Morita-Baylis-Hillman adduct 2-(3-hydroxy-2-oxoindolin-3-yl)acrylonitrile (ISACN) modulates the inflammatory process during LPS-induced acute lung injury.

BACKGROUND: Despite its homeostatic role, inflammation is involved in several pathologies, such as acute lung injury. Morita-Ballys-Hilman adducts (MBHA) are a group of synthetic molecules and present a wide range of biological activities, including anti-inflammatory action. Thus, this study aimed to assess whether ISACN, an MBHA, modulates inflammation during acute lung injury induced by lipopolysaccharide (LPS). METHODS: BALB/c mice were intraperitoneally treated with 24 mg/kg ISACN and challenged with LPS (2.5 mg/kg). On bronchoalveolar lavage fluid (BALF), we assessed the total and differential leukocyte count and measurement of protein leakage, cytokines (IL-1ß, IL-6, and TNF-α), and chemokine (CXCL-1). Additionally, lung histopathology was also performed (H&E staining). In vitro studies were conducted with peritoneal macrophages to assess the possible mechanism of action. They were cultured in the presence of ISACN (5 and 10 µM) and stimulated by LPS (1 µg/mL). RESULTS: ISACN reduced neutrophil migration, protein leakage, and inflammatory cytokines (IL-1ß, IL-6, and TNF-α) without interfering with the production of CXCL1. In addition, ISACN caused a decrease in LPS-induced lung injury as evident from histopathological changes. In peritoneal macrophages, ISACN diminishes the nitric oxide and cytokine levels (IL-1ß, IL-6, and TNF-α). The treatment with ISACN (10 µM) also reduced LPS-induced TLR4, CD69, iNOS overexpression, and the LPS-induced ERK, JNK, and p38 phosphorylation. CONCLUSION: Thus, this work showed for the first time the immunomodulatory action of MBHA in LPS-induced acute lung injury and provided new evidence for the mechanisms related to the anti-inflammatory effect of ISACN.

Integrated QSAR and Adverse Outcome Pathway Analysis of Chemicals Released on 3D Printing Using Acrylonitrile Butadiene Styrene.

Additive manufacturing commonly known as 3D printing has numerous applications in several domains including material and biomedical technologies and has emerged as a tool of capabilities by providing fast, highly customized, and cost-effective solutions. However, the impact of the printing materials and chemicals present in the printing fumes has raised concerns about their adverse potential affecting humans and the environment. Thus, it is necessary to understand the properties of the chemicals emitted during additive manufacturing for developing safe and biocompatible fibers having controlled emission of fumes including its sustainable usage. Therefore, in this study, we have developed a computational predictive risk-assessment framework on the comprehensive list of chemicals released during 3D printing using the acrylonitrile butadiene styrene (ABS) filament. Our results showed that the chemicals present in the fumes of the ABS-based fiber used in additive manufacturing have the potential to lead to various toxicity end points such as inhalation toxicity, oral toxicity, carcinogenicity, hepatotoxicity, and teratogenicity. Moreover, because of their absorption, distribution in the body, metabolism, and excretion properties, most of the chemicals exhibited a high absorption level in the intestine and the potential to cross the blood-brain barrier. Furthermore, pathway analysis revealed that signaling like alpha-adrenergic receptor signaling, heterotrimeric G-protein signaling, and Alzheimer's disease-amyloid secretase pathway are significantly overrepresented given the identified target proteins of these chemicals. These findings signify the adversities associated with 3D printing fumes and the necessity for the development of biodegradable and considerably safer fibers for 3D printing technology.

Acrylonitrile induced cell cycle arrest and apoptosis by promoting the formation of reactive oxygen species in human choriocarcinoma cells.

Acrylonitrile (AN), which is widely utilized in the manufacture of plastics, acrylamide, acrylic fibers, and resins, is also one of main components of cigarette smoke (CS). In this study, we examined the effects of AN on the cell viability and apoptosis of JEG-3 and BeWo human choriocarcinoma cancer cell lines. A cell viability assay confirmed that AN decreased the cell proliferation of JEG-3 and BeWo cells in a dose-dependent manner. Additionally, Western blot assay revealed that protein expression of cyclin D and cyclin E decreased, while protein expression of p21 and p27 increased in response to AN treatment for 48 hr. The changes in reactive oxygen species (ROS) levels in JEG-3 and BeWo cells exposed to AN were also measured by a dichlorofluorescein diacetate (DCFH-DA) assay, which revealed that ROS levels increased in response to AN treatment for 48 hr. Moreover, western blot assay confirmed that AN treatment of JEG-3 and BeWo cells for 4 hr promoted the expression of phosphorylated eukaryotic initiation factor 2 alpha protein (p-eIF2α), C/EBP homologous protein (CHOP) and caspase 12, which are known to be involved in ROS-mediated endoplasmic reticulum stress (ER-stress)-related apoptosis. Overall, the protein expression of p53 and Bax (a pro-apoptosis marker) increased, while the expression of Bcl-xl (an anti-apoptotic marker) decreased and the number of apoptotic cells increased in response to AN treatment for 48 hr. Taken together, these results suggest that AN has the potential to induce apoptosis of JEG-3 and BeWo human choriocarcinoma cancer cells by activating ROS.

Onco-Nephrology: Cancer, chemotherapy and kidney. / Onco-Nefrología: cáncer, quimioterapia y riñón.

Chronic kidney disease (CKD), cancer and haematological diseases share areas of reciprocal influence. Cancer can affect the kidney either as glomerular lesions or as a result of the toxic effects of medication or radiation with acute (thrombotic microangiopathy, acute kidney injury, interstitial nephropathies among others) or chronic processes (worsening of CKD after nephrectomy due to renal cancer, interstitial fibrosis, hydroelectrolytic disorders). On the other hand, patients who require renal replacement therapy with dialysis and particularly with kidney transplantation are at high risk of onset of cancer due to the immunosuppression situation that they generate. In addition to conventional chemotherapy, innovative treatments have been developed: target agents against growth factors and their receptor; anti-angiogenic drugs; immunoregulatory proteins; cell cycle regulators; and enzyme inhibitors. Other immunotherapeutic approaches have also been developed, such as vaccines, adoptive cell therapy (CAR T cells) or development of antibodies. All these therapeutic advances will improve the outcomes against cancer and haematological diseases, but they are not free from secondary renal problems. Onco-Nephrology is already an important area for the Spanish Society of Nephrology with a large number of inter-consultations. Nephrologists need a better understanding of rapidly evolving areas of cancer biology and its treatment in order to become valued members of the cancer care team and to provide the best nephrology care possible.

Longitudinal stability in cigarette smokers of urinary biomarkers of exposure to the toxicants acrylonitrile and acrolein.

The urinary metabolites cyanoethyl mercapturic acid (CEMA) and 3-hydroxypropyl mercapturic acid (3-HPMA) have been widely used as biomarkers of exposure to acrylonitrile and acrolein, respectively, but there are no published data on their consistency over time in the urine of cigarette smokers. We provided, free of charge over a 20 week period, Spectrum NRC600/601 research cigarettes to cigarette smokers in the control arm of a randomized clinical trial of the reduced nicotine cigarette. Urine samples were collected at weeks 4, 8, 12, 16, and 20 and analyzed for CEMA and 3-HPMA, and total nicotine equivalents (TNE) using validated methods. Creatinine-corrected intra-class correlation coefficients for CEMA, 3-HPMA, and TNE were 0.67, 0.46, and 0.68, respectively, indicating good longitudinal consistency for CEMA, while that of 3-HPMA was fair. A strong correlation between CEMA and TNE values was observed. These data support the use of CEMA as a reliable biomarker of tobacco smoke exposure. This is the first report of the longitudinal stability of the biomarkers of acrylonitrile and acrolein exposure in smokers. The data indicate that CEMA, the biomarker of acrylonitrile exposure, is consistent over time in cigarette smokers, supporting its use. While 3-HPMA levels were less stable over time, this biomarker is nevertheless a useful monitor of human acrolein exposure because of its specificity to this toxicant.

Xanthogranulomatous reaction to trametinib for metastatic malignant melanoma.

Trametinib, a mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, has demonstrated great promise in treating metastatic melanoma associated with BRAF V600E and V600K mutations; however, it also is highly associated with cutaneous adverse events (AEs). As both BRAF and MEK inhibitors become increasingly used to treat malignant melanoma, it is important to better characterize these AEs so that we can manage them. Herein, we present a case of a 66-year-old man who developed erythematous scaly papules on the face and bilateral upper extremities after beginning therapy with trametinib. The severity of the reaction worsened on trametinib monotherapy compared to combination therapy with a BRAF inhibitor. Biopsy revealed a xanthogranulomatous reaction.

Protective Effect of Apigenin on Acrylonitrile-Induced Inflammation and Apoptosis in Testicular Cells via the NF-κB Pathway in Rats.

Apigenin (AP) as a plant flavonoid is found to attenuate acrylonitrile (ACN) toxicity by reducing ROS production and inhibiting apoptosis. Therefore, the present study aimed to evaluate the role of AP on ACN-induced inflammation and apoptosis in germ cells and whether it is through the NF-κB signaling pathway. AP increased the concentrations of lactate dehydrogenase isozyme (LDH) and sorbitol dehydrogenase (SDH), while the concentrations of interleukin ß (IL-1ß), tumor-necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were significantly reduced. AP could downregulate the expression of the nuclear factor of kappa B (NF-κB) and inhibit phosphorylation of the inhibitory κBα (IκBα). Cleaved caspase-3 was also upregulated by AP, and the apoptotic were less than those in the ACN group. These results suggest that AP might improve maturation and energy metabolism of testes, inhibit NF-κB activation. Then AP could further downregulate NF-κB signal and inhibit the germ cell apoptosis and reduce inflammatory caused by ACN.

[Determination of acrylonitrile in injection molding process: data analysis and recommendations].

Objective: To investigate whether the identification of acrylonitrile, an occupational hazard factor for the industry of injection molding and plastic products, reported in literature is reasonable, and to put forward some recommendations. Methods: Professional articles published from 1990 to 2016 were searched, and an analysis was performed for the data on the determination of acrylonitrile in the industry of injection molding and plastic products from 2003 to 2016 in Longhua Center for Disease Control and Prevention of Shenzhen. Results: According to the literature, the detection rate of acrylonitrile was 10.7%, and the detection results did not exceed the limit. Conclusion: At present, acrylonitrile may not be used as a routine test item for the industry of injection molding and plastic products, in order to save manpower and material resources.

Separation of outer retinal layers secondary to selumetinib.

New therapeutic agents targeting the mitogen-activated protein (MAP) kinase pathway, including MEK inhibitors, are currently being evaluated in phase 1 and 2 clinical trials for pediatric brain tumors. Ophthalmologic side effects from MEK inhibitors have previously only been reported in adults and included retinal vein occlusion, central retinal artery occlusion, and separation of the neurosensory retina. We report 2 patients with optic pathway gliomas who developed outer retinal layer separation visualized by optical coherence tomography while taking the MEK inhibitor selumetinib. After discontinuation of selumetinib, the outer retinal layer separation resolved without visual sequelae. One patient has been retreated with selumetinib and experienced recurrence of these findings.

A mitogen-activated protein kinase kinase inhibitor induced compound skin toxicity with oedema in metastatic malignant melanoma.

We report three cases of skin toxicity associated with oral mitogen-activated protein kinase kinase (MEK) inhibitor treatment for metastatic malignant melanoma (MM). All three patients developed oedema, and a single patient experienced eyelash trichomegaly. This is the first known report of eyelash trichomegaly secondary to MEK inhibitor use. We also discuss possible mechanisms for MEK inhibitor-associated oedema development. This series supports the role of the dermatologist in the screening and management of patients in the rapidly developing oncology setting, as new targeted agents can give rise to marked skin toxicity.

AN69-ST membrane, a useful option in two cases of severe dialysis reactions.

Adverse reactions during hemodialysis (HD) sessions although infrequent can be severe. We report two cases of recurrent adverse reactions to HD biocompatible synthetic membranes. Change to AN-69 dialyzer allowed subsequent uneventful HD sessions. This may be due to the surface treated membrane, which provides greater adsorption capacity and improved biocompatibility.

Serum cytokeratin 18 and cytokine elevations suggest a high prevalence of occupational liver disease in highly exposed elastomer/polymer workers.

OBJECTIVE: Cytokeratin 18 (CK18) is a novel serologic biomarker for occupational liver disease. The purpose of this study is to determine the prevalence of CK18 elevation in elastomer/polymer workers exposed to acrylonitrile, 1,3-butadiene, and styrene. METHODS: A total of 82 chemical workers were evaluated. Cytokeratin 18 was determined by enzyme-linked immunosorbent assay and proinflammatory cytokines were measured by multi-analyte chemiluminescent detection. RESULTS: Thirty-nine percent (32 of 82) had elevated CK18 levels, which were not explained by alcohol or obesity, except in potentially four cases. The pattern of CK18 elevation was consistent with toxicant-associated steatohepatitis (TASH) in the majority of cases (78%). Tumor necrosis factor α, interleukin-6, interleukin-8, monocyte chemotactic protein-1, and plasminogen activator inhibitor-1 were increased in these workers compared with those with normal CK18 levels. CONCLUSIONS: These results suggest a high prevalence of occupational liver disease and TASH in elastomer/polymer workers with elevated proinflammatory cytokines.

Provisional Advisory Levels (PALs) for acrylonitrile.

Application of Provisional Advisory Level (PAL) protocols was performed for acrylonitrile, as experimental data permitted. Three levels (PAL 1, PAL 2, and PAL 3), distinguished by severity of toxic effects, are developed for 24-hour, 30-day, 90-day, and 2-year durations of potential drinking water and inhalation exposures for the general public. For background on the PAL Program and a description of the methodology used in deriving PALs, the reader is referred to accompanying papers in this Supplement. Human data were limited to inhalation exposures. The animal experimental data set for this chemical was robust for inhalation and oral studies, with the exception of appropriate data for inhalation 30-day, 90-day, and 2-year PAL 3 values. PAL estimates were approved by the Expert Consultation Panel for Provisional Advisory Levels in October 2007. Oral 24-hour PALs for acrylonitrile are PAL 1 = 7 mg/L; PAL 2 = 23 mg/L; and PAL 3 = 88 mg/L. Oral 30-day and 90-day PALs are PAL 1 = 0.35 mg/L; PAL 2 = 7 mg/L; and PAL 3 = 17 mg/L. Oral 2-year PALs are PAL 1 = 0.35 mg/L; PAL 2 = 3.5 mg/L; and PAL 3 = 12 mg/L. Acrylonitrile inhalation PAL values for 24-hour exposure are PAL 1 = 0.17 ppm; PAL 2 = 3.5 ppm; and PAL 3 = 5.1 ppm; the 30-day and 90-day inhalation exposure values are PAL 1 = 0.15 ppm and PAL 2 = 0.60 ppm. The 2-year inhalation values are PAL 1 = 0.014 ppm and PAL 2 = 0.12 ppm. PAL 3 values for 30 days, 90 days, and 2 years are not recommended due to insufficient data.

[Nervous system disorders in workers engaged into acrylonitrile production].

The article deals with results of clinical examination covering workers of acrylonitrile production on Krasnoyarsk synthetic rubber plant. The authors first described nervous system disorders in people having variable duration of exposure to acrylonitrile. Severity of these disorders was connected with the poison concentration in workplace, with content of inclusion complex containing acrylonitrile and hemoglobin in RBC of the exposed individuals.

Mortality among workers exposed to acrylonitrile in fiber production: an update.

OBJECTIVE: The investigation updates the mortality experience through 2002 for a cohort of workers exposed to acrylonitrile (AN). METHODS: Standardized mortality ratios (SMR) were estimated based on two reference populations: the US population and a regional employee population. Exposure-response analyses were conducted using Cox regression models for cumulative and mean intensity exposure measures. RESULTS: In the cohort of 2548 workers, 839 deaths have occurred with 91 deaths due to respiratory system cancer. Most standardized mortality ratio estimates are at or near no-effects levels. Hazard ratio (HR) estimates indicate no increased mortality risk for respiratory system cancer (adjusted HR = 0.96, 95% confidence interval: 0.74, 1.25). CONCLUSIONS: In summary, no mortality outcome of a priori interest, principally respiratory system cancer, is associated with increased AN exposure among fiber production workers over five decades of follow-up.