Synthesis and anti-liver fibrosis activity of imidazole and thiazole compounds containing amino acids.

Four series of imidazoles (15a-g, 20c, and 20d) and thiazoles (18a-g, 22a, and 22b) possessing various amino acids were synthesized and evaluated for activin receptor-like kinase 5 (ALK5) inhibitory activities in an enzymatic assay. Among them, compounds 15g and 18c showed the highest inhibitory activity against ALK5, with IC50 values of 0.017 and 0.025 µM, respectively. Compounds 15g and 18c efficiently inhibited extracellular matrix (ECM) deposition in TGF-ß-induced hepatic stellate cells (HSCs), and eventually suppressed HSC activation. Moreover, compound 15g showed a good pharmacokinetic (PK) profile with a favorable half-life (t1/2 = 9.14 h). The results indicated that these compounds exhibited activity targeting ALK5 and may have potential in the treatment of liver fibrosis; thus they are worthy of further study.

Insights into the time-course cellular effects triggered by iron oxide nanoparticles by combining proteomics with the traditional pharmacology strategy.

In recent years, a number of initially approved magnetic iron oxide nanoparticle (IONP)-based nano-medicines have been withdrawn due to the obscure nano-bio effects. Therefore, there is an urgent need to study the cellular effects triggered by IONPs on cells. In this study, we investigate the time-course cellular effects on the response of RAW 264.7 cells caused by Si-IONPs via pharmacological and mass spectrometry-based proteomics techniques. Our results revealed that Si-IONPs were internalized by clathrin-mediated endocytosis within 1 hour, and gradually degraded in endolysosomes over time, which might influence autophagy, oxidative stress, innate immune response, and inflammatory response after 12 hours. Our research provides a necessary assessment of Si-IONPs for further clinical treatment.

Glycyrrhetinic acid inhibits non-small cell lung cancer via promotion of Prdx6- and caspase-3-mediated mitochondrial apoptosis.

Glycyrrhetinic acid (GA) shows great efficiency against non-small cell lung cancer (NSCLC), but the detailed mechanism is unclear, which has limited its clinical application. Herein, we investigated the potential targets of GA against NSCLC by activity-based protein profiling (ABPP) technology and the combination of histopathology and proteomics validation. In vitro and in vivo results indicated GA significantly inhibited NSCLC via promotion of peroxiredoxin-6 (Prdx6) and caspase-3 (Casp3)-mediated mitochondrial apoptosis. This original finding will provide theoretical and data support to improve the treatment of NSCLC with the application of GA.

Carbon Capture: Theoretical Guidelines for Activated Carbon-Based CO2 Adsorption Material Evaluation.

Activated carbon (AC)-based materials have shown promising performance in carbon capture, offering low cost and sustainable sourcing from abundant natural resources. Despite ACs growing as a new class of materials, theoretical guidelines for evaluating their viability in carbon capture are a crucial research gap. We address this gap by developing a hierarchical guideline, based on fundamental gas-solid interaction strength, that underpins the success and scalability of AC-based materials. The most critical performance indicator is the CO2 adsorption energy, where an optimal range (-0.41 eV) ensures efficiency between adsorption and desorption. Additionally, we consider thermal stability and defect sensitivity to ensure consistent performance under varying conditions. Further, selectivity and capacity play significant roles due to external variables such as partial pressure of CO2 and other ambient air gases (N2, H2O, O2), bridging the gap between theory and reality. We provide actionable examples by narrowing our options to methylamine- and pyridine-grafted graphene.

Which is More Important, Proposer Identity or Allocation Motive? Event-Related Potential in Economic Decision-Making.

Purpose: Most studies have supported the view that individuals prefer to reward the in-group and discriminate against the out-group in response to unfair offers in the Ultimatum Game. However, the current study advanced a different view, that is, the "black sheep effect", in which in-group members were punished more severely compared with out-group members. This study aimed to incorporate proposer identity and allocation motive as possible explanations for offer rejection. Methods: In the current study, the in-group and out-group identities were distinguished by their health condition, and the allocation motive was defined according to its benefit maximization. With a total of 89 healthy college student participants, a mixed design of 2 (proposer identity: out-group vs in-group) × 2 (allocation motive: selfish vs random) × 2 (offer type: unfair vs fair) was used in the Ultimatum Game. Event-related potential (ERP) technology was used, and ERPs were recorded while participants processed the task. Results: The behavioral result showed that the "black sheep effect" was found on the fair offer when a random allocation motive was used. Our ERP result suggested that feedback-related negativity (FRN) and P300 were modulated by proposer identity but not by allocation motive. However, the allocation motive interacted with proposer identity affecting FRN and P300 when the fair offer was proposed. Conclusion: These findings demonstrated that the "black sheep effect" was related to the experience of the out-group member, such as disadvantage or distress, but it was also modulated by allocation motive. Meanwhile, the out-group (depressed college students) captured more attention because they violated individual expectations, according to the P300. This finding plays an integral role in understanding the mechanism of response to the "black sheep effect".

Synthesis and antimicrobial activity evaluation of pyrazole derivatives containing the imidazo[2,1-b][1,3,4]thiadiazole moiety.

Four series of novel pyrazole derivatives (compounds 17a-m, 18a-m, 19a-g, and 20a-g) were synthesized, and their antibacterial and antifungal activities were evaluated. Most of the target compounds (17a-m, 18k-m, and 19b-g) showed strong antifungal activity and high selectivity relative to both Gram-positive and Gram-negative bacteria. Among them, compounds 17l (minimum inhibitory concentration [MIC] = 0.25 µg/mL) and 17m (MIC = 0.25 µg/mL) showed the strongest antifungal activity, being 2- and 4-fold more active than the positive controls gatifloxacin and fluconazole, respectively. In particular, compound 17l showed little cytotoxicity against human LO2 cells and did not exhibit hemolysis at ultrahigh concentrations, as did the positive control compounds gatifloxacin and fluconazole. These results indicate that these compounds are valuable for further development as antifungal agents.

Advanced Strategies for Overcoming Endosomal/Lysosomal Barrier in Nanodrug Delivery.

Nanocarriers have therapeutic potential to facilitate drug delivery, including biological agents, small-molecule drugs, and nucleic acids. However, their efficiency is limited by several factors; among which, endosomal/lysosomal degradation after endocytosis is the most important. This review summarizes advanced strategies for overcoming endosomal/lysosomal barriers to efficient nanodrug delivery based on the perspective of cellular uptake and intracellular transport mechanisms. These strategies include promoting endosomal/lysosomal escape, using non-endocytic methods of delivery to directly cross the cell membrane to evade endosomes/lysosomes and making a detour pathway to evade endosomes/lysosomes. On the basis of the findings of this review, we proposed several promising strategies for overcoming endosomal/lysosomal barriers through the smarter and more efficient design of nanodrug delivery systems for future clinical applications.

Synthesis and Antibacterial Activity Evaluation of Imidazole Derivatives Containing 6-Methylpyridine Moiety.

A series of 2-cyclopropyl-5-(5-(6-methylpyridin-2-yl)-2-substituted-1H-imidazol-4-yl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazoles (15a-t and 16a-f) were synthesized and their antibacterial activities were evaluated. More than half of the compounds showed moderate or strong antibacterial activity. Among them, compounds 15t (MIC=1-2 µg/mL) and 16d (MIC=0.5 µg/mL) showed the strongest antibacterial activities. Notably, compound 16d did not exhibit cytotoxicity in HepG2 cells and did not show hemolysis like the positive control compound Gatifloxacin. The results suggest that compound 16d should be further investigated as a candidate antibacterial agent.

Advanced strategies for nucleic acids and small-molecular drugs in combined anticancer therapy.

Cancer has been considered as complex malignant consequence of genetic mutations that control the cellular proliferation, differentiation and homeostasis, thus making tumor treatment extremely challenging. To date, a variety of cargo molecules, including nucleic acids drugs (pDNA, miRNA and siRNA), therapeutic drugs (doxorubicin, paclitaxel, daunomycin and gefitinib) and imaging agents (radioisotopes, fluorescence dyes, and MRI contrast agents) have been regarded as the potential medicines in clinical application. However, non-single therapeutic drug could induce the satisfied clinical results because of tumor heterogeneity and multiple drug resistance and the nanotechnology-based combined therapy is becoming an advanced important mode for enhanced anticancer effects. The review gathers the current advanced development to co-deliver small-molecular drugs and nucleic acids for the anticancer therapy with nanomedicine-based combination. Furthermore, the superiority is definitely presented and the barriers are detail discussed to surmount the clinical challenges. In final, future perspectives in rational direction for combined tumor therapy of drugs and nucleic acids are exhibited.

The Synergistic Mechanism of Total Saponins and Flavonoids in Notoginseng-Safflower against Myocardial Infarction Using a Comprehensive Metabolomics Strategy.

Notoginseng and safflower are commonly used traditional Chinese medicines for benefiting qi and activating blood circulation. A previous study by our group showed that the compatibility of the effective components of total saponins of notoginseng (NS) and total flavonoids of safflower (SF), named NS-SF, had a preventive effect on isoproterenol (ISO)-induced myocardial infarction (MI) in rats. However, the therapeutic effect on MI and the synergistic mechanism of NS-SF are still unclear. Therefore, integrated metabolomics, combined with immunohistochemistry and other pharmacological methods, was used to systematically research the therapeutic effect of NS-SF on MI rats and the synergistic mechanism of NS and SF. Compared to NS and SF, the results demonstrated that NS-SF exhibited a significantly better role in ameliorating myocardial damage, apoptosis, easing oxidative stress and anti-inflammation. NS-SF showed a more significant regulatory effect on metabolites involved in sphingolipid metabolism, glycine, serine, and threonine metabolism, primary bile acid biosynthesis, aminoacyl-tRNA biosynthesis, and tricarboxylic acid cycle, such as sphingosine, lysophosphatidylcholine (18:0), lysophosphatidylethanolamine (22:5/0:0), chenodeoxycholic acid, L-valine, glycine, and succinate, than NS or SF alone, indicating that NS and SF produced a synergistic effect on the treatment of MI. This study will provide a theoretical basis for the clinical development of NS-SF.

Preparation and application of calcium phosphate nanocarriers in drug delivery.

Calcium phosphate nanoparticles represent promising materials for drug delivery because of its favorable properties, including biocompatibility, biodegradability and strong affinity for binding to nucleic acids (pDNA, siRNA, miRNA, etc.) and therapeutic drugs (cisplatin, carboplatin, paclitaxel, gefitinib, doxorubicin, etc.). Various strategies to prepare the size-controllable, stable, targeting and pH-responsive CaP nanocarriers have been extensively developed as the potential candidates in clinic. This review discusses the mostly recent developments in the design of calcium phosphate nanocarriers as drug delivery systems and therapeutic agents. Additionally, the advantage is unquestionably demonstrated and the obstacles are thoroughly examined in order to overcome future clinical issues.

Electrochemical Response of Mixed Conducting Perovskite Enables Low-Cost High-Efficiency Hydrogen Sensing.

High-performance noble metal-free gas sensors are crucial for widespread applications in various areas. Non-Nernstian electrochemical sensors have attracted tremendous attention, but are limited by the high cost and low efficiency of Pt electrode. Moreover, responses from different electrodes usually have the same polarity, degrading the sensor performance. Here we report a reverse response on a series of mixed ionic-electronic conductors (MIECs). Exemplary SrFe0.5Ti0.5O3-δ (SFT50) perovskite shows excellent H2 sensing properties, including high sensitivity and selectivity, humidity resistance, and long-term stability. Strikingly, the response is positive, as opposed to the usual one. Such an unusual response is ascribed to the change of the surface electrostatic potential due to the gas chemical reaction, which outcompetes traditional mechanisms, thereby reversing the response polarity. A conceptual noble-metal-free sensor with dual oxide electrodes of opposite polarity is designed by substituting SFT50 for the benchmark Pt, achieving a 1.5-2.0× increase in H2 response, sensitivity, and selectivity and a low limit of detection of 16 ppb. The ideal unity of excellent sensing and unusual polarity for MIECs can be used to optimize the performance of a variety of conventional sensors while reducing the cost. Our findings provide new insights into electrochemical gas sensing and offer a facile approach for developing low-cost high-performance gas sensors.

Identification of antimalarial targets of chloroquine by a combined deconvolution strategy of ABPP and MS-CETSA.

BACKGROUND: Malaria is a devastating infectious disease that disproportionally threatens hundreds of millions of people in developing countries. In the history of anti-malaria campaign, chloroquine (CQ) has played an indispensable role, however, its mechanism of action (MoA) is not fully understood. METHODS: We used the principle of photo-affinity labeling and click chemistry-based functionalization in the design of a CQ probe and developed a combined deconvolution strategy of activity-based protein profiling (ABPP) and mass spectrometry-coupled cellular thermal shift assay (MS-CETSA) that identified the protein targets of CQ in an unbiased manner in this study. The interactions between CQ and these identified potential protein hits were confirmed by biophysical and enzymatic assays. RESULTS: We developed a novel clickable, photo-affinity chloroquine analog probe (CQP) which retains the antimalarial activity in the nanomole range, and identified a total of 40 proteins that specifically interacted and photo-crosslinked with CQP which was inhibited in the presence of excess CQ. Using MS-CETSA, we identified 83 candidate interacting proteins out of a total of 3375 measured parasite proteins. At the same time, we identified 8 proteins as the most potential hits which were commonly identified by both methods. CONCLUSIONS: We found that CQ could disrupt glycolysis and energy metabolism of malarial parasites through direct binding with some of the key enzymes, a new mechanism that is different from its well-known inhibitory effect of hemozoin formation. This is the first report of identifying CQ antimalarial targets by a parallel usage of labeled (ABPP) and label-free (MS-CETSA) methods.

A highly efficient protein corona-based proteomic analysis strategy for the discovery of pharmacodynamic biomarkers.

The composition of serum is extremely complex, which complicates the discovery of new pharmacodynamic biomarkers via serum proteome for disease prediction and diagnosis. Recently, nanoparticles have been reported to efficiently reduce the proportion of high-abundance proteins and enrich low-abundance proteins in serum. Here, we synthesized a silica-coated iron oxide nanoparticle and developed a highly efficient and reproducible protein corona (PC)-based proteomic analysis strategy to improve the range of serum proteomic analysis. We identified 1,070 proteins with a median coefficient of variation of 12.56% using PC-based proteomic analysis, which was twice the number of proteins identified by direct digestion. There were also more biological processes enriched with these proteins. We applied this strategy to identify more pharmacodynamic biomarkers on collagen-induced arthritis (CIA) rat model treated with methotrexate (MTX). The bioinformatic results indicated that 485 differentially expressed proteins (DEPs) were found in CIA rats, of which 323 DEPs recovered to near normal levels after treatment with MTX. This strategy can not only help enhance our understanding of the mechanisms of disease and drug action through serum proteomics studies, but also provide more pharmacodynamic biomarkers for disease prediction, diagnosis, and treatment.

Surface and Bulk Oxygen Kinetics of BaCo0.4Fe0.4Zr0.2-XYXO3-δ Triple Conducting Electrode Materials.

Triple ionic-electronic conductors have received much attention as electrode materials. In this work, the bulk characteristics of oxygen diffusion and surface exchange were determined for the triple-conducting BaCo0.4Fe0.4Zr0.2-XYXO3-δ suite of samples. Y substitution increased the overall size of the lattice due to dopant ionic radius and the concomitant formation of oxygen vacancies. Oxygen permeation measurements exhibited a three-fold decrease in oxygen permeation flux with increasing Y substitution. The DC total conductivity exhibited a similar decrease with increasing Y substitution. These relatively small changes are coupled with an order of magnitude increase in surface exchange rates from Zr-doped to Y-doped samples as observed by conductivity relaxation experiments. The results indicate that Y-doping inhibits bulk O2- conduction while improving the oxygen reduction surface reaction, suggesting better electrode performance for proton-conducting systems with greater Y substitution.

Study towards improving artemisinin-based combination therapies.

Covering: Up to 2020 Artemisinin has made a significant contribution towards global malaria control since its initial discovery. Countless lives have been saved by this unique and miraculous molecule. In 2006, artemisinin-based combination therapies (ACTs) were recommended by the World Health Organization (WHO) as the first-line treatment for uncomplicated malaria infection and have since remained as the mainstays of the antimalarial treatment. Even so, substantial efforts to pursue better curative effects for the treatment of malaria have never ceased, particularly with regards to the circumstances surrounding the appearance of delayed clearance of malaria parasites by 3 day ACT treatments in South-East Asian countries. Strategies to further optimize artemisinin-based therapies, including synthesizing better artemisinin derivatives, developing advanced drug delivery systems, and diversifying artemisinin partner drugs, have been proposed over the past few years. Here, we provide an updated account of the continuous efforts in improving ACTs for better efficacy in curing malarial infection.

Recent pharmacological advances in the repurposing of artemisinin drugs.

Artemisinins are a family of sesquiterpene lactones originally derived from the sweet wormwood (Artemisia annua). Beyond their well-characterized role as frontline antimalarial drugs, artemisinins have also received increased attention for other potential pharmaceutical effects, which include antiviral, antiparsitic, antifungal, anti-inflammatory, and anticancer activities. With concerted efforts in further preclinical and clinical studies, artemisinin-based drugs have the potential to be viable treatments for a great variety of human diseases. Here, we provide a comprehensive update on recent reports of pharmacological actions and applications of artemisinins outside of their better-known antimalarial role and highlight their potential therapeutic viability for various diseases.

Evaluation of the effects of notoginseng total saponins (NS), safflower total flavonoids (SF), and the combination of NS and SF (CNS) on the activities of cytochrome P450 enzymes using a cocktail method in rats.

Notoginseng total saponins (NS), safflower total flavonoids (SF), and the combination of NS and SF, namely CNS, are used for the treatment of cardiovascular diseases in clinic. This study developed a cocktail assay involving seven cytochrome P450 (CYP) enzymes to elucidate the effect of NS, SF, and CNS on CYP enzymes and to explore the synergistic effect of CNS in terms of CYP enzymes. Ultra-performance liquid chromatography-MS and reverse-transcription polymerase chain reaction were applied to detect the activities and mRNA expression levels of CYP enzymes. SF exhibited inhibitory effects on CYP1A2, 2B1, 2E1, and 2C11 and induction effects on CYP2C19 and 2D4. NS exhibited induction effects on CYP1A2, 2B1, 2E1, 2C11, 2C19, and 2D4. CNS exhibited induction effects on CYP1A2, 2B1, 2E1, 2C19, and 2D4 and inhibitory effects on CYP3A1 in vivo. Moreover, mRNA expression results were consistent with pharmacokinetic results. Potential herb-drug interactions should be studied closely when SF, NS, or CNS with clinical drugs are metabolized by CYP1A2, 2B1, 2E1, 2C11, 2C19, 2D4, and 3A1. CNS could change the inhibition or induction effects of CYP compared to the NS group, which might be one of the causes for the synergistic effects of the combination of NS and SF.

Target Profiling of an Anticancer Drug Curcumin by an In Situ Chemical Proteomics Approach.

Interdisciplinary chemical proteomics approaches have been widely applied to the identification of specific targets of bioactive small molecules or drugs. In this chapter, we describe the application of a cell-permeable activity-based curcumin probe (Cur-P) with an alkyne moiety to detect and identify specific binding targets of curcumin in HCT116 colon cancer cells. Through click chemistry, a fluorescent tag or a biotin tag is attached to the probe-modified curcumin targets for visualization or affinity purification followed by mass spectrometric identification. A quantitative proteomics approach of isobaric tags for relative and absolute quantification (iTRAQ)™ is applied to distinguish specific curcumin targets from nonspecific binding proteins.