Differential Inhibitory Effects Research Articles

Experimental study on inhibition of coal spontaneous combustion by carbon dioxide and nitrogen

ABSTRACT Injecting CO2 and N2 to reduce the concentration of O2 in the air is a commonly used measure to prevent coal spontaneous combustion (CSC). To study the difference in inhibitory effects of CO2 and N2 on coal oxidation, experiments in this study were conducted using a setup of self-developed gas-bath coal oxidation for low temperatures. The oxidation process of the coal-oxygen system was then analyzed using reaction kinetics. Two different coal samples were tested in experiments under two inert gas environments, i.e. CO2 and N2 with various O2 concentrations, respectively. The changes in O2 and CO concentrations were measured during the oxidation process. By studying the standard oxygen consumption rate (SOCR) and the apparent activation energy of the coal-oxygen reaction system, inhibitory effects of CO2 and N2 on CSC were analyzed and compared. The results showed that the SOCR of the same coal sample remained consistent and independent of the O2 concentration within the same inert gas environment although under different O2 levels. In both CO2-O2 and N2-O2 environments, the SOCR of the coal sample exhibits exponential growth with temperature. The SOCR was found to have a functional connection with temperature, it can be represented as y = a ⋅ e bT , and the R 2 (determination coefficients) of the fitting formulas are all greater than 0.94. In the correlation, the inert gas environment has minimal impact on coefficient “b,” while in the CO2-O2 environment, reducing the value of coefficient “a” can effectively lower the coal sample’s SOCR. The GBMK sample and YMWK sample have an “a” value that is 20% of the value in the N2-O2 environment when oxidizing in the CO2-O2 environment. The SOCR in the CO2-O2 environment showed a decrement of between 26.0% and 52.1% when compared to that in the N2-O2 environment, whereas the activation energy showed an increment between 1.4% and 18.6%. The findings in this work provide an in-depth understanding of the prevention of CSC in the gob for risk mitigation.

Exploring the potential of silymarin-loaded nanovesicles as an effective drug delivery system for cancer therapy: in vivo, in vitro, and in silico experiments.

We aimed to perform a comprehensive study on the development and characterization of silymarin (Syl)-loaded niosomes as potential drug delivery systems. The results demonstrate significant novelty and promising outcomes in terms of morphology, size distribution, encapsulation efficiency, in vitro release behavior, free energy profiles of Syl across the niosome bilayer, hydrogen bonding interactions, antimicrobial properties, cytotoxicity, and in vivo evaluations. The physical appearance, size, and morphology assessment of free niosomes and Syl-loaded niosomes indicated stable and well-formed vesicular structures suitable for drug delivery. Transmission electron microscopy (TEM) analysis revealed spherical shapes with distinct sizes for each formulation, confirming uniform distribution. Dynamic light scattering (DLS) analysis confirmed the size distribution results with higher polydispersity index for Syl-loaded niosomes. The encapsulation efficiency of Syl in the niosomes was remarkable at approximately 91%, ensuring protection and controlled release of the drug. In vitro release studies showed a sustained release profile for Syl-loaded niosomes, enhancing therapeutic efficacy over time. Free energy profiles analysis identified energy barriers hindering Syl permeation through the niosome bilayer, emphasizing challenges in drug delivery system design. Hydrogen bonding interactions between Syl and niosome components contributed to energy barriers, impacting drug permeability. Antimicrobial assessments revealed significant differences in inhibitory effects against S. aureus and E. coli. Cytotoxicity evaluations demonstrated the superior tumor-killing potential of Syl-loaded niosomes compared to free Syl. In vivo studies indicated niosome formulations' safety profiles in terms of liver and kidney parameters compared to bulk Syl, showcasing potential for clinical applications. Overall, this research highlights the promising potential of Syl-loaded niosomes as effective drug delivery systems with enhanced stability, controlled release, and improved therapeutic outcomes.

Modulating Proteasome Function with Polyphenol Metabolites: A Promising Therapeutic Avenue for Alzheimer's Disease

Alzheimer's disease (AD) presents many difficulties and has few available therapies. Because of their many advantages, polyphenolic metabolites of flavan-3-ol have gained attention as possible candidates for AD treatment. This work investigates the impact of these compounds on proteasome function in neuronal cells expressing genes related to AD. It finds that these compounds have inhibitory effects on proteasomes, especially in cells that have mutations in genes related to AD. Amyloid plaques, neurofibrillary tangles, oxidative stress, compromised autophagy, and proteasome systems, which affect protein clearance, are all components of AD pathology. Rich in anti-inflammatory and antioxidant qualities, polyphenols change into bioactive metabolites such as phenyl-γ-valerolactones. These metabolites alter Aβ oligomers and mitigate Aβ toxicity, potentially providing a therapeutic intervention for AD. The presented findings underscore the potential of various compounds, including C1, C2, C3, PGPH, and BrAAP, as modulators of proteasome function. The differential inhibitory effects observed on both constitutive (ChT-L) and immunoproteasome (T-L) activities signify the nuanced impact of these compounds. Notably, the selectivity of certain compounds towards either proteasome subtype suggests the possibility of targeted therapeutic strategies, particularly in the context of diseases associated with proteasome dysfunction, such as neurodegenerative disorders like Alzheimer's Disease. This study looks at how flavan-3-ol metabolites affect proteasome function and how they might be used as AD treatment agents. Understanding their effects on proteasomes opens avenues for novel AD treatments at a molecular level.

Reduced form of Galectin-1 Suppresses Osteoclastic Differentiation of Human Peripheral Blood Mononuclear Cells and Murine RAW264 Cells In Vitro.

Galectin-1 (Gal-1) is an evolutionarily conserved sugar-binding protein found in intra- and extracellular spaces. Extracellularly, it binds to glycoconjugates with β-galactoside(s) and functions in various biological phenomena, including immunity, cancer, and differentiation. Under extracellular oxidative conditions, Gal-1 undergoes oxidative inactivation, losing its sugar-binding ability, although it exhibits sugar-independent functions. An age-related decrease in serum Gal-1 levels correlates with decreasing bone mass, and Gal-1 knockout promotes osteoclastic bone resorption and suppresses bone formation. However, the effect of extracellular Gal-1 on osteoclast differentiation remains unclear. Herein, we investigated the effects of extracellular Gal-1 on osteoclastogenesis in human peripheral blood mononuclear cells (PBMCs) and mouse macrophage RAW264 cells. Recombinant Gal-1 suppressed the macrophage colony-stimulating factor and receptor activator of nuclear factor-κB ligand-dependent osteoclast formation, actin ring formation, and bone-resorption activity of human PBMCs. Similar results were obtained for RAW264 cells. Gal-1 knockdown increased osteoclast-like cell formation, suggesting that it affected differentiation in an autocrine-like manner. Oxidized Gal-1 slightly affected differentiation, and in the presence of lactose, the differentiation inhibitory effect of galectin-1 was not observed. These findings suggest that extracellular Gal-1 inhibits osteoclast differentiation in a β-galactoside-dependent manner, and an age-related decrease in serum Gal-1 levels may contribute to reduced osteoclast activity and decreasing bone mass.

Study of Allelopathic Effects of Argemone mexicana L. Root Extract on Seed Germination and Growth of Triticum aestivum L. under in vitro Condition

The present study was conducted in Department of Botany, Institute of Science, Nagpur, to investigate the allelopathic effects of Mexican poppy (Argemone mexicana L.) on wheat. Wheat is the most important edible cereal crop. Wheat can grow in a wide variety of soils and temperatures, but thrives in humid regions with 30-90 cm of precipitation. Argemone mexicana L. is a rapidly expanding weed and an important competitor of wheat (in terms of allelochemicals). Weed is one of major cause of crop production loss. The entire plants of Argemone mexicana L. were harvested, rinse with tap water to remove soil debris, roots are dried in shade which kept at 25 degrees celcius (±2) for 72 hours. To demonstrate the germination of seeds of two locally grown wheat varieties (Sharabati and Lokwan), five concentrations of different ratios of root aqueous extract were obtained. A bioassay of a petri dish was carried out to assess the allelopathic potential of Argemone mexicana L. on the germination of Triticum aestivum L. seeds. The water based root extracts of weeds were used for treatment. The differential inhibitory effect of Argemone mexicana L. on Sharbati and Lokwan variety of wheat was observed.

Comparison of the Preadipocyte Differentiation Inhibitory Effects and Antioxidant Activities of Immature and Mature Yuzu Peel Hot Water Extracts In Vitro

Comparison of the Preadipocyte Differentiation Inhibitory Effects and Antioxidant Activities of Immature and Mature Yuzu Peel Hot Water Extracts <i>In Vitro</i>

The inhibitory mechanism of humic acids on photocatalytic generation of reactive oxygen species by TiO2 depends on the crystalline phase

To enable the practical use of TiO2 for photocatalytic water treatment, it is important to understand how dissolved natural organic matter affects its photocatalytic activity and the mechanisms involved in generating reactive oxygen species (ROS). In this study, we systematically investigated the inhibitory effects of humic acids (HA) on 4-chlorophenol (4-CP) degradation using two common TiO2 crystalline phases (anatase and rutile) individually. HA strongly hindered the photocatalytic activity of anatase, with an Ra (the ratio of the first-order rate constant for 4-CP degradation in the absence vs. presence of 30 mg/L HA) of 2.30 (±0.13). This ratio was significantly higher than that of rutile (Rr = 1.21 ± 0.08), which was less susceptible to this inhibitory effect and even exhibited improved photocatalytic activity at HA concentrations below 20 mg/L. Similar trends were observed for various HA sources, corroborating the crystalline-phase-dependent effect of HA. Adsorption experiments, Fourier transform infrared spectroscopy, and photoelectrochemical analyses suggested that the adsorption mechanisms and hole-scavenging effect of HA on the two TiO2 polymorphs did not differ. Importantly, scavenger, probe, and electron spin resonance experiments revealed that the difference in inhibitory effects of HA originate from the distinct ROS generation mechanisms for the two polymorphs. The oxygen reduction pathway for OH generation over anatase was hindered by surface-adsorbed HA, while the water oxidation pathway for OH generation over rutile was less affected. Furthermore, surface-adsorbed HA boosted O2− generation on rutile, increasing 4-CP degradation efficiency. This mechanistic insight into NOM-TiO2 interactions informs materials selection and strategies for higher TiO2 photocatalytic performance in different water matrices.

Protective effects and microarray-based mechanism of sea cucumber hydrolysates against high-glucose induced nephrotoxicity in mouse glomerulus mesangial cells

Diabetic nephropathy (DN) is a common type of end-stage renal disease and glomerular mesangial cells (GMCs) are widely used as a cell model for DN. This study firstly investigated the inhibitory effects of the Apostichopus japonicus and Acaudina leucoprocta hydrolysates on cellular growth under high-glucose treatment, better inhibitory effect of A. japonicus hydrolysate was observed compared to that of A. leucoprocta hydrolysate. Subsequently, the global transcription profiles obtained via microarray analysis showed that 6 070 and 7 015 genes were identified in the A. japonicus and A. leucoprocta groups compared with the model group, respectively. Among them, transcriptions of the slc30a4, slc35d1, tppp3, tp53inp1, bcl-2, apaf1, alox12b and adrala genes were restored from the levels of the model group to those of the control group, contributed to cell mitosis and proliferation in both treatment groups. In addition, other apoptosis-related genes, such as bcl-6, clu, foxo3 and aktl, showed opposite trends between two groups, which might cause the difference in inhibitory effect. We preliminarily proposed that the regulation effects of A. japonicus and A. leucoprocta on the genes involved in cellular mitosis, proliferation and apoptosis, might contribute to their inhibitory activity on GMCs under high-glucose environment.

Predominant contribution of an endogenous cellulase (OlCel) to the cellulolysis in the digestive system of larvae of banana pseudostem weevil, Odoiporus longicollis (Coleoptera: Curculionidae).

Insects have evolved with effective strategies to utilize cellulose as an energy source by possessing cellulolytic enzymes which can be used as an optimal resource in the bioenergy sector. The study was aimed at evaluating the cellulolytic enzyme in the larval gut of the banana pseudostem weevil, Odoiporus longicollis Olivier (Coleoptera: Curculionidae). Primarily, cellulase activity was localized along the gut, in which the midgut showed the highest activity (2858 U/mg). The thermo-tolerance of cellulase activity was found to be up to 80°C (highest at 60°C), and the enzyme was stable at a pH between 5 and 6. Various concentrations of divalent cations (CaCl2 , MgCl2 , and CuCl2 ) have differential enhancing and inhibitory effects on cellulase activity. The cellulase (OlCel) was purified using anion exchange chromatography. The molecular weight of the cellulase was determined to be 47 kDa. The physicochemical parameters of the purified enzyme were similar to that of enzyme activity of whole gut extract. Mass spectrometry results identified sequence similarities of purified cellulase to the glycosyl hydrolase family 5 (GHF5) family. The gut microbial cellulase activity as exogenous source showed no competence compared with the endogenous activity.

Charge modifications of graphene oxide enhance the inhibitory effect on insulin amyloid fibrillation based on electrostatic interactions

Graphene oxide (GO) is a biocompatible nanomaterial that has an inhibitory effect on insulin amyloid fibrillation. In order to enhance the inhibitory effect of GO and explore the rules of electrostatic interactions on the inhibitory effect, carboxyl group, PEI and PEG were coupled to the GO nanoplatelet surface to prepare inhibitors of different surface electrical properties. The effects of surface electrical properties of inhibitors on insulin fibrillation were investigated. The results showed that GO, carboxyl group modified GO (GO-COOH), PEI modified GO (GO-PEI), and PEG modified GO (GO-PEG) inhibited insulin fibrillation in a dose-dependent manner. Compared with GO, positive charge-modified GO-PEI and negative charge-modified GO-COOH enhanced the inhibitory effect, while uncharged polymer-modified GO-PEG weakened the inhibitory effect. The inhibitory effect of the inhibitors increased with the increase of surface charge density. The difference in inhibitory effect between GO-PEI and GO-COOH was due to the different electrostatic interactions between inhibitors and insulin, and the different inhibition mechanisms. In addition, inhibitors mainly interact with insulin during the nucleation phase to hinder insulin fibrillation. The charge modifications of graphene oxide enhanced the inhibitory effect on insulin fibrillation based on electrostatic interactions, which will provide new thoughts for the development of anti-amyloid fibrillation drugs.

Different Inhibition of Nrf2 by Two Keap1 Isoforms α and β to Shape Malignant Behaviour of Human Hepatocellular Carcinoma.

Nrf2 (nuclear factor E2-related factor 2, encoded by Nfe2l2) acts as a master transcriptional regulator in mediating antioxidant, detoxification, and cytoprotective responses against oxidative, electrophilic, and metabolic stress, but also plays a crucial role in cancer metabolism and multiple oncogenic pathways, whereas the redox sensor Keap1 functions as a predominant inhibitor of Nrf2 and, hence, changes in its expression abundance directly affect the Nrf2 stability and transcriptional activity. However, nuanced functional isoforms of Keap1 α and β have rarely been identified to date. Herein, we have established four distinct cell models stably expressing Keap1−/−, Keap1β(Keap1Δ1–31), Keap1-Restored, and Keap1α-Restored aiming to gain a better understanding of similarities and differences of two Keap1 isoforms between their distinct regulatory profiles. Our experimental evidence revealed that although Keap1 and its isoforms are still localized in the cytoplasmic compartments, they elicited differential inhibitory effects on Nrf2 and its target HO-1. Furthermore, transcriptome sequencing unraveled that they possess similar but different functions. Such functions were further determined by multiple experiments in vivo (i.e., subcutaneous tumour formation in nude mice) and in vitro (e.g., cell cloning, infection, migration, wound healing, cell cycle, apoptosis, CAT enzymatic activity, and intracellular GSH levels). Of note, the results obtained from tumourigenesis experiments in xenograft model mice were verified based on the prominent changes in the PTEN signaling to the PI3K-AKT-mTOR pathways, in addition to substantially aberrant expression patterns of those typical genes involved in the EMT (epithelial–mesenchymal transition), cell cycle, and apoptosis.

Volatile and Non-Volatile Allelopathic Characteristics in Thermally Processed Needles of Two Conifers.

With allelopathic composts, potential merits for preventing initial weed infestations have been observed in crop transplantation. However, previous studies have rarely investigated whether high temperatures, generated during composting, decrease allelopathic ability. This study evaluated the thermal allelopathic effect of two coniferous plants (Pinus densiflora and P. koraiensis) on Brassica napus germination and seedling growth using their characterized allelochemical destinations. The 90 °C dry treatment of P. densiflora extract exhibited stronger inhibitory effect on germination than its 30 °C dry treatment. In a range from 0.25 to 1 mg mL−1, the germination rate was decreased to 38.1 and 64.3% of control with P. densiflora extract dried at 90 and 30 °C, respectively. However, P. koraiensis showed potent inhibition of the germination process with no statistical difference in inhibitory effects regardless of the dry temperature. Regarding B. napus seedling root growth, the allelopathic effects of aqueous extracts of both conifers were not reduced with the 90 °C treatment, but it was lost in seedling shoot growth. GC-MS/MS confirmed that high temperature treatment drastically decreased volatile contents to 53.2% in P. densiflora, resulting in reduced allelopathic abilities. However, a relatively lower decrease to 83.1% in volatiles of P. koraiensis accounts for less loss of the root-specific inhibitory effect on B. napus seedlings even after 90 °C treatment. Foliar tissues of both conifers with species-specific thermal resistance have potentially valuable functions regarding allelopathic use in horticultural compost processing ingredients, demonstrating their weed control ability during the early cultivation season where crops are transplanted in the facilitated area.

Dissolved xylan inhibits cellulosome-based saccharification by binding to the key cellulosomal component of Clostridium thermocellum

Polysaccharides derived from lignocellulose are promising sustainable carbon sources. Cellulosome is a supramolecular machine integrating multi-function enzymes for effective lignocellulose bio-saccharification. However, how various non-cellulose components of lignocellulose affect the cellulosomal saccharification is hitherto unclear. This study first investigated the stability and oxygen sensitivity of the cellulosome from Clostridium thermocellum during long-term saccharification process. Then, the differential inhibitory effects of non-cellulose components, including lignin, xylan, and arabinoxylan, on the cellulosome-based saccharification were determined. The results showed that lignin played inhibitory roles by non-productively adsorbing extracellular proteins of C. thermocellum. Differently, arabinoxylan preferred to bind with the cellulosomal components. Almost no adsorption of cellulosomal proteins on solid xylan was detected. Instead, xylan in water-dissolved form interacted with the cellulosomal proteins, especially the key exoglucanase Cel48S, leading to the xylan inhibitory effect. Compared to xylan, xylooligosaccharides influenced the cellulosome activity slightly. Hence, this work demonstrates that the timely hydrolysis or removal of dissolved xylan is important for cellulosome-based lignocellulose saccharification.

In Vitro Assessment of Transporter Mediated Perpetrator DDIs for Several Hepatitis C Virus Direct-Acting Antiviral Drugs and Prediction of DDIs with Statins Using Static Models.

Inhibitory effects of asunaprevir, daclatasvir, grazoprevir, paritaprevir, simeprevir, and voxilaprevir, direct-acting antiviral (DAA) drugs for the treatment of chronic hepatitis C virus (HCV) infection, were evaluated in vitro against a range of clinically important drug transporters. In vitro inhibition studies were conducted using transporter transfected cells and membrane vesicles. The risk of clinical drug-drug interactions (DDIs) was assessed using simplified static models recommended by regulatory agencies. Furthermore, we refined and developed static models to predict complex DDIs with several statins (pitavastatin, rosuvastatin, atorvastatin, and pravastatin) by mechanistically assessing differential inhibitory effects of perpetrator drugs on multiple transporters, such as organic anion transporting polypeptides (OATP1B), breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), organic anion transporter 3 (OAT3), and cytochrome P450 CYP3A enzyme, as they are known to contribute to absorption, distribution, metabolism and excretion (ADME) of above statins. These models successfully predicted a total of 46 statin DDIs, including above DAA drugs and their fix-dose combination regimens. Predicted plasma area under curve ratio (AUCR) with and without perpetrator drugs was within ~ 2-fold of observed values. In contrast, simplified static R-value model resulted in increased false negative and false positive predictions when different prediction cut-off values were applied. Our studies suggest that mechanistic static model is a promising and useful tool to provide more accurate prediction of the risk and magnitude of DDIs with statins in early drug development and may help to improve the management of clinical DDIs for HCV drugs to ensure effective and safe HCV therapy. GRAPHICAL ABSTRACT.

Cooling Uncouples Differentially ROS Production from Respiration and Ca2+ Homeostasis Dynamic in Brain and Heart Mitochondria.

Hypothermia provides an effective neuro and cardio-protection in clinical settings implying ischemia/reperfusion injury (I/R). At the onset of reperfusion, succinate-induced reactive oxygen species (ROS) production, impaired oxidative phosphorylation (OXPHOS), and decreased Ca2+ retention capacity (CRC) concur to mitochondrial damages. We explored the effects of temperature from 6 to 37 °C on OXPHOS, ROS production, and CRC, using isolated mitochondria from mouse brain and heart. Oxygen consumption and ROS production was gradually inhibited when cooling from 37 to 6 °C in brain mitochondria (BM) and heart mitochondria (HM). The decrease in ROS production was gradual in BM but steeper between 31 and 20 °C in HM. In respiring mitochondria, the gradual activation of complex II, in addition of complex I, dramatically enhanced ROS production at all temperatures without modifying respiration, likely because of ubiquinone over-reduction. Finally, CRC values were linearly increased by cooling in both BM and HM. In BM, the Ca2+ uptake rate by the mitochondrial calcium uniporter (MCU) decreased by 2.7-fold between 25 and 37 °C, but decreased by 5.7-fold between 25 and 37 °C in HM. In conclusion, mild cold (25–37 °C) exerts differential inhibitory effects by preventing ROS production, by reverse electron transfer (RET) in BM, and by reducing MCU-mediated Ca2+ uptake rate in BM and HM.

Differential tumor inhibitory effects induced by HER3 extracellular subdomain-specific mouse monoclonal antibodies.

The therapeutic potential of targeting the human epidermal growth factor receptor-3 (ErbB3/HER3) has long been ignored due to impaired tyrosine kinase function and low expression level in tumor cells compared with EGFR and HER2. Although recent investigations have explored the potential benefit of HER3 targeting and several anti-HER3 agents have been developed, there is still a critical need to design and produce more efficient therapeutics. This study was designed to develop tumor inhibitory monoclonal antibodies (MAbs) against different extracellular subdomains of HER3. Distinct extracellular subdomains of HER3 (DI+II and DIII+IV) were utilized to produce MAbs by hybridoma technology. Biochemical and functional characteristics of these MAbs were then investigated by various methodologies, including immunoblotting, flow cytometry, cell proliferation, cell signaling, and enzyme-linked immunosorbent assays. Four anti-DI+II and six anti-DIII+IV MAbs were obtained, selected based on their ability to bind recombinant full HER3 extracellular domain (ECD). Our data showed that only one anti-DI+II and four anti-DIII+IV MAbs recognized the native form of HER3 by immunoblotting. Four MAbs recognized the membranous HER3 by flow cytometry leading to induction of different levels of receptor internalization and subsequent degradation. Results of cell proliferation assays using these MAbs indicated that they differentially inhibited proliferation of HER3-expressing cancer cells and showed considerable synergistic effects in combination with trastuzumab. Selected MAb with the highest inhibitory effect significantly inhibited the phosphorylation of AKT and ERK1/2 molecules. Some of the anti-HER3 MAbs produced in this study displayed tumor inhibitory function and may be considered promising candidates for future HER3-targeted cancer therapy.

Different Transcutaneous Auricular Vagus Nerve Stimulation Parameters Modulate the Anti-Inflammatory Effects on Lipopolysaccharide-Induced Acute Inflammation in Mice.

Vagus nerve stimulation (VNS) is considered a potential method for anti-inflammation due to the involvement of the VN in the cholinergic anti-inflammatory pathway (CAP) formation of a connection between the central nervous system and peripheral immune cells that help relieve inflammation. However, whether a non-invasive transcutaneous auricular VNS (taVNS) modulates the inflammation levels via altering the parameter of taVNS is poorly understood. This study aimed to determine the differential inhibitory effects of taVNS on lipopolysaccharide (LPS)-induced systemic inflammation using electrical stimulation parameters such as pulse frequency and time. The taVNS-promoted CAP activity significantly recovered LPS-induced tissue injuries (lung, spleen, and intestine) and decreased inflammatory cytokine levels and tissue-infiltrated immune cells. Interestingly, the anti-inflammatory capacity of taVNS with 15 Hz was much higher than that of taVNS with 25 Hz. When a cytokine array was used to investigate the changes of inflammation and immune response-related cytokines/chemokines expression in taVNS with 15 Hz or 25 Hz treatment in LPS-induced endotoxemia in mice, most of the expression of cytokines/chemokines associated with pro-inflammation was severely decreased in taVNS with 15 Hz compared to 25 Hz. This study demonstrated that the taVNS parameter could differentially modulate the inflammation levels of animals, suggesting the importance of taVNS parameter selection for use in feasible interventions for acute inflammation treatment.

Pain-induced changes in motor unit discharge depend on recruitment threshold and contraction speed.

At high forces, the discharge rates of lower- and higher-threshold motor units (MU) are influenced in a different way by muscle pain. These differential effects may be particularly important for performing contractions at different speeds since the proportion of lower- and higher-threshold MUs recruited varies with contraction velocity. We investigated whether MU discharge and recruitment strategies are differentially affected by pain depending on their recruitment threshold (RT), across a range of contraction speeds. Participants performed ankle dorsiflexion sinusoidal-isometric contractions at two frequencies (0.25 and 1 Hz) and two modulation amplitudes [5% and 10% of the maximum voluntary contraction (MVC)] with a mean target torque of 20%MVC. High-density surface electromyography recordings from the tibialis anterior muscle were decomposed and the same MUs were tracked across painful (hypertonic saline injection) and nonpainful conditions. Torque variability, mean discharge rate (MDR), DR variability (DRvar), RT, and the delay between the cumulative spike train and the resultant torque output (neuromechanical delay, NMD) were assessed. The average RT was greater at faster contraction velocities (P = 0.01) but was not affected by pain. At the fastest contraction speed, torque variability and DRvar were reduced (P < 0.05) and MDR was maintained. Conversely, MDR decreased and DRvar and NMD increased significantly during pain at slow contraction speeds (P < 0.05). These results show that reductions in contraction amplitude and increased recruitment of higher-threshold MUs at fast contraction speeds appear to compensate for the inhibitory effect of nociceptive inputs on lower-threshold MUs, allowing the exertion of fast submaximal contractions during pain.NEW & NOTEWORTHY Pain induces changes in motor performance, motor unit recruitment, and rate coding behavior that varies across different contraction speeds. Here we show that that pain reduces motor unit discharge rate and prolongs the neuromechanical delay at slow contraction speeds only. This new evidence suggests that there are differential nociceptive inhibitory effects across the motor unit pool, which allows fast submaximal contractions to be exerted despite the presence of pain.

The Differential Growth Inhibition of Phytophthora spp. Caused by the Rare Sugar Tagatose Is Associated With Species-Specific Metabolic and Transcriptional Changes.

Tagatose is a rare sugar with no negative impacts on human health and selective inhibitory effects on plant-associated microorganisms. Tagatose inhibited mycelial growth and negatively affected mitochondrial processes in Phytophthora infestans, but not in Phytophthora cinnamomi. The aim of this study was to elucidate metabolic changes and transcriptional reprogramming activated by P. infestans and P. cinnamomi in response to tagatose, in order to clarify the differential inhibitory mechanisms of tagatose and the species-specific reactions to this rare sugar. Phytophthora infestans and P. cinnamomi activated distinct metabolic and transcriptional changes in response to the rare sugar. Tagatose negatively affected mycelial growth, sugar content and amino acid content in P. infestans with a severe transcriptional reprogramming that included the downregulation of genes involved in transport, sugar metabolism, signal transduction, and growth-related process. Conversely, tagatose incubation upregulated genes related to transport, energy metabolism, sugar metabolism and oxidative stress in P. cinnamomi with no negative effects on mycelial growth, sugar content and amino acid content. Differential inhibitory effects of tagatose on Phytophthora spp. were associated with an attempted reaction of P. infestans, which was not sufficient to attenuate the negative impacts of the rare sugar and with an efficient response of P. cinnamomi with the reprogramming of multiple metabolic processes, such as genes related to glucose transport, pentose metabolism, tricarboxylic acid cycle, reactive oxygen species detoxification, mitochondrial and alternative respiration processes. Knowledge on the differential response of Phytophthora spp. to tagatose represent a step forward in the understanding functional roles of rare sugars.

Revealing the role of fluorine pharmacophore in chalcone scaffold for shifting the MAO-B selectivity: investigation of a detailed molecular dynamics and quantum chemical study

The development of highly selective monoamine oxidase-B (MAO-B) inhibitors has great therapeutic benefit in treatment of various neurodegenerative disorders. Recent study documented that shifting of fluorine atom from para to ortho position on the phenyl B ring of heteroaryl chalcones shown a remarkable shift in the selectivity and potency between MAO-A and MAO-B isoforms. Despite the large plethora of the design of new selective MAO-B inhibitors, the current paper illustrates the role and orientation of fluorine atom with remarkable MAO-B selectivity of three compounds (O23, O24 and O25), which differ from all other substituents encountered in the chalcone scaffolds is recently reported by our group. Conformational analyses of differential inhibitory effects of O23, O24 and O25 on MAO-A and MAO-B, differential analyses of complementary interactions at MAO-A/-B active sites and differential analysis of affinity binding and per-residue energy contributions are calculated by molecular dynamics study. Density functional theory based electronic structure calculations were employed with special emphasis to electrostatic potential and frontier molecular orbitals. Results of the current study can be used for lead modification and a new insight for the development of novel fluorinated chalcones for the treatment of various neurodegenerative disorders. Communicated by Ramaswamy H. Sarma