N-maleimidato) 2a, 2b, 3b and CpFe(CO)(P(OiPr)3)(η1-N-maleimidato) 3c have the greatest potential to bind to mismatched DNA. Our studies demonstrated that the iron(II) complex 1 and 2b are the most interesting compounds in terms of selective cytotoxic action against cancer cells. However, the cellular mechanism of their anticancer activity requires further research.

Impact of aluminum phosphide on development of the forensically important fly, Chrysomya albiceps (Diptera: Calliphoridae).

Chrysomya albiceps (Calliphoridae) is among the earliest successional fauna on human and animal cadavers. Some immature Calliphoridae can be useful for determination of post-mortem interval. Toxins, particularly pesticides, can affect the rate of insect growth. Aluminum phosphide (AlP) is an affordable insecticide that has not been adequately entomotoxicologically evaluated. So, the impact of AlP on the developmental rate of different stages of C. albiceps was investigated. Larvae of C. albiceps were reared on the rabbit carcasses containing AlP as a treated group, and distilled water as a control group. The substances were administered by a gastric tube. The duration needed for development of C. albiceps stages was documented. Body length, width and weight of larvae were measured after 24, 48, 72 and 96 h from egg hatching. The duration of development increased significantly in the treated group compared to the control group. Larvae body measurements were significantly smaller in the treated group than in the control group. Therefore, it was demonstrated that AlP significantly influences the size of C. albiceps larvae and extends their development. During forensic application, interpretation of C. albiceps data should be used with caution when aluminum phosphide may be the cause of death.

Chronic exposure to tris (2-chloroethyl) phosphate (TCEP) induces brain structural and functional changes in zebrafish (Danio rerio): A comparative study on the environmental and LC50 concentrations of TCEP.

Tris (2-chloroethyl) phosphate (TCEP) is a crucial organophosphorus flame retardant widely used in many industrial and commercial products. Available reports reported that TCEP could cause various toxicological effects on organisms, including humans. Unfortunately, toxicity data for TCEP (particularly on neurotoxicity) on aquatic organisms are lacking. In the present study, Danio rerio were exposed to different concentrations of TCEP for 42 days (chronic exposure), and oxidative stress, neurotoxicity, sodium, potassium-adenosine triphosphatase (Na+, K+-ATPase) activity, and histopathological changes were evaluated in the brain. The results showed that TCEP (100 and 1500 µg L-1) induced oxidative stress and significantly decreased the activities of antioxidant enzymes (SOD, CAT and GR) in the brain tissue of zebrafish. In contrast, the lipid peroxidation (LPO) level was increased compared to the control group. Exposure to TCEP inhibited the acetylcholinesterase (AChE) and Na+,K+-ATPase activities in the brain tissue. Brain histopathology after 42 days of exposure to TCEP showed cytoplasmic vacuolation, inflammatory cell infiltration, degenerated neurons, degenerated purkinje cells and binucleate. Furthermore, TCEP exposure leads to significant changes in dopamine and 5-HT levels in the brain of zebrafish. The data in the present study suggest that high concentrations of TCEP might affect the fish by altering oxidative balance and inducing marked pathological changes in the brain of zebrafish. These findings indicate that chronic exposure to TCEP may cause a neurotoxic effect in zebrafish.

Tris(2-chloroethyl) phosphate (TCEP) exposure inhibits the epithelial-mesenchymal transition (EMT), mesoderm differentiation, and cardiovascular development in early chicken embryos.

Tris(2-chloroethyl) phosphate (TCEP) is an organophosphorus flame retardant used worldwide and has been detected in the tissues and eggs of wild birds. Our previous study reported that exposure to TCEP induced developmental delay and cardiovascular dysfunction with attenuated heart rate and vasculogenesis in early chicken embryos. This study aimed to investigate the molecular mechanisms underlying the cardiovascular effects of TCEP on chicken embryos using cardiac transcriptome analysis and to examine whether TCEP exposure affects epithelial-mesenchymal transition (EMT) and mesoderm differentiation during gastrulation. Transcriptome analysis revealed that TCEP exposure decreased the expression of cardiac conduction-related genes and transcription factors on day 5 of incubation. In extraembryonic blood vessels, the expression levels of genes related to fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) were significantly reduced by TCEP exposure and vasculogenesis was suppressed. TCEP exposure also attenuated Snail family transcriptional repressor 2 (SNAI2) and T-box transcription factor T (TBXT) signaling in the chicken primitive streak, indicating that TCEP inhibits EMT and mesoderm differentiation during gastrulation at the early developmental stage. These effects on EMT and mesoderm differentiation may be related to subsequent phenotypic defects, including suppression of heart development and blood vessel formation.

Do the same chlorinated organophosphorus flame retardants that cause cytotoxicity and DNA damage share the same pathway?

Organophosphorus flame retardants (OPFRs) have been frequently detected with relatively high concentrations in various environmental media and are considered emerging environmental pollutants. However, their biological effect and underlying mechanism is still unclear, and whether chlorinated OPFRs (Cl-OPFRs) cause adverse outcomes with the same molecular initial events or share the same key events (KEs) remains unknown. In this study, in vitro bioassays were conducted to analyze the cytotoxicity, mitochondrial impairment, DNA damage and molecular mechanisms of two Cl-OPFRs. The results showed that these two Cl-OPFRs, which have similar structures, induced severe cellular and molecular damages via different underlying mechanisms. Both tris(2-chloroethyl) phosphate (TCEP) and tris(1-chloro-2-propyl) (TCPP) induced oxidative stress-mediated mitochondrial impairment and DNA damage, as shown by the overproduction of intracellular reactive oxygen species (ROS) and mitochondrial superoxide. Furthermore, the DNA damage caused by TCPP resulted in p53/p21-mediated cell cycle arrest, as evidenced by flow cytometry and real-time PCR. At the cellular and molecular levels, TCPP increased the sub-G1 apoptotic peak and upregulated the p53/Bax apoptosis pathway, possibly resulted in apoptosis associated with its stronger cytotoxicity. Although structurally similar to TCPP, TCEP did not induce mitochondrial impairment and DNA damage by the same KEs. These results provide insight into the toxicity of Cl-OPFRs with similar structures but different mechanisms, which is of great significance for constructing adverse outcome pathways or determining intermediate KEs.

Paraptotic Cell Death as an Unprecedented Mode of Action Observed for New Bipyridine-Silver(I) Compounds Bearing Phosphane Coligands.

In this work, we investigated the anticancer activity of several novel silver(I) 2,2'-bipyridine complexes containing either triphenylphosphane (PPh3) or 1,2-bis(diphenylphosphino)ethane (dppe) ligands. All compounds were characterized by diverse analytical methods including ESI-MS spectrometry; NMR, UV-vis, and FTIR spectroscopies; and elemental analysis. Moreover, several compounds were also studied by X-ray single-crystal diffraction. Subsequently, the compounds were investigated for their anticancer activity against drug-resistant and -sensitive cancer cells. Noteworthily, neither carboplatin and oxaliplatin resistance nor p53 deletion impacted on their anticancer efficacy. MES-OV cells displayed exceptional hypersensitivity to the dppe-containing drugs. This effect was not based on thioredoxin reductase inhibition, enhanced drug uptake, or apoptosis induction. In contrast, dppe silver drugs induced paraptosis, a novel recently described form of programmed cell death. Together with the good tumor specificity of this compound's class, this work suggests that dppe-containing silver complexes could be interesting drug candidates for the treatment of resistant ovarian cancer.