Effective control of two genotypes of Phytophthora infestans in the field by three oxathiapiprolin fungicidal mixtures.

In two field experiments, performed in 2020 and 2021, potato Nicola plants were sprayed once with three (Exp. 1) or two (Exp. 2) doses of Zorvec Vinabel (oxathiapiprolin+ zoxamide = ZZ), Zorvec Encantia (oxathiapiprolin+ famoxadone = ZF), Zorvec Endavia (oxathiapiprolin+ benthiavalicarb = ZE), Infinito (= INF) or Mefenoxam (= MFX) and thereafter inoculated with genotype 23A1 or 36A2 of Phytophthora infestans. Disease development was recorded at periodic intervals for a month. In both experiments, Zorvec mixtures were significantly more effective in suppressing the disease than INF or MFX. They delayed the onset of the disease and its progress, regardless the genotype used for inoculation. Among the three Zorvec mixtures, ZZ was least effective and ZE most effective. Sensitivity monitoring assays revealed zero mutants of P. infestans resistant to oxathiapiprolin. The data confirmed good efficacy of Zorvec mixtures, especially ZE, in field-grown potato crops as evident by the very effective control of late blight for one month.

Apoptotic cell-mimicking gold nanocages loaded with LXR agonist for attenuating the progression of murine systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) constitutes an autoimmune disease characterized by the breakdown of tolerance to self-antigens, sustained production of pathogenic autoantibodies, and damage to multiple organs and tissues. Nanoparticle (NP)-based therapeutics have demonstrated efficacy in attenuating the progression of SLE. However, investigations of nano-drugs that address the crucial initiating factor in the pathogenesis of SLE; e.g., inefficient clearance of apoptotic cells by phagocytes and consequent accumulation of self-antigens, have seldom been reported. Here, an apoptotic cell-mimicking gold nanocage (AuNC)-based nano drug carrier capable of correcting the impaired clearance of apoptotic cells in SLE was rationally designed and generated by conjugating phosphatidylserine (PS) on the surface of liposome-coated AuNCs for liver X receptor (LXR) agonist T0901317 delivery. Notably, PS-lipos-AuNC@T0901317 could efficiently enhance apoptotic cell clearance by elevating the expression of Mer, one of the pivotal phagocytosis-associated receptors on macrophages, resulting in decreased production of anti-dsDNA autoantibodies, reduced inflammatory response, and alleviation of kidney damage in lupus model mice. Additionally, PS-lipos-AuNC could be tracked by photoacoustic imaging for nano drug carrier biodistribution. By addressing the crucial pathogenic factor of SLE, the NP-based delivery system in this study is envisioned to provide a promising strategy to treat this complex and challenging disease.

Effects of fluorotelomer alcohol 8:2 FTOH on steroidogenesis in H295R cells: targeting the cAMP signalling cascade.

Previous studies have demonstrated that perfluorinated chemicals (PFCs) can affect reproduction by disruption of steroidogenesis in experimental animals. However, the underlying mechanism(s) of this disruption remain unknown. Here we investigated the effects and mechanisms of action of 1H, 1H, 2H, 2H-perfluoro-decan-1-ol (8:2 FTOH) on steroidogenesis using a human adrenocortical carcinoma cell line (H295R) as a model. H295R cells were exposed to 0, 7.4, 22.2 or 66.6 microM 8:2 FTOH for 24h and productions of progesterone, 17alpha-OH-progesterone, androstenedione, testosterone, deoxycorticosterone, corticosterone and cortisol were quantified by HPLC-MS/MS. With the exception of progesterone, 8:2 FTOH treatment significantly decreased production of all hormones in the high dose group. Exposure to 8:2 FTOH significantly down-regulated cAMP-dependent mRNA expression and protein abundance of several key steroidogenic enzymes, including StAR, CYP11A, CYP11B1, CYP11B2, CYP17 and CYP21. Furthermore, a dose-dependent decrease of cellular cAMP levels was observed in H295R cells exposed to 8:2 FTOH. The observed responses are consistent with reduced cellular cAMP levels. Exposure to 8:2 FTOH resulted in significantly less basal (+GTP) and isoproterenol-stimulated adenylate cyclase activities, but affected neither total cellular ATP level nor basal (-GTP) or NaF-stimulated adenylate cyclase activities, suggesting that inhibition of steroidogenesis may be due to an alteration in membrane properties. Metabolites of 8:2 FTOH were not detected by HPLC-MS/MS, suggesting that 8:2 FTOH was not metabolized by H295R cells. Overall, the results show that 8:2 FTOH may inhibit steroidogenesis by disrupting the cAMP signalling cascade.

Hydroxamic acid and fluorinated derivatives of valproic acid: anticonvulsant activity, neurotoxicity and teratogenicity.

PURPOSE: Fluorinated and non-fluorinated valproic acid (VPA) analogues with hydroxamic acid moieties were tested for their teratogenic, anticonvulsant and neurotoxic potencies in mice. METHODS: Compounds were synthesized from their corresponding acids. The induction of neural tube defects (exencephaly) of the resulting hydroxamates (applied on day 8.25 of gestation) was tested in the offspring of pregnant animals (Han:NMRI mice). The anticonvulsant activity was evaluated in the subcutaneous pentylenetetrazole (PTZ) seizure threshold test and neurotoxicity in the rotorod neurotoxicity test. RESULTS: All tested hydroxamates showed no or greatly reduced teratogenic potency in mice compared to the free acids. Furthermore all compounds exhibited anticonvulsant activity with ED(50) doses ranging from 0.16 mmol/kg to 0.59 mmol/kg (VPA 0.57 mmol/kg). Neurotoxicity of the hydroxamates was increased compared to VPA. TD(50) doses range from 0.70 mmol/kg to 1.42 mmol/kg (VPA 1.83 mmol/kg). CONCLUSION: Hydroxamic acid derivatives of VPA with improved protective index and little or undetectable teratogenic potency compared to the free acids are described. alpha-fluorination of VPA also resulted in loss of teratogenic activity. Such fluorination of the hydroxamic acids also led to compounds with an improved anticonvulsant profile compared to non-fluorinated hydroxamates. The non-chiral 2-Fluoro-VPA-hydroxamic acid was the most promising compound with a protective index (ratio of TD(50) to ED(50)) of 4.4 compared to 3.2 for VPA. This compound combines an improved ratio of anticonvulsant potency/neurotoxicity with the advantage of not being teratogenic in the mouse neural tube defect model used.

A study on reference standard for cytotoxicity assay of biomaterials.

The objective of the present study was to find a standard substance for use as a reference in the cytotoxicity assay of biomaterials, as an alternative to animal experiments in recent years. Eight kinds of rubber were made in a plate shape to keep their surface area at 1 cm2 against 10 ml of extract volume. They were extracted by the following three extraction methods (a) dynamic extraction at 200 rpm gyration on alumina balls at 37 degrees C for 24 h; (b) static extraction at 37 degrees C for 24 h and (c) extraction by heating in an autoclave at 121 degrees C for 60 min. At the end of each period each extract was examined for cell viability based on an evaluation by neutral red uptake. These methods were repeated up to seven times. Two kinds of chemicals were also tested. The extracts obtained were used to treat human gingival fibroblasts that have been cultured with DMEM supplemented with 5% fetal bovine serum into a 96 well tissue culture plate by 1 x 10(5) cells/ml, in an incubator aerated with 5% CO2, and 95% humidified air at 37 degrees C for 48 h. The extracts of ethylene-propylene, butyl, nitrile rubbers, and two kinds of chemicals yielded strong cytotoxicity in all three kinds of extraction methods, while chloroprene, fluorine-contained, isoprene, India, and silicone rubbers showed little cytotoxicity. The results obtained by the three kinds of extraction methods revealed no differences in the order of cytotoxicity of the materials tested.(ABSTRACT TRUNCATED AT 250 WORDS)

CFC replacements: safety testing, approval for use in metered dose inhalers.

HFA-134a and HFA-227 (chlorine free hydrofluoro-alkanes) are at present in extensive nonclinical safety testing sponsored by two joint research consortia (IPACT-I, IPACT-II) of companies interested in metered dose inhalers (MDI). The rationale for toxicity testing of these CFC replacements is to predict safety of their use as drug propellants in MDI. Frequency of use, intervals and systemic exposure levels are key parameters. Intact animals and in-vitro systems repeatedly exposed to multiples of patient doses, under conditions comparable to human administration should not show adverse reactions. With an emphasis different from non-U.S. Health Authorities, the U.S. FDA insists on proof of toxic effects which may require excessive doses. This principle is questioned for essentially inert gases such as CFCs and HFA-134a and HFA-227 which only through the effects of oxygen deprivation at unreasonably high concentrations of the inhaled propellant/air mixture indirectly cause mild toxic effects in animals. Provided that no intrinsic toxic effects will be detected, chances are good that these CFC replacements will eventually be approved. In view of the estimated 5-year testing time frame and the risks involved, CFCs should remain available for MDI for some time in the future.

Variations in onset of porcine malignant hyperthermia.

Variations in the onset of malignant hyperthermia were observed in five Poland China swine. These pigs were equivalently susceptible to malignant hyperthermia, based on the rapid onset in response to mask inhalation induction with halothane (five pigs) or sevoflurane (two pigs). A moderate dose of thiopental delayed the response to sevoflurane 10 minutes (one pig) and larger doses delayed it more than 60 minutes (two pigs). Total paralysis with pancuronium in the absence of other drugs delayed the response to halothane 30 and 60 minutes (two pigs). The results suggest that drugs that decrease either neuromuscular transmission or reflex responsiveness can delay the onset of episodes of malignant hyperthermia. These data suggest pancuronium as a relaxant of choice in anesthesia for susceptible subjects. Correlation with other data suggests that malignant hyperthermia may be difficult to initiate in subjects paralyzed by non-depolarizing relaxants in the absence of exposure to potent volatile agents. Thus the use of relaxant-induced paralysis might aid in the care of patients who develop recurrent malignant hyperthermia.