National Center for Drug Screening

Fungal-derived natural compounds serve as a crucial resource for new drug development and have witnessed significant progress in recent years. Researchers have screened multiple bioactive compounds from fungal extracts. Epilepsy, a neurological disorder affecting tens of millions of people worldwide, presents substantial therapeutic challenges due to its complex pathogenesis. Neuronal apoptosis plays a critical role in epileptogenesis and seizure generation. In this study, we screened a fungal-derived natural compound, chaetosemin J, with antiepileptic activity using zebrafish and cell models. Screening assays using the zebrafish model demonstrated that chaetosemin J alleviated epileptiform behavior and downregulated seizure-induced epilepsy marker genes. In parallel, cell-based assays showed that chaetosemin J enhanced cell viability. The anti-epileptic pathways and associated targets of chaetosemin J were predicted using transcriptomics and molecular docking techniques. Furthermore, its anti-epileptic mechanism was validated through real-time quantitative polymerase chain reaction experiments and calcium ion reflow assays. Collectively, our findings suggested that chaetosemin J may alleviate epileptic seizures by downregulating the expression of integrin-related genes in the extracellular matrix/focal adhesion signaling pathway, reversing the abnormal elevation of intracellular calcium ion concentration during epileptic seizures, and thereby reducing the activation of the apoptosis-related factor Calpain-2. This study provides a new candidate molecule for the development of antiepileptic drugs.

The first total synthesis of the anti-inflammatory Ganoderma meroterpenoid dimers dispirocochlearoids A-C, along with five of their diastereomers─potential unreported natural products─has been accomplished using a convergent strategy that leveraged common intermediates derived from dayaolingzhiol M. The synthesis features several key steps: a hetero-Diels-Alder reaction, a hydrolysis/double-bond migration cascade to assemble the D/E-bicyclic core, and a condensation/intramolecular aldol/lactonization cascade that constructs the final B/C-bicyclic system of dispirocochlearoids A-C.

Abstract Metabolic dysfunction‐associated steatotic liver disease (MASLD) has become an important liver disease worldwide due to the rising rate of type 2 diabetes, obesity, and other metabolic disorders. The early detection of MASLD is vital to slow progression to cirrhosis and hepatocellular carcinoma; yet, existing research tools for studying hepatic steatosis are limited in terms of their effectiveness and invasiveness. Herein, a near‐infrared (NIR) fluorescent probe, TCF‐FBN, for the selective imaging of lipid droplets (LDs) in MASLD is reported. TCF‐FBN exhibits bright NIR fluorescence and a large Stokes shift in nonpolar solvents, and minimal fluorescence in polar solvents, making it suitable for biological imaging. The probe is bound to bovine serum albumin (BSA) through supramolecular forces to enhance its biocompatibility, and the resulting TCF‐FBN@BSA ensemble is used for fluorescence imaging of LDs generated in hepatocytes. Notably, the modification of TCF‐FBN@BSA with galactosyl ligands producing TCF‐FBN@Gal‐BSA enables the targeted imaging of the liver of mice with MASLD via asialoglycoprotein receptor (ASGPR)‐mediated biorecognition.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, emphasizing the urgent need for novel therapeutic strategies. In this study, we investigate the anti-tumor potential of CC-885, a cereblon (CRBN) modulator known for its efficacy in targeting neoplastic cells through proteasomal degradation pathways. Our findings demonstrate that CC-885 exhibits potent anti-tumor activity against HCC. In vitro assays revealed that CC-885 significantly inhibits the proliferation, migration, and invasion of HCC cells. These effects were corroborated in vivo, where CC-885 markedly suppressed tumor growth and angiogenesis in chick embryos and impeded the progression of orthotopic liver tumors in murine models. Mechanistically, CC-885 selectively reduces GOLM1 protein levels via ubiquitin-mediated proteasomal degradation. Knockdown of GOLM1 recapitulated the anti-proliferative effects of CC-885, while overexpression of GOLM1 conferred resistance to CC-885-induced apoptosis and growth inhibition. Further investigation revealed that CC-885 facilitates the interaction between GOLM1 and the E3 ubiquitin ligase CRBN, promoting the ubiquitination and subsequent degradation of GOLM1. Transcriptomic analyses showed that both CC-885 treatment and GOLM1 knockdown modulate critical pathways involved in apoptosis. These findings position CC-885 as a promising therapeutic candidate for HCC, acting primarily through CRBN-dependent degradation of GOLM1, and support its further development for clinical application.

Although the development of SHP2 inhibitors has made striking progress, there is no inhibitor in clinical evaluation because of the potential side effects induced by poor drug distribution. Fluorescence imaging technology is widely used in the process of diagnosis and treatment of diseases because of the advantages of rapid imaging and non-destructive detection and might provide a new way to explore the mechanism of drug-target interactions in intact tissue. A series of 2-quinolone derivatives as fluorescent inhibitors against SHP2 were designed and synthesized, and their spectral properties and biological activities were evaluated in this report. The representative compound 8A had excellent fluorescence properties (λemimax : 562 nm, Stokes shift: 170 nm, fluorescence quantum yield: 0.072) and optical stability. Moreover, compound 8A emitted a blue signal in SHP2WT U2OS cells and inhibited the SHP2 enzyme abilities (IC50: 20.16 ± 0.95 μM) without the extra combination of suitable fluorophores, linker, or selectiveactivated molecules. Therefore, we hope that compound 8A could act as a lead to develop novel, convenient, and bifunctional chemical tools to explore the mechanism of drug-target interactions in intact tissue and promote the integrated research progress of diagnosis and treatment of SHP2 related diseases.

Nanomaterials with unparalleled physical and chemical attributes have become a cornerstone in the field of nanomedicine delivery. These materials can be engineered into various functionalized nanocarriers, which have become the focus of research. Stimulus-responsive nanodrug delivery systems (SRDDS) stand out as a sophisticated class of nanocarriers that can release drugs in response to environmental cues. Due to the complex pathogenesis and the multifaceted pathological environment of the nervous system, developing accurate and effective drug therapy with low side-effects is a formidable task. In recent years, SRDDS have been widely used in the treatment of neurological diseases. By customizing SRDDS to align with the specific microenvironment of the nervous system tissues or external stimulation, the efficacy of drug delivery can be enhanced. This review provides an in-depth look at the characteristics of the microenvironment of neurological diseases and highlights case studies of SRDDS tailored to treat these disorders based on theunique stimulation criteria of nervous system tissues or external triggers. Additionally, this review provides a comprehensive overview of the progress and future prospects of SRDDS technology in the treatment of neurological diseases, providing valuable guidance for its transition from fundamental research to clinical application.

DNA methylation and demethylation are key epigenetic events that regulate gene expression and cell fate. DNA demethylation via oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) is typically mediated by TET (ten-eleven translocation) enzymes. The 5hmC modification is considered an intermediate state of DNA demethylation; it is particularly prevalent in the brain and is believed to play a role in the development of many cell types in the brain. Our previous studies have identified that vitamin C (Vc) and MEK inhibitor PD0325901 could significantly promote OPC (oligodendrocyte progenitor cell)-to-OL (oligodendrocyte) differentiation. Here we discovered that Vc and PD0325901 may promote OPC-to-OL differentiation by inducing DNA demethylation via hydroxymethylation. Blocking 5hmC formation almost totally blocked Vc- and PD0325901-stimulated OPC-to-OL differentiation. In addition, TET1 is not involved in Vc,- and PD0325901-promoted OL generation. We also found a synergistic effect between the two compounds in inducing OL generation, suggesting the possibility of a combination therapy for demyelination diseases in the future.