Screening Of Compounds Research Articles

Analysis of Drugs from Biological Samples

Samples which are obtained from the biological sources like human beings are analyzed for various biochemical compounds for screening. these samples are subjected to various methods of preparation to achieve the desired information. However, we need to consider the various parameters of biological samples while preparation of samples. degradation of samples reduced by the checking of physicochemical parameters. there are several types of methodes for estimation and extraction of biochemical compounds like SPE, LLE. as part to know the quantity of the chemical we need to analyses through the HPLC, HPTLC, LC-MS.

ChemFH: an integrated tool for screening frequent false positives in chemical biology and drug discovery.

High-throughput screening rapidly tests an extensive array of chemical compounds to identify hit compounds for specific biological targets in drug discovery. However, false-positive results disrupt hit compound screening, leading to wastage of time and resources. To address this, we propose ChemFH, an integrated online platform facilitating rapid virtual evaluation of potential false positives, including colloidal aggregators, spectroscopic interference compounds, firefly luciferase inhibitors, chemical reactive compounds, promiscuous compounds, and other assay interferences. By leveraging a dataset containing 823391 compounds, we constructed high-quality prediction models using multi-task directed message-passing network (DMPNN) architectures combining uncertainty estimation, yielding an average AUC value of 0.91. Furthermore, ChemFH incorporated 1441 representative alert substructures derived from the collected data and ten commonly used frequent hitter screening rules. ChemFH was validated with an external set of 75 compounds. Subsequently, the virtual screening capability of ChemFH was successfully confirmed through its application to five virtual screening libraries. Furthermore, ChemFH underwent additional validation on two natural products and FDA-approved drugs, yielding reliable and accurate results. ChemFH is a comprehensive, reliable, and computationally efficient screening pipeline that facilitates the identification of true positive results in assays, contributing to enhanced efficiency and success rates in drug discovery. ChemFH is freely available via https://chemfh.scbdd.com/.

Unlocking the potential of icaritin derivatives: Synthesis, characterization, and antiproliferative activity against MCF-7 breast cancer cells

Natural products serve as ideal templates for drug development, and screening compounds derived from natural products has been a prominent and viable approach for discovering new drugs, especially in the field of cancer treatment. Icaritin (ICT), a prenylated flavonol glycoside natural product, has demonstrated significant anti-breast cancer activity. In this study, we used ICT as a template to chemically synthesize 16 icariin derivatives and evaluated their effects on the proliferation of the human breast cancer cell line MCF-7 using the CCK-8 assay. Eight of these compounds exhibited significant antitumor activity (IC50 < 20 μM), with the most potent compounds being T14 (IC50 = 2.69 ± 0.28 μM) and T16 (IC50 = 4.72 ± 0.63 μM). Through a structure-activity relationship (SAR) study of ICT, we determined the key features for ICT's in vitro anti-breast cancer activity: the presence of the 8-prenyl group is not essential for activity; the 7-OH group is crucial for activity; replacing the 6-H with a Minnich base enhances activity; acetylation of the 7-OH, 5-OH, and 3-OH groups significantly increases activity; and the nature of the substituent at the 3-OH group plays a critical role in activity, with even minor changes to the substituent having a significant impact on activity.

P35 Adaptation of a phenotypic screening assay to incorporate 384-well plates: opening the door to high-throughput screening

Abstract Introduction and aims High-throughput screening has significantly impacted drug discovery by increasing speed of experiments and reducing reagent and sample costs. We have previously developed several screening assays to measure myofibroblast inhibition via quantification of α-smooth muscle actin (α-SMA) expression, in a 96-well format. Currently, there are no drugs for the treatment of hypertrophic scarring, a major side-effect of burn injuries that occurs by myofibroblast transformation, leaving a huge gap in this sector. The aim for this project was to adapt our current assay for use in 384-well microplates. Methods Human primary dermal fibroblasts were transformed to myofibroblasts using 10 ng mL−1 transforming growth factor (TGF)-β1. α-SMA expression was measured using the In-Cell enzyme-linked immunosorbent assay method, with cell viability measured using DRAQ5 nuclear staining. Assay accuracy and reliability was determined by calculating the robust z-factor, with guidelines set to an average score over 0.5, with a minimum score per plate above 0.4. To further validate the assay, concentration-response curves (CRCs) for the drug vehicle [dimethyl sulfoxide (DMSO)] and our tool compound (SB-505124) were constructed at varying concentrations, in coincubation with TGF-β1. Results Optimization of well metrics was performed, producing an average robust z-factor of 0.52, confirming the assay Results are reliable and reproducible. The DMSO CRC produced no significant drop in cell viability at concentrations that are expected to be used in the screening of compounds. Our tool compound (SB-505124) produced a concentration-dependant curve for the inhibition of myofibroblast transformation. Conclusions A 384-well assay has been designed, tested and validated for the determination of myofibroblast transformation in human primary dermal fibroblasts. The assay has been shown to deliver an average robust z-factor of above 0.5, it contains a positive control and is compatible with compounds stored in up to 100% DMSO.

A Review on Indole-triazole Molecular Hybrids as a Leading Edge in Drug Discovery: Current Landscape and Future Perspectives.

Molecular hybridization is a rational design strategy used to create new ligands or pro-totypes by identifying and combining specific pharmacophoric subunits from the molecular struc-tures of two or more known bioactive derivatives. Molecular hybridization is a valuable technique in drug discovery, enabling the modulation of unwanted side effects and the creation of potential dual-acting drugs that combine the effects of multiple therapeutic agents. Indole-triazole conju-gates have emerged as promising candidates for new drug development. The indole and triazole moieties can be linked through various synthetic strategies, such as click chemistry or other cou-pling reactions, to generate a library of diverse compounds for biological screening. The achieva-ble structural diversity with indole-triazole conjugates offers avenues to optimize their pharmaco-kinetic and pharmacodynamic attributes, amplifying their therapeutic efficacy. Researchers have extensively tailored both indole and triazole frameworks with diverse modifications to compre-hend their impact on the drug's pharmacokinetic and pharmacodynamic characteristics. The cur-rent review article endeavours to explore and discuss various research strategies to design indole-triazole hybrids and elucidate their significance in a variety of pathological conditions. The in-sights provided herein are anticipated to be beneficial for the researchers and will likely encour-age further exploration in this field.

Dynamic microfluidic single-cell screening identifies pheno-tuning compounds to potentiate tuberculosis therapy

Drug-recalcitrant infections are a leading global-health concern. Bacterial cells benefit from phenotypic variation, which can suggest effective antimicrobial strategies. However, probing phenotypic variation entails spatiotemporal analysis of individual cells that is technically challenging, and hard to integrate into drug discovery. In this work, we develop a multi-condition microfluidic platform suitable for imaging two-dimensional growth of bacterial cells during transitions between separate environmental conditions. With this platform, we implement a dynamic single-cell screening for pheno-tuning compounds, which induce a phenotypic change and decrease cell-to-cell variation, aiming to undermine the entire bacterial population and make it more vulnerable to other drugs. We apply this strategy to mycobacteria, as tuberculosis poses a major public-health threat. Our lead compound impairs Mycobacterium tuberculosis via a peculiar mode of action and enhances other anti-tubercular drugs. This work proves that harnessing phenotypic variation represents a successful approach to tackle pathogens that are increasingly difficult to treat.

Jnk1 and downstream signalling hubs regulate anxiety-like behaviours in a zebrafish larvae phenotypic screen

Current treatments for anxiety and depression show limited efficacy in many patients, indicating the need for further research into the underlying mechanisms. JNK1 has been shown to regulate anxiety- and depressive-like behaviours in mice, however the effectors downstream of JNK1 are not known. Here we compare the phosphoproteomes from wild-type and Jnk1-/- mouse brains and identify JNK1-regulated signalling hubs. We next employ a zebrafish (Danio rerio) larvae behavioural assay to identify an antidepressant- and anxiolytic-like (AA) phenotype based on 2759 measured stereotypic responses to clinically proven antidepressant and anxiolytic (AA) drugs. Employing machine learning, we classify an AA phenotype from extracted features measured during and after a startle battery in fish exposed to AA drugs. Using this classifier, we demonstrate that structurally independent JNK inhibitors replicate the AA phenotype with high accuracy, consistent with findings in mice. Furthermore, pharmacological targeting of JNK1-regulated signalling hubs identifies AKT, GSK-3, 14–3-3 ζ/ε and PKCε as downstream hubs that phenocopy clinically proven AA drugs. This study identifies AKT and related signalling molecules as mediators of JNK1-regulated antidepressant- and anxiolytic-like behaviours. Moreover, the assay shows promise for early phase screening of compounds with anti-stress-axis properties and for mode of action analysis.

In Silico Search for Drug Candidates Targeting the PAX8-PPARγ Fusion Protein in Thyroid Cancer.

The PAX8/PPARγ rearrangement, producing the PAX8-PPARγ fusion protein (PPFP), is thought to play an essential role in the oncogenesis of thyroid follicular tumors. To identify PPFP-targeted drug candidates and establish an early standard of care for thyroid tumors, we performed ensemble-docking-based compound screening. Specifically, we investigated the pocket structure that should be adopted to search for a promising ligand compound for the PPFP; the position of the ligand-binding pocket on the PPARγ side of the PPFP is similar to that of PPARγ; however, the shape is slightly different between them due to environmental factors. We developed a method for selecting a PPFP structure with a relevant pocket and high prediction accuracy for ligand binding. This method was validated using PPARγ, whose structure and activity values are known for many compounds. Then, we performed docking calculations to the PPFP for 97 drug or drug-like compounds registered in the DrugBank database with a thiazolidine backbone, which is one of the characteristics of ligands that bind well to PPARγ. Furthermore, the binding affinities of promising ligand candidates were estimated more reliably using the molecular mechanics Poisson-Boltzmann surface area method. Thus, we propose promising drug candidates for the PPFP with a thiazolidine backbone.

Systematic screening of synthetic organochalcogen compounds with anticancer activity using human lung adenocarcinoma spheroids

Lung adenocarcinoma stands as a leading global cause of cancer-related fatalities, with current therapeutic approaches remaining unsatisfactory. Given the association between elevated oxidative markers and the aggressive nature of cancer cells (including multidrug resistance and metastatic potential) that can predict poor outcome of lung adenocarcinoma patients, any compounds that interfere with their aberrant redox biology should be rationally explored as innovative intervention strategies. This study was designed to screen potential anticancer activities within nine newly synthesized organochalcogen – compounds characterized by the presence of oxygen, sulfur, or selenium elements in their structure and exhibiting antioxidant activity – and systematically evaluated their performance against cisplatin, the cornerstone therapeutic agent for lung adenocarcinoma. Our methodology involved the establishment of optimal conditions for generating single tumor spheroids using A549 human lung adenocarcinoma cell line. The initiation interval for spheroid formation was determined to be four days in vitro (DIV), and these single spheroids demonstrated sustained growth over a period of 20 DIV. Toxic dose-response curves were subsequently performed for each compound after 24 and 48 h of incubation at the 12th DIV. Our findings reveal that at least two of the synthetic organochalcogen compounds exhibited noteworthy anticancer activity, surpassing cisplatin in key parameters such as lower LD (Lethal Dose) 50, larger drug activity area, and maximum amplitude of effect, and are promising drugs for futures studies in the treatment of lung adenocarcinomas. Physicochemical descriptors and prediction ADME (absorption, distribution, metabolism, and excretion) parameters of selected compounds were obtained using SwissADME computational tool; Molinspiration server was used to calculate a biological activity score, and possible molecule targets were evaluated by prediction with the SwissTargetPrediction server. This research not only sheds light on novel avenues for therapeutic exploration but also underscores the potential of synthetic organochalcogen compounds as agents with superior efficacy compared to established treatments.

The application of natural language processing for the extraction of mechanistic information in toxicology.

To study the ways in which compounds can induce adverse effects, toxicologists have been constructing Adverse Outcome Pathways (AOPs). An AOP can be considered as a pragmatic tool to capture and visualize mechanisms underlying different types of toxicity inflicted by any kind of stressor, and describes the interactions between key entities that lead to the adverse outcome on multiple biological levels of organization. The construction or optimization of an AOP is a labor intensive process, which currently depends on the manual search, collection, reviewing and synthesis of available scientific literature. This process could however be largely facilitated using Natural Language Processing (NLP) to extract information contained in scientific literature in a systematic, objective, and rapid manner that would lead to greater accuracy and reproducibility. This would support researchers to invest their expertise in the substantive assessment of the AOPs by replacing the time spent on evidence gathering by a critical review of the data extracted by NLP. As case examples, we selected two frequent adversities observed in the liver: namely, cholestasis and steatosis denoting accumulation of bile and lipid, respectively. We used deep learning language models to recognize entities of interest in text and establish causal relationships between them. We demonstrate how an NLP pipeline combining Named Entity Recognition and a simple rules-based relationship extraction model helps screen compounds related to liver adversities in the literature, but also extract mechanistic information for how such adversities develop, from the molecular to the organismal level. Finally, we provide some perspectives opened by the recent progress in Large Language Models and how these could be used in the future. We propose this work brings two main contributions: 1) a proof-of-concept that NLP can support the extraction of information from text for modern toxicology and 2) a template open-source model for recognition of toxicological entities and extraction of their relationships. All resources are openly accessible via GitHub (https://github.com/ontox-project/en-tox).

A genetically encoded biosensor to monitor dynamic changes of c-di-GMP with high temporal resolution

Monitoring changes of signaling molecules and metabolites with high temporal resolution is key to understanding dynamic biological systems. Here, we use directed evolution to develop a genetically encoded ratiometric biosensor for c-di-GMP, a ubiquitous bacterial second messenger regulating important biological processes like motility, surface attachment, virulence and persistence. The resulting biosensor, cdGreen2, faithfully tracks c-di-GMP in single cells and with high temporal resolution over extended imaging times, making it possible to resolve regulatory networks driving bimodal developmental programs in different bacterial model organisms. We further adopt cdGreen2 as a simple tool for in vitro studies, facilitating high-throughput screens for compounds interfering with c-di-GMP signaling and biofilm formation. The sensitivity and versatility of cdGreen2 could help reveal c-di-GMP dynamics in a broad range of microorganisms with high temporal resolution. Its design principles could also serve as a blueprint for the development of similar, orthogonal biosensors for other signaling molecules, metabolites and antibiotics.

Metabolomics for Clinical Biomarker Discovery and Therapeutic Target Identification.

As links between genotype and phenotype, small-molecule metabolites are attractive biomarkers for disease diagnosis, prognosis, classification, drug screening and treatment, insight into understanding disease pathology and identifying potential targets. Metabolomics technology is crucial for discovering targets of small-molecule metabolites involved in disease phenotype. Mass spectrometry-based metabolomics has implemented in applications in various fields including target discovery, explanation of disease mechanisms and compound screening. It is used to analyze the physiological or pathological states of the organism by investigating the changes in endogenous small-molecule metabolites and associated metabolism from complex metabolic pathways in biological samples. The present review provides a critical update of high-throughput functional metabolomics techniques and diverse applications, and recommends the use of mass spectrometry-based metabolomics for discovering small-molecule metabolite signatures that provide valuable insights into metabolic targets. We also recommend using mass spectrometry-based metabolomics as a powerful tool for identifying and understanding metabolic patterns, metabolic targets and for efficacy evaluation of herbal medicine.

Screening of Bioactive Compounds, Antioxidant and Antimicrobial Properties in the Leaf Extracts of Two Castanopsis Species

ABSTRACT The phytochemical compounds in the leaf extracts of Castanopsis indica and C. tribuloides were evaluated, and their antioxidant and antimicrobial potential were assessed. The TPC was found to be 193.12 and 159.49 mg GAE g−1 dry weight, and the TFC was 108.12 and 96.49 mg QE g−1 dry weight, for C. indica and C. tribuloides, respectively. C. indica had higher DPPH scavenging activity, with an IC50 value of 15.10 μg mL−1. Both extracts showed substantial antimicrobial activity against the tested bacteria. GC-MS analysis showed the presence of 76 VoCs in C. indica leaf, and 71 VoCs in C. tribuloides.

Targeting EMT using low-dose Teniposide by downregulating ZEB2-driven activation of RNA polymerase I in breast cancer

Metastatic dissemination from the primary tumor is a complex process that requires crosstalk between tumor cells and the surrounding milieu and involves the interplay between numerous cellular-signaling programs. Epithelial–mesenchymal transition (EMT) remains at the forefront of orchestrating a shift in numerous cellular programs, such as stemness, drug resistance, and apoptosis that allow for successful metastasis. Till date, there is limited success in therapeutically targeting EMT. Utilizing a high throughput screen of FDA-approved compounds, we uncovered a novel role of the topoisomerase inhibitor, Teniposide, in reversing EMT. Here, we demonstrate Teniposide as a potent modulator of the EMT program, specifically through an IRF7–NMI mediated response. Furthermore, Teniposide significantly reduces the expression of the key EMT transcriptional regulator, Zinc Finger E-Box Binding Homeobox 2 (ZEB2). ZEB2 downregulation by Teniposide inhibited RNA polymerase I (Pol I) activity and rRNA biogenesis. Importantly, Teniposide treatment markedly reduced pulmonary colonization of breast cancer cells. We have uncovered a novel role of Teniposide, which when used at a very low concentration, mitigates mesenchymal-like invasive phenotype. Overall, its ability to target EMT and rRNA biogenesis makes Teniposide a viable candidate to be repurposed as a therapeutic option to restrict breast cancer metastases.

Two-point immobilization of M3 muscarinic receptor: a method for recognizing receptor antagonists in natural products

In the investigation of active ingredients from natural products, current technologies relying on drug–target affinity recognition analysis face significant challenges. This is primarily due to their limited specificity and inability to provide downstream pharmacodynamic information, such as agonistic or antagonistic activity. In this study, a two-point method was developed by immobilizing M3 acetylcholine receptor (M3R) through the combination of the conformation-specific peptide BJ-PRO-13a and the HaloTag trap system. We systematically assessed the specificity of the immobilized M3R using known M3R antagonists (pirenzepine and atropine) and agonists (cevimeline and pilocarpine). By frontal analysis and nonlinear chromatography, the performance of immobilized M3R was evaluated in terms of binding kinetics and thermodynamics of four drugs to the immobilized M3R. Additionally, we successfully identified two M3R antagonists within an extract from Daturae Flos (DF), specifically hyoscyamine and scopolamine. Our findings demonstrate that this immobilization method effectively captures receptor-ligand binding interactions and can discern receptor agonists from antagonists. This innovation enhances the efficiency of receptor chromatography to determine binding-affinity in the development of new drugs, offering promise for the screening and characterization of active compounds, particularly within complex natural products.

Phytochemical screening and antimicrobial activities of Guizotia abyssinica L. leaf and flower extracts

Sustainable agricultural systems demand less or no use of synthetic chemicals, which have various adverse effects on the environment and human health. In this context, studies on phytochemicals with antimicrobial and antioxidant properties hold great promise to suppress plant diseases and, thereby, reducing the application of synthetic chemical pesticides. Such an alternative approach requires screening and identification of bioactive compounds from various plant species. In the present study, Guizotia abyssinica L., an oilseed crop plant that usually requires less water with no pesticide inputs to grow, was screened for its potential antioxidant and antimicrobial phytochemicals. The methanolic and aqueous extracts of leaves and flowers of G. abyssinica were tested for their polyphenol content (total phenols and flavonoids) and antioxidant potential. The antioxidant and free radical scavenging activities of both methanolic and aqueous extracts were higher in comparison to many previously reported plant extracts. Furthermore, leaf extracts of G. abyssinica have shown slightly higher antioxidant activity than flower extracts. In vitro antimicrobial studies confirmed the inhibitory effect of methanolic extracts of leaves and flowers against phytopathogens like Xanthomonas oryzae RR24, Fusarium sp. and Alternaria sp. The chemical nature and composition of these crude extracts were analyzed by Fourier Transform Infrared Spectroscopy (FTIR) and Gas Chromatography Mass Spectrometry (GC-MS). Approximately, 28 bioactive compounds detected in GC-MS were predicted to have antimicrobial activity. Based on our results, we conclude that the extracts derived from G. abyssinica have demonstrated remarkable efficacy in inhibiting the proliferation of phytopathogens, thus exhibiting immense potential in promoting sustainable agricultural practices.

Abstract PO5-27-02: A Tumor Emboli Platform for Morphometric Analysis, Drug screening and for Intravital Optical Imaging in a Murine Model to Simulate Clinicopathological Features of Inflammatory Breast Cancer

Abstract Background: Inflammatory breast cancer (IBC) is distinguished by the presence of tumor emboli, clusters of tumor cells, found within breast parenchyma and dermal lymphatic vessels. These emboli serve as a crucial clinicopathological hallmark, believed to underlie the characteristic diffuse growth pattern and aggressive progression observed in IBC patients, with nearly 30% of patients presenting with metastatic disease at diagnosis. However, the rarity of this cancer and the absence of a solid tumor mass pose challenges in obtaining biospecimens, particularly those with evidence of tumor emboli. To address this pressing need for preclinical models that replicate this distinctive tumor growth pattern, we describe a tumor emboli culture platform that facilitates live imaging, enables compound screening by assessing various phenotypes of the emboli, and permits evaluation of emboli in an in vivo murine model. Methods: The tumor emboli culture system was evaluated for physiological measurements corresponding to dermal lymphatic vessels and subsequently employed to generate tumor emboli from diverse patient-derived cell lines and PDX. Confocal microscopy was employed to characterize cellular information across multiple slices of the tumor emboli. This provided a comprehensive, multi-parametric analysis of single-cell and spheroid phenotypes, including measurements of number, size, shape, and viability of the organoids. Furthermore, we developed imaging algorithms to evaluate phenotypic changes in tumor emboli in response to anti-cancer drug treatment. We also optimized a technique that allows for in vivo tumor emboli implantation including in a transgenic mice with red fluorescent lymphatic vasculature that were surgically implanted with a dorsal skin window chamber. This allowed for intravital optical imaging of the local tumor microenvironment and adjacent skin. Results: Our culture platform enables live imaging of the tumor emboli generated over a span of 7-10 days, maintaining key parameters including kinematic and dynamic viscosity, density along with sheer wall stress within the reported physiological range for lymphatics. Through higher resolution confocal image acquisition and multi-parametric analysis, we conducted particle counting and classification, providing statistically significant insights into the integrity of tumor emboli over time. Additionally, the developed algorithms allowed for quantitative analysis of images from tumor emboli cultures subjected to anti-cancer drugs, revealing disparities in drug efficacy on tumor emboli integrity and dispersion including inter-cluster space within the emboli. Intravital optical imaging, coupled with quantitative analysis of dispersion characteristics of the tumor emboli implanted in the murine model over 5-6 days, demonstrated a diffuse spread reminiscent of observations in IBC patients. Furthermore, immunohistochemistry staining showed marked Ki67, CD45, F4-80 revealing a proliferative tumor microenvironment with high levels of macrophage infiltration. Conclusions: As of now specific targeted therapies for IBC patients remain elusive. Our culture platform for tumor emboli, when combined with advanced imaging techniques both in vitro and in vivo and traditional approaches like immunohistochemistry and genomic evaluation, forms a powerful toolkit for assessing the phenotype and dispersion characteristics of this unique pathological feature in IBC. This preclinical model offers crucial insights, potentially paving the way for precision medicine strategies in the treatment of this understudied cancer. Funding in part from American Cancer Society Mission Boost MBG-20-141-01-MBG grant (GRD), Department of Defense W81XWH-20-1-0153 (GRD), Duke Consortium for Inflammatory Breast Cancer Education (AB, CW, RE). Citation Format: Dorababu Sannareddy, Theresa Charity, Alexandra Bennion, Caroline Way, Edwin Yu, Ralph Erdmann, Gregory M Palmer, Gayathri R Devi. A Tumor Emboli Platform for Morphometric Analysis, Drug screening and for Intravital Optical Imaging in a Murine Model to Simulate Clinicopathological Features of Inflammatory Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-27-02.

Aluminum chloride and D-galactose induced a zebrafish model of Alzheimer's disease with cognitive deficits and aging

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder. Transgenic and pharmacological AD models are extensively studied to understand AD mechanisms and drug discovery. However, they are time-consuming and relatively costly, which hinders the discovery of potential anti-AD therapeutics. Here, we established a new model of AD in larval zebrafish by co-treatment with aluminum chloride (AlCl3) and D-galactose (D-gal) for 72h. In particular, exposure to 150μM AlCl3 + 40mg/mL D-gal, 200μM AlCl3 + 30mg/mL D-gal, or 200μM AlCl3 + 40mg/mL D-gal successfully induced AD-like symptoms and aging features. Co-treatment with AlCl3 and D-gal caused significant learning and memory deficits, as well as impaired response ability and locomotor capacity in the plus-maze and light/dark test. Moreover, increased acetylcholinesterase and β-galactosidase activities, β-amyloid 1–42 deposition, reduced telomerase activity, elevated interleukin 1 beta mRNA expression, and enhanced reactive oxygen species production were also observed. In conclusion, our zebrafish model is simple, rapid, effective and affordable, incorporating key features of AD and aging, thus may become a unique and powerful tool for high-throughput screening of anti-AD compounds in vivo.

Antimicrobial and cytotoxic naphthoquinones from microbial origin: An updated review.

Naphthoquinones (NQs) are small molecules bearing two carbonyl groups. They have been the subject of much research due to their significant biological activities such as antiproliferative, antimicrobial, anti-inflammatory, antioxidant, and antimalarial effects. NQs are produced mainly by bacteria, fungi and higher plants. Among them, microorganisms are a treasure of NQs with diverse skeletons and pharmacological properties. The purpose of the present study is to provide a comprehensive update on the structural diversity and biological activities of 91 microbial naphthoquinones isolated from 2015 to 2022, with a special focus on antimicrobial and cytotoxic activities. During this period, potent cytotoxic NQs such as naphthablin B (46) and hygrocin C (30) against HeLa (IC50=0.23 µg/ml) and MDA-MB-431 (IC50=0.5 µg/ml) cell lines was reported, respectively. In addition, rubromycin CA1 (39), exhibited strong antibacterial activity against Staphylococcus aureus (MIC of 0.2 µg/ml). As importance bioactive compounds, NQs may open new horizon for treatment of cancer and drug resistant bacteria. As such, it is hoped that this review article may stimulates further research into the isolation of further NQs from microbial, and other sources as well as the screening of such compounds for biological activity and beneficial uses.

A pipeline for senolytics.

There is intense interest in identifying compounds that selectively kill senescent cells, termed senolytics, for ameliorating age-related comorbidities. However, screening for senolytic compounds currently relies on primary cells or cell lines where senescence is induced in vitro. Given the complexity of senescent cells across tissues and diseases, this approach may not target the senescent cells that develop under specific conditions in vivo. In this issue of the JCI, Lee et al. describe a pipeline for high-throughput drug screening of senolytic compounds where senescence was induced in vivo and identify the HSP90 inhibitor XL888 as a candidate senolytic to treat idiopathic pulmonary fibrosis.