Effects of imidacloprid on the survival and biomarker responses of Eristalis tenax larvae (Diptera: Syrphidae): a comparative study between indoor and outdoor exposures.

Imidacloprid is a widely used pesticide in agriculture. It is being found in aquatic ecosystems in agricultural regions. This study aimed to evaluate its effects on the survival rates, acetylcholinesterase (AChE) and catalase (CAT) responses of larval Eristalis tenax hoverflies. The larvae were exposed for 3, 7 and 14 days to increasing concentrations of imidacloprid (0, 0.1, 0.5 and 2 mg L-1) both indoors at a constant temperature of 20 °C and outdoors under varying environmental conditions. The results revealed that indoors and outdoors, the mortality of E. tenax significantly increased with increasing imidacloprid concentration and duration of exposure. Median lethal concentrations (LC50) varied from 0.03 to 0.17 mg L-1 depending on the duration and conditions of exposure. Indoors, AChE activity decreased in all the treatments for all three exposure durations, whereas outdoors the decrease was observed after the short (3-day) and long (14-day) exposure durations. AChE inhibition ranged from 6% to 62% (indoors) and 12% to 62% (outdoors). Variations in CAT activity were observed for both experimental setups, with a decrease outdoors in larvae exposed to 0.5 mg L-1 for 7 days and a gradual dose-dependent increase indoors for exposure lasting 3 and 7 days. This study sheds light on the potential ecological implications of imidacloprid contamination which may cause the decline of aquatic insect populations and pollination rates, leading to disruptions of the food chain and the overall decline of aquatic and terrestrial ecosystem health.

Imidacloprid reduces the mating success of males in bumblebees.

Bumblebees play a vital role in both natural and agricultural environments, but there has been a noticeable decline in their populations. Pesticides, particularly neonicotinoids, are widely regarded as a substantial contributing factor to the decline in bumblebee populations, as evidenced by the detrimental impacts documented across many stages of their life cycle. Mating is vital for the population maintenance of bumblebees. Nevertheless, there is a scarcity of research conducted on the effects of pesticides on the mating process. In this study, we individually examined the impact of imidacloprid on the mating behavior of bumblebee males and queens. A competitive mating experiment was conducted to evaluate the effect on the competitive prowess of male individuals and the mate selection behavior of female individuals. The study revealed that the mating rate of bumblebees exposed to a concentration of 10 ppb of imidacloprid was 3 %. This finding demonstrated a statistically significant impact when compared to the control group, which exhibited a mating rate of 58 % in the normal mating experiment. Furthermore, in the competitive mating experiment, we found that the competitive mating success rate of treated males (1 %) was significantly lower than that of untreated males (35 %). Hence, it provides evidence that neonicotinoid imidacloprid negatively affects bumblebee mating success and cautions us to protect bumblebees from pesticide exposure to prevent a severe impact on their populations.

The Imidazolium Ionic Liquids Toxicity is Due to Their Effect on the Plasma Membrane.

Ionic liquids (ILs) are organic salts with a low melting point. This is due to the fact that their alkyl side chains, which are covalently connected to the ion, hinder the crystallization of ILs. The low melting point of ILs has led to their widespread use as relatively harmless solvents. However, ILs do have toxic properties, the mechanism of which is largely unknown, so identifying the cellular targets of ILs is of practical importance. In our work, we showed that imidazolium ILs are not able to penetrate model membranes without damaging them. We also found that inactivation of multidrug resistance (MDR) pumps in yeast cells does not increase their sensitivity to imidazolium ILs. The latter indicates that the target of toxicity of imidazolium ILs is not in the cytoplasm. Thus, it can be assumed that the disruption of the barrier properties of the plasma membrane is the main reason for the toxicity of low concentrations of imidazolium ILs. We also showed that supplementation with imidazolium ILs restores the growth of cells with kinetically blocked glycolysis. Apparently, a slight disruption of the plasma membrane caused by ILs can, in some cases, be beneficial for the cell.

Sub-lethal effects of the insecticide, imidacloprid, on the responses of damselfly larvae to chemosensory cues indicating predation risk.

Insecticides, including the widely used neonicotinoids, can affect both pest and non-target species. In addition to lethal effects, these insecticides at sub-lethal levels may cause disruption to sensory perception and processing leading to behavioural impairments. In this laboratory experiment, we investigated the effects of a 10-day exposure to the neonicotinoid insecticide, imidacloprid, on the behaviour of larvae of the damselfly, Lestes congener. In tests of baseline activity, imidacloprid concentrations of 1.0 and 10.0 µg/L caused significant reductions in foraging behaviour. Moreover, in response to chemical cues that indicate a potential risk to the larvae, imidacloprid caused the loss of an appropriate antipredator response (reduced foraging) depending on the concentration and duration of exposure. Imidacloprid at 0.1 µg/L caused the loss of responses toward the odour of a beetle (Dytiscus spp.) predator after 10 days of exposure, whereas 1.0 µg/L caused lost responses toward both the predator odour and injured conspecific cues (i.e., alarm cues) and after only 2 days of exposure. However, at 10.0 µg/L, larvae responded appropriately to both cues throughout the duration of the study, suggesting compensatory responses to imidacloprid at higher concentrations. Hence, the lack of appropriate responses at 1.0 µg/L likely resulted from a cognitive impairment rather than chemical alteration of these important chemosensory cues. In the natural environment, such effects will likely cause decreased survivorship in predator encounters. Hence, imidacloprid exposure, even at low concentrations, could have adverse consequences for chemosensory ecology of this damselfly species.

Undifferentiated HepaRG cells show reduced sensitivity to the toxic effects of M8OI through a combination of CYP3A7-mediated oxidation and a reduced reliance on mitochondrial function.

The methylimidazolium ionic liquid M8OI (1-octyl-3-methylimidazolium chloride, also known as [C8mim]Cl) has been detected in the environment and may represent a hazard trigger for the autoimmune liver disease primary biliary cholangitis, based in part on studies using a rat liver progenitor cell. The effect of M8OI on an equivalent human liver progenitor (undifferentiated HepaRG cells; u-HepaRG) was therefore examined. u-HepaRG cells were less sensitive (>20-fold) to the toxic effects of M8OI. The relative insensitivity of u-HepaRG cells to M8OI was in part, associated with a detoxification by monooxygenation via CYP3A7 followed by further oxidation to a carboxylic acid. Expression of CYP3A7 - in contrast to the related adult hepatic CYP3A4 and CYP3A5 forms - was confirmed in u-HepaRG cells. However, blocking M8OI metabolism with ketoconazole only partly sensitized u-HepaRG cells. Despite similar proliferation rates, u-HepaRG cells consumed around 75% less oxygen than B-13 cells, reflective of reduced dependence on mitochondrial activity (Crabtree effect). Replacing glucose with galactose, resulted in an increase in u-HepaRG cell sensitivity to M8OI, near similar to that seen in B-13 cells. u-HepaRG cells therefore show reduced sensitivity to the toxic effects of M8OI through a combination of metabolic detoxification and their reduced reliance on mitochondrial function.

Leaching of unexpected cyazofamid degradation products into groundwater demonstrates gaps in current pesticide risk assessment.

To investigate the formation and leaching potential of degradation products N,N-dimethylsulfamide (DMS) and dimethylsulfamic acid (DMSA) from cyazofamid under real-world agricultural conditions, the fungicide cyazofamid was applied in a potato crop as part of the Danish Pesticide Leaching Assessment Programme (PLAP). Leaching of DMS, DMSA, 4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile (CCIM), and 4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carboxylicacid (CTCA) was monitored in water from the variably saturated zone (suction cups) and groundwater for more than two years following the applications. In total, 424 samples were analyzed for the content of the four degradation products. An additional laboratory study was executed in parallel with the field monitoring study. Here, cyazofamid was applied to soil columns and leaching of the four degradation products was studied under controlled conditions. In the EFSA conclusion on cyazofamid, CCIM and CTCA are mentioned as major relevant metabolites; DMS is not mentioned in the risk assessment and DMSA is only included in acute oral toxicity studies and an in vitro bacterial mutation assay. In contrast to the EFSA conclusion on cyazofamid, our studies showed no leaching of the two major metabolites, CTCA and CCIM, but instead, major leaching of DMS and DMSA in both the field and laboratory studies was observed. That is, both DMS and DMSA leached to the groundwater in concentrations >0.1 µg/L for more than half a year. Based on this, we suggest improvements to the current pesticide risk assessment.

Potential risk of drug-drug interactions of ponatinib via inhibition against human UDP-glucuronosyltransferases.

Ponatinib is an efficient oral tyrosine kinase inhibitor (TKI) for T315I-positive Ph + ALL and T315I-positive chronic myeloid leukemia (CML) or BCR-ABL when no other TKIs can be prescribed. In this research, we evaluated the inhibitory effects of ponatinib on human recombinant UDP-glucuronosyltransferases (UGTs) and predicted the magnitude of potential drug-drug interaction (DDI) risk of co-treatment with ponatinib and UGTs substrates by using in vitro-in vivo extrapolation (IVIVE) method. Our study presented that ponatinib showed a broad-spectrum inhibition against UGTs. Particularly, ponatinib exhibited potent inhibitory effects towards UGT1A7, UGT1A1, and UGT1A9 with IC50 values of 0.37, 0.41, and 0.89 µM, respectively, which might lead to clinically significant DDI.

Chronic and intergenerational toxic effects of 1-decyl-3-methylimidazolium hexafluorophosphate on the water flea, Moina macrocopa.

With the increasing use and production of "green solvents" ionic liquids (ILs) and their known stability in the environment, the potential adverse effects of ILs have become a focus of research. In the present study, acute, chronic, and intergenerational toxic effects of an imidazolium-based ionic liquid, 1-decyl-3-methylimidazolium hexafluorophosphate ([Demim]PF6), on Moina macrocopa were investigated following the parental exposure. The results showed that [Demim]PF6 exhibited high toxicity to M. macrocopa, and the long-term exposure significantly inhibited the survivorship, development, and reproduction of the water flea. Furthermore, it is also observed that [Demim]PF6 induced toxic effects in the following generation of M. macrocopa, resulting in the complete cessation of reproduction in the first offspring generation, and the growth of the organisms was also significantly affected. These findings provided a novel insight into the intergenerational toxicity induced by ILs to crustaceans and suggested that these compounds pose potential risks to the aquatic ecosystem.

Lysosomal trapping of 4-dimethylamino-1-{3-(1-methyl-1H-imidazole-2-yl)propanoyl}piperidine, a hydrophilic and weakly basic amine, in human aortic vascular smooth muscle cells.

Some weakly basic compounds lead to cell death accompanied by cellular vacuolation. The novel analgesic agent, 4-dimethylamino-1-{3-(1-methyl-1H-imidazole-2-yl)propanoyl}piperidine (DMIP), is a hydrophilic and weakly basic compound that induces vacuolation in the vascular smooth muscle cells in dogs. Here, we investigated the vacuolation mechanism and the potential cytotoxicity of DMIP using human aortic vascular smooth muscle cells. When cells were treated with DMIP (0.1, 0.3, and 1 mM) for 6, 24, and 48 h, clear cytoplasmic vacuolation was observed at 1 mM after 24 and 48 h, along with an increase in the intracellular DMIP concentration. The vacuolation and intracellular DMIP were markedly reduced by bafilomycin A1, a vacuolar H+-ATPase inhibitor. The late endosome marker Rab7 and lysosome marker LAMP-2 were highly expressed but the early endosome marker Rab5 and autophagosome marker LC3 were not expressed specifically on the vacuolar membranes. These results suggested that the most vacuoles were enlarged late endosomes/lysosomes, resulting from the accumulation of DMIP by ion trapping. Moreover, DMIP did not affect lysosomal membrane integrity and was less cytotoxic than chloroquine, an inducer of phospholipidosis. The current study provides further insight into the mechanisms of vacuolation and lysosomal trapping induced by the hydrophilic and weakly basic amine DMIP.

Comparative toxicity of two neonicotinoid insecticides at environmentally relevant concentrations to telecoprid dung beetles.

Dung beetles (Coleoptera: Scarabaeinae) frequently traverse agricultural matrices in search of ephemeral dung resources and spend extended periods of time burrowing in soil. Neonicotinoids are among the most heavily applied and widely detected insecticides used in conventional agriculture with formulated products designed for row crop and livestock pest suppression. Here, we determined the comparative toxicity of two neonicotinoids (imidacloprid and thiamethoxam) on dung beetles, Canthon spp., under two exposure profiles: direct topical application (acute) and sustained contact with treated-soil (chronic). Imidacloprid was significantly more toxic than thiamethoxam under each exposure scenario. Topical application LD50 values (95% CI) for imidacloprid and thiamethoxam were 19.1 (14.5-25.3) and 378.9 (200.3-716.5) ng/beetle, respectively. After the 10-day soil exposure, the measured percent mortality in the 3 and 9 µg/kg nominal imidacloprid treatments was 35 ± 7% and 39 ± 6%, respectively. Observed mortality in the 9 µg/kg imidacloprid treatment was significantly greater than the control (p = 0.04); however, the 3 µg/kg imidacloprid dose response may be biologically relevant (p = 0.07). Thiamethoxam treatments had similar mortality as the controls (p > 0.8). Environmentally relevant concentrations of imidacloprid measured in airborne particulate matter and non-target soils pose a potential risk to coprophagous scarabs.

Sensitivity to imidacloprid insecticide varies among some social and solitary bee species of agricultural value.

Pollinator health risks from long-lasting neonicotinoid insecticides like imidacloprid has primarily focused on commercially managed, cavity-nesting bees in the genera Apis, Bombus, and Osmia. We expand these assessments to include 12 species of native and non-native crop pollinators of differing levels of body size, sociality, and floral specialization. Bees were collected throughout 2016 and 2017 from flowering blueberry, squash, pumpkin, sunflower and okra in south Mississippi, USA. Within 30-60 minutes of capture, bees were installed in bioassay cages made from transparent plastic cups and dark amber jars. Bees were fed via dental wicks saturated with 27% (1.25 M) sugar syrup containing a realistic range of sublethal concentrations of imidacloprid (0, 5, 20, or 100 ppb) that are often found in nectar. Bees displayed no visible tremors or convulsions except for a small sweat bee, Halictus ligatus, and only at 100ppb syrup. Imidacloprid shortened the captive longevities of the solitary bees. Tolerant bee species lived ~10 to 12 days in the bioassays and included two social and one solitary species: Halictus ligatus, Apis mellifera and Ptilothrix bombiformis (rose mallow bees), respectively. No other bee species tolerated imidacloprid as well as honey bees did, which exhibited no appreciable mortality and only modest paralysis across concentration. In contrast, native bees either lived shorter lives, experienced longer paralysis, or endured both. Overall, longevity decreased with concentration linearly for social bees and non-linearly for solitary species. The percentage of a bee's captive lifespan spent paralyzed increased logarithmically with concentration for all species, although bumble bees suffered longest. Of greatest concern was comparable debilitation of agriculturally valuable solitary bees at both low and high sublethal rates of imidacloprid.

Toxicity of ionic liquids against earthworms (Eisenia fetida).

Ionic liquids (ILs) are widely used in frontier fields because of their highly tunable properties. Although ILs may have adverse effects on organisms, few studies have focused on their effect on earthworm gene expression. Herein we investigated the toxicity mechanism of different ILs towards Eisenia fetida using transcriptomics. Earthworms were exposed to soil containing different concentrations and types of ILs, and behavior, weight, enzymatic activity and transcriptome were analyzed. Earthworms exhibited avoidance behavior towards ILs and growth was inhibited. ILs also affected antioxidant and detoxifying enzymatic activity. These effects were concentration and alkyl chain length-dependent. Analysis of intrasample expression levels and differences in transcriptome expression levels showed good parallelism within groups and large differences between groups. Based on functional classification analysis, we speculate that toxicity mainly occurs through translation and modification of proteins and intracellular transport functions, which affect protein-related binding functions and catalytic activity. KEGG pathway analysis revealed that ILs may damage the digestive system of earthworms, among other possible pathological effects. Transcriptome analysis reveals mechanisms that cannot be observed by conventional toxicity endpoints. This is useful to evaluate the potential environmental adverse effects of the industrial use of ILs.

The methylimidazolium ionic liquid M8OI is a substrate for OCT1 and p-glycoprotein-1 in rat.

The methylimidazolium ionic liquid M8OI was recently found to be present in both the environment and man. In this study, M8OI disposition and toxicity were examined in an established rat progenitor-hepatocyte model. The progenitor B-13 cell was approx. 13 fold more sensitive to the toxic effects of M8OI than the hepatocyte B-13/H cell. However, this difference in sensitivity was not associated with a difference in metabolic capacities. M8OI toxicity was significantly decreased in a dose-dependent manner by co-addition of the OCT1 (SLC22A1) inhibitor clonidine, but not by OCT2 or OCT3 inhibitors in B-13 cells. M8OI toxicity was also dose-dependently increased by the co-addition of p-glycoprotein-1 (ABCB1B, multi drug resistant protein 1 (MDR1)) substrates/inhibitors. Excretion of B-13-loaded fluorophore Hoechst 33342 was also inhibited by the p-glycoproteins substrate cyclosporin A and by M8OI in a dose-dependent manner. Comparing levels of OCT and p-glycoprotein transcripts and proteins in B-13 and B-13/H cells suggest that the lower sensitivity to M8OI in B-13/H cells is predominantly associated with their higher expression of p-glycoprotein-1. These data together therefore suggest that a determinant in M8OI toxicity in rats is the expression and activity of the p-glycoprotein-1 transporter.

Hormone-mediated multi- and trans-generational reproductive toxicities of 1-ethyl-3-methylimidazolium hexafluorophosphate on Caenorhabditis elegans.

Ionic liquids (ILs) are emergent pollutants and their reproductive toxicities show hormesis, earning attentions on their environmental risk. Yet, their reproductive effects over generations and the mechanisms were seldom explored. In the present study, the reproductive effects of 1-ethyl-3-methylimidazolium hexafluorophosphate ([C2mim]PF6) on Caenorhabditis elegans were measured in 11 continuously exposed generations (F1 to F11) to explore the multi-generational effects, and also in the non-exposed generations of F1 and F11 (i.e., their great-grand-daughters, T4 and T4') to explore the trans-generational effects. In multi-generational reproductive effects, there were concentration-dependent hormetic effects with hazard-benefit alteration between low and high concentrations (e.g., in F3). There were also generation-dependent hormetic effects with hazard-benefit alterations over generations (e.g., between F4 and F5, between F8 and F9, and between F10 and F11). Meanwhile, the results also showed benefit-hazard alteration between F2 and F3, between F6 and F7, and between F9 and F10. Trans-generational effects showed common inhibitions in T4 and T4' at both low and high concentrations. In the biochemical analysis, hormones and hormone-like substances including progesterone (P), estradiol (E2), prostaglandin (PG) and testosterone (T) showed multi- and trans-generational changes with inhibition and stimulation, which contributed to the reproductive outcomes in each generation. Such contribution was also observed in the hormones' precursor cholesterol and the proteins that are essential for reproduction including vitellogenin (Vn) and major sperm protein (MSP). Moreover, the biochemicals showed significant involvement in the connection among generations. Furthermore, the multi- and trans-generational effects of [C2mim]PF6 and histidine showed similar modes of actions despite some differences, implying the contribution of their shared imidazole structure.

The flavonoid rutin protects the bumble bee Bombus impatiens against cognitive impairment by imidacloprid and fipronil.

The ongoing decline of bee populations and its impact on food security demands integrating multiple strategies. Sublethal impairments associated with exposure to insecticides, affecting the individual and the colony levels, have led to insecticide moratoria and bans. However, legislation alone is not sufficient and remains a temporary solution to an evolving market of insecticides. Here, we asked whether bees can be prophylactically protected against sublethal cognitive effects of two major neurotoxic insecticides, imidacloprid and fipronil, with different mechanisms of action. We evaluated the protective effect of the prophylactic administration of the flavonoid rutin, a secondary plant metabolite, present in nectar and pollen, and known for its neuroprotective properties. Following controlled or ad libitum administration of rutin, foragers of the North American bumble bee Bombus impatiens received oral administration of the insecticides at sublethal realistic dosages. Learning acquisition, memory retention and decision speed were evaluated using olfactory absolute conditioning of the proboscis extension response. We show that the insecticides primarily impair acquisition but not retention or speed of the conditioned proboscis extension response. We further show that the administration of the flavonoid rutin successfully protects the bees against impairments produced by acute and chronic administration of insecticides. Our results suggest a new avenue for the protection of bees against sublethal cognitive effects of insecticides.

Imidacloprid-based commercial pesticide causes behavioral, biochemical, and hematological impairments in Wistar rats.

Imidacloprid (IMI) is a neonicotinoid insecticide employed worldwide for crop protection. IMI's mode of action occurs through the agonism of postsynaptic nicotinic acetylcholine receptors (nAChRs), with high specificity for insect nAChRs although there are reports of mammals' toxicity. Studies on IMI's neurotoxicity are not conclusive; therefore, the aim of this study was to evaluate the subchronic toxic effects of an IMI based commercial pesticide on rats. Adult male Wistar rats received an IMI suspension via the oral route at doses of 1.5, 5, and 15 mg/kg for 45 consecutive days. IMI caused an increase in rearing and time spent at the periphery in the locomotor activity test and a decrease in time spent to finish the OX maze task (p < 0.05; ANOVA/Bonferroni). In blood, there was a decrease in mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration (p < 0.05; ANOVA/Bonferroni) and an increase in serum butyrylcholinesterase activity (p < 0.001; ANOVA/Bonferroni). Therefore, subchronic administration of an IMI-based-pesticide caused behavioral and systemic impairments in rats.

Imazalil and its metabolite imazalil-M caused developmental toxicity in zebrafish (Danio rerio) embryos via cell apoptosis mediated by metabolic disorders.

Imazalil (IMZ) is a highly effective fungicide employed in crop production. It has been consistently detected in aquatic environments. The main environmental metabolite of IMZ is imazalil-M (IMZ-M). Limited studies have focused on the toxicity of IMZ and IMZ-M in aquatic organisms. This study systematically evaluated the developmental toxicity of IMZ and IMZ-M on zebrafish (Danio rerio) embryos and explored the potential mechanisms involved. The results showed that IMZ and IMZ-M caused developmental toxicity, characterized by decreased heart rate, hatching inhibition, and pericardial cyst in zebrafish embryos. Subsequently, acridine orange (AO) staining revealed cell apoptosis in the area around the heart regions of zebrafish larvae. Besides, the expression levels of apoptosis-related genes also varied significantly. Furthermore, 1H NMR-based metabolomics analysis showed that IMZ and IMZ-M exposure could induce metabolic profiles disorder in zebrafish larvae. Importantly, zebrafish exposure to IMZ and IMZ-M significantly affected the metabolism of branched - chain amino acids, energy, and ketone bodies, which are related to cell apoptosis. Overall, the toxicity of IMZ and IMZ-M in zebrafish embryos and larvae was characterized, suggesting a theoretical basis for the potential environmental risks of IMZ and its metabolite IMZ-M on non-target organisms.

Short-term exposure to pharmaceuticals negatively impacts marine flatfish species: Histological, biochemical and molecular clues for an integrated ecosystem risk assessment.

The marine habitat and its biodiversity can be impacted by released pharmaceuticals. The short-term (7 days) effect of 3 commonly used drugs - warfarin, dexamethasone and imidazole - on Senegalese sole (Solea senegalensis) juveniles was investigated. Occurrence of hemorrhages, histopathological alterations, antioxidant status, activity of antioxidant enzymes and expression of genes involved in the xenobiotic response (pxr, abcb1 and cyp1a), were evaluated. The results showed a time and drug-dependent effect. Warfarin exposure induced hemorrhages, hepatocyte vacuolar degeneration, and altered the activity of glutathione peroxidase (GPx) and the expression of all the studied genes. Dexamethasone exposure increased liver glycogen content, altered antioxidant status, GPx and superoxide dismutase activities, as well as abcb1 and cyp1a expression. Imidazole induced hepatocyte vacuolar degeneration and ballooning, and altered the antioxidant status and expression of the tested genes. The present work anticipates a deeper impact of pharmaceuticals on the aquatic environment than previously reported, thus underlining the urgent need for an integrated risk assessment.

Dabrafenib- and trametinib-associated glomerular toxicity: A case report.

RATIONALE: Combined treatment with dabrafenib, a B-RAF inhibitor, and trametinib, a mitogen-activated protein kinase inhibitor, is an effective option for patients with metastatic melanoma. A few cases of acute kidney injury associated with tubulointerstitial nephritis and 1 case of nephrotic syndrome have been reported in patients on this drug combination; however, progressive renal injury has not been reported. In this case study, we report a patient with metastatic melanoma who developed glomerular capillary endothelial toxicity and progressive glomerular sclerosis during combination therapy. PATIENT CONCERN: Our patient was an 80-year-old woman with a history of type 2 diabetes and chronic kidney disease. DIAGNOSIS AND INTERVENTION: She was diagnosed with metastatic melanoma and commenced combination therapy with dabrafenib and trametinib. OUTCOMES: Her renal function progressively deteriorated; by month 20 after treatment commencement, her serum creatinine level had increased from 1.59 to 3.74 mg/dL. The first kidney biopsy revealed marked glomerular and endothelial cell damage. Her medication was stopped, but no improvement was evident. At 5 months after the first biopsy, her serum creatinine level had increased to 5.46 mg/dL; a second kidney biopsy revealed focal segmental glomerular sclerosis and marked tubulointerstitial fibrosis. She was started on hemodialysis. LESSONS: We describe a patient with a metastatic melanoma who developed progressive kidney failure during treatment with dabrafenib and trametinib. The most prominent microscopy findings were glomerular endothelial damage in the initial kidney biopsy and accelerated glomerular sclerosis and tubulointerstitial fibrosis in the follow-up biopsy. We hypothesize that a decreased renal reserve and impairment of kidney repair capacity caused by inhibition of B-RAF, a downstream mediator of vascular endothelial growth factor, may explain the progressive kidney injury.

Physiological responses of Pichia stipitis to imidazolium chloride ionic liquids with different carbon chain length.

Ionic liquids (ILs) are used as detoxication agents for fermentation of lignin into ethanol because of their good applicability. However, the residual ILs may be toxic to the yeast. In order to improve the use of ILs for fermentation and protected environment, the toxicity of ILs with different carbon chain length to Pichia stipitis was studied in this paper. Four kinds of common imidazolium chloride ILs ([C4mim]Cl, [C6mim]Cl, [C8mim]Cl and [C10mim]Cl) were selected. ILs can inhibit the proliferation of Pichia stipitis and increase their mortality. Oxidative stress reaction occurred in the cells, and the activities of antioxidant enzymes are affected. Comparing with the integrated biomarker response (IBR) index, it was found that the toxicity increases with increasing chain length. ILs may enter cells by damaging cell membranes and reduce ethanol production by damaging organelles such as mitochondria. ILs caused wrinkles and dents on the surface of cells up to cell deformation and even rupture. The toxicity sequence was as follows: [C10mim]Cl> [C8mim]Cl>[C6mim]Cl>[C4mim]Cl. Due to this toxicity to Pichia stipitis, these compounds should be used carefully in the fermentation process and also to avoid toxic effects on other organisms in the environment.