PM2.5 exposure promotes the progression of acute kidney injury by activating NLRP3-mediated macrophage inflammatory response.

AIM: We reveal the mechanism of action whereby ambient PM2.5 promotes kidney injury. METHODS: Using C57BL/6 mice, the effects of PM2.5 exposure on the acute kidney injury (AKI) were investigated, including renal function changes, expression of inflammatory cytokines, histopathological changes, as well as activation of nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3（NLRP3）. The effects of PM2.5 on renal injury after NLRP3 inhibition were explored using NLRP3 inhibitor (MCC950) and NLRP3 knockout mice. The effects of PM2.5 on the inflammatory response of renal macrophages were investigated at the cellular level. RESULTS: PM2.5 exposure could promote kidney injury, NLRP3 activation and inflammatory response in mice. After using MCC950 and NLRP3 knockout mice, the effects of PM2.5 and the kidney injury could be inhibited. The cellular-level results also suggested that MCC950 could inhibit the effects of PM2.5. CONCLUSION: PM2.5 can promote the progression of AKI and aggravate tissue inflammation through NLRP3, which is an important environmental toxicological mechanism of PM2.5.

Suppression of MYC transcription activators by the immune cofactor NPR1 fine-tunes plant immune responses.

Plants tailor immune responses to defend against pathogens with different lifestyles. In this process, antagonism between the immune hormones salicylic acid (SA) and jasmonic acid (JA) optimizes transcriptional signatures specifically to the attacker encountered. Antagonism is controlled by the transcription cofactor NPR1. The indispensable role of NPR1 in activating SA-responsive genes is well understood, but how it functions as a repressor of JA-responsive genes remains unclear. Here, we demonstrate that SA-induced NPR1 is recruited to JA-responsive promoter regions that are co-occupied by a JA-induced transcription complex consisting of the MYC2 activator and MED25 Mediator subunit. In the presence of SA, NPR1 physically associates with JA-induced MYC2 and inhibits transcriptional activation by disrupting its interaction with MED25. Importantly, NPR1-mediated inhibition of MYC2 is a major immune mechanism for suppressing pathogen virulence. Thus, NPR1 orchestrates the immune transcriptome not only by activating SA-responsive genes but also by acting as a corepressor of JA-responsive MYC2.

Coronatine is more potent than jasmonates in regulating Arabidopsis circadian clock.

Recent studies establish a crucial role of the circadian clock in regulating plant defense against pathogens. Whether pathogens modulate host circadian clock as a potential strategy to suppress host innate immunity is not well understood. Coronatine is a toxin produced by the bacterial pathogen Pseudomonas syringae that is known to counteract Arabidopsis defense through mimicking defense signaling molecules, jasmonates (JAs). We report here that COR preferentially suppresses expression of clock-related genes in high throughput gene expression studies, compared with the plant-derived JA molecule methyl jasmonate (MJ). COR treatment dampens the amplitude and lengthens the period of all four reporters tested while MJ and another JA agonist JA-isoleucine (JA-Ile) only affect some reporters. COR, MJ, and JA-Ile act through the canonical JA receptor COI1 in clock regulation. These data support a stronger role of the pathogen-derived molecule COR than plant-derived JA molecules in regulating Arabidopsis clock. Further study shall reveal mechanisms underlying COR regulation of host circadian clock.

Scalable total synthesis and comprehensive structure-activity relationship studies of the phytotoxin coronatine.

Natural phytotoxins are valuable starting points for agrochemical design. Acting as a jasmonate agonist, coronatine represents an attractive herbicidal lead with novel mode of action, and has been an important synthetic target for agrochemical development. However, both restricted access to quantities of coronatine and a lack of a suitably scalable and flexible synthetic approach to its constituent natural product components, coronafacic and coronamic acids, has frustrated development of this target. Here, we report gram-scale production of coronafacic acid that allows a comprehensive structure-activity relationship study of this target. Biological assessment of a >120 member library combined with computational studies have revealed the key determinants of potency, rationalising hypotheses held for decades, and allowing future rational design of new herbicidal leads based on this template.

Indaziflam: a new cellulose-biosynthesis-inhibiting herbicide provides long-term control of invasive winter annual grasses.

BACKGROUND: Indaziflam is a cellulose-biosynthesis-inhibiting (CBI) herbicide that is a unique mode of action for resistance management and has broad spectrum activity at low application rates. This research further explores indaziflam's activity on monocotyledons and dicotyledons and evaluates indaziflam's potential for restoring non-crop sites infested with invasive winter annual grasses. RESULTS: Treated Arabidopsis, downy brome, feral rye and kochia were all susceptible to indaziflam in a dose-dependent manner. We confirmed that indaziflam has increased activity on monocots (average GR50  = 231 pm and 0.38 g AI ha-1 ) at reduced concentrations compared with dicots (average GR50  = 512 pm and 0.87 g AI ha-1 ). Fluorescence microscopy confirmed common CBI symptomologies following indaziflam treatments, as well as aberrant root and cell morphology. Across five application timings, indaziflam treatments resulted in superior invasive winter annual grass control 2 years after treatment (from 84 ± 5.1% to 99 ± 0.5%) compared with imazapic (36% ± 1.2%). Indaziflam treatments significantly increased biomass and species richness of co-occurring species 2 years after treatment. CONCLUSION: Indaziflam's increased activity on monocots could provide a new alternative management strategy for long-term control of multiple invasive winter annual grasses that invade >23 million ha of US rangeland. Indaziflam could potentially be used to eliminate the soil seed bank of these invasive grasses, reduce fine fuel accumulation and ultimately increase the competitiveness of perennial co-occuring species. © 2017 Society of Chemical Industry.

Impact of acute fat mobilisation on the pharmacokinetics of the highly fat distributed compound TAK-357, investigated by physiologically based pharmacokinetic (PBPK) modeling and simulation.

In a dog toxicokinetic study, an unusual plasma concentration increase of the highly lipophilic compound TAK-357 was observed 2 weeks after termination of a 2-week repeated dosing in one dog with acute body weight loss. The present study investigates the cause of this increase. A physiologically based pharmacokinetic (PBPK) model was constructed using the rat and dog pharmacokinetic data. Using the constructed model, the TAK-357 concentration profile in the case of body weight change was simulated. The PBPK model-derived simulation suggested that redistribution from adipose tissues to plasma due to a loss of body fat caused the observed concentration increase of TAK-357 in dog plasma. The analysis demonstrates that the disposition of a highly lipophilic and fat-distributed compound can be affected by acute changes in adipose tissue mass. PBPK modeling and simulation proved to be efficient tools for the quantitative hypothesis testing of apparently atypical PK phenomena resulting from acute physiological changes.

Pharmacological characterization of N-[(2S)-5-(6-fluoro-3-pyridinyl)-2, 3-dihydro-1H-inden-2-yl]-2-propanesulfonamide: a novel, clinical AMPA receptor positive allosteric modulator.

BACKGROUND AND PURPOSE: AMPA receptor positive allosteric modulators represent a potential therapeutic strategy to improve cognition in people with schizophrenia. These studies collectively constitute the preclinical pharmacology data package used to build confidence in the pharmacology of this molecule and enable a clinical trial application. EXPERIMENTAL APPROACH: [N-[(2S)-5-(6-fluoro-3-pyridinyl)-2,3-dihydro 1H-inden-2-yl]-2-propanesulfonamide] (UoS12258) was profiled in a number of in vitro and in vivo studies to highlight its suitability as a novel therapeutic agent. KEY RESULTS: We demonstrated that UoS12258 is a selective, positive allosteric modulator of the AMPA receptor. At rat native hetero-oligomeric AMPA receptors, UoS12258 displayed a minimum effective concentration of approximately 10 nM in vitro and enhanced AMPA receptor-mediated synaptic transmission at an estimated free brain concentration of approximately 15 nM in vivo. UoS12258 reversed a delay-induced deficit in novel object recognition in rats after both acute and sub-chronic dosing. Sub-chronic dosing reduced the minimum effective dose from 0.3 to 0.03 mg·kg-1 . UoS12258 was also effective at improving performance in two other cognition models, passive avoidance in scopolamine-impaired rats and water maze learning and retention in aged rats. In side-effect profiling studies, UoS12258 did not produce significant changes in the maximal electroshock threshold test at doses below 10 mg·kg-1 . CONCLUSION AND IMPLICATIONS: We conclude that UoS12258 is a potent and selective AMPA receptor modulator exhibiting cognition enhancing properties in several rat behavioural models superior to other molecules that have previously entered clinical evaluation.

Reproductive toxicity of brazilein in ICR mice.

Brazilein is an active small molecular compound extracted from Caesalpinia sappan L. with favorable pharmacological properties on immune system, cardiovascular system, and nervous system. C. sappan has been used as a traditional medicine in China for hundreds of years for various diseases. However, the general reproductive toxicity of brazilein is still unknown. The purpose of the present study was to thoroughly evaluate the general reproductive toxicity of brazilein in ICR mice to support the future drug development and modernization of this potent traditional Chinese medicine. The results showed that, although no apparent toxicity on the reproducibility of the male was observed, brazilein might cause considerable risks to the fetuses and females as indicated by the ratios of dead fetuses and reabsorptions. In conclusion, our results from the present study provided some useful insights about the safety profile of brazilein, suggesting that brazilein should be used with caution in pregnant women.

Synthesis of mono Mannich bases of 2-(4-hydroxybenzylidene)-2,3-dihydroinden-1-one and evaluation of their cytotoxicities.

Chalcones and Mannich bases are a group of compounds known for their cytotoxicities. In this study restricted chalcone analogue, compound 2-(4-hydroxybenzylidene)-2,3-dihydroinden-1-one MT1, was used as a starting compound to synthesize new mono Mannich bases since Mannich bases may induce more cytotoxicity than chalcone analogue that they are derived from by producing additional alkylating center for cellular thiols. In this study, cyclic and acyclic amines were used to synthesize Mannich bases. All compounds were tested against Ca9-22 (gingival carcinoma), HSC-2, HSC-3 and HSC-4 (oral squamous cell carcinoma) as tumour cell lines and HGF (gingival fibroblasts), HPC (pulp cells) and HPLF (periodontal ligament fibroblasts) human normal oral cells as non tumour cell lines. Cytotoxicity, selectivity index (SI) values and potency selectivity expression (PSE) values expressed as a percentage were determined for the compounds. According to data obtained, the compound MT8 with the highest PSE value bearing N-methylpiperazine moiety seems to be a good candidate to develop new cytotoxic compounds and is suited for further investigation.

Muscular performance characterization in athletes: a new perspective on isokinetic variables

Background: Isokinetic dynamometry allows the measurement of several variables related to muscular performance, many of which are seldom used, while others are redundantly applied to the characterization of muscle function. Objectives: The present study aimed to establish the particular features of muscle function that are captured by the variables currently included in isokinetic assessment and to determine which variables best represent these features in order to achieve a more objective interpretation of muscular performance. Method: This study included 235 male athletes. They performed isokinetic tests of concentric knee flexion and extension of the dominant leg at a velocity of 60º/s. An exploratory factor analysis was performed. Results: The findings demonstrated that isokinetic variables can characterize more than muscle torque production and pointed to the presence of 5 factors that enabled the characterization of muscular performance according to 5 different domains or constructs. Conclusions: The constructs can be described by torque generation capacity; variation of the torque generation capacity along repetitions; movement deceleration capacity; mechanical/physiological factors of torque generation; and acceleration capacity (torque development). Fewer than eight out of sixteen variables are enough to characterize these five constructs. Our results suggest that these variables and these 5 domains may lead to a more systematic and optimized interpretation of isokinetic assessments. .

Identification of 1-chloro-2-formyl indenes and tetralenes as novel antistaphylococcal agents exhibiting sortase A inhibition.

Tetralene and indene compounds have shown inhibitory activity against human pathogen, Mycobacterium tuberculosis. Their potential use as antistaphylococcal agent against drug-resistant Staphylococcus aureus has not been explored so far. We determined in vitro antistaphylococcal activity and mechanism of action of these compounds as sortase A inhibitors through in silico analysis followed by biological assays. Tetralene and indene series were tested against S. aureus strains MTCC96, MRSA, and VA30. Three compounds showed significant reduction in MIC in both wild-type and drug-resistant S. aureus strains. In silico absorption, distribution, metabolism, excretion, and toxicity analysis of identified leads and cytotoxicity testing with colorimetric method using Vero and WRL-68 cell lines showed no significant cytotoxic effects. Molecular docking of these molecules with sortase A (PDB: 2KID) showed H-bond interaction with functional site residue Arg197 of sortase A. Sortase A inhibition assay was developed by expressing SrtA∆N from S. aureus strain MTCC96. Tetralene and indene compounds were found to have sortase A inhibitory potential. S. aureus strain MTCC96 treated with these compounds showed surface-sorting inhibition of fibronectin-binding protein and reduction in adherence to host extracellular matrix protein, fibronectin. 1-Chloro, 2-formyl, 6-methoxy, 1-tetralene (Tet-5), 1,5-dichloro, 2-formyl, 1-indene (Tet-20) and 1-chloro, 2-formyl, 5,6-methylenedioxy, and 1-indene (Tet-21) exhibited antistaphylococcal activity along with sortase A inhibition. The results also indicate the possible role of these leads in other reactions essential for cell viability.