Novel biocompatible N-rich AIE fluorescent probe for live cell imaging and visual onsite detection of uranium.

A sensitive and biocompatible N-rich probe for rapid visual uranium detection was constructed by grafting two trianiline groups to 2,6-bis(aminomethyl)pyridine. Possessing excellent aggregation-induced emission (AIE) property and the advantages to form multidentate chelate with U selectively, the probe has been applied successfully to visualize uranium in complex environmental water samples and living cells, demonstrating outstanding anti-interference ability against large equivalent of different ions over a wide effective pH range. A large linear range (1.0 × 10-7-9.0 × 10-7 mol/L) and low detection limit (72.6 nmol/L, 17.28 ppb) were achieved for the visual determination of uranium. The recognition mechanism, photophysical properties, analytical performance and cytotoxicity were systematically investigated, demonstrating high potential for fast risk assessment of uranium pollution in field and in vivo.

Toxic effects of aniline in liver, gills and kidney of freshwater fish Channa punctatus after acute exposure.

Aniline (C6H5NH2) is one of the hazardous aromatic amine where an amino group -NH2) is connected to phenyl ring (C6H5). Based on the evaluation of the 96-hour LC50 of aniline, two sublethal concentrations (4.19 mg/l and 8.39 mg/l) were selected for acute exposure tests in freshwater fish Channa punctatus. The liver, gills and kidney of fish being the principal sites of xenobiotic material accumulation, respiration, biotransformation, and excretion are the focus of the present study. Throughout the exposure time, the comet assay revealed increased tail length and tail DNA percentage indicating maximum damage to liver, gills and kidney of treated group after 96 h. After acute exposure, there was a significant (p ≤ 0.05) increase in the enzymatic activity of glutathione-S-transferase (GST) and acetylcholinesterase (AChE), whereas decline in superoxide dismutase (SOD) and catalase (CAT) activity was observed. Meanwhile, levels of malondialdehyde (MDA) increased over the exposure period for both concentrations. After 96 h of exposure, degree of tissue change (DTC) was evaluated in liver, gill and kidney of aniline exposed fish. Additionally, light microscopy revealed multiple abnormalities in liver, gills and kidney of all the treated groups. Significant changes were observed in the levels of biochemical markers viz., glucose, triglyceride, cholesterol, aspartate transaminase, alanine transaminase and urea following a 96-hour exposure to aniline. Studies using ATR-FTIR and transmission electron microscopy (TEM) revealed changes in biomolecules and structural abnormalities in several tissues of the aniline-exposed groups in comparison to the control group respectively.

Synergistic detoxification efficiency and mechanism of triclocarban degradation by a bacterial consortium in the liver-gut-microbiota axis of zebrafish (Danio rerio).

Triclocarban (TCC), an emerging organic contaminant, poses a potential threat to human health with long-term exposure. Here, Rhodococcus rhodochrous BX2 and Pseudomonas sp. LY-1 were utilized to degrade TCC at environmental related concentrations for enhancing TCC biodegradation and investigating whether the toxicity of intermediate metabolites is lower than that of the parent compound. The results demonstrated that the bacterial consortium could degrade TCC by 82.0% within 7 days. The calculated 96 h LC50 for TCC, as well as its main degradation product 3,4-Dichloroaniline (DCA) were 0.134 mg/L and 1.318 mg/L respectively. Biodegradation also alleviated histopathological lesions induced by TCC in zebrafish liver and gut tissues. Liver transcriptome analysis revealed that biodegradation weakened differential expression of genes involved in disrupted immune regulation and lipid metabolism caused by TCC, verified through RT-qPCR analysis and measurement of related enzyme activities and protein contents. 16 S rRNA sequencing indicated that exposure to TCC led to gut microbial dysbiosis, which was efficiently improved through TCC biodegradation, resulting in decreased relative abundances of major pathogens. Overall, this study evaluated potential environmental risks associated with biodegradation of TCC and explored possible biodetoxification mechanisms, providing a theoretical foundation for efficient and harmless bioremediation of environmental pollutants.

Mechanistic insights into aniline-induced liver injury: Role of the mmu_circ_26984/Myh9/NLRP3 axis and modulation by N-acetylcysteine.

Aniline is a widely used chemical. Chronic or high-dose exposure to aniline can lead to hepatocellular damage. Although the hepatic pathogenicity of aniline has been established in previous studies, studies involving pathogenic genes during aniline-induced liver injury are limited. Our study first discovered and identified the role and mechanism underlying a new circRNA mmu_circ_26984 in aniline-induced chemical liver injury. Further, we discuss the protective effect of N-acetylcysteine (NAC) in this pathway. After constructing in vitro and in vivo models of aniline treatment, we screened the circRNA with significant differences in expression in AML12 cells from control and aniline-treated groups by circRNA microarray analysis. Next, using RNA pulldown, liquid chromatography-mass spectrometry (LC-MS), and RNA immunoprecipitation, we analyzed the relationship between mmu_circ_26984 and myosin heavy chain 9 (Myh9). Subsequently, we determined the specific mechanism of action of mmu_circ_26984 and Myh9 in aniline-induced liver injury and the protective effect of NAC against aniline-induced liver injury process using Cell Counting Kit-8, Western blot, RNA extraction, a reverse transcription quantitative polymerase chain reaction (RT-qPCR), fluorescence in situ hybridization, immunohistochemistry, and immunofluorescence. The expression of mmu_circ_26984 was significantly increased in liver tissues and AML12 cells of aniline-treated mice compared with the control group. This high expression of mmu_circ_26984 increased the expression of injury-related inflammatory factors, such as NLRP3, Caspase-1, IL-18, and IL-1ß in vivo and ex vivo, which exacerbated the level of liver injury. The interaction of mmu_circ_26984 with Myh9 also affected the course of liver injury. Mmu_circ_26984 overexpression and reduced treatment affected the levels of Myh9 expression in AML12 cells, as well as downstream inflammatory factors associated with injury, such as NLRP3. In addition, NAC reduced the process of liver injury mediated by the mmu_circ_26984/Myh9/NLRP3 axis. In conclusion, mmu_circ_26984 is a potential molecular marker and therapeutic target in the process of aniline-induced liver injury that can mediate aniline-exposure-induced liver injury via modulation of the mmu_circ_26984/Myh9/NLRP3 axis, and NAC can effectively attenuate the effect of this liver injury.

Evaluation of haematological, genotoxic, cytotoxic and ATR-FTIR alterations in blood cells of fish Channa punctatus after acute exposure of aniline.

Aniline (C6H5NH2) an important intermediate in the organic and fine chemical industry, is ubiquitously used worldwide. It is one of the important building block for manufacturing of 4,4-methylene diphenyl diisocyanate (MDI), accelerators in rubber processing, dyes, tattoo inks, photographic chemicals, antioxidants, corrosion inhibitors, pharmaceuticals and antiseptics. The current study evaluated 96 h LC50 of aniline and based on this, two sublethal concentrations (4.19 mg/l and 8.39 mg/l) were selected for acute exposure studies in freshwater food fish Channa punctatus. Erythrocytes of fish are nucleated hence they play an important role in physiology, immune system, protein signalling and haemostatic condition along with respiration. Blood samples were collected after 24, 48, 72, and 96 h of exposure to study haematological, cytotoxic and genotoxic effects of sublethal concentrations of aniline in C. punctatus. Symbolic elevation in time and dose dependent DNA damage was observed by comet assay as well as micronuclei assay revealing maximum damage after 96 h of exposure. After aniline exposure, scanning electron microscopy and ATR-FTIR studies showed anomalies in structure and alterations in biomolecules of RBCs of aniline exposed group as compared to control group respectively. Semi prep HPLC studies revealed bioaccumulation potential of aniline in higher concentration exposed group.

Pendimethalin induces apoptotic cell death through activating ER stress-mediated mitochondrial dysfunction in human umbilical vein endothelial cells.

Pendimethalin is globally registered for control of a wide range of weeds in agriculture and home landscaping. Human exposure to pendimethalin can occur by the oral route through food and other sources. Endothelial function is vital to numerous biological processes, and endothelial dysfunction and poor vascular health is associated with increased atherosclerotic events; however, no study has yet investigated the potential effect of pendimethalin on endothelial function and vasculature formation. The objective of the current study is to investigate if pendimethalin may affect the viability and function of vascular endothelial cells. We observed that pendimethalin significantly repressed viability of human endothelial cells, inducing G1 cell cycle arrest and apoptotic/necrotic cell death. Pendimethalin treatment also activated ER stress and autophagy, leading to loss of mitochondrial membrane potential. In addition, pendimethalin impaired the tube forming and migratory abilities of endothelial cells. This study provides previously unrecognized adverse effects of pendimethalin in vascular endothelial cells, mediated by ER stress-induced mitochondrial dysfunction.

Aniline exposure activates receptor-interacting serine/threonineprotein kinase 1 and causes necroptosis of AML12 cells.

With the increased use of aniline, potential impacts on human health cannot be ignored. The hepatotoxicity of aniline is largely unknown and the underlying mechanism remains unclear. Therefore, the aim of the present study was to investigate the hepatotoxicity of aniline and elucidate the underlying mechanism. AML12 cells were exposed to different concentrations of aniline (0, 5, 10, or 20 mM) to observe changes to reactive oxygen species (ROS) production and the expression patterns of necroptosis-related proteins (RIPK1, RIPK3, and MLKL). The potential mechanism underlying aniline-induced hepatotoxicity was explored by knockout of RIPK1. The results showed that aniline induced cytotoxicity in AML12 cells in a dose-dependent manner in addition to the production of ROS and subsequent necroptosis of AML12 cells. Silencing of RIPK1 reversed upregulation of necroptosis-related proteins in AML12 cells exposed to aniline, demonstrating that aniline-induced ROS production was related to necroptosis of AML12. Moreover, aniline promoted intracellular RIPK1 activation, suggesting that the RIPK1/ROS pathway plays an important role in aniline-induced hepatotoxicity. NAC could quench ROS and inhibit necroptosis. These results provide a scientific basis for future studies of aniline-induced hepatotoxicity for the prevention and treatment of aniline-induced cytotoxicity.

Comparative evaluation of three methylene dianiline isomers in the bacterial reverse mutation assay, the in vitro gene mutation test, and the in vitro chromosomal aberration test.

4,4'-MDA is classified as a genotoxic carcinogen based on numerous in vitro and animal data. The consequential assumption that a safe threshold does not exist is not only applied to 4,4'-MDA but also to its structural isomers and impurities 2,2'- and 2,4'-MDA in the absence of substance-specific data. This constitutes a problem in human risk assessments for all three substances as the inherent risks of 2,2'- and 2,4'-MDA and their contribution as impurities to that of 4,4'-MDA are essentially unknown. A comparative in vitro genotoxicity dataset consisting of the bacterial reverse mutation (Ames) test and the chromosomal aberration test in human lymphocytes (both performed according to the current OECD Guidelines) was generated for all three isomers. Furthermore, an in vitro gene mutation test in Chinese hamster ovary (CHO) cells (HPRT locus assay) was conducted with 2,4'-MDA. The results indicate differences regarding the genotoxic mechanism and potential, respectively, between the three structures and suggest that the no-threshold assumption for 4,4'-MDA may not be appropriate for 2,2'- and 2,4'-MDA.

Clinicohematological, Mutagenic, and Oxidative Stress Induced by Pendimethalin in Freshwater Fish Bighead Carp (Hypophthalmichthys nobilis).

Currently, aquatic and terrestrial ecosystems are continuously and chronically polluted by cocktails of countless chemical compounds. The susceptibility to infections is tremendously increasing in a variety of organisms due to exposure to environmental pollutants. Pendimethalin, an herbicide, is continuously used in agriculture to remove unwanted broadleaf weeds across the globe. Therefore, this study investigates the mechanisms of toxicity of pendimethalin in freshwater fish bighead carp upon exposure to low and environmentally relevant concentrations. For this purpose, 48 fish without any clinical abnormalities were kept in a glass aquarium in different experimental groups (T0, T1, T2, and T3). These groups were treated with pendimethalin at 0.00, 0.25, 0.50, and 0.75 mg/L, respectively. Four fish were randomly picked from each experimental group and killed at 72, 96, and 120 hours of the trial to study hematobiochemical parameters and visceral tissues including the brain, liver, heart, gills, and kidneys for histopathology. Herbicide-treated fish indicated various physical and behavioral abnormalities including hypersecretion of mucus, erratic swimming, operculum movement, air gulping, tremors of fins, loss of equilibrium, and increased surface breathing. Histopathologically, gills tissues of treated fish indicated atrophied lamellae, uplifting of secondary lamellae, necrosis of primary and secondary lamellar epithelial cells, telogenesis, congestion, and lamellar fusion. Histopathological examination of liver tissues of treated fish showed mild to moderate congestion, necrosis of hepatocytes, and atrophy of hepatocytes while kidneys revealed degeneration of renal tubules, glomerular atrophy, ceroid, and necrosis of renal tubules. The erythrocyte counts, monocyte and lymphocyte counts, and hemoglobin values were significantly (P < 0.05) reduced in pendimethalin-treated fish. Results on serum biochemistry showed that the biomarkers of kidneys, heart, and liver were significantly higher in fish of treated groups. In addition, values of different biochemical reactions like reactive oxygen species (ROS), thiobarbituric acid reactive species (TBARS), total proteins, and quantity of different antioxidant enzymes including reduced glutathione (GSH), catalase, and superoxide dismutase (SOD) were significantly different when compared to untreated fish. Moreover, the percentile of different nuclear abnormalities in red blood cells and frequency of DNA damage increased significantly in treated fish. It can be concluded from the findings that pendimethalin causes its toxic effects via disruption of physiological and hematobiochemical reactions of fish.

Dinitroaniline herbicide pendimethalin affects development and induces biochemical and histological alterations in zebrafish early-life stages.

Pendimethalin (PND) is a dinitroaniline preemergent herbicide widely used to control grasses and weeds. The present study aimed to evaluate the PND potential effects on the development of zebrafish early-life stages. The research focuses first on acute toxicity, followed by the integration of toxicity results through histopathology, oxidative status, and neurotoxicity evaluation of sublethal and environmentally relevant concentrations. Zebrafish larvae exposed to PND showed mortality and developed sublethal alterations including impaired fin development, lordosis, scoliosis, blood congestion, impaired blood flow, and reduced heartbeat. PND exposure (0.5 mg/L) affects musculoskeletal development leading to delayed and reduced ossification of the vertebral centra in the developing vertebral column and disruption of muscle morphology. Herbicide exposure (0.5 mg/L and 0.05 mg/L) led also to biochemical changes of antioxidant enzymes, increasing the activity of CAT, GR, and GPx, while no effects were observed on the activity of SOD and GST in zebrafish larvae. Lastly, AChE activity, a biochemical marker of neurotoxicity, was also increased in zebrafish larvae exposed to 0.5 mg/L of PND. These results confirm the developmental toxicity of PND in zebrafish early-life stages, pointing out the potential role of oxidative stress in the onset of sublethal alterations.

Assessment of the ameliorative effect of curcumin on pendimethalin-induced genetic and biochemical toxicity.

The present study aimed to assess the toxic effects of pendimethalin herbicide and protective role of curcumin using the Allium test on cytological, biochemical and physiological parameters. The effective concentration (EC50) of pendimethalin was determined at 12 mg/L by the root growth inhibition test as the concentration reducing the root length by 50%. The roots of Allium cepa L. was treated with tap water (group I), 5 mg/L curcumin (group II), 10 mg/L curcumin (group III), 12 mg/L pendimethalin (group IV), 12 mg/L pendimethalin + 5 mg/L curcumin (group V) and 12 mg/L pendimethalin + 10 mg/L curcumin (group VI). The cytological (mitotic index, chromosomal abnormalities and DNA damage), physiological (rooting percentage, root length, growth rate and weight gain) and oxidative stress (malondialdehyde level, superoxide dismutase level, catalase level and glutathione reductase level) indicators were determined after 96 h of treatment. The results revealed that pendimethalin treatment reduced rooting percentage, root length, growth rate and weight gain whereas induced chromosomal abnormalities and DNA damage in roots of A. cepa L. Further, pendimethalin exposure elevated malondialdehyde level followed by antioxidant enzymes. The activities of superoxide dismutase and catalase were up-regulated and glutathione reductase was down-regulated. The molecular docking supported the antioxidant enzymes activities result. However, a dose-dependent reduction of pendimethalin toxicity was observed when curcumin was supplied with pendimethalin. The maximum recovery of cytological, physiological and oxidative stress parameters was recorded at 10 mg/L concentration of curcumin. The correlation studies also revealed positive relation of curcumin with rooting percentage, root length, weight gain, mitotic activity and glutathione reductase enzyme level while an inverse correlation was observed with chromosomal abnormalities, DNA damage, superoxide dismutase and catalase enzyme activities, and lipid peroxidation indicating its protective effect.

Benchmark dose and the adverse effects of exposure to pendimethalin at low dose in female rats.

Pendimethalin (PND) is a dinitroaniline herbicide widely used to control broadleaf and annual grasses. Although the acute oral toxicity of PND is >5 g/kg b.wt. in humans (LD50 for rats >5000 g/kg b.wt.), it has been classified as a possible human carcinogen. It is still used in agriculture so agricultural workers and their families, as well as consumers, can be exposed to this herbicide. The present study is the first report investigating the dose-response effect using the benchmark dose (BMD) and the adverse effects of exposure to PND at low dose via apoptosis responses linked to the expression of tumour necrosis factor-α (TNF-α), FAS and BAX proteins; oxidative stress; and DNA and liver damage in female rats. The rats were exposed to PND via drinking water at doses equivalent to no-observed-adverse-effect level (NOAEL = 100 mg/kg b.wt.), 200 and 400 mg/kg b.wt. for 28 days. PND caused the overexpression of TNF-α, FAS and BAX; increased the levels of serum liver biomarkers; and increased oxidative stress in the liver and erythrocytes. Furthermore, it induced DNA and liver damage in a dose-dependent manner. The BMD showed that serum alkaline phosphatase (ALP) and total antioxidant capacity (78.4 and 30.1 mg/kg b.wt./day, respectively), lipid peroxidation in liver tissue (30.9 mg/kg b.wt./day), catalase in erythrocytes (14.0 mg/kg b.wt./day) and FAS expression in liver tissue (6.89 mg/kg b.wt./day) were highly sensitive biomarkers of PND toxicity. Our findings suggest the generation of reactive oxygen species as a possible mechanism of PND-induced gene overexpression of tumour necrosis factor-α (TNF-α), FAS and BAX proteins, oxidative stress and DNA and liver damage in female rats.

Potential role of dietary chitosan nanoparticles against immunosuppression, inflammation, oxidative stress, and histopathological alterations induced by pendimethalin toxicity in Nile tilapia.

A 21-days feeding screening period was conducted to highlight the protective efficacy of dietary chitosan nanoparticles (CSNPs) on pendimethalin (PD)-induced toxicity in Nile tilapia (Oreochromis niloticus). Hematology, non-specific immune response, the antioxidative enzymes [superoxide dismutase (SOD) and catalase (CAT), glutathione reduced (GSH), and glutathione peroxidase (GPx)] in the liver and anterior kidney, changes of pro-inflammatory cytokine genes [interleukins-8 (IL-8), interleukins-1ß (IL-1ß), and tumor necrosis-α (TNF-α)] in the anterior kidney and histopathological alterations were assessed. Fish (50 ± 7.5 g) were randomly assigned into four groups (Three replicates), the first group served as the negative control and fed on the control diet only, and the second group served as the positive control and fed on the control diet supplemented with CSNPs (1 g kg-1 diet). The two other groups were exposed to 1/10 96-h LC50 PD (0.5 mg L-1) in rearing water and simultaneously fed the control diet alone or supplemented with CSNPs (1 g kg-1 diet), respectively. Fish were fed on the experimental diets twice a day for 21 days. The results revealed that PD exposure caused a significant decline in the survival rate of the Nile tilapia, as well as in most of the hematological indices, respiratory burst activity, phagocytic activity, total immunoglobulin levels, lysozyme, and bactericidal activity. Additionally, PD toxicity markedly suppressed most of the antioxidative enzymatic activities in both tissues together with upregulation of immune genes (IL-8 and TNF-α); however, IL-1ß expression remained unaffected. The histopathological results revealed marked pathological changes in spleen, liver and intestine with a notable decrease of intestinal goblet cells in PD-exposed groups. Conversely, CSNPs exerted protective effects through improving the above mentioned parameters. Thus, CSNPs supplementation exhibited defensive effects against PD toxicity in Nile tilapia that might provide an insight into the promising role of CSNPs as a potential immunomodulatory feed additive for tilapia in aquaculture.

Chemical characterization of anemia-inducing aniline-related substances and their application to the construction of a decision tree-based anemia prediction model.

Anemia is a well-observed toxicity of chemical substances, and aniline is a typical anemia-inducing substance. However, it remains unclear whether all aniline-like substances with various substituents could induce anemia. We thus investigated the physicochemical characteristics of anemia-inducing substances by decision tree analyses. Training and validation substances were selected from a publicly available database of rat repeated-dose toxicity studies, and discrimination models were constructed by decision tree and bootstrapping methods with molecular descriptors as explanatory variables. To improve the accuracy of discrimination, we individually evaluated the explanatory variables to modify them, established "prerules" that were applied before subjecting a substance to a decision tree by considering metabolism, such as azo reduction and N-dealkylation, and introduced the idea of "partly negative" evaluation for substances having multiple aniline-like substructures. The final model obtained showed 79.2% and 77.5% accuracy for the training and validation dataset, respectively. In addition, we identified some chemical properties that reduce the anemia inducibility of aniline-like substances, including the addition of a sulfonate or carboxy functional group and/or a bulky multiring structure to anilines. In conclusion, the present findings will provide a novel insight into the mechanistic understanding of chemically induced anemia and help to develop a prediction system.

Differences in Pharmacokinetics and Haematotoxicities of Aniline and Its Dimethyl Derivatives Orally Administered in Rats.

Aniline and its dimethyl derivatives reportedly become haematotoxic after metabolic N-hydroxylation of their amino groups. The plasma concentrations of aniline and its dimethyl derivatives after single oral doses of 25 mg/kg in rats were quantitatively measured and semi-quantitatively estimated using LC-tandem mass spectrometry. The quantitatively determined elimination rates of aniline; 2,4-dimethylaniline; and 3,5-dimethylaniline based on rat plasma versus time curves were generally rapid compared with those of 2,3-; 2,5-; 2,6-; and N,2-dimethylaniline. The primary acetylated metabolites of aniline; 2,4-dimethylaniline; and 3,5-dimethylaniline, as semi-quantitatively estimated based on their peak areas in LC analyses, were more extensively formed than those of 2,3-; 2,5-; 2,6-; and N,2-dimethylaniline. The areas under the curve of unmetabolized (remaining) aniline and its dimethyl derivatives estimated using simplified physiologically based pharmacokinetic models (that were set up using the experimental plasma concentrations) showed an apparently positive correlation with the reported lowest-observed-effect levels for haematotoxicity of these chemicals. In the case of 2,4-dimethylaniline, a methyl group at another C4-positon would be one of the determinant factors for rapid metabolic elimination to form aminotoluic acid. These results suggest that rapid and extensive metabolic activation of aniline and its dimethyl derivatives occurred in rats and that the presence of a methyl group at the C2-positon may generally suppress fast metabolic rates of dimethyl aniline derivatives that promote metabolic activation reactions at NH2 moieties.

DNA Damage and Expression Profile of Genes Associated with Nephrotoxicity Induced by Butralin and Ameliorating Effect of Arabic Gum in Female Rats.

Nephrotoxicity induced by exposure to environmental pollution, including herbicides, is becoming a global problem. Natural products are the prime alternative scientific research as they express better medicinal activity and minor side effects compared with a variety of synthetic drugs. This study was performed to evaluate the nephroprotective proficiency of Arabic gum against butralin-induced nephrotoxicity. Adult female rats were supplemented with Arabic gum (4.3 g/kg b.wt) and/or butralin (312 mg/L) in drinking water for 30 days. The results found that markers of serum kidney function, oxidative stress biomarkers, DNA damage, and expression of kidney specific genes (Acsm2, Ace, and Ace2) as well as histopathological examination in treated rats were conducted. Butralin-treated rats showed a rise in serum creatinine (41%), BUN (47.3%), and MDA (140.9%) as well as decrease in activity of the antioxidant markers (CAT (-21%); GPx (-70.7%); and TAC (43.2%)) in comparison with the control group. In addition, butralin treatment increased the DNA damage (221%); altered the expression levels of Acsm2, Ace, and Ace2 (-51.6%, 141.6%, and 143% respectively); and elevated histopathological lesions in the kidney tissues. Pretreatment of Arabic gum prevented butralin-prompted degenerative changes of kidney tissues. The results suggested that the protective effect provided by Arabic gum on renal tissues exposed to the herbicide butralin could be attributed to enhancement of antioxidants and increase the free radical scavenging activity in vivo.

Calcium-activated chloride channel is involved in the onset of diarrhea triggered by EGFR tyrosine kinase inhibitor treatment in rats.

EGFR tyrosine kinase inhibitors (TKIs) are mainly used to treat non-small cell lung cancer; however, adverse effects such as severe diarrhea represent a major obstacle towards the continuation of EGFR-TKIs therapy. Chloride channels, which control the fluid flow in the intestinal lumen, are proposed as an important target to remediate EGFR-TKIs-induced diarrhea, but the mechanism remains unclear. The aim of this study was to clarify the mechanism underlying EGFR-TKIs-induced diarrhea with a particular focus on the role of intestinal chloride channels. Here, we show that osimertinib-treated rats exhibit diarrhea and an increase in fecal water content without showing any severe histopathological changes. This diarrhea was attenuated by intraperitoneal treatment with the calcium-activated chloride channel (CaCC) inhibitor CaCCinh-A01. These findings were confirmed in afatinib-treated rats with diarrhea. Moreover, treatment with the Japanese traditional herbal medicine, hangeshashinto (HST), decreased fecal water content and improved fecal appearance in rats treated with EGFR-TKIs. HST inhibited the ionomycin-induced CaCC activation in HEK293 cells in patch-clamp current experiments and its active ingredients were identified. In conclusion, secretory diarrhea induced by treatment with EGFR-TKIs might be partially mediated by the activation of CaCC. Therefore, blocking the CaCC could be a potential new treatment for EGFR-TKI-induced diarrhea.

NIR-Triggered Blasting Nanovesicles for Targeted Multimodal Image-Guided Synergistic Cancer Photothermal and Chemotherapy.

Escorting therapeutics for malignancies by nano-encapsulation to ameliorate treatment effects and mitigate side effects has been pursued in precision medicine. However, the majority of drug delivery systems suffer from uncontrollable drug release kinetics and thus lead to unsatisfactory triggered-release efficiency along with severe side effects. Herein, we developed a unique nanovesicle delivery system that shows near-infrared (NIR) light-triggered drug release behavior and minimal premature drug release. By co-encapsulation of superparamagnetic iron oxide (SPIO) nanoparticles, the ultrasound contrast agent perfluorohexane (PFH), and cisplatin in a silicate-polyaniline vesicle, we achieved the controllable release of cisplatin in a thermal-responsive manner. Specifically, vaporization of PFH triggered by the heat generated from NIR irradiation imparts high inner vesicle pressure on the nanovesicles, leading to pressure-induced nanovesicle collapse and subsequent cisplatin release. Moreover, the multimodal imaging capability can track tumor engagement of the nanovesicles and assess their therapeutic effects. Due to its precise inherent NIR-triggered drug release, our system shows excellent tumor eradication efficacy and biocompatibility in vivo, empowering it with great prospects for future clinical translation.

Identification of optimal dosing schedules of dacomitinib and osimertinib for a phase I/II trial in advanced EGFR-mutant non-small cell lung cancer.

Despite the clinical success of the third-generation EGFR inhibitor osimertinib as a first-line treatment of EGFR-mutant non-small cell lung cancer (NSCLC), resistance arises due to the acquisition of EGFR second-site mutations and other mechanisms, which necessitates alternative therapies. Dacomitinib, a pan-HER inhibitor, is approved for first-line treatment and results in different acquired EGFR mutations than osimertinib that mediate on-target resistance. A combination of osimertinib and dacomitinib could therefore induce more durable responses by preventing the emergence of resistance. Here we present an integrated computational modeling and experimental approach to identify an optimal dosing schedule for osimertinib and dacomitinib combination therapy. We developed a predictive model that encompasses tumor heterogeneity and inter-subject pharmacokinetic variability to predict tumor evolution under different dosing schedules, parameterized using in vitro dose-response data. This model was validated using cell line data and used to identify an optimal combination dosing schedule. Our schedule was subsequently confirmed tolerable in an ongoing dose-escalation phase I clinical trial (NCT03810807), with some dose modifications, demonstrating that our rational modeling approach can be used to identify appropriate dosing for combination therapy in the clinical setting.

Pendimethalin-based herbicide impairs cellular immune response and haemocyte morphology in a beneficial ground beetle.

Herbicides have become the most commonly applied agrochemicals in agroecosystems. Thus, basic knowledge of their physiological effects on insects is needed, especially for understanding their impact on beneficial insect species. In this study, we evaluated the effect of a pendimethalin-based herbicide (PND) on the cellular immune response of the carabid beetle Harpalus (Pseudoophonus) rufipes (De Geer 1774) (Coleoptera, Carabidae), acting as biocontrol agent in agroecosystems. Total and differential haemocyte counts and phagocytosis assay, performed by injecting in vivo carboxylate-modified polystyrene latex beads, were measured in beetles exposed to a recommended field dose (4L per ha) of PND to evaluate the exposure effects over the time. The pattern of haemocyte subpopulations and the decrease of the phagocytic index after the exposure to PND suggested a lowering of P. rufipes ability to face an infection performing a cell-mediated response. PND was also found to cause cytotoxic effects on the haemocyte ultrastructure. Ultrastructural alterations such as irregular shape, large vacuolization of the cytoplasm, and condensation of marginated chromatin were recorded from 2d of exposure. The loss of RER, Golgi apparatus, mitochondria integrity and the swelling of the outer nuclear membrane found in some haemocytes suggested an interference of PND with the membrane permeability. Results indicated that the exposure to PND impairs the distribution, morphology and physiological functions of haemocytes causing a decrease of P. rufipes immunocompetence. Moreover, the sensitivity to herbicide exposure makes this species a suitable model and a useful bioindicator for monitoring exposure effects on non-target species. This study provides useful information to protect and preserve biodiversity of insects in agroecosystems.