Search Results (31)

(1) Background: The complete signalling pathway leading to light-induced chloroplast movement in plant cells is not yet fully understood. The process may involve GLR channels, which have previously been shown to participate in light signalling in plants. Therefore, using in vivo photometry we analysed chloroplast movements in the water plant Lemna trisulca treated with GLR channel inhibitors, MK-801 and CNQX. (2) Results: MK-801, a non-competitive antagonist that blocks NMDA channels was found to inhibit the avoidance response of chloroplasts controlled by phototropin2. This inhibition depends on pH and requires alkaline conditions. On the contrary, CNQX, a competitive receptor antagonist that blocks AMPA channels did not change the parameters of chloroplast movements in either mild alkaline or acidic conditions. (3) Conclusions: Our study reveals that GLR NMDA channels play a role in chloroplast movements and provides new insights into the phot2 signalling pathway. The results also suggest that the activity of these channels depends on pH, similar to NMDA receptors present in animal cells. Full article

Matrix metalloproteinases 2 and 9 (MMP-2, MMP-9) have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, their protein levels and correlation with other biomarkers are not well understood. We measured total and active MMP-2/-9 and additional biomarkers (creatinine, neurofilament light, cystatin C, and alkaline phosphatase) in the serum of people with ALS (ALS, n = 30) and compared their levels with age-matched healthy controls (HC, n = 20) and other neurological diseases (diabetic nephropathy, Alzheimer’s disease, Parkinson’s disease; n = 8 each). We also measured MMP-2/-9 in a set of CSF samples from ALS (n = 30) and age-matched other neurological diseases (OND, n = 14). Lastly, we measured the competitive binding behavior of a dual MMP-2/MMP-9 inhibitor, AQU-118, against active MMP-9 in situ within the serum of ALS. We found significantly elevated levels of both total MMP-9 protein (two studies, 7.5 and 9.5-fold; both p < 0.0001) and active MMP-9 (2.5-fold; p < 0.0001) in ALS serum compared to HC. Serum NfL was significantly elevated (6-fold, p < 0.0001) and serum creatinine was significantly decreased (40%, p < 0.0001) in ALS compared to HC. There were significantly decreased levels of MMP-2 (two studies, 26 and 33%; p < 0.001 and p = 0.0001, respectively) in the serum of ALS as compared to HC. ALS also had significantly higher active MMP-9 in serum than patients with Alzheimer’s disease and higher than Parkinson’s disease or diabetic nephropathy. We confirmed that active MMP-9 in ALS is fully available for proteolytic activity in both serum and CSF and can be inhibited using an MMP-2/-9 inhibitor. Active MMP-9 is systemically elevated in ALS and therefore a therapeutic target for ALS drug development. Full article

A group of sulfonium and selenonium salts bearing diverse benzylidene acetal substituents on their side chain moiety were designed and synthesized. Compared with our previous study, structural modifications in this study focused on multi-substitution of the phenyl ring and bioisosteric replacements at the sulfonium cation center. In vitro biological evaluation showed that selenonium replacement could significantly improve their α-glucosidase inhibitory activity. The most potent inhibitor 20c (10.0 mg/kg) reduced postprandial blood glucose by 48.6% (15 min), 52.8% (30 min), and 48.1% (60 min) in sucrose-loaded mice, outperforming acarbose (20.0 mg/kg). Docking studies of 20c with ntMGAM presented a new binding mode. In addition to conventional hydrogen bonding and electrostatic interaction, amino residue Ala-576 was first identified to contribute to binding affinity through π-alkyl and alkyl interactions with the chlorinated substituent and aromatic ring. The selected compounds exhibited a high degree of safety in cytotoxicity tests against normal cells. Kinetic characterization of α-glucosidase inhibition confirmed a fully competitive inhibitory mode of action for these sulfonium salts. Full article

Background/Objectives: Pinocembrin is a promising drug candidate for treating ischemic stroke. The interaction of pinocembrin with drug transporters and drug-metabolizing enzymes is not fully revealed. The present study aims to evaluate the interaction potential of pinocembrin with cytochrome P450 (CYP450: CYP2B6, CYP2C9, and CYP2C19) and drug transporters including organic anion transporters (OAT1 and OAT3), organic cation transporters (OCT1 and OCT2), multidrug and toxin extrusion (MATE1 and MATE2, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Methods: The interactions of pinocembrin on drug transporters were determined in the Madin–Darby canine kidney (MDCK) cells overexpressing human (h)OAT1 or hOAT3 and in the Chinese hamster ovary (CHO-K1) cells overexpressing hOCT1, hOCT2, hMATE1, or hMATE2. The interactions of pinocembrin with BCRP and P-glycoprotein were determined in Caco-2 cells. The CYP450 enzyme inhibitory activity was assessed by a cell-free CYP450 screening assay. Results: Pinocembrin effectively inhibited the function of OAT1 and OAT3 with a half-inhibitory concentration (IC₅₀) and inhibitory constant (Ki) of ∼2 μM. In addition, it attenuated the toxicity of tenofovir, a substrate of hOAT1, in cells overexpressing hOAT1. Based on the kinetic study and molecular docking, pinocembrin inhibited OAT1 and OAT3 via a competitive inhibition. In contrast to hOAT1 and hOAT3, pinocembrin did not significantly inhibit the function of OCT1, OCT2, MATE1, MATE2, BCRP, and P-glycoprotein. In addition, pinocembrin potently inhibited the activity of CYP2C19, whereas it exhibited low inhibitory potency on CYP2B6 and CYP2C9. Conclusions: The present study reveals the potential drug interaction of pinocembrin on OAT1, OAT3, and CYP2C19. Co-administration with pinocembrin might affect OAT1-, OAT3-, and CYP2C19-mediated drug pharmacokinetic profiles. Full article

The adsorption of toxic metals onto iron oxides is a prevalent geochemical process in natural environments. Organic acids are known to modify the adsorption features of toxic ions through either competitive or cooperative effects. Nowadays, the toxic metal adsorption influenced by organic acids on iron oxides with varying facet exposures is not fully understood. This study explored how L-Aspartic acid (LA) influences Cr(VI) adsorption on two different exposure facets of lepidocrocite through batch adsorption experiments, in situ ATR-FTIR spectroscopy, and 2D-COS analysis. The results reveal that LA competes for available binding sites on lepidocrocite, consequently inhibiting the adsorption of Cr(VI). Rod-shaped lepidocrocite (R-LEP) owns more (001) facets and shows stronger Cr(VI) adsorption and LA competition than plate-like lepidocrocite (P-LEP), which mainly has (010) facets. The data for Cr(VI) uptake on both P-LEP and R-LEP within the effect of LA are well-fitted by the pseudo-second-order kinetics and the Freundlich isotherm model, suggesting chemical interaction as the dominant process for Cr(VI) coordination on lepidocrocite. Cr(VI) ions favor interaction with R-LEP over P-LEP, forming inner-sphere complexes on (001) facets. Concurrently, LA’s carboxyl groups can compete for the active sites on the lepidocrocite surfaces, engaging in anion exchange with hydroxyl groups, and forming outer-sphere and inner-sphere structures. This competitive effect is particularly pronounced in the R-LEP system. The current findings are expected to broaden insights into how the exposed facets of lepidocrocite influence the fate of Cr(VI) in the organic acid coexistence environment. Full article

Cancer, a group of diseases characterized by uncontrollable cell proliferation and metastasis, remains a global health challenge. This study investigates quercetin, a natural compound found in many fruits and vegetables, for its potential to inhibit the phosphomonoesterase activity of protein tyrosine phosphatase nonreceptor type 22 (PTPN22), a key immune response regulator implicated in cancer and autoimmune diseases. We started by screening seven (7) natural compounds against the activities of PTPN22 in vitro. The initial screening identified quercetin with the highest percentage inhibition (81%) among the screened compounds when compared with ursolic acid that has 84%. After the identification of quercetin, we proceeded by investigating the effect of increasing concentrations of the compound on the activity of PTPN22. In vitro studies showed that quercetin inhibited PTPN22 with an IC₅₀ of 29.59 μM, outperforming the reference standard ursolic acid, which had an IC₅₀ of 37.19 μM. Kinetic studies indicated a non-competitive inhibition by quercetin with a Ki of 550 μM. In silico analysis supported these findings, showing quercetin’s better binding affinity (ΔGbind −24.56 kcal/mol) compared to ursolic acid, attributed to its higher reactivity and electron interaction capabilities at PTPN22′s binding pocket. Both quercetin and ursolic acid improved the structural stability of PTPN22 during simulations. These results suggest quercetin’s potential as an anticancer agent, meriting further research. However, in vivo studies and clinical trials are necessary to fully assess its efficacy and safety, and to better understand its mechanisms of action. Full article

Spinal muscular atrophy (SMA) is a rare, genetic neurodegenerative disorder caused by insufficient production of survival motor neuron (SMN) protein. Diminished SMN protein levels lead to motor neuron loss, causing muscle atrophy and weakness that impairs daily functioning and reduces quality of life. SMN upregulators offer clinical improvements and increased survival in SMA patients, although significant unmet needs remain. Myostatin, a TGF-β superfamily signaling molecule that binds to the activin II receptor, negatively regulates muscle growth; myostatin inhibition is a promising therapeutic strategy for enhancing muscle. Combining myostatin inhibition with SMN upregulation, a comprehensive therapeutic strategy targeting the whole motor unit, offers promise in SMA. Taldefgrobep alfa is a novel, fully human recombinant protein that selectively binds to myostatin and competitively inhibits other ligands that signal through the activin II receptor. Given a robust scientific and clinical rationale and the favorable safety profile of taldefgrobep in patients with neuromuscular disease, the RESILIENT phase 3, randomized, placebo-controlled trial is investigating taldefgrobep as an adjunct to SMN upregulators in SMA (NCT05337553). This manuscript reviews the role of myostatin in muscle, explores the preclinical and clinical development of taldefgrobep and introduces the phase 3 RESILIENT trial of taldefgrobep in SMA. Full article

Associated with more ambitious targets for reducing emissions, the European Union (EU) plans to implement the Carbon Border Adjustment Mechanism (CBAM) fully in 2026, aiming to reduce carbon leakage and competitiveness concerns by imposing tariffs on carbon-intensive imports, which is expected to significantly impact its trade partners. Existing research has focused on CBAM’s impact on macroeconomic indicators but has insufficiently addressed its effects on global and regional carbon leakage, especially in non-EU countries like China. This research offers a detailed analysis of industry-specific leakage rates and integrates both global and regional impacts by employing the dynamic recursive GTAP-E general equilibrium model to numerically simulate CBAM’s inhibitory effect on carbon leakage under different carbon tariff scenarios, while also exploring the synergistic effects of anti-leakage policies in non-EU countries. Our simulations indicate the following: (1) CBAM effectively inhibits carbon leakage, with greater inhibition observed at higher tax rates and with the expansion of covered industries. (2) Establishing China’s domestic carbon market pricing can further reduce regional carbon leakage rates. Implementing global export carbon tax policies will significantly diminish the risk of global carbon leakage. (3) The implementation of CBAM is projected to reduce China’s total exports to the EU, though this loss will be partly offset by trade diversion effects. Carbon-intensive industries are more adversely affected in the short term, while all industries except fossil fuels face inevitable long-term negative impacts. Full article

Neutrophil elastase (HNE), like other members of the so-called GASPIDs (Granule-Associated Serine Peptidases of Immune Defense), is activated during protein biosynthesis in myeloid precursors and stored enzymatically active in cytoplasmic granules of resting neutrophils until secreted at sites of host defense and inflammation. Inhibitors thus could bind to the fully formed active site of the protease intracellularly in immature progenitors, in circulating neutrophils, or to HNE secreted into the extracellular space. Here, we have compared the ability of a panel of diverse inhibitors to inhibit HNE in the U937 progenitor cell line, in human blood-derived neutrophils, and in solution. Most synthetic inhibitors and, surprisingly, even a small naturally occurring proteinaceous inhibitor inhibit HNE intracellularly, but the extent and dynamics differ markedly from classical enzyme kinetics describing extracellular inhibition. Intracellular inhibition of HNE potentially affects neutrophil functions and has side effects, but it avoids competition of inhibitors with extracellular substrates that limit its efficacy. As both intra- and extracellular inhibition have advantages and disadvantages, the quantification of intracellular inhibition, in addition to classical enzyme kinetics, will aid the design of novel, clinically applicable HNE inhibitors with targeted sites of action. Full article

Erythritol has shown excellent insecticidal performance against a wide range of insect species, but the molecular mechanism by which it causes insect mortality and sterility is not fully understood. The mortality and sterility of Drosophila melanogaster were assessed after feeding with 1M erythritol for 72 h and 96 h, and gene expression profiles were further compared through RNA sequencing. Enrichment analysis of GO and KEGG revealed that expressions of the adipokinetic hormone gene (Akh), amylase gene (Amyrel), α-glucosidase gene (Mal-B1/2, Mal-A1-4, Mal-A7/8), and triglyceride lipase gene (Bmm) were significantly up-regulated, while insulin-like peptide genes (Dilp2, Dilp3 and Dilp5) were dramatically down-regulated. Seventeen genes associated with eggshell assembly, including Dec-1 (down 315-fold), Vm26Ab (down 2014-fold) and Vm34Ca (down 6034-fold), were significantly down-regulated or even showed no expression. However, there were no significant differences in the expression of three diuretic hormone genes (DH44, DH31, CAPA) and eight aquaporin genes (Drip, Big brain, AQP, Eglp1, Eglp2, Eglp3, Eglp4 and Prip) involved in osmolality regulation (all p value > 0.05). We concluded that erythritol, a competitive inhibitor of α-glucosidase, severely reduced substrates and enzyme binding, inhibiting effective carbohydrate hydrolysis in the midgut and eventually causing death due to energy deprivation. It was clear that Drosophila melanogaster did not die from the osmolality of the hemolymph. Our findings elucidate the molecular mechanism underlying the mortality and sterility in Drosophila melanogaster induced by erythritol feeding. It also provides an important theoretical basis for the application of erythritol as an environmentally friendly pesticide. Full article

Arboviruses such as Dengue, yellow fever, West Nile, and Zika are flaviviruses vector-borne RNA viruses transmitted biologically among vertebrate hosts by blood-taking vectors. Many flaviviruses are associated with neurological, viscerotropic, and hemorrhagic diseases, posing significant health and socioeconomic concerns as they adapt to new environments. Licensed drugs against them are currently unavailable, so searching for effective antiviral molecules is still necessary. Epigallocatechin molecules, a green tea polyphenol, have shown great virucidal potential against flaviviruses, including DENV, WNV, and ZIKV. The interaction of EGCG with the viral envelope protein and viral protease, mainly identified by computational studies, describes the interaction of these molecules with viral proteins; however, how the viral NS2B/NS3 protease interacts with epigallocatechin molecules is not yet fully deciphered. Consequently, we tested the antiviral potential of two epigallocatechin molecules (EGC and EGCG) and their derivative (AcEGCG) against DENV, YFV, WNV, and ZIKV NS2B/NS3 protease. Thus, we assayed the effect of the molecules and found that a mixture of the molecules EGC (competitive) and EGCG (noncompetitive) inhibited the virus protease of YFV, WNV, and ZIKV more effectively with IC₅₀ values of 1.17 ± 0.2 µM, 0.58 ± 0.07 µM, and 0.57 ± 0.05 µM, respectively. As these molecules fundamentally differ in their inhibitory mode and chemical structure, our finding may open a new line for developing more effective allosteric/active site inhibitors to combat flaviviruses infection. Full article

The aim of the present study was to develop an experimental system for an exploration of ethylene-dependent responses using intact growing Ranunculus sceleratus plants and to approbate the system for assessing the role of ethylene in salinity tolerance and ion accumulation. Plants were cultivated in sealed plastic containers in a modified gaseous atmosphere by introducing ethylene or 1-methylcyclopropene (1-MCP), a competitive inhibitor of ethylene action. High humidity inside the containers induced a fast elongation of the leaf petioles of R. sceleratus. The effect was ethylene-dependent, as 1-MCP completely blocked it, but exogenous ethylene further promoted petiole elongation. Exogenous ethylene decreased (by 48%) but 1-MCP increased (by 48%) the Na⁺ accumulation in leaf blades of NaCl-treated plants. The experimental system was further calibrated with ethylene and silica xerogel, and the optimum concentrations were found for inducing leaf petiole elongation (10 μL L^–1 ethylene) and preventing leaf petiole elongation (200 g silica xerogel per 24 L), respectively. The second experiment involved a treatment with NaCl in the presence of 1-MCP, ethylene, or 1-MCP + ethylene, both in normal and high air humidity conditions. In high humidity conditions, NaCl inhibited petiole elongation by 25% and ethylene treatment fully reversed this inhibition and stimulated elongation by 12% in comparison to the response of the control plants. Treatment with 1-MCP fully prevented this ethylene effect. In normal humidity conditions, NaCl inhibited petiole elongation by 20%, which was reversed by ethylene without additional elongation stimulation. However, 1-MCP only partially inhibited the ethylene effect on petiole elongation. In high humidity conditions, ethylene inhibited Na⁺ accumulation in NaCl-treated plants by 14%, but 1-MCP reversed this effect. In conclusion, the stimulation of endogenous ethylene production in R. sceleratus plants at a high air humidity or in flooded conditions reverses the inhibitory effect of salinity on plant growth and concomitantly inhibits the accumulation of Na⁺ in tissues. R. sceleratus is a highly promising model species for use in studies regarding ethylene-dependent salinity responses and ion accumulation potential involving the manipulation of a gaseous environment. Full article

Adults commonly struggle with perceiving and recognizing the sounds and words of a second language (L2), especially when the L2 sounds do not have a counterpart in the learner’s first language (L1). We examined how L1 Mandarin L2 English speakers learned pseudo English words within a cross-situational word learning (CSWL) task previously presented to monolingual English and bilingual Mandarin-English speakers. CSWL is ambiguous because participants are not provided with direct mappings of words and object referents. Rather, learners discern word-object correspondences through tracking multiple co-occurrences across learning trials. The monolinguals and bilinguals tested in previous studies showed lower performance for pseudo words that formed vowel minimal pairs (e.g., /dit/-/dɪt/) than pseudo word which formed consonant minimal pairs (e.g., /bɔn/-/pɔn/) or non-minimal pairs which differed in all segments (e.g., /bɔn/-/dit/). In contrast, L1 Mandarin L2 English listeners struggled to learn all word pairs. We explain this seemingly contradicting finding by considering the multiplicity of acoustic cues in the stimuli presented to all participant groups. Stimuli were produced in infant-directed-speech (IDS) in order to compare performance by children and adults and because previous research had shown that IDS enhances L1 and L2 acquisition. We propose that the suprasegmental pitch variation in the vowels typical of IDS stimuli might be perceived as lexical tone distinctions for tonal language speakers who cannot fully inhibit their L1 activation, resulting in high lexical competition and diminished learning during an ambiguous word learning task. Our results are in line with the Second Language Linguistic Perception (L2LP) model which proposes that fine-grained acoustic information from multiple sources and the ability to switch between language modes affects non-native phonetic and lexical development. Full article

The hydrogenation of polyaromatic compounds (PACs) present in mineral oils is of great importance when it comes to the desired product properties and the minimization of health hazards; however, the presence of organonitrogen inhibits the conversion of these compounds. In this study, the inhibition effects of different types of organonitrogen compounds (acridine (ACR) and carbazole (CBZ)-basic and nonbasic organonitrogen) on the hydrodearomatization (HDA) of phenanthrene over a sulfided commercial NiMo/Al₂O₃ catalyst were investigated in a microflow trickle-bed reactor at a temperature range of 280 to 320 °C and at a total pressure of 120 barg. Analysis of the experimental results shows that the hydrogenation of phenanthrene is significantly decreased in the presence of organonitrogen, with acridine showing stronger inhibiting effects. The extent of hydrodenitrogenation (HDN) is shown to correlate with the inhibition degree with a higher extent of HDN being achieved for carbazole than for acridine. Results from co-feeding different nitrogen types (acridine and carbazole) indicate that basic nitrogen is the dominating type of organonitrogen inhibitor. Recovery of catalyst activity in the absence of organonitrogen indicates fully reversible deactivation suggesting that inhibition relates to competitive adsorption and slower reaction rate of HDN compared to HDA. Full article

Proline-rich antimicrobial peptides (PrAMPs) are promising candidates to treat bacterial infections. The designer peptide ARV-1502 exhibits strong antimicrobial effects against Enterobacteriaceae both in vitro and in vivo. Since the inhibitory effects of ARV-1502 reported for the 70 kDa heat-shock protein DnaK do not fully explain the antimicrobial activity of its 176 substituted analogs, we further studied their effect on the bacterial 70S ribosome of Escherichia coli, a known target of PrAMPs. ARV-1502 analogues, substituted in positions 3, 4, and 8 to 12 (underlined) of the binding motif D³KPRPYLPRP¹² with aspartic acid, lysine, serine, phenylalanine or leucine, were tested in a competitive fluorescence polarization (FP) binding screening assay using 5(6)-carboxyfluorescein-labeled (Cf-) ARV-1502 and the 70S ribosome isolated from E. coli BW25113. While their effect on ribosomal protein expression was studied for green fluorescent protein (GFP) in a cell-free expression system (in vitro translation), the importance of known PrAMP transporters SbmA and MdtM was investigated using E. coli BW25113 and the corresponding knockout mutants. The dissociation constant (K_d) of 201 ± 16 nmol/L obtained for Cf-ARV-1502 suggests strong binding to the E. coli 70S ribosome. An inhibitory binding assay indicated that the binding site overlaps with those of other PrAMPs including Onc112 and pyrrhocoricin as well as the non-peptidic antibiotics erythromycin and chloramphenicol. All these drugs and drug candidates bind to the exit-tunnel of the 70S ribosome. Substitutions of the C-terminal fragment of the binding motif YLPRP reduced binding. At the same time, inhibition of GFP expression increased with net peptide charge. Interestingly, the MIC values of wild-type and ΔsbmA and ΔmdtM knockout mutants indicated that substitutions in the ribosomal binding motif altered also the bacterial uptake, which was generally improved by incorporation of hydrophobic residues. In conclusion, most substituted ARV-1502 analogs bound weaker to the 70S ribosome than ARV-1502 underlining the importance of the YLPRP binding motif. The weaker ribosomal binding correlated well with decreased antimicrobial activity in vitro. Substituted ARV-1502 analogs with a higher level of hydrophobicity or positive net charge improved the ribosome binding, inhibition of translation, and bacterial uptake. Full article