ABSTRACT
Lupeol is a natural pentacyclic triterpenoid with a wide range of biological activities. To improve the water solubility and targeting of lupeol, in the following study, we synthesized 27 lupeol derivatives in the first series by introducing lipophilic cations with lupeol as the lead compound. Through the screening of different cancer cells, we found that some of the derivatives showed better activity than cisplatin against human non-small cell lung cancer A549 cells, among which compound 6c was found to have an IC50 value of 1.83 µM and a selectivity index of 21.02 (IC50MRC-5/IC50A549) against A549 cells. To further improve the antiproliferative activity of the compounds, we replaced the ester linkage of the linker with a carbamate linkage and synthesized a second series of five lupeol derivatives which were screened for activity, among which compound 14f was found to have an IC50 value of 1.36 µM and a selectivity index of 15.60 (IC50MRC-5/IC50A549) against A549 cells. We further evaluated the bioactivity of compounds 6c and 14f and found that both compounds induced apoptosis in A549 cells, promoted an increase in intracellular reactive oxygen species and decrease in mitochondrial membrane potential, and inhibited the cell cycle in the S phase. Of the compounds, compound 14f showed stronger bioactivity than compound 6c. We then selected compound 14f for molecular-level Western blot evaluation and in vivo evaluation in the zebrafish xenograft A549 tumor cell model. Compound 14f was found to significantly downregulate Bcl-2 protein expression and upregulate Bax, Cyt C, cleaved caspase-9, and cleaved caspase-3 protein expression, and 14f was found to be able to inhibit the proliferation of A549 cells in the zebrafish xenograft model. The above results suggest that compound 14f has great potential in the development of antitumor drugs targeting mitochondria.
Subject(s)
Antineoplastic Agents , Apoptosis , Cell Proliferation , Drug Design , Drug Screening Assays, Antitumor , Pentacyclic Triterpenes , Zebrafish , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Animals , Pentacyclic Triterpenes/pharmacology , Pentacyclic Triterpenes/chemistry , Pentacyclic Triterpenes/chemical synthesis , Structure-Activity Relationship , Cell Proliferation/drug effects , Apoptosis/drug effects , Molecular Structure , Dose-Response Relationship, Drug , Organophosphorus Compounds/pharmacology , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/chemical synthesis , Cell Line, Tumor , Membrane Potential, Mitochondrial/drug effects , Reactive Oxygen Species/metabolism , LupanesABSTRACT
Prenylated-FMN (prFMN) is the cofactor used by the UbiD-like family of decarboxylases that catalyzes the decarboxylation of various aromatic and unsaturated carboxylic acids. prFMN is synthesized from reduced FMN and dimethylallyl phosphate (DMAP) by a specialized prenyl transferase, UbiX. UbiX catalyzes the sequential formation of two bonds, the first between N5 of the flavin and C1 of DMAP, and the second between C6 of the flavin and C3 of DMAP. We have examined the reaction of UbiX with both FMN and riboflavin. Although UbiX converts FMN to prFMN, we show that significant amounts of the N5-dimethylallyl-FMN intermediate are released from the enzyme during catalysis. With riboflavin as the substrate, UbiX catalyzes only a partial reaction, resulting in only N5-dimethylallyl-riboflavin being formed. Purification of the N5-dimethylallyl-FMN adduct allowed its structure to be verified by 1H NMR spectroscopy and its reactivity to be investigated. Surprisingly, whereas reduced prFMN oxidizes in seconds to form the stable prFMN semiquinone radical when exposed to air, N5-dimethylallyl-FMN oxidizes much more slowly over several hours; in this case, oxidation is accompanied by spontaneous hydrolysis to regenerate FMN. These studies highlight the important contribution that cyclization of the prenyl-derived ring of prFMN makes to the cofactor's biological activity.
Subject(s)
Dimethylallyltranstransferase , Flavin Mononucleotide , Prenylation , Flavin Mononucleotide/metabolism , Flavin Mononucleotide/chemistry , Dimethylallyltranstransferase/metabolism , Dimethylallyltranstransferase/chemistry , Escherichia coli Proteins/metabolism , Escherichia coli Proteins/chemistry , Riboflavin/biosynthesis , Riboflavin/analogs & derivatives , Riboflavin/metabolism , Riboflavin/chemistry , Organophosphorus Compounds/metabolism , Organophosphorus Compounds/chemistry , Catalysis , Allyl Compounds/metabolism , Allyl Compounds/chemistry , Escherichia coli/metabolism , Escherichia coli/genetics , Carboxy-Lyases , HemiterpenesABSTRACT
(-)-Epigallocatechin-3-gallate (EGCG) is reported to have benefits for the treatment of Alzheimer's disease by binding with acetylcholinesterase (AChE) to enhance the cholinergic neurotransmission. Organophosphorus pesticides (OPs) inhibited AChE and damaged the nervous system. This study investigated the combined effects of EGCG and OPs on AChE activities in vitro & vivo. The results indicated that EGCG significantly reversed the inhibition of AChE caused by OPs. In vitro, EGCG reactived AChE in three group tubes incubated for 110 min, and in vivo, it increased the relative activities of AChE from less than 20% to over 70% in brain and vertebral of zebrafish during the exposure of 34 h. The study also proposed the molecular interaction mechanisms through the reactive kinetics and computational analyses of density functional theory, molecular docking, and dynamic modeling. These analyses suggested that EGCG occupied the key residues, preventing OPs from binding to the catalytic center of AChE, and interfering with the initial affinity of OPs to the central active site. Hydrogen bonding, conjugation, and steric interactions were identified as playing important roles in the molecular interactions. The work suggests that EGCG antagonized the inhibitions of OPs on AChE activities and potentially offered the neuroprotection against the induced damage.
Subject(s)
Acetylcholinesterase , Catechin , Cholinesterase Inhibitors , Molecular Docking Simulation , Pesticides , Zebrafish , Catechin/analogs & derivatives , Catechin/pharmacology , Catechin/chemistry , Catechin/metabolism , Animals , Acetylcholinesterase/metabolism , Acetylcholinesterase/chemistry , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/chemistry , Pesticides/pharmacology , Pesticides/chemistry , Pesticides/metabolism , Organophosphorus Compounds/pharmacology , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/metabolism , KineticsABSTRACT
By inhibiting acetylcholinesterase (AChE) activity, organophosphate compounds (OPs) can quickly cause severe injury to the nervous system and death, making it extremely difficult to rescue victims after OP exposure. However, it is quite challenging to construct scavengers that neutralize and eliminate these harmful chemical agents promptly in the blood circulation system. Herein, we report an enzyme-armed biomimetic nanoparticle that enables a 'targeted binding and catalytic degradation' action mechanism designed for highly efficient in vivo detoxification (denoted as 'Nanocleaner'). Specifically, the resulting Nanocleaner is fabricated with polymeric cores camouflaged with a modified red blood cell membrane (RBC membrane) that is inserted with the organophosphorus hydrolase (OPH) enzyme. In such a subtle construct, Nanocleaner inherits abundant acetylcholinesterase (AChE) on the surface of the RBC membrane, which can specifically lure and neutralize OPs through biological binding. The OPH enzyme on the membrane surface breaks down toxicants catalytically. The in vitro protective effects of Nanocleaner against methyl paraoxon (MPO)-induced inhibition of AChE activity were validated using both preincubation and competitive regimens. Furthermore, we selected the PC12 neuroendocrine cell line as an experimental model and confirmed the cytoprotective effects of Nanocleaner against MPO. In mice challenged with a lethal dose of MPO, Nanocleaner significantly reduces clinical signs of intoxication, rescues AChE activity and promotes the survival rate of mice challenged with lethal MPO. Overall, these results suggest considerable promise of enzyme-armed Nanocleaner for the highly efficient removal of OPs for clinical treatment.
Subject(s)
Acetylcholinesterase , Cholinesterase Inhibitors , Organophosphorus Compounds , Animals , Acetylcholinesterase/metabolism , Mice , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/chemistry , Rats , Organophosphorus Compounds/chemistry , Erythrocyte Membrane , PC12 Cells , Paraoxon/toxicity , Paraoxon/analogs & derivatives , Nanoparticles/chemistry , Aryldialkylphosphatase/metabolism , Aryldialkylphosphatase/chemistry , Male , Organophosphate Poisoning/drug therapyABSTRACT
BACKGROUND: Poisoning is a significant health hazard and a leading cause of morbidity and mortality worldwide. India, being a predominantly agrarian country, routinely employs organophosphate (OP) pesticides in farming, and they are readily available "over the counter." OPs exert their toxicity by interfering with the normal function of acetylcholine, an essential neurotransmitter throughout the autonomic and central nervous systems. Due to the limited availability of facilities and resources in health-care systems, and economically restraining patients, it is necessary to rely more on clinical features to assess the severity of poisoning and manage the condition properly. METHODOLOGY: It was a hospital-based prospective observational study that included patients aged >13 years in a tertiary care hospital. All patients were clinically evaluated based on their history and examination. The diagnosis was made based on characteristic clinical manifestations or evidence of exposure to organophosphorus compounds (corroborative evidence such as empty containers and the odor of gastric aspirates). Clinical severity was assessed and categorized according to the Peradeniya Organophosphorus Poisoning Scale (POP scale). A score of 0-3 is considered mild poisoning, 4-7 as moderate poisoning, and 8-11 as severe poisoning. RESULTS: Out of the 50 patients enrolled in the study, 17 (34.00%) were aged <20 years, 19 (38%) were in the 20-30 years age group, and 14 (28%) were aged >30 years. Ingestion is the only mode of exposure to poisoning. None of the patients had history of contact or inhalational exposure. Of the 50 cases, 12 (24.0%) were in the mild category, 26 (52.0%) in the moderate category, and 12 (24%) in the severe category on the POP grading. A comparison of the mean serum pseudocholinesterase, troponin-T, and pro-BNP levels with severity was performed. In mild OP poisoning, the mean serum PChE level was 2766.58 ± 1120.44; in moderate, it was 1969.35 ± 1330.07, and in severe, it was 701.83 ± 961.17. Pseudocholinesterase levels decreased progressively with increasing clinical severity from mild-to-severe cases, and this association was statistically significant (P < 0.001). Two-dimensional echocardiography screening done in all patients did not show any significant abnormalities. CONCLUSION: This study shows that serum PCE is reduced in OP poisoning and correlates with the clinical severity grading done by the POP scale and is also associated with an increase in the duration of intensive care unit stay. No significant evidence of direct cardiac injury was observed in this study. A low Glasgow Coma Scale score and an increased respiratory rate at presentation are associated with poor outcomes.
Résumé Contexte:L'empoisonnement est un risque important pour la santé et une cause principale de morbidité et de mortalité dans le monde. L'Inde, étant principalement pays agraire, utilise régulièrement des pesticides organophosphotés (OP) dans l'agriculture, et ils sont facilement disponibles «en vente libre¼. OPS exerce leur toxicité en interférant avec la fonction normale de l'acétylcholine, un neurotransmetteur essentiel à travers l'autonomie et le centre systèmes nerveux. En raison de la disponibilité limitée des installations et des ressources dans les systèmes de soins de santé, et de la contention économique des patients, il est nécessaire pour s'appuyer davantage sur les caractéristiques cliniques pour évaluer la gravité de l'empoisonnement et gérer correctement la condition.Méthodologie:c'était un Étude d'observation prospective basée à l'hôpital qui comprenait des patients âgés de> 13 ans dans un hôpital de soins tertiaires. Tous les patients étaient cliniquement évalué en fonction de leur histoire et de leur examen. Le diagnostic a été posé sur la base de manifestations cliniques caractéristiques ou de preuves de Exposition aux composés organophosphores (preuves corroborantes telles que les conteneurs vides et l'odeur des aspirations gastriques). Gravité clinique a été évalué et classé selon l'échelle d'empoisonnement de Peradeniya organophosphorus (échelle pop). Un score de 0 à 3 est considéré comme doux Empoisonnement, 47 comme empoisonnement modéré et 8-11 comme empoisonnement sévère.Résultats:Sur les 50 patients inscrits à l'étude, 17 (34,00%) étaient âgés de <20 ans, 19 ans (38%) dans le groupe d'âge de 20 à 30 ans et 14 (28%) étaient âgés de> 30 ans. L'ingestion est le seul mode d'exposition à empoisonnement. Aucun des patients n'avait des antécédents de contact ou d'inhalation. Sur les 50 cas, 12 (24,0%) étaient dans la catégorie légère, 26 (52,0%) Dans la catégorie modérée, et 12 (24%) dans la catégorie sévère sur le classement POP. Une comparaison de la pseudocholinestérase sérique moyenne, Les niveaux de troponine - T et pro-BNP avec gravité ont été réalisés. Dans l'empoisonnement à l'op léger, le taux de PCHE sérique moyen était de 2766,58 ± 1120,44; dans Modéré, c'était 1969.35 ± 1330,07, et en sévère, il était de 701,83 ± 961,17. Les niveaux de pseudocholinestérase ont diminué progressivement avec l'augmentation Gravité clinique des cas légers à sévère, et cette association était statistiquement significative ( P <0,001). Échocardiographie bidimensionnelle Le dépistage effectué chez tous les patients n'a montré aucune anomalie significative.Conclusion:cette étude montre que le PCE sérique est réduit en op empoisonnement et corréler avec le classement de gravité clinique effectué par l'échelle POP et est également associé à une augmentation de la durée de séjour de l'unité de soins intensifs. Aucune preuve significative de lésion cardiaque directe n'a été observée dans cette étude. Un score d'échelle de coma à faible Glasgow et un Une fréquence respiratoire accrue à la présentation est associée à de mauvais résultats.
Subject(s)
Butyrylcholinesterase , Organophosphate Poisoning , Severity of Illness Index , Humans , Organophosphate Poisoning/blood , Female , Male , Adult , Prospective Studies , Middle Aged , India/epidemiology , Young Adult , Butyrylcholinesterase/blood , Adolescent , Pesticides/poisoning , Organophosphorus Compounds , Biomarkers/blood , AgedABSTRACT
OBJECTIVE: The main adjuvant therapies for anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer include ALK tyrosine kinase inhibitors (TKI) and chemotherapy. We aimed to compare differences in the incidence of thromboembolism (TE) among different treatment options. DESIGN: Using a systematic review and Bayesian network meta-analysis (NMA). DATA SOURCES: We searched PubMed, Embase, Cochrane Library, ClinicalTrials.gov and Web of Science databases before 10 June 2023. ELIGIBILITY CRITERIA: We included published randomised controlled trials (RCT) involving comparisons of treatments between chemotherapy and ALK-TKI drugs. DATA EXTRACTION AND SYNTHESIS: Assessed risk bias with Cochrane tool. Conducted NMA with GEMTC in R, we evaluate the model fit using the deviation information criteria. Estimated posterior distribution using Markov Chain Monte Carlo, 4 chains, 10 fine-tuned iterations, 10 000 iterations per chain, total 50 000 iterations. Monitored potential scale reduction factor for convergence. And checked convergence with Gelman-Rubin statistics and trace plot. Provided surface under the cumulative ranking, lower values indicate less TE event probability. RESULTS: Analysis of eight RCTs showed that, compared with that for crizotinib, there was a lower risk of total TE with chemotherapy (OR, 0.28; 95% credible intervals (CrI) 0.11 to 0.63), brigatinib (OR 0.31; 95% CrI 0.11 to 0.79) and ceritinib (OR 0.13; 95% CrI 0.03 to 0.45). In addition, analysis of venous TE (VTE) showed similar results, with a lower occurrence for chemotherapy (OR 0.27; 95% CrI 0.1 to 0.62), brigatinib (OR 0.18; 95% CrI 0.04 to 0.6) and ceritinib (OR 0.1; 95% CrI 0.02 to 0.43) compared with that for crizotinib. There were no significant differences in the occurrence of arterial TE among the different treatment options. CONCLUSION: Compared with chemotherapy, alectinib, lorlatinib, brigatinib and ceritinib, crizotinib significantly increased the risk of TE and VTE. PROSPERO REGISTRATION NUMBER: CRD42023373307.
Subject(s)
Anaplastic Lymphoma Kinase , Carcinoma, Non-Small-Cell Lung , Crizotinib , Lung Neoplasms , Network Meta-Analysis , Protein Kinase Inhibitors , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Anaplastic Lymphoma Kinase/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , Crizotinib/therapeutic use , Bayes Theorem , Pyrimidines/therapeutic use , Piperidines/therapeutic use , Antineoplastic Agents/therapeutic use , Randomized Controlled Trials as Topic , Thrombosis , Crown Ethers/therapeutic use , Organophosphorus Compounds/therapeutic use , Molecular Targeted Therapy , Carbazoles , SulfonesABSTRACT
PURPOSE: The present study aimed to investigate the effects of endurance training (ET) in combination with MitoQ supplementation on antioxidant indices and the expression of sesterin-2 (SESN2) as an anti-aging factor and AMPK as an energy sensor in aged male Wistar rats. METHODS: Twenty-eight aged Wistar rats (410 ± 15 g, 22 ± 1.5 months old) were randomly divided into four groups (n = 7): Control, ET (eight weeks endurance training on the treadmill), MitoQ (250 µ/L in drinking water), and ET + MitoQ. We measured the protein and gene expression of SESN2 and AMPK in the heart tissue by western blotting and real-time PCR, respectively. In addition, antioxidant indices, superoxide dismutase (SOD), and glutathione peroxidase (GPx) activity, and oxidant malondialdehyde (MDA) concentration in the cardiac tissue and serum were measured. RESULTS: SESN2 and AMPK protein expression significantly increased in the MitoQ group compared to the control group (P = 0.002, P = 0.0003). MDA content in tissue and serum remained unchanged in all groups (P > 0.05). MitoQ supplementation significantly increased SOD and GPx enzyme activity in serum and cardiac tissue (P = 0.001). CONCLUSION: Overall, ET and MitoQ alone and in combination have anti-aging effects and improve the expression of AMPK and SESN2. Additionally, ET and MitoQ lead to improved antioxidant capacity in aged rats by ameliorating the activity of antioxidant enzymes.
Subject(s)
Aging , Antioxidants , Myocardium , Organophosphorus Compounds , Ubiquinone , Animals , Male , Rats , Aging/metabolism , Aging/drug effects , AMP-Activated Protein Kinases/metabolism , Antioxidants/metabolism , Antioxidants/pharmacology , Dietary Supplements , Endurance Training , Glutathione Peroxidase/metabolism , Malondialdehyde/metabolism , Myocardium/metabolism , Nuclear Proteins/metabolism , Organophosphorus Compounds/pharmacology , Oxidative Stress/drug effects , Physical Conditioning, Animal/physiology , Rats, Wistar , Sestrins , Superoxide Dismutase/metabolism , Ubiquinone/analogs & derivatives , Ubiquinone/pharmacologyABSTRACT
Prenatal exposure to organophosphorus flame retardants (OPFRs) has been linked with adverse effects on reproductive health, and new OPFRs are continually emerging. In this study, emerging OPFRs, such as bis(2-ethylhexyl) phenyl phosphate (BEHPP), triamyl phosphate (TAP), tris(4-tert-butylphenyl) phosphate (T4tBPPP), oxydi-2,1-ethanediyl phosphoric acid tetrakis(2 chloro-1-methylethyl) ester (RDT905), cresyl diphenyl phosphate (CDP), and 2-isopropylphenyl diphenyl phosphate (2IPPDPP), were detected in 84 %, 100 %, 100 %, 52 %, 40 %, and 40 % of 25 decidua samples with average concentrations of 2.36, 6.21, 1.5, 2.6, 1.07, and 0.09 ng/g of dry weight (dw), respectively. Six of the aforementioned emerging OPFRs (BEHPP, T4tBPPP, RDT905, 2IPPDPP, CDP, and TAP) were simultaneously detected in paired chorionic villus samples, and their average concentrations were 11.3, 1.77, 3.64, 0.11, 0.58, and 3.34 ng/g, which were significantly higher than and positively correlated with those in decidua samples. The geometric mean concentration ratios between chorionic villus and decidua samples for BEHPP, T4tBPPP, RDT905, 2IPPDPP, CDP, and TAP were 4.02, 1.61, 1.73, 1.48, 0.82, and 0.69, respectively, consistent with transthyretin binding-dependent behavior. Prenatal exposure to such emerging OPFRs, especially for BEHPP with relatively high concentration and maternal transfer, is of high concern from the view of women's reproductive health.
Subject(s)
Flame Retardants , Maternal Exposure , Organophosphates , Flame Retardants/analysis , Female , Humans , Pregnancy , Organophosphorus Compounds/analysis , Adult , Young Adult , Environmental Pollutants/analysis , Maternal-Fetal ExchangeABSTRACT
Organophosphorus pesticides (OPPs) are a group of pesticides that are most widely used in the agricultural sector, and farmers are exposed to these chemicals more than other members of society. In this work, an environmentally friendly, simple, and safe ultrasound-assisted dispersive liquid-liquid microextraction (USA-DLLME) method using alcohol-based hydrophobic deep eutectic solvents (HDESs) followed by gas chromatography-mass spectroscopy (GC-MS) was developed for the extraction and determination of OPPs in the blood of farmers studied in Ravansar cohort. DESs synthesized from thymol as hydrogen bond donor (HBD) and aliphatic alcohols as hydrogen bond acceptor (HBA) have been used as extractants. Under optimal experimental conditions, the reproducibility of the method based on 7 replicate measurements of 10 µg L-1 of OPPs in blood samples was in the range of 1.4-3.8%. The method showed a linearity in the range of 0.01-150 µg L-1. The limits of detection and limits of quantification were between 0.003 and 0.02 µg L-1 and 0.01-0.05 µg L-1, respectively. The matrix effect and accuracy of the method were confirmed by spiking different amounts of OPPs in real blood samples and obtaining relative recoveries in the range of 91-112%. The results showed that the concentration of OPPs in the case group was significantly higher than in the control group, which is because the case group was exposed to OPPs during the spraying of agricultural products.
Subject(s)
Farmers , Gas Chromatography-Mass Spectrometry , Liquid Phase Microextraction , Organophosphorus Compounds , Pesticides , Organophosphorus Compounds/chemistry , Pesticides/blood , Humans , Deep Eutectic Solvents/chemistry , Solvents/chemistry , Hydrophobic and Hydrophilic Interactions , Alcohols/chemistryABSTRACT
Tris(1,3-dichloro-2-propyl) phosphate (TCPP), a prevalent organophosphorus flame retardant in aquatic environments, has raised significant concerns regarding its ecological risks. This study aims to explore the impacts of TCPP on the reproductive functions of zebrafish and delineate its gender-related toxic mechanisms. By assessing the effects on zebrafish of 10 mg/L TCPP exposure from 30 to 120 days post-fertilization (dpf), we thoroughly evaluated the reproductive capability and endocrine system alterations. Our findings indicated that TCPP exposure disrupted gender differentiation in zebrafish and markedly impaired their reproductive capacity, resulting in decreased egg laying and offspring development quality. Histological analyses of gonadal tissues showed an abnormal increase in immature oocytes in females and a reduction in mature sperm count and spermatogonial structure integrity in males, collectively leading to compromised embryo quality. Additionally, molecular docking results indicated that TCPP showed a strong affinity for estrogen receptors, and TCPP-treated zebrafish exhibited imbalanced sex hormones and increased estrogen receptor expression. Alterations in genes associated with the hypothalamic-pituitary-gonadal (HPG) axis and activation of the steroidogenesis pathway suggested that TCPP targets the HPG axis to regulate sex hormone homeostasis. Tamoxifen (TAM), as a competitive inhibitor of estrogen, exhibited a biphasic effect, as evidenced by the counteraction of TCPP-induced effects in both male and female zebrafish after TAM addition. Overall, our study underscored the gender-dependent reproductive toxicity of TCPP exposure in zebrafish, characterized by diminished reproductive capacity and hormonal disturbances, likely due to interference in the HPG axis and steroidogenesis pathways. These findings emphasize the critical need to consider gender differences in chemical risk assessments for ecosystems and highlight the importance of understanding the mechanisms underlying the effects of chemical pollutants on the reproductive health of aquatic species.
Subject(s)
Flame Retardants , Hypothalamo-Hypophyseal System , Reproduction , Water Pollutants, Chemical , Zebrafish , Animals , Zebrafish/physiology , Water Pollutants, Chemical/toxicity , Male , Female , Reproduction/drug effects , Flame Retardants/toxicity , Hypothalamo-Hypophyseal System/drug effects , Endocrine Disruptors/toxicity , Organophosphorus Compounds/toxicity , Gonads/drug effects , Hypothalamic-Pituitary-Gonadal AxisABSTRACT
We previously reported that normothermic ex vivo kidney perfusion (NEVKP) is superior in terms of organ protection compared to static cold storage (SCS), which is still the standard method of organ preservation, but the mechanisms are incompletely understood. We used a large animal kidney autotransplant model to evaluate mitochondrial function during organ preservation and after kidney transplantation, utilizing live cells extracted from fresh kidney tissue. Male porcine kidneys stored under normothermic perfusion showed preserved mitochondrial function and higher ATP levels compared to kidneys stored at 4 °C (SCS). Mitochondrial respiration and ATP levels were further enhanced when AP39, a mitochondria-targeted hydrogen sulfide donor, was administered during warm perfusion. Correspondingly, the combination of NEVKP and AP39 was associated with decreased oxidative stress and inflammation, and with improved graft function after transplantation. In conclusion, our findings suggest that the organ-protective effects of normothermic perfusion are mediated by maintenance of mitochondrial function and enhanced by AP39 administration. Activation of mitochondrial function through the combination of AP39 and normothermic perfusion could represent a new therapeutic strategy for long-term renal preservation.
Subject(s)
Kidney Transplantation , Kidney , Mitochondria , Organ Preservation , Perfusion , Warm Ischemia , Animals , Mitochondria/metabolism , Kidney/metabolism , Organ Preservation/methods , Male , Swine , Perfusion/methods , Hydrogen Sulfide/metabolism , Hydrogen Sulfide/pharmacology , Adenosine Triphosphate/metabolism , Oxidative Stress , Organophosphorus Compounds , ThionesABSTRACT
Colorimetry based on the bioenzyme inhibition strategy holds promising application prospects in the field of organophosphorus pesticide (OPs) detection. However, overcoming the challenges of the high cost and low stability of bioenzymes remains crucial. In this study, we successfully synthesized a peroxidase vanadium-based metal-organic framework (MOF) nanozyme named MIL-88B(V) and employed its mediated bioenzyme-free colorimetric strategy for direct OPs detection. The experimental results demonstrated that MIL-88B(V) exhibited a remarkable affinity and a remarkable catalytic rate. When the OPs target is added, it can be anchored on the MOF surface through a V-O-P bond, effectively inhibiting the MOF's activity. Subsequently, leveraging the advantages of smartphones such as convenience, speed, and sensitivity, we developed a paper sensor integrated into a smartphone for efficient OPs detection. The as-designed nanozyme-based colorimetric assay and paper sensor presented herein offer notable advantages, including affordability, speed, stability, wide adaptability, low cost, and accuracy in detecting OPs, thus providing a versatile and promising analytical approach for real sample analysis and allowing new applications of V-based MOF nanozymes.
Subject(s)
Colorimetry , Metal-Organic Frameworks , Organophosphorus Compounds , Pesticides , Colorimetry/methods , Metal-Organic Frameworks/chemistry , Pesticides/analysis , Organophosphorus Compounds/analysis , Vanadium/chemistry , Vanadium/analysis , Peroxidase/chemistry , Peroxidase/metabolism , Peroxidases/chemistry , Peroxidases/metabolismABSTRACT
Microplastics (MPs) and organophosphate flame retardants (OPFRs) have recently become ubiquitous and cumulative pollutants in the oceans. Since OPFRs are added to or adsorbed onto MPs as additives, it is necessary to study the composite contamination of OPFRs and MPs, with less focus on bio-based PLA. Therefore, this study focused on the ecotoxicity of the biodegradable MP polylactic acid (PLA) (5 µm, irregular fragments, 102 and 106 particles/L), and a representative OPFRs tris(1-chloro-2-propyl) phosphate (TCPP, 0.5 and 50 µg/L) at environmental and high concentrations. The mussel Mytilus coruscus was used as a standardised bioindicator for exposure experiments. The focus was on examining oxidative stress (catalase, CAT, superoxide dismutase, SOD, malondialdehyde, MDA), immune responses acid (phosphatase, ACP, alkaline phosphatase, AKP, lysozyme, LZM), neurotoxicity (acetylcholinesterase, AChE), energy metabolism (lactate dehydrogenase, LDH, succinate dehydrogenase, SDH, hexokinase, HK), and physiological indices (absorption efficiency, AE, excretion rate, ER, respiration rate, RR, condition index, CI) after 14 days exposure. The results of significantly increased oxidative stress and immune responses, and significantly disturbed energy metabolism and physiological activities, together with an integrated biomarker response (IBR) analysis, indicate that bio-based PLA MPs and TCPP could cause adverse effects on mussels. Meanwhile, TCPP interacted significantly with PLA, especially at environmental concentrations, resulting in more severe negative impacts on oxidative and immune stress, and neurotoxicity. The more severe adverse effects at environmental concentrations indicate higher ecological risks of PLA, TCPP and their combination in the real marine environment. Our study presents reliable data on the complex effects of bio-based MP PLA, TCPP and their combination on marine organisms and the environment.
Subject(s)
Flame Retardants , Microplastics , Mytilus , Oxidative Stress , Polyesters , Water Pollutants, Chemical , Animals , Mytilus/drug effects , Water Pollutants, Chemical/toxicity , Flame Retardants/toxicity , Oxidative Stress/drug effects , Microplastics/toxicity , Organophosphates/toxicity , Organophosphorus CompoundsABSTRACT
Fenamiphos (FNP) is an organophospate pesticide that causes many potential toxicities in non-target organisms. Naringenin (NAR) has protective properties against oxidative stress. In this study, FNP (0.76 mg/kg bw) toxicity and the effect of NAR (50 mg/kg bw) on the liver and kidney of rats were investigated via biochemical, oxidative stress, immunohistochemical, cytopathological and histopathologically. As a result of biochemical studies, FNP caused oxidative stress in tissues with a change in total antioxidant/oxidant status. After treatment with FNP, hepatic and renal levels of AChE were significantly reduced while 8-OHdG and IL-17 levels, caspase-3 and TNF-α immunoreactivity increased compared to the control group. It also changed in serum biochemical markers such as ALT, AST, BUN, creatinine. Exposure to FNP significantly induced cytopathological, histopathological and immunohistochemical changes through tissue damage. NAR treatment restored biochemical parameters, renal/hepatic AChE, ultrastructural, histopathological and immunohistochemical changes modulated and blocked the increasing effect of FNP on tissues caspase-3 and TNF-α expressions, 8-OHdG and IL-17 levels. In electron microscopy studies, swelling was observed in the mitochondria of the cells in both tissues of the FNP-treated rats, while less ultrastructural changes in the FNP plus NAR-treated rats.
Subject(s)
Biomarkers , Caspase 3 , Flavanones , Kidney , Liver , Organophosphorus Compounds , Oxidative Stress , Animals , Flavanones/pharmacology , Oxidative Stress/drug effects , Kidney/drug effects , Kidney/metabolism , Kidney/ultrastructure , Kidney/pathology , Liver/drug effects , Liver/metabolism , Liver/ultrastructure , Liver/pathology , Rats , Male , Caspase 3/metabolism , Organophosphorus Compounds/toxicity , Biomarkers/metabolism , Chemical and Drug Induced Liver Injury/prevention & control , Chemical and Drug Induced Liver Injury/drug therapy , Rats, Wistar , Tumor Necrosis Factor-alpha/metabolism , Acetylcholinesterase/metabolism , Interleukin-17/metabolism , Immunohistochemistry , 8-Hydroxy-2'-Deoxyguanosine/metabolismABSTRACT
In recent years, organophosphorus flame retardants (OPFRs) have been widely used as substitutes for brominated flame retardants with excellent properties, and their initial toxicological effects on the water ecosystem and human health have gradually emerged. However, to date, research on the cytotoxicity and health risks of OPFRs is still limited. Therefore, this study aims to systematically explore the cytotoxic effects and toxic mechanisms of OPFRs on cells. Human liver cancer (HepG2) cells were adopted as an ideal model for toxicity evaluation due to their rapid growth and metabolism. This study proposes a sensitive electrochemical cell-based sensor constructed on a graphitized multi-walled carbon nanotube/ionic liquid/gold nanoparticle-modified electrode. The sensor was used to detect the cytotoxicity of tri(2-butylxyethyl) phosphate (TBEP), tributyl phosphate (TnBP), triphenyl phosphate (TPhP), tri(1,3-dichloro-2-propyl) phosphate (TDCIPP), tri(2-chloropropyl) phosphate (TCPP) and tri(2-chloroethyl) phosphate (TCEP) in the liquid medium, providing insight into their toxicity in water environments. The half-maximal inhibitory concentration (IC50) of TBEP, TnBP, TPhP, TDCIPP, TCPP and TCEP on HepG2 cells were 179.4, 194.9, 219.8, 339.4, 511.8 and 859.0 µM, respectively. Additionally, the cytotoxic mechanism of six OPFRs was discussed from the perspective of oxidative stress and apoptosis, and four indexes were correlated with toxicity. Furthermore, transcriptome sequencing was conducted, followed by a thorough analysis of the obtained sequencing results. This analysis demonstrated a significant enrichment of the p53 and PPAR pathways, both of which are closely associated with oxidative stress and apoptosis. This study presents a simplified and efficient technique for conducting in vitro toxicity studies on organophosphorus flame retardants in a water environment. Moreover, it establishes a scientific foundation for further investigation into the mechanisms of cytotoxicity associated with these compounds.
Subject(s)
Biosensing Techniques , Flame Retardants , Organophosphorus Compounds , Flame Retardants/toxicity , Humans , Organophosphorus Compounds/toxicity , Hep G2 CellsABSTRACT
Chemical nerve agents are hazardous compounds that terrorists can exploit to pose a significant threat to public safety and national security. The nucleophilic behaviour of these agents enables their interaction with acetyl cholinesterase in the body, leading to paralysis and potentially fatal consequences. Therefore, developing robust and efficient detection methods for these agents is crucial for preventing their misuse. In this manuscript, (E)-12-(1-hydrazineylideneethyl)benzo[f]pyrido[1,2-a]indole-6,11-dione (HBID) is developed as a novel colorimetric and fluorometric probe for the detection of specific chemical nerve agent simulants in both liquid and vapor phase. HBID reacts rapidly with diethyl chlorophosphate (DCP), a common nerve agent simulant, leading to a significant increase in the fluorescence intensity. Under optimized conditions, HBID exhibits high sensitivity, good recyclability, fast response and low limit of detection (0.092 µM). NMR and mass spectral studies suggest that the reaction involves the nucleophilic addition of HBID to DCP, forming a phosphate ester. Additionally, the developed sensor demonstrates viscosity-sensitive AIE phenomena thus greatly expanding its potential applications in biological systems. This sensitivity enables precise detection and visualization of viscosity changes within cellular environments, making the sensor an invaluable tool for studying complex biological processes. The developed probe also detects pH within biologically relevant range (4-6). In practical applications, the probe-treated strips efficiently detected DCP vapor in real time, showing a noticeable fluorescence response. Further, the probe has a strong potential to detect the presence of DCP in the soil samples.
Subject(s)
Nerve Agents , Nerve Agents/analysis , Nerve Agents/chemistry , Fluorescent Dyes/chemistry , Colorimetry/methods , Organophosphates/chemistry , Organophosphates/analysis , Spectrometry, Fluorescence , Limit of Detection , Reproducibility of Results , Chemical Warfare Agents/analysis , Chemical Warfare Agents/chemistry , Indoles/chemistry , Fluorometry/methods , Organophosphorus CompoundsABSTRACT
INTRODUCTION: With multiple targeted therapies approved for anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), it is increasingly important to understand outcomes with various sequences of next-generation ALK tyrosine kinase inhibitors (TKIs). We describe contemporary sequencing patterns and treatment effectiveness of first-line (1L) and second-line (2L) treatments in patients who received second-generation ALK TKIs in the 1L treatment of ALK-positive NSCLC in the United States. METHODS: A cohort of adults with ALK-positive advanced NSCLC who initiated treatment with 1L alectinib or brigatinib between June 2017 and April 2021 in the Flatiron Health electronic health record-derived de-identified database were followed through April 2023. Time to treatment discontinuation (TTD) in 1L and 2L, TTD on 1L plus 2L sequential therapy (TTD2), and total time on sequential ALK TKI therapy (including beyond 2L) were evaluated. RESULTS: Patients (N=273) were followed up for a median duration of 28.9 months. Among patients who discontinued 1L therapy, 22% died after 1L discontinuation (median time from discontinuation to death, 4.0 months) without receiving 2L therapy. Median (95% confidence interval [CI]) TTD was 21.9 (15.2-25.8) and 7.3 (5.3-10.2) months in 1L and 2L, respectively. Median (95% CI) TTD2 was 29.4 (25.1-36.1) months and total time on sequential ALK TKI treatment was 28.0 (23.6-32.9) months. CONCLUSIONS: In this large real-world study, TTD2 and the total time on sequential ALK TKIs was approximately 2.5 years. The high attrition rate from 1L to 2L and the longest clinical benefit observed with 1L therapy support using the drug with the longest 1L effectiveness up front in patients with ALK-positive advanced NSCLC.
Subject(s)
Anaplastic Lymphoma Kinase , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Protein Kinase Inhibitors , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/mortality , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Anaplastic Lymphoma Kinase/genetics , Anaplastic Lymphoma Kinase/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , Female , Middle Aged , Aged , Adult , Aged, 80 and over , Treatment Outcome , Follow-Up Studies , Retrospective Studies , Piperidines/therapeutic use , Carbazoles , Organophosphorus Compounds , PyrimidinesABSTRACT
2-ethylhexyl diphenyl phosphate (EHDPHP) is a widely used organophosphorus flame retardant and plasticizer, which is commonly found in the environment. EHDPHP not only potentially harms the environment but also causes different degrees of damage to the organism. In this study, the duodenum of chicks was selected as the potential toxic target organ to explore the mechanism of duodenal injury induced by EHDPHP exposure. Ninety one-day-old healthy male chicks were selected and randomly divided into C1(control group), C2(solvent control group), L(800â¯mg/kg), M(1600â¯mg/kg), H(3200â¯mg/kg) according to different doses of EHDPHP after one week of environmental adaptation. The chicks were given continuous gavage for 14 d, 28 d, and 42 d. It was found that constant exposure to EHDPHP caused an increase in duodenal MDA content, a decrease in P-gp, SOD, GSH-Px activities, and a decrease in duodenal mucosal immune factor (sIgA, GSH-Px). The expression of sIgM and mucosal link proteins (CLDN, OCLN, ZO-1, JAM) decreased, and the expression of the inflammatory protein (NF-κB, COX2) in duodenal tissues was up-regulated. The results showed that continuous exposure to EHDPHP could cause duodenal oxidative stress, inflammation, and mucosal barrier damage in chicks, which provided a basis for studying the mechanism of toxic damage caused by EHDPHP in poultry.
Subject(s)
Chickens , Duodenum , Flame Retardants , Oxidative Stress , Animals , Oxidative Stress/drug effects , Duodenum/drug effects , Duodenum/pathology , Duodenum/metabolism , Male , Flame Retardants/toxicity , Inflammation/chemically induced , Inflammation/pathology , Intestinal Mucosa/drug effects , Intestinal Mucosa/pathology , Intestinal Mucosa/metabolism , Organophosphorus Compounds/toxicity , Organophosphates/toxicityABSTRACT
BACKGROUND: Overcoming radio-resistance and enhance radio-sensitivity to obtain desired therapeutic outcome plays an important role in treating cancer. METHODS: Here we constructed a versatile enzyme-like nano-radiosensitizer MDP. MDP is composed of MnCO decorated and Ru-based nanozyme with triphenylphosphine (TPP) group coordinated on the surface. RESULTS: Due to the mitochondria-targeting ability of TPP and enhanced permeability and retention effect (EPR) effect of MDP, MDP accumulated in the mitochondria of tumor cells. Therefore, quantities of reactive oxygen species were produced via multiple enzyme-like properties including peroxidase (POD) and catalase (CAT) in a tumor microenvironment mimicking status. In additional, more energy of radiation ionizing was deposed in tumor site via Compton effect and secondary electron scattering by Ru element. Impressively, it was disclosed that the nanozyme can act as a cGAS-STING agonist to provoke immune response of the system, which hereby further elevated this combined therapy. CONCLUSIONS: Collectively, we fabricated a novel nanozyme with POD and CAT mimicking properties for the combination therapy of catalytical therapy, radiotherapy as well as immune therapy to eliminate cancer.
Subject(s)
Mitochondria , Humans , Mitochondria/metabolism , Mitochondria/drug effects , Animals , Nucleotidyltransferases/metabolism , Nucleotidyltransferases/antagonists & inhibitors , Membrane Proteins/metabolism , Mice , Reactive Oxygen Species/metabolism , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/pharmacology , Radiation-Sensitizing Agents/chemistry , Radiation-Sensitizing Agents/pharmacology , Catalase/metabolism , Cell Line, Tumor , Catalysis , Nanoparticles/chemistry , Ruthenium/chemistry , Ruthenium/pharmacology , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Neoplasms/therapy , Surface Properties , Particle Size , Peroxidase/metabolismABSTRACT
Food safety is an important issue to protect humane health and improve the life quality. Hence, analysis of the possible contaminants in food samples is essential. A rapid and efficient vortexed-assisted dispersive µ-solid-phase extraction coupled with gas chromatography-mass spectrometry was proposed for simultaneous separation/preconcentration and determination of five commonly used organophosphorus pesticides. Reduced graphene oxide decorated NiCo2(OH)6 nanoflowers as a novel nanostructure was synthetized and introduced for separation of the target pesticides from the wheat flour, rice flour, and baby food cereal samples. The characterization of the nanoflowers was accomplished by SEM-EDX, XRD, and FT-IR techniques. The main factors including pH, the amount of nanoflower, the volume of sample solution, salt concentration (ionic strength), desorption conditions (i.e. desorption solvent type and volume, and desorption time) on the pesticides extraction efficiencies were inquired using matrixed match method. Applying the optimum conditions, the linearity of 0.100-500.000 µg kg-1, LODs and LOQs in the range of 0.03-0.04 µg kg-1 and 0.1 µg kg-1 for the studied food samples were obtained. The repeatability (intra-day precision (n = 5)) of ≤ 2.0 % and reproducibility (inter-day precision, days = 5, n = 3) of ≤3.1 % and were appraise at three concentration levels (10, 50 and 100 µg kg-1 of each analyte). High relative recoveries of 90.0-99.3 % ascertained high potential of the presented method for complex matrix analysis.