Inhibition Of Activity Research Articles

Fluorescent covalent organic framework as an ultrasensitive fluorescent probe for tyrosinase activity monitoring and inhibitor screening

BackgroundAs a significant biomarker of melanocytic lesions, tyrosinase (TYR) plays an essential role in the clinical diagnosis and treatment of melanin-related diseases. Thus, it is important to develop robust methods for assessing TYR activity. Covalent organic frameworks (COFs) have garnered considerable attention owing to their unique properties, including high chemical stability, good biocompatibility, and large surface area compared with organic dyes, noble metal nanoclusters, and semiconductor quantum dots. However, most COFs are insoluble in water and exhibit weak or no fluorescence emission. Therefore, the development of a water-soluble fluorescent COF for detecting TYR activity in biological samples remains highly desired. ResultsIn this work, a sensitive and facile fluorometric method based on fluorescent COF was constructed for the detection of TYR activity in human serum samples. The water-soluble COF was fabricated through the condensation polymerization of 4′,4‴,4′′′′′,4′′′′′′′-(1,2-ethene-diylidene) tetrakis [1,1′-biphenyl]-4-carboxaldehyde and 2,4,6-tris-(4-aminophenyl)-triazine. The resulting COF displayed yellow-green fluorescence with a maximum emission peak at 560 nm. Tyrosine was catalyzed by TYR to produce melanin-like polymers which formed a coating on the surface of COF and effectively quenched its fluorescence due to fluorescence resonance energy transfer. The proposed approach demonstrated a strong linear correlation in the range of 0.5–80 U/L with a low detection limit of 0.09 U/L. Additionally, the limit of detection for kojic acid, serving as a representative TYR inhibitor, was determined to be 0.0004 μg/mL. SignificanceOur proposed fluorometric sensing platform exhibited exceptional selectivity, sensitivity, and satisfactory recoveries in human serum samples, which is of paramount importance for the clinical diagnostics of melanin-related diseases. Furthermore, the proposed approach was further employed for the screening of TYR inhibitors, suggesting the potential applications in clinical treatment and pharmaceutical research.

Screening and identification of peptidyl arginine deiminase 4 inhibitors from herbal plants extracts and purified natural products by a trypsin assisted sensitive immunoassay based on streptavidin magnetic beads

Peptidyl arginine deiminase 4 (PAD4) plays a critical role in many autoimmune diseases including rheumatoid arthritis. Herein, a trypsin assisted highly immunoassay method was established to determine PAD4 activity and screen potent inhibitors from herbal plants extracts and purified natural products. The method was applied to determine endogenous PAD4 activity in both cell and tissue lysates, as well as the inhibitory effects of 20 herbal plants and 50 purified natural products. The Cinnamomi ramulus extract showed strongest inhibitory potency with IC50 value lower than 5 μg/mL. Meanwhile, pyrroloquinoline quinone (PQQ), widely used as a dietary supplement, was discovered as a promising PAD4 inhibitor with an IC50 value lower than 4 μM. The inhibition kinetic analysis, drug affinity response target stability (DARTS) and molecular docking were performed to confirm the interaction between PQQ and PAD4. This method has great potential for researchers to monitor activities and discover potential inhibitors of PAD4.

Benzimidazole-oxindole hybrids: A novel class of selective dual CDK2 and GSK-3β inhibitors of potent anticancer activity.

A new series of benzimidazole-oxindole hybrids 8a-x was discovered as dual cyclin-dependent kinase (CDK2) and glycogen synthase kinase-3-beta (GSK-3β) inhibitors with potent anticancer activity. The synthesized hits displayed potent anticancer activity against national cancer institute cancer cell lines in single-dose and five-dose assays. Moreover, the derivatives 8k, 8l, 8n, 8o, and 8p demonstrated potent cytotoxic activity against PANC-1 cells with IC50 = 1.88-2.79 µM. In addition, the hybrids 8l, 8n, 8o, and 8p displayed potent antiproliferative activity on the MG-63 cell line (IC50 = 0.99-1.90 µM). Concurrently, the benzimidazole-oxindole hybrid 8v exhibited potent dual CDK2/GSK-3β inhibitory activity with IC50 values of 0.04 and 0.021 µM, respectively. In addition, 8v displayed more than 10-fold higher selectivity toward CDK2 and GSK-3 β over CDK1, CDK5, GSK-3α, vascular endothelial growth factor receptor-2, and B-rapidly accelerated fibrosarcoma. Screening of the effect of 8n and 8v on the cell cycle and apoptosis of PANC-1 and MG-63 cells displayed their ability to arrest their cell cycle at the G2-M phase and to potentiate the apoptosis of both cell lines. In silico docking of the benzimidazole-oxindole hybrid 8v into the catalytic pocket of both CDK2 and GSK-3β revealed its perfect fitting through the formation of hydrogen bonding and hydrophobic interactions with the key amino acids in the binding sites. In addition, in silico absorption, distribution, metabolism, excretion studies proved that 8a-x exhibit satisfactory drug-likeness properties for drug development.

Lawsonia inermis as an Active Corrosion Inhibitor for Mild Steel in Hydrochloric Acid

Corrosion is a pervasive issue affecting metallic materials, with significant economic losses and safety risks in various industries. Mild steel, extensively used in construction and infrastructure, faces corrosion challenges, needing continuous research to effectively tackle them. Natural compounds, because of their eco-friendliness and corrosion inhibition potential, are attracting increasing interest for corrosion control. Lawsonia inermis (LI), or henna, a plant native to North Africa and South Asia, has bioactive compounds exhibiting corrosion inhibitive properties. This study comprehensively explores Lawsonia inermis’s effectiveness as a corrosion inhibitor for mild steel, filling a gap in the existing research. Various concentrations of Lawsonia inermis extract were tested in acidic solutions to evaluate corrosion inhibition. Experimental results indicate a significant reduction in the corrosion rate with increasing inhibitor concentration. Langmuir adsorption isothermal analyses reveal the adsorption mechanism as being an interplay between physisorption and weak chemisorption. Electrochemical measurements demonstrate Lawsonia inermis’s capability to alter both cathodic and anodic reactions, leading to improved corrosion resistance. Scanning electron microscopy reveals a more even surface morphology in the presence of the Lawsonia inermis, indicating corrosion inhibition. Gas chromatography–mass spectrometry (GC-MS) analyses identified organic compounds in Lawsonia inermis extract responsible for corrosion inhibition. Overall, Lawsonia inermis emerges as a promising corrosion inhibitor for mild steel, offering excellent inhibition efficiencies. This study sheds light on its adsorption behaviour and provides insights into its mechanism of action. These findings underscore Lawsonia inermis’s potential as a green corrosion inhibitor, paving the way for its practical application in industrial corrosion protection strategies.

Design, Synthesis, and Evaluation of the Selective and Orally Active LSD1 Inhibitor with the Potential of Treating Heart Failure.

LSD1 has become an appealing target for the development of new pharmacologic agents to treat cardiovascular diseases, including heart failure. Herein, we reported the design, synthesis, and structure-activity relationship of a series of TCP-based derivatives targeting LSD1. Docking studies were employed to successfully elucidate the SAR. Particularly, compound 7d, characterized by low toxicity, demonstrated a high affinity for LSD1 at molecular and cellular levels. It also displayed favorable pharmacokinetic properties for oral dosing (e.g., F = 77.61%), effectively alleviating Ang II-induced NRCFs activation in vitro and reducing pathological myocardial remodeling in TAC-induced cardiac remodeling and heart failure in vivo. Additionally, mechanism studies revealed that suppression of myocardial dysfunction by compound 7d is related to LSD1 inhibition-induced TGFβ signaling pathway repressing. In summary, the current report presents compound 7d as a potent LSD1 inhibitor with the potential for further development as a therapeutic agent for pressure overload-related heart failure.

A Systematic Hierarchical Virtual Screening Model for RhlR Inhibitors Based on PCA, Pharmacophore, Docking, and Molecular Dynamics.

RhlR plays a key role in the quorum sensing of Pseudomonas aeruginosa. The current structure-activity relationship (SAR) studies of RhlR inhibitors mainly focus on elucidating the functional groups. Based on a systematic review of previous research on RhlR inhibitors, this study aims to establish a systematic, hierarchical screening model for RhlR inhibitors. We initially established a database and utilized principal component analysis (PCA) to categorize the inhibitors into two classes. Based on the training set, pharmacophore models were established to elucidate the structural characteristics of ligands. Subsequently, molecular docking, molecular dynamics simulations, and the calculation of binding free energy and strain energy were performed to validate the crucial interactions between ligands and receptors. Then, the screening criteria for RhlR inhibitors were established hierarchically based on ligand structure characteristics, ligand-receptor interaction, and receptor affinity. Test sets were finally employed to validate the hierarchical virtual screening model by comparing it with the current SAR studies of RhlR inhibitors. The hierarchical screening model was confirmed to possess higher accuracy and a true positive rate, which holds promise for subsequent screening and the discovery of active RhlR inhibitors.

Developing Lead Compounds of eEF2K Inhibitors Using Ligand–Receptor Complex Structures

The eEF2K, a member of the α-kinase family, plays a crucial role in cellular differentiation and the stability of the nervous system. The development of eEF2K inhibitors has proven to be significantly important in the treatment of diseases such as cancer and Alzheimer’s. With the advancement of big data in pharmaceuticals and the evolution of molecular generation technologies, leveraging artificial intelligence to expedite research on eEF2K inhibitors shows great potential. Based on the recently published structure of eEF2K and known inhibitor molecular structures, a generative model was used to create 1094 candidate inhibitor molecules. Analysis indicates that the model-generated molecules can comprehend the principles of molecular docking. Moreover, some of these molecules can modify the original molecular frameworks. A molecular screening strategy was devised, leading to the identification of five promising eEF2K inhibitor lead compounds. These five compound molecules demonstrated excellent thermodynamic performance when docked with eEF2K, with Vina scores of −12.12, −16.67, −15.07, −15.99, and −10.55 kcal/mol, respectively, showing a 24.27% improvement over known active inhibitor molecules. Additionally, they exhibited favorable drug-likeness. This study used deep generative models to develop eEF2K inhibitors, enabling the treatment of cancer and neurological disorders.

In silico exploration of 4(α-l-rhamnosyloxy)-benzyl isothiocyanate: A promising phytochemical-based drug discovery approach for combating multi-drug resistant Staphylococcus aureus

Multidrug-resistant (MDR) Staphylococcus aureus infections significantly threaten global health. With rising resistance to current antibiotics and limited solutions, the urgent discovery of new, effective, and affordable antibacterials with low toxicity is imperative to combat diverse MDR S. aureus strains. Hence, in this study, we introduce an in silico phytochemical-based approach for discovering novel antibacterial agents, underscoring the potential of computational approaches in therapeutic discovery. Glucomoringin Isothiocyanate (GMG-ITC) from Moringa oleifera Lam. is one of the phytochemical compounds with several biological activities, including antimicrobial, anti-inflammatory, and antioxidant activities, and is also effective against S. aureus. This study focuses on screening GMG-ITC as a potential drug candidate to combat MDR S. aureus infections through a molecular docking approach. Moreover, interaction amino acid analysis, in silico pharmacokinetics, compound target prediction, pathway enrichment analysis and molecular dynamics (MD) simulations were conducted for further investigation. Molecular docking and interaction analysis showed strong binding affinity towards S. aureus lipase, dihydrofolate reductase, and other MDR S. aureus proteins, including penicillin-binding protein 2a, MepR, D-Ala:D-Ala ligase, and RPP TetM, through hydrophilic and hydrophobic interactions. GMG-ITC also showed a strong binding affinity to cyclooxygenase-2 and FAD-dependent NAD(P)H oxidase, suggesting that it is a potential anti-inflammatory and antioxidant candidate that may eliminate inflammation and oxidative stress associated with S. aureus infections. MD simulations validated the stability of the GMG-ITC molecular interactions determined by molecular docking. In silico pharmacokinetic analysis highlights its potency as a drug candidate, showing strong absorption, distribution, and excretion properties in combination with low toxicity. It acts as an active protease and enzyme inhibitor with moderate activity against GPCR ligands, ion channels, nuclear receptor ligands, and kinases. Enrichment analysis further elucidated its involvement in important biological, molecular, and cellular functions with potential therapeutic applications in diseases like cancer, hepatitis B, and influenza. Results suggest that GMG-ITC is an effective antibacterial agent that could treat MDR S. aureus-associated infections.

Methyl Syringate: A Primary Driving Factor in Manuka Honeys Ability to Ameliorate Neutrophil Intracellular ROS Activity and NETosis.

Neutrophils use both the production of reactive oxygen species (ROS) and a specialized process called NETosis to defend the body from material deemed foreign. While these neutrophil behaviors are critical in preventing infection, a dysregulated response can lead to tissue damage and fibrosis at host-biomaterial interfaces. It was hypothesized that applying the flavonoids found in Manuka honey: chrysin, pinocembrin, and pinobanksin, and the phenolic compound methyl syringate to neutrophils exhibiting pro-inflammatory behavior will reduce ROS activity and prevent NETosis in primary human neutrophils. Using primary human neutrophils isolated from donor (n = 5) peripheral blood, concentrations between 1 nM and 10 µM of each flavonoid, 10 µM and 2 mM of methyl syringate, 0.1% v/v and 10% v/v Manuka honey, and combinations of both 1 nM-10 µM of each flavonoid and 10 µM-2 mM of methyl syringate were assayed for reductions in NETosis using Sytox orange extracellular DNA staining and reduction in intracellular ROS activity via standard dichloro-dihydro-fluorescein diacetate (DCFH-DA) oxidation assay. Compared to positive control levels, individual flavonoids showed moderate effect sizes. Higher concentrations of flavonoids, especially in combination, stimulated ROS activity by up to 105%. Whole Manuka honey reduced neutrophil extracellular trap (NET) levels by up to 91% but only reduced ROS activity by 36%. However, methyl syringate reduced NET levels by up to 68% and ROS activity by 66%. Methyl syringate and whole Manuka honey are potent inhibitors of neutrophil intracellular ROS activity and NET formation. Methyl syringate potentially drives the anti-inflammatory capabilities of Manuka honey demonstrated by previous studies.

Improving inhibition efficiency of 304 stainless steel using an organic extract in acidic and high temperature environment: Experimental and theoretical studies

Many organic inhibitors have been proposed for corrosion protection of 304 stainless steel (SS), but its effectiveness in acidic and high temperature environment is challenged. We utilized Tithonia diversifolia (Hemsl) A. grey leaf extract (TDLE) as an eco-friendly organic inhibitor to protect 304 stainless steel (SS) in acidic environment (1 M HCl) at high temperature (65 °C). The performance of TDLE was studied electrochemically using potentiodynamic polarization and electrochemical impedance spectroscopy techniques. The surface of the metal was characterized using scanning electron microscopy (SEM). The theoretical calculation was also studied to understand the inhibition process. The corrosion inhibition efficiency increases reaching 98.48 % at 65 °C in the presence of 3.5 g/L TDLE. The inhibition of TDLE on 304 SS surface was adsorption spontaneously based in Langmuir's adsorption isotherm. The SEM images show significant improvement of the 304 SS surface with TDLE. A theoretical study indicates that methyl 3.5-dicaffeoyl quinate is the most active inhibitor in TDLE. The study revealed that TDLE had good performance for inhibiting in acidic and high temperature environment.

Skin Malignant Melanoma and Matrix Metalloproteinases: Promising Links to Efficient Therapies.

Skin malignant melanoma (MM) is one of the most frequent and aggressive neoplasia worldwide. Its associated high mortality rates are mostly due to its metastases, while diagnosis and treatment of MM in its early stages is of favorable prognostic. Even skin superficial MMs at incipient local stages can already present with lymph node invasion and distant metastases. Therefore, knowledge of the controllable risk factors and pathogenic mechanisms of MM development, spreading, and metastatic pattern, as well as early diagnosis, are essential to decrease the high mortality rates associated with cutaneous malignant melanoma. Genetic factors are incriminated, although lifetime-acquired genetic mutations appear to be even more frequently involved in the development of MM. Skin melanocytes divide only twice per year and have time to accumulate genetic mutations as a consequence of environmental aggressive factors, such as UV exposure. In the search for more promising therapies, matrix metalloproteinases have become of significant interest, such as MMP-1, MMP-2, MMP-9, and MMP-13, which have been linked to more aggressive forms of cancer and earlier metastases. Therefore, the development of specific synthetic inhibitors of MMP secretion or activity could represent a more promising and effective approach to the personalized treatment of MM patients.

Many human pharmaceuticals are weak inhibitors of the cytochrome P450 system in rainbow trout (Oncorhynchus mykiss) liver S9 fractions.

Pharmaceutical residues are widely detected in aquatic environment and can be taken up by nontarget species such as fish. The cytochromes P450 (CYP) represent an important detoxification mechanism in fish, like in humans. In the present study, we assessed the correlation of the substrate selectivities of rainbow trout CYP1A and CYP3A homologues with those of human, through determination of the half-maximal inhibitory concentrations (IC50) of a total sixteen human pharmaceuticals toward CYP1A-like ethoxyresorufin O-deethylase (EROD) and CYP3A-like 7-benzyloxy-4-trifluoromethylcoumarin O-debenzylase (BFCOD) in rainbow trout (Oncorhynchus mykiss) liver S9 fractions (RT-S9). The inhibitory impacts (IC50) of atomoxetine, atorvastatin, azelastine, bimatoprost, clomethiazole, clozapine, desloratadine, disulfiram, esomeprazole, felbinac, flecainide, orphenadrine, prazosin, quetiapine, sulpiride, and zolmitriptan toward the EROD and BFCOD activities in RT-S9 were determined using the IC50 shift assay, capable of identifying time-dependent inhibitors (TDI). Additionally, the nonspecific binding of the test pharmaceuticals to RT-S9 was assessed using equilibrium dialysis. Most test pharmaceuticals were moderate to weak inhibitors of both EROD and BFCOD activity in RT-S9, even if most are noninhibitors of human CYP1A or CYP3A. Only bimatoprost, clomethiazole, felbinac, sulpiride, and zolmitriptan did not inhibit either activity in RT-S9. EROD inhibition was generally stronger than that of BFCOD and some substances (atomoxetine, flecainide, and prazosin) inhibited selectively only EROD activity. The strongest EROD inhibition was detected with azelastine and esomeprazole (unbound IC50 of 3.8 ± 0.5µM and 3.0 ± 0.8µM, respectively). None of the test substances were TDIs of BFCOD, but esomeprazole was a TDI of EROD. Apart from clomethiazole and disulfiram, the nonspecific binding of the test pharmaceuticals to the RT-S9 was extensive (unbound fractions <0.5) and correlated well (R 2 = 0.7135) with their water-octanol distribution coefficients. The results indicate that the P450 interactions in RT-S9 cannot be explicitly predicted based on human data, but the in vitro data reported herein can shed light on the substrate selectivity of rainbow trout CYP1A1 and CYP3A27 in comparison to their human homologues. The IC50 concentrations are however many orders of magnitude higher than average environmental concentrations of pharmaceuticals. The time-dependent EROD inhibition by esomeprazole could warrant further research to evaluate its possible interlinkages with hepatotoxic impacts on fish.

Restorer of fertility like 30, encoding a mitochondrion-localized pentatricopeptide repeat protein, regulates wood formation in poplar.

Nuclear-mitochondrial communication is crucial for plant growth, particularly in the context of cytoplasmic male sterility (CMS) repair mechanisms linked to mitochondrial genome mutations. The restorer of fertility-like (RFL) genes, known for their role in CMS restoration, remain largely unexplored in plant development. In this study, we focused on the evolutionary relationship of RFL family genes in poplar specifically within the dioecious Salicaceae plants. PtoRFL30 was identified to be preferentially expressed in stem vasculature, suggesting a distinct correlation with vascular cambium development. Transgenic poplar plants overexpressing PtoRFL30 exhibited a profound inhibition of vascular cambial activity and xylem development. Conversely, RNA interference-mediated knockdown of PtoRFL30 led to increased wood formation. Importantly, we revealed that PtoRFL30 plays a crucial role in maintaining mitochondrial functional homeostasis. Treatment with mitochondrial activity inhibitors delayed wood development in PtoRFL30-RNAi transgenic plants. Further investigations unveiled significant variations in auxin accumulation levels within vascular tissues of PtoRFL30-transgenic plants. Wood development anomalies resulting from PtoRFL30 overexpression and knockdown were rectified by NAA and NPA treatments, respectively. Our findings underscore the essential role of the PtoRFL30-mediated mitochondrion-auxin signaling module in wood formation, shedding light on the intricate nucleus-organelle communication during secondary vascular development.

Random Forests Regression and Rescoring Strategy for Identifying Inhibitors of Ubiquitin Specific Protease-7

Ubiquitin-specific protease-7 (USP7) is a potential target for cancer therapy. In this work, the evaluation and design of USP7 inhibitors are conducted employing a comprehensive computational approach. Initially, a large database of compounds undergoes preliminary screening via similarity and pharmacophore analyses. Subsequently, a secondary selection process is executed based on both quantitative structure–activity relationship modeling and molecular docking. The final selection is refined through rescoring treatments via consensus scores and MM/GBSA binding free energy. A total of 138 experimental USP7 inhibitors were collected for the construction of random forest regression models using four different feature selection methods. 17 top experimentally active inhibitors were used as models in similarity searching, and eight representative USP7-ligand binding models were used in pharmacophore screening, performed over a database of 14 million compounds. The rescoring approach applied in this study offers an alternative and beneficial method for the ranking and selection of desired molecules. Based on the molecular scaffolds of the highly active inhibitors, some new derivatives have been designed and received high predicted scores for inhibition.

Docking and Simulation Studies on Novel Analogues of 3,4,5-Trihydroxy Benzoic Acid as HSP90Alpha Inhibitors

Abstract: HSP90 assists as a crucial molecular chaperone that responds to environmental stressors and helps in the survival of cells in microorganisms. This protein is integral to the stress response, aiding in the stabilization of various proteins essential for microbial survival. Consequently, the ability of a number of tissues to adjust to endogenous stress depends critically on appropriate chaperone activity. Modulators of chaperone activity, however, have emerged as a novel and developing area of drug discovery due to the association between changed chaperone function and the development of numerous illnesses. Inhibition of HSP90alpha can disrupt proper protein folding, thus impairing growth and virulence in fungi. In this work, we selected novel leads of gallic acid derivatives with the help of OSIRIS Property Explorer and DruLiTo software. Selected leads were subjected to ADME-T studies for further screening. Docking and molecular simulation studies on selected compounds were performed using Schrodinger v21 and GROMACS software to predict the bioactivity of novel leads of 3,4,5 trihydroxy benzoic acid for suppression of the HSP90alpha enzyme. Compounds 4N, 18N, 15N, and 14N showed good docking scores of -6.5, -6.4, -5.91, and -5.98, respectively, which was comparable to standard ciprofloxacin. Compound 4N and compound 14N demonstrated notable binding interactions and were selected for further investigation through molecular dynamics studies with HSP90alpha (PDB ID: 1YC1). RMSD, H BOND, and RMSF analysis confirmed the stable binding of compounds 4N and 14 N with the HSP90 enzyme. The RMSF plot showed less than 0.35 nm fluctuation for the HSP90alpha enzyme in complex with different ligands. It can be concluded that ligand binding can cause stability to the conformation of the protein. Compounds 4N and 14N are considered to be the best theoretical lead, which can further be studied experimentally as HSP90 alpha inhibitors for antimicrobial activity. other: Ongoing research aims to uncover more insights into the specific mechanisms of action, optimize structural features for enhanced efficacy, and explore potential synergies with existing antimicrobial agents. As a result, these derivatives hold promise as candidates for the development of novel antimicrobial agents with a broad spectrum of activity against bacteria and fungi

The detrimental role of galectin-3 and endoplasmic reticulum stress in the cardiac consequences of myocardial ischemia in the context of obesity.

The association between cardiac fibrosis and galectin-3 was evaluated in patients with acute myocardial infarction (MI). The role of galectin-3 and its association with endoplasmic reticulum (ER) stress activation in the progression of cardiovascular fibrosis was also evaluated in obese-infarcted rats. The inhibitor of galectin-3 activity, modified citrus pectin (MCP; 100 mg/kg/day), and the inhibitor of the ER stress activation, 4-phenylbutyric acid (4-PBA; 500 mg/kg/day), were administered for 4 weeks after MI in obese rats. Overweight-obese patients who suffered a first MI showed higher circulating galectin-3 levels, higher extracellular volume, and LV infarcted size, as well as lower E/e'ratio and LVEF compared with normal-weight patients. A correlation was observed between galectin-3 levels and extracellular volume. Obese-infarcted animals presented cardiac hypertrophy and reduction in LVEF, and E/A ratio as compared with control animals. They also showed an increase in galectin-3 gene expression, as well as cardiac fibrosis and reduced autophagic flux. These alterations were associated with ER stress activation characterized by enhanced cardiac levels of binding immunoglobulin protein, which were correlated with those of galectin-3. Both MCP and 4-PBA not only reduced cardiac fibrosis, oxidative stress, galectin-3 levels, and ER stress activation, but also prevented cardiac functional alterations and ameliorated autophagic flux. These results show the relevant role of galectin-3 in the development of diffuse fibrosis associated with MI in the context of obesity in both the animal model and patients. Galectin-3 in tandem with ER stress activation could modulate different downstream mechanisms, including inflammation, oxidative stress, and autophagy.

Inhibiting Dissolution of Active Sites in 80 °C Alkaline Water Electrolysis by Oxyanion Engineering

AbstractCommercial alkaline water electrolysers typically operate at 80 °C to minimize energy consumption. However, NiFe‐based catalysts, considered as one of the most promising candidates for anode, encounter the bottleneck of high solubility at such temperatures. Herein, we discover that the dissolution of NiFe layered double hydroxides (NiFe‐LDH) during operation not only leads to degradation of anode itself, but also deactivates cathode for water splitting, resulting in decay of overall electrocatalytic performance. Aiming to suppress the dissolution, we employed oxyanions as inhibitors in electrolyte. The added phosphates to the electrolyte inhibit the loss of NiFe‐LDH active sites at 400 mA cm−2 to 1/3 of the original amount, thus reducing the rate of performance decay by 25‐fold. Furthermore, the usage of borates, sulfates, and carbonates yields similar results, demonstrating the reliability and universality of the active site dissolution inhibitor, and its role in elevated water electrolysis.

Inhibiting Dissolution of Active Sites in 80 °C Alkaline Water Electrolysis by Oxyanion Engineering.

Commercial alkaline water electrolysers typically operate at 80 °C to minimize energy consumption. However, NiFe-based catalysts, considered as one of the most promising candidates for anode, encounter the bottleneck of high solubility at such temperatures. Herein, we discover that the dissolution of NiFe layered double hydroxides (NiFe-LDH) during operation not only leads to degradation of anode itself, but also deactivates cathode for water splitting, resulting in decay of overall electrocatalytic performance. Aiming to suppress the dissolution, we employed oxyanions as inhibitors in electrolyte. The added phosphates to the electrolyte inhibit the loss of NiFe-LDH active sites at 400 mA cm-2 to 1/3 of the original amount, thus reducing the rate of performance decay by 25-fold. Furthermore, the usage of borates, sulfates, and carbonates yields similar results, demonstrating the reliability and universality of the active site dissolution inhibitor, and its role in elevated water electrolysis.

Visualization of intracellular ATP dynamics in different nephron segments under pathophysiological conditions using the kidney slice culture system

ATP depletion plays a central role in the pathogenesis of kidney diseases. Recently, we reported spatiotemporal intracellular ATP dynamics during ischemia reperfusion (IR) using GO-ATeam2 mice systemically expressing an ATP biosensor. However, observation from the kidney surface did not allow visualization of deeper nephrons or accurate evaluation of ATP synthesis pathways. Here, we established a novel ATP imaging system using slice culture of GO-ATeam2 mouse kidneys, evaluated the ATP synthesis pathway, and analyzed intracellular ATP dynamics using an exvivo IR-mimicking model and a cisplatin nephropathy model. Proximal tubules (PTs) were found to be strongly dependent on oxidative phosphorylation (OXPHOS) using the inhibitor oligomycin A, whereas podocytes relied on both OXPHOS and glycolysis using phloretin an active transport inhibitor of glucose. We also confirmed that an exvivo IR-mimicking model could recapitulate ATP dynamics invivo; ATP recovery in PTs after reoxygenation varied depending on anoxic time length, whereas ATP in distal tubules (DTs) recovered well even after long-term anoxia. After cisplatin administration, ATP levels in PTs decreased first, followed by a decrease in DTs. An organic cation transporter 2 inhibitor, cimetidine, suppressed cisplatin uptake in kidney slices, leading to better ATP recovery in PTs, but not in DTs. Finally, we confirmed that a mitochondria protection reagent (Mitochonic Acid 5) delayed the cisplatin-induced ATP decrease in PTs. Thus, our novel system may provide new insights into the energy dynamics and pathogenesis of kidney disease.

Synthesis and biological evaluation of O4′-benzyl-hispidol derivatives and analogs as dual monoamine oxidase-B inhibitors and anti-neuroinflammatory agents

Design, synthesis, and biological evaluation of two series of O4′-benzyl-hispidol derivatives and the analogous corresponding O3′-benzyl derivatives aiming to develop selective monoamine oxidase-B inhibitors endowed with anti-neuroinflammatory activity is reported herein. The first O4′-benzyl-hispidol derivatives series afforded several more potentially active and MAO-B inhibitors than the O3′-benzyl derivatives series. The most potential compound 2e of O4′-benzyl derivatives elicited sub-micromolar MAO-B IC50 of 0.38 µM with a selectivity index >264 whereas most potential compound 3b of O3′-benzyl derivatives showed only 0.95 MAO-B IC50 and a selectivity index >105. Advancement of the most active compounds showing sub-micromolar activities to further cellular evaluations of viability and induced production of pro-neuroinflammatory mediators confirmed compound 2e as a potential lead compound inhibiting the production of the neuroinflammatory mediator nitric oxide significantly by microglial BV2 cells at 3 µM concentration without significant cytotoxicity up to 30 µM. In silico molecular docking study predicted plausible binding modes with MAO enzymes and provided insights at the molecular level. Overall, this report presents compound 2e as a potential lead compound to develop potential multifunctional compounds.