Assessing the impact of antiviral drugs commonly utilized during the COVID-19 pandemic on the embryonic development of Xenopus laevis.

The antiviral drugs favipiravir and oseltamivir are widely used to treat viral infections, including coronavirus 2019 (COVID-19), and their levels are expected to increase in the aquatic environment. In this study, the potential toxic and teratogenic effects of these drugs were evaluated using the frog embryo teratogenesis assay Xenopus (FETAX). In addition, glutathione S-transferase (GST), glutathione reductase (GR), catalase, carboxylesterase (CaE), and acetylcholinesterase (AChE) enzyme activities and malondialdehyde levels were measured as biochemical markers in embryos and tadpoles for comparative assessment of the sublethal effects of the test compounds. Prior to embryo exposure, drug concentrations in the exposure medium were measured with high-performance liquid chromatography. The 96-h median lethal concentration (LC50) was 137.9 and 32.3 mg/L for favipiravir and oseltamivir, respectively. The teratogenic index for favipiravir was 4.67. Both favipiravir and oseltamivir inhibited GR, CaE, and AChE activities in embryos, while favipiravir increased the GST and CaE activities in tadpoles. In conclusion, favipiravir, for which teratogenicity data are available in mammalian test organisms and human teratogenicity is controversial, inhibited Xenopus laevis embryo development and was teratogenic. In addition, sublethal concentrations of both drugs altered the biochemical responses in embryos and tadpoles, with differences between the developmental stages.

Discovery of new N-Phenylamide Isoxazoline derivatives with high insecticidal activity and reduced honeybee toxicity.

Isoxazoline is a novel structure with strong potential for controlling agricultural insect pests, but its high toxicity to honeybees limits its development in agriculture. Herein, a series of N-phenylamide isoxazoline derivatives with low honeybee toxicity were designed and synthesized using the intermediate derivatization method. Bioassay results showed that these compounds exhibited good insecticidal activity. Compounds 3b and 3f showed significant insecticidal effects against Plutella xylostella (P. xylostella) with median lethal concentrations (LC50) of 0.06 and 0.07 mg/L, respectively, comparable to that of fluralaner (LC50 = 0.02 mg/L) and exceeding that of commercial insecticide fluxametamide (LC50 = 0.52 mg/L). It is noteworthy that the acute honeybee toxicities of compounds 3b and 3f (LD50 = 1.43 and 1.63 µg/adult, respectively) were significantly reduced to 1/10 of that of fluralaner (LD50 = 0.14 µg/adult), and were adequate or lower than that of fluxametamide (LD50 = 1.14 µg/adult). Theoretical simulation using molecular docking indicates that compound 3b has similar binding modes with fluralaner and a similar optimal docking pose with fluxametamide when binding to the GABA receptor, which may contribute to its potent insecticidal activity and relatively low toxicity to honey bees. This study provides compounds 3b and 3f as potential new insecticide candidates and provides insights into the development of new isoxazoline insecticides exhibiting both high efficacy and environmental safety.

Biochemical and histopathological evaluation of systemic and ocular toxicity of favipiravir in rats.

Purpose: Favipiravir (FAV) used against COVID-19 is an antiviral drug that causes adverse reactions, such as hyperuricaemia, liver damage, and hematopoetic toxicity. The aim of the study was to investigate the systemic and ocular side-effects of FAV in rats, for the first time.Materials and methods: A total of 18 albino male Wistar rats were used in the study. The rats were divided into 3 groups as the healthy group (HG), the group given 50 mg/kg/day favipiravir (FAV50), and the group given 200 mg/kg/d favipiravir (FAV200). These doses were given to the experimental groups for one week. At the end of the experiment histopathological examinations were performed on the conjunctiva and sclera of the eye. In addition, malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), interleukin-1ß (IL-1ß), and tumor necrosis factor alpha (TNF-α) levels were measured in blood samples taken from rats. Results: Compared to HG, the MDA (1.37 ± 0.61 vs. 4.82 ± 1.40 µmol/mL), IL-1ß (2.52 ± 1.14 vs. 6.67 ± 1.99 pg/mL), and TNF-α levels (3.28 ± 1.42 vs. 8.53 ± 3.06 pg/mL) of the FAV200 group were higher. The levels of tGSH (7.58 ± 1.98 vs. 2.50 ± 0.98 nmol/mL) and SOD (13.63 ± 3.43 vs. 3.81 ± 1.43 U/mL) the FAV200 group were lower than the HG (p < 0.05, for all). The degree of damage to the cornea and sclera of the FAV200 group was quite high according to HG (p < 0.001). Conclusions: FAV can cause damage to rat conjunctiva and sclera by increasing oxidant stress and inflammation at high dose.

Local anesthetic dosing and toxicity of adult truncal catheters: a narrative review of published practice.

BACKGROUND/IMPORTANCE: Anesthesiologists frequently use truncal catheters for postoperative pain control but with limited characterization of dosing and toxicity. OBJECTIVE: We reviewed the published literature to characterize local anesthetic dosing and toxicity of paravertebral and transversus abdominis plane catheters in adults. EVIDENCE REVIEW: We searched the literature for bupivacaine or ropivacaine infusions in the paravertebral or transversus abdominis space in humans dosed for 24 hours. We evaluated bolus dosing, infusion dosing and cumulative 24-hour dosing in adults. We also identified cases of local anesthetic systemic toxicity and toxic blood levels. FINDINGS: Following screening, we extracted data from 121 and 108 papers for ropivacaine and bupivacaine respectively with a total of 6802 patients. For ropivacaine and bupivacaine, respectively, bolus dose was 1.4 mg/kg (95% CI 0.4 to 3.0, n=2978) and 1.0 mg/kg (95% CI 0.18 to 2.1, n=2724); infusion dose was 0.26 mg/kg/hour (95% CI 0.06 to 0.63, n=3579) and 0.2 mg/kg/hour (95% CI 0.06 to 0.5, n=3199); 24-hour dose was 7.75 mg/kg (95% CI 2.1 to 15.7, n=3579) and 6.0 mg/kg (95% CI 2.1 to 13.6, n=3223). Twenty-four hour doses exceeded the package insert recommended upper limit in 28% (range: 17%-40% based on maximum and minimum patient weights) of ropivacaine infusions and 51% (range: 45%-71%) of bupivacaine infusions. Toxicity occurred in 30 patients and was associated with high 24-hour dose, bilateral catheters, cardiac surgery, cytochrome P-450 inhibitors and hypoalbuminemia. CONCLUSION: Practitioners frequently administer ropivacaine and bupivacaine above the package insert limits, at doses associated with toxicity. Patient safety would benefit from more specific recommendations to limit excessive dose and risk of toxicity.

Evaluation of the toxicological effects of favipiravir (T-705) on liver and kidney in rats: biochemical and histopathological approach.

Favipiravir is a selective RNA polymerase inhibitor and a broad-spectrum antiviral drug, an important agent used in viral infections, including Ebola, Lassa, and COVID-19. This study aims to evaluate the potential toxicological effects of favipiravir administration on rats' liver and kidney tissues. Favipiravir was applied for five and ten days in the present study. During this period, it was aimed to determine possible toxic effects on the liver and kidney. For this purpose, the impact of favipiravir on liver and kidney tissues were examined using histopathologic and biochemical methods. The present study showed that favipiravir administration led to an elevation in the liver and kidney serum enzymes and oxidative and histopathologic damages. Favipiravir administration caused apoptotic cell death (Caspase-3 and Bcl-2), inflammation (NF-κB and IL-6), and a decrease in renal reabsorption (AQP2) levels. In the evaluation of the findings obtained in this study, it was determined that the favipiravir or metabolites caused liver and kidney damages.

Substance P and Glucagon-like Peptide-17-36 Amide Mediate Anorexic Responses to Trichothecene Deoxynivalenol and Its Congeners.

Type B trichothecenes commonly contaminate cereal grains and include five structurally related congeners: deoxynivalenol (DON), 3-acetyldeoxynivalenol (3-ADON), 15-acetyldeoxynivalenol (15-ADON), fusarenon X (FX), and nivalenol (NIV). These toxins are known to have negative effects on human and animal health, particularly affecting food intake. However, the pathophysiological basis for anorexic effect is not fully clarified. The purpose of this study is to explore the potential roles of the brain-gut peptides substance P (SP) and glucagon-like peptide-17-36 amide (GLP-1) in anorexic responses induced by type B trichothecenes following both intraperitoneal (IP) and oral administration. SP and GLP-1 were elevated at 1 or 2 h and returned to basal levels at 6 h following exposure to DON and both ADONs. FX induced the production of both brain gut peptides with initial time at 1 or 2 h and duration > 6 h. Similar to FX, exposing IP to NIV caused elevations of SP and GLP-1 at 1 h and lasted more than 6 h, whereas oral exposure to NIV only increased both brain gut peptides at 2 h. The neurokinin-1 receptor (NK-1R) antagonist Emend® dose-dependently attenuated both SP- and DON-induced anorexic responses. Pretreatment with the GLP-1 receptor (GLP-1R) antagonist Exending9-39 induced a dose-dependent attenuation of both GLP-1- and DON-induced anorexic responses. To summarize, the results suggest that both SP and GLP-1 play important roles in anorexia induction by type B trichothecenes.

Dermatitis por Paederus. Acerca de tres casos / Paederus dermatitis. About three cases

Resumen La "dermatitis por Paederus", es una dermatitis vesicante secundaria al contacto con coleópteros de este género. Se describen más de 600 especies de Paederus, con predominio en áreas tropicales y subtropicales, varias de ellas se asocian a dermatitis. Al ser apretado o aplastado contra la piel, la hemolinfa que contiene paederina, lesiona la epidermis, por medio del bloqueo de la mitosis de células epiteliales basales y células suprabasales. Se exponen tres casos clínicos dermatológicos con lesiones características compatibles con "dermatitis por Paederus". Se realiza además una revisión bibliográfica sobre el tema, a fin de exponer los puntos más importantes de esta patología de gran interés médico y que representa en muchas ocasiones desafíos diagnósticos.

Summary "Paederus dermatitis" is a vesicant dermatitis secondary to contact with this beetle. There are more than 600 species of Paederus described, with a predominance in tropical and subtropical areas, some of these are associated with dermatitis. When they are pressed or crushed against the skin, releases secretions with pederin, that causes an injury in the epidermis, by mitosis blocking of basal and suprabasal epithelial cells. This article describes three dermatological clinical cases with charac-teristic lesions compatible with "Paederus dermatitis". In addition a bibliographic review is presented in order to expose the most important points of this medical interest pathology, that frequently represents diagnostic challenges.

Potential Common Mechanisms of Cytotoxicity Induced by Amide Herbicides via TRPA1 Channel Activation.

The "Multi-Threat Medical Countermeasure (MTMC)" strategy was proposed to develop a single drug with therapeutic efficacy against multiple pathologies or broad-spectrum protection against various toxins with common biochemical signals, molecular mediators, or cellular processes. This study demonstrated that cytotoxicity, expression of transient receptor potential cation channel subfamily A member 1 (TRPA1) mRNA, and intracellular calcium influx were increased in A549 cells exposed to amide herbicides (AHs), in which the order of cytotoxicity was metolachlor > acetochlor > propisochlor > alachlor > butachlor > propanil > pretilachlor, based on IC50 values of 430, 524, 564, 565, 619, 831, and 2333 µM, respectively. Inhibition/knockout of TRPA1 efficiently protected against cytotoxicity, decreased TRPA1 mRNA expression, and reduced calcium influx. The results suggested that the TRPA1 channel could be a key common target for AHs poisoning. The order of TRPA1 affinity for AHs was propanil > pretilachlor > metolachlor > (propiso/ala/aceto/butachlor), based on KD values of 16.2, 309, and 364 µM, respectively. The common molecular mechanisms of TRPA1-AHs interactions were clarified, including toxicity-effector groups (benzene ring, nitrogen/oxygen-containing functional groups, halogen) and residues involved in interactions (Lys787, Leu982). This work provides valuable information for the development of TRPA1 as a promising therapeutic target for broad-spectrum antitoxins.

Design, Synthesis, and Structure-Activity Relationship Studies of Bisamide Derivatives of Amphotericin B with Potent Efficacy and Low Toxicity.

Amphotericin B (AMB, 1) is the most powerful antibiotic in treating potentially life-threatening invasive fungal infections (IFIs), though severe toxicity derived from self-aggregation greatly limits its clinical application. Herein, we applied a bisamidation strategy at the C16-COOH and C3'-NH2 to improve the therapeutic properties by suppressing self-aggregation. It was found that basic amino groups at the residue of C16 amide were beneficial to activity, while lipophilic fragments contributed to toxicity reduction. Additionally, N-methyl-amino acetyl and amino acetyl moieties at C3' amide could help keep the fungistatic effectiveness. The modification work culminated in the discovery of 36 (ED50 = 0.21 mg/kg), which exerted a 1.5-fold stronger antifungal efficacy than amphamide, the optimal derivative theretofore, in mice, low self-aggregation propensity, and thus low acute toxicity. With the improvement in therapeutic index and good PK profile, 36 is promising for further development as a second-generation polyene antifungal agent.

Effects of nalbuphine on the cardiotoxicity of ropivacaine in rats.

When combined with nalbuphine, local anesthetics show a longer duration of nerve block without increasing complications. However, no evidence is available concerning the effect of nalbuphine on the cardiotoxicity of local anesthetics. The objective of this work is to investigate whether nalbuphine pretreatment can increase the lethal dose threshold of ropivacaine in rats. Anesthetized Sprague Dawley rats were pretreated with different doses of nalbuphine (0.4, 0.8, 1.5, 3.0, 5.0 mg/kg) or NS (normal saline, negative control) or 30% LE (lipid emulsion, positive control) 2 ml/kg/min for 5 min (n = 6). Then 0.5% ropivacaine was infused at a rate of 2.5 mg/kg/min until asystole occurs. Time of arrhythmia, 50% mean arterial pressure- and 50% heart rate-reduction, and asystole were recorded, and ropivacaine doses were calculated. Nalbuphine (0.4-5.0 mg/kg) did not affect ropivacaine-induced arrhythmia, 50% mean arterial pressure-reduction and 50% heart rate-reduction, and asystole in rats compared with NS pre-treatment. The asystole dose threshold (in milligrams per kilogram) of group LE was higher than that of group NS (NS 28.25(6.32) vs. LE, 41.58(10.65); P = 0.04; 95% confidence interval 0.23 to 26.45), while thresholds of arrhythmia, 50% mean arterial pressure-reduction, and 50% heart rate-reduction were not affected by LE. Nalbuphine doses of 0.4-5.0 mg/kg pretreatment did not increase the threshold of ropivacaine cardiotoxicity compared with NS control; 30% LE increases the lethal dose threshold of ropivacaine in rats.

Ropivacaine-loaded, hydroxypropyl chitin thermo-sensitive hydrogel combined with hyaluronan: an injectable, sustained-release system for providing long-lasting local anesthesia in rats.

BACKGROUND AND OBJECTIVE: Ropivacaine hydrochloride is a commonly used local anesthetic in clinics. However, local injection or continuous infusion of ropivacaine has been associated with several disadvantages. Accordingly, it is important to develop a new controlled release system for local administration of ropivacaine to achieve a prolong anesthetic effect, improve efficacy, and minimize the side effects. METHODS: We developed injectable hydroxypropyl chitin thermo-sensitive hydrogel (HPCH) combined with hyaluronan (HA), which was used to synthesize a ropivacaine (R)-loaded controlled release system. We then conducted drug release test and cytotoxicity assay in vitro. Importantly, we examined the analgesic effects and biocompatibility of this system in vivo by injecting different concentrations of R-HPCH-HA (7.5, 15, 22.5 mg/mL), ropivacaine hydrochloride (RHCL, 7.5 mg/mL), or saline (all in 0.5 mL) near the sciatic nerve in rats. RESULTS: R-HPCH-HA induced concentration-dependent thermal-sensory blockade and motor blockade in vivo. In hot plate test, R-HPCH-HA (22.5 mg/mL) induced a significant longer thermal-sensory blockade (17.7±0.7 hours), as compared with RHCL (7.5 mg/mL, 5.7±0.8 hours, n=6/group, p<0.05). It also produced a more prolonged motor blockade (6.8±0.8 hours) than RHCL (3.5±0.8 hours, p<0.05). R-HPCH-HA caused less cytotoxicity than RHCL, as indicated by the higher cell viability in vitro (n=8/group). CONCLUSION: Our findings in a sciatic nerve block model demonstrated that the injectable, ropivacaine-loaded controlled release system effectively prolonged the local analgesic effect in rats without notable side effects.

Favipiravir exposure and pregnancy outcome of COVID-19 patients.

OBJECTIVE: COVID-19 is a rapidly spreading disease and many people have been infected in a short time. Favipiravir is under investigation for the treatment of COVID-19 and given to patients in many countries following emergency use approval. Based on data from animal studies, favipiravir use is contraindicated during pregnancy. Currently, there is no human data except for a single case report on use of favipiravir in pregnancy. STUDY DESIGN: This article includes the outcomes of 29 pregnancies reported to the Clinical Pharmacology and Toxicology Unit regarding favipiravir use in pregnancy. For drug risk assessment, maternal characteristics were obtained at first contact. After the expected day of delivery, follow-up is conducted by phone call and all relevant data regarding pregnancy and newborn outcome were documented. RESULTS: Of the 29 pregnancies exposed to favipiravir, 5 were electively terminated and 24 resulted in live birth. There were no miscarriages or no stillbirths. There were 25 live births including one pair of twins. Three children were born premature, and one infant had patent foramen ovale. Birth weights, lengths and head circumferences of all infants were within normal range. CONCLUSION: The results of the study indicate that favipiravir is unlikely to be a major human teratogen, but experience is still limited for a well-grounded risk assessment. Although these findings may be useful for the physicians and patients, larger studies are needed due to small number of cases.

SDHI Fungicide Toxicity and Associated Adverse Outcome Pathways: What Can Zebrafish Tell Us?

Succinate dehydrogenase inhibitor (SDHI) fungicides are increasingly used in agriculture to combat molds and fungi, two major threats to both food supply and public health. However, the essential requirement for the succinate dehydrogenase (SDH) complex-the molecular target of SDHIs-in energy metabolism for almost all extant eukaryotes and the lack of species specificity of these fungicides raise concerns about their toxicity toward off-target organisms and, more generally, toward the environment. Herein we review the current knowledge on the toxicity toward zebrafish (Brachydanio rerio) of nine commonly used SDHI fungicides: bixafen, boscalid, fluxapyroxad, flutolanil, isoflucypram, isopyrazam, penthiopyrad, sedaxane, and thifluzamide. The results indicate that these SDHIs cause multiple adverse effects in embryos, larvae/juveniles, and/or adults, sometimes at developmentally relevant concentrations. Adverse effects include developmental toxicity, cardiovascular abnormalities, liver and kidney damage, oxidative stress, energy deficits, changes in metabolism, microcephaly, axon growth defects, apoptosis, and transcriptome changes, suggesting that glycometabolism deficit, oxidative stress, and apoptosis are critical in the toxicity of most of these SDHIs. However, other adverse outcome pathways, possibly involving unsuspected molecular targets, are also suggested. Lastly, we note that because of their recent arrival on the market, the number of studies addressing the toxicity of these compounds is still scant, emphasizing the need to further investigate the toxicity of all SDHIs currently used and to identify their adverse effects and associated modes of action, both alone and in combination with other pesticides.

Toxicity of the insecticide sulfoxaflor alone and in combination with the fungicide fluxapyroxad in three bee species.

The sulfoximine insecticide sulfoxaflor is regarded as a potential substitute for neonicotinoids that were recently banned in the EU due to their side effects on bees. Like neonicotinoids, sulfoxaflor acts as a competitive modulator of nicotinic acetylcholine receptors. In agricultural environments, bees are commonly exposed to combinations of pesticides, and neonicotinoids are known to interact synergistically with fungicides. The objective of our study is to assess the acute oral toxicity of sulfoxaflor alone and in combination with a single dose of fluxapyroxad, a succinate dehydrogenase inhibitor (SDHI) fungicide, in three bee species: Apis mellifera, Bombus terrestris and Osmia bicornis. Because synergism may be dose-dependent, we tested a range of sulfoxaflor doses. Synergistic effects were assessed using three different approaches: Bliss criterion of drugs independence, ratio test comparing LD50s and model deviation ratio. Osmia bicornis was the most sensitive species to sulfoxaflor and both O. bicornis and A. mellifera showed significant synergism between the insecticide and the fungicide. For the most part, these synergistic effects were weak and only occurred at early assessment times and intermediate sulfoxaflor doses. The potential ecological relevance of these effects should be confirmed in field and/or cage studies. Overall, our laboratory results demonstrate that sulfoxaflor is somewhat less toxic than the recently banned neonicotinoids imidacloprid, thiamethoxam and clothianidin, but much more toxic than other neonicotinoids (acetamiprid, thiacloprid) still in use in the EU at the time this study was conducted.

Acute and subacute inhalation toxicity assessment of WS-23 in Sprague-Dawley rats.

2-isopropyl-N,2,3-trimethylbutyramide (WS-23) is a well-known artificial synthesis cooling agent widely used in foods, medicines, and tobaccos. As a commonly cooling agent in e-cigarette liquids, WS-23 has led to concerns about the inhalation toxicity with the prosperous of e-cigarettes in recent years. Thus, the aim of this study is to assess the acute and subacute inhalation toxicity of WS-23 in Sprague-Dawley (SD) rats according to the Organization for Economic Cooperation and Development (OECD) guidelines. In the acute toxicity study, there was no mortality and behavioral signs of toxicity at the limit test dose level (340.0 mg/m3 ) in the exposure period and the following 14-day observation period. In the subacute inhalation toxicity study, there was no significant difference observed in the body weights, feed consumption, and relative organ weights. Haematological, serum biochemical, urine, and bronchoalveolar lavage fluid (BALF) analysis revealed the non-adverse effects after 28-day repeated WS-23 inhalation (342.85 mg/m3 ), accompanied by slight changes in few parameters which returned to normal during the 28-day recovery period. The histopathologic examination also did not show any differences in vital organs. In conclusion, the maximum tolerated dose for WS-23 acute inhalation is not less than 340.0 mg/m3 , and the No Observed Adverse Effect Level (NOAEL) of WS-23 subacute inhalation was determined to be over 342.85 mg/m3 .

Succinate dehydrogenase inhibitors: in silico flux analysis and in vivo metabolomics investigations show no severe metabolic consequences for rats and humans.

Succinate dehydrogenase complex II inhibitors (SDHIs) are widely used fungicides since the 1960s. Recently, based on published in vitro cell viability data, potential health effects via disruption of the mitochondrial respiratory chain and tricarboxylic acid cycle have been postulated in mammalian species. As primary metabolic impact of SDH inhibition, an increase in succinate, and compensatory ATP production via glycolysis resulting in excess lactate levels was hypothesized. To investigate these hypotheses, genome-scale metabolic models of Rattus norvegicus and Homo sapiens were used for an in silico analysis of mammalian metabolism. Moreover, plasma samples from 28-day studies with the SDHIs boscalid and fluxapyroxad were subjected to metabolome analyses, to assess in vivo metabolite changes induced by SDHIs. The outcome of in silico analyses indicated that mammalian metabolic networks are robust and able to compensate different types of metabolic perturbation, e.g., partial or complete SDH inhibition. Additionally, the in silico comparison of rat and human responses suggested no noticeable differences between both species, evidencing that the rat is an appropriate testing organism for toxicity of SDHIs. Since no succinate or lactate accumulation were found in rats, such an accumulation is also not expected in humans as a result of SDHI exposure.

Fenhexamid induces cancer growth and survival via estrogen receptor-dependent and PI3K-dependent pathways in breast cancer models.

Fenhexamid (Fen), a fungicide used to treat gray mold of fruits and vegetables, is reported to function as an endocrine disrupting chemical via the estrogen receptors (ER), despite low-toxicity of the pesticide. In this study, we elucidated that the disrupting effects of Fen are exerted via the ER and phosphatidylinositol 3-kinase (PI3K) pathways in breast cancer models. The WST assay, live cell monitoring, cell cycle analysis, colony formation assay, apoptotic analysis by JC-1 dyeing, and Western blot analysis were applied in ER positive MCF-7 and ER negative MDA-MB-231 breast cancer cells, after exposure to 17ß-estradiol (E2), Fen, ICI 182,780 (ICI; an ER antagonist) and/or Pictilisib (Pic; a PI3K inhibitor). Exposure to E2 and Fen induced the cell growth and survival ability of MCF-7 cells by increasing the S-phase cells and regulating the cell cycle-related proteins (Cyclin D1 and E1, p21 and p27). In addition, E2 and Fen treatment resulted in elevated levels of the survival-related proteins (Survivin and PCNA), and inhibited apoptosis by increasing the mitochondrial membrane potential and regulating the apoptosis-related proteins (BAX, BCL-2, and Caspase-9). These changes were reversed to the same level as the control group when exposed to their respective inhibitors, thereby indicating that the changes are exerted via the ER and PI3K pathways. In particular, co-treatment with these inhibitors induced greater inhibition than single treatment. Conversely, no alterations were observed in the ER-negative MDA-MB-231 breast cancer cells. Taken together, these results indicate that Fen promotes the growth of breast cancer cells via the ER and/or PI3K pathways, similar to the E2 mechanism. Although a relatively safe pesticide, Fen possibly exerts its influence as an endocrine disrupting chemical in ER-positive breast cancer cells via the ER and PI3K pathways.

Differences in Cytotoxicity of Lidocaine, Ropivacaine, and Bupivacaine on the Viability and Metabolic Activity of Human Adipose-Derived Mesenchymal Stem Cells.

PURPOSE: We evaluated biological effects of distinct local anesthetics on human adipose-derived mesenchymal stem cells when applied to reduce periprocedural pain during mesenchymal stem cell injections. METHODS AND MATERIALS: Metabolic activity (MTS assay), viability (Live/Dead stain), and gene expression (quantitative real-time reverse-transcriptase polymerase chain reaction) were measured in mesenchymal stem cells incubated with various concentrations of lidocaine, ropivacaine, or bupivacaine during a 12-hr time course. RESULTS: Cell viability and metabolic activity decreased in a dose, time, and substance-specific manner after exposure to lidocaine, ropivacaine, and bupivacaine, with ropivacaine being the least cytotoxic. Cell viability decreases after brief exposure (<1.5 hrs) at clinically relevant concentrations (eg, 8 mg/ml of lidocaine, 2.5 mg/ml of ropivacaine or bupivacaine). Mesenchymal stem cells exposed to local anesthetics change their expression of mRNA biomarkers for stress response (EGR1, EGR2), proliferation (MKI67, HIST2H4A), ECM (COL1A1, COL3A1), and cell surface marker (CD105). CONCLUSIONS: Local anesthetics are cytotoxic to clinical-grade human mesenchymal stem cells in a dose-, time-, and agent-dependent manner and change expression of ECM, proliferation, and cell surface markers. Lidocaine and bupivacaine are more cytotoxic than ropivacaine. Single-dose injections of local anesthetics may affect the biological properties of mesenchymal stem cells in vitro but may not affect the effective dose of MSCs in a clinical setting.

Dissipation kinetics and biological degradation by yeast and dietary risk assessment of fluxapyroxad in apples.

The aim of this study was to investigate the dissipation kinetics of fluxapyroxad in apples, the influence of biological treatment with yeast, and the estimation of dietary exposure for consumers, both adults and children. The gas chromatography technique with the electron capture detector was used to analyse the fluxapyroxad residues. Samples of apples were prepared by the quick, easy, cheap, effective, rugged and safe (QuEChERS) method. The average fluxapyroxad recoveries in apple samples ranged from 107.9 to 118.4%, the relative standard deviations ranged from 4.2 to 4.7%, and the limit of quantification was 0.005 mg/kg. The dissipation half-lives in Gala and Idared varieties were 8.9 and 9.0 days, respectively. Degradation levels of the tested active substance after application of yeast included in a biological preparation Myco-Sin were 59.9% for Gala and 43.8% for Idared. The estimated dietary risk for fluxapyroxad in apples was on the acceptable safety level (below 9.8% for children and 1.9% for adults) and does not pose a danger to the health of consumers.