Cluster-based read-across of ToxCast data identifies buprofezin as a partial PPARγ agonist with obesogenic potential.

The identification of environmental obesogens has become increasingly urgent amid rising rates of metabolic disorders linked to chemical exposures. Here, we employed a cluster-based read-across framework that integrates structural descriptors with high-throughput screening (HTS) data from the ToxCast database to systematically identify potential obesogens. A total of 8971 chemicals were represented in a 2,217-dimensional structure-activity matrix, combining 1905 chemical fingerprints and 312 bioactivity endpoints, which were reduced and clustered into 135 distinct chemical groups.

CXCL12 Drives Reversible Fibroimmune Remodeling in Androgenetic Alopecia Revealed by Single-Cell RNA Sequencing.

Androgenetic alopecia (AGA) is a common form of hair loss characterized by androgen-driven tissue remodeling, including progressive follicular miniaturization and dermal fibrosis, which is accompanied by low-grade immune activation. However, the molecular mechanisms underlying this fibroimmune dysfunction remain poorly understood. Dermal fibroblasts (DFs) have been suggested as androgen-responsive stromal cells and a potential source of CXCL12, a chemokine implicated in fibroimmune pathology, but their precise role in AGA has not been fully established.

Dimethyl Sulfoxide Shifts Human Mesenchymal Stem Cell Differentiation toward Adipogenesis over Osteogenesis.

Dimethyl sulfoxide (DMSO) is extensively used as a solvent in bioactive compound screening due to its capacity to solubilize a wide range of chemical compounds. This study demonstrates that DMSO significantly influences lineage commitment in human bone marrow-derived mesenchymal stem cells (hBM-MSCs) by enhancing adipogenesis and inhibiting osteogenesis. At concentrations above 25 mM (0.

Therapeutic Intervention of an Intranasally Administered Monoclonal Antibody Targeting the SARS-CoV-2 Omicron Spike Protein Against SARS-CoV-2 Omicron Infection in Mice.

SARS-CoV-2 has evolved into several variants of concern, with Omicron and its subvariants currently being the most prevalent. Previously, we developed a mouse monoclonal antibody (m1E3H12 mAb) specific to the receptor binding domain of SARS-CoV-2 Omicron spike protein, and the mAb showed neutralizing activity against SARS-CoV-2 Omicron BA.1 and its subvariants BA.

InertDB as a generative AI-expanded resource of biologically inactive small molecules from PubChem.

The development of robust artificial intelligence (AI)-driven predictive models relies on high-quality, diverse chemical datasets. However, the scarcity of negative data and a publication bias toward positive results often hinder accurate biological activity prediction. To address this challenge, we introduce InertDB, a comprehensive database comprising 3,205 curated inactive compounds (CICs) identified through rigorous review of over 4.

The Involvement of RIPK1 in Alopecia Areata.

We have previously demonstrated that receptor-interacting serine threonine kinase 1 (RIPK1) is expressed in hair follicles and regulates the hair cycle. In a mouse model, RIPK1 inhibitors also accelerated the telogen-to-anagen transition and elongated the anagen period. Here, we first investigated the involvement of RIPK1 in alopecia areata (AA).

Differential Expression of CXCL12 in Human and Mouse Hair: Androgens Induce CXCL12 in Human Dermal Papilla and Dermal Sheath Cup.

We previously demonstrated that C-X-C Motif Chemokine Ligand 12 (CXCL12) is primarily secreted by dermal fibroblasts in response to androgens and induces hair miniaturization in the mouse androgenic alopecia (AGA) model. However, the direct effects of androgen-induced CXCL12 on dermal papilla cells (DPCs) and dermal sheath cup cells (DSCs) have not been demonstrated. First, we compared single-cell RNA sequencing data between mouse and human skin, and the results show that CXCL12 is highly co-expressed with the androgen receptor (AR) in the DPCs and DSCs of only human hair.

Design, synthesis and biological evaluation of truncated 1'-homologated 4'-selenonucleosides as PPARγ/δ dual modulators.

This study explores the synthesis and evaluation of truncated 1'-homologated 4'-selenonucleosides as dual modulators of PPARγ and PPARδ. Starting with d-lyxose, a 4'-selenosugar was synthesized and condensed with a nucleobase via an S2 reaction, followed by modifications at the C2- and N-positions, yielding compounds 3a-l. Structure-activity trend analysis identified compound 3h, featuring 2-chloro and N-3-iodobenzylamine substituents, as a potent PPARγ partial agonist and PPARδ antagonist (PPARγ K = 2.

Humanized CXCL12 antibody delays onset and modulates immune response in alopecia areata mice: insights from single-cell RNA sequencing.

It has been demonstrated that CXCL12 inhibits hair growth via CXCR4, and its neutralizing antibody (Ab) increases hair growth in alopecia areata (AA). However, the molecular mechanisms have not been fully elucidated. In the present study, we further prepared humanized CXCL12 Ab for AA treatment and investigated underlying molecular mechanisms using single-cell RNA sequencing.

Auranofin as a Novel Anticancer Drug for Anaplastic Thyroid Cancer.

Anaplastic thyroid cancer (ATC) is an aggressive and rare cancer with a poor prognosis, and traditional therapies have limited efficacy. This study investigates drug repositioning, focusing on auranofin, a gold-based drug originally used for rheumatoid arthritis, as a potential treatment for ATC. Auranofin was identified from an FDA-approved drug library and tested on two thyroid cancer cell lines, 8505C and FRO.

Cheminformatic Read-Across Approach Revealed Ultraviolet Filter Cinoxate as an Obesogenic Peroxisome Proliferator-Activated Receptor γ Agonist.

This study introduces a novel cheminformatic read-across approach designed to identify potential environmental obesogens, substances capable of disrupting metabolism and inducing obesity by mainly influencing nuclear hormone receptors (NRs). Leveraging real-valued two-dimensional features derived from chemical fingerprints of 8435 Tox21 compounds, cluster analysis and subsequent statistical testing revealed 385 clusters enriched with compounds associated with specific NR targets. Notably, one cluster exhibited selective enrichment in peroxisome proliferator-activated receptor γ (PPARγ) agonist activity, prominently featuring methoxy cinnamate ultraviolet (UV) filters and obesogen-related compounds.

Unraveling Stereochemical Structure-Activity Relationships of Sesquiterpene Lactones for Inhibitory Effects on STAT3 Activation.

Sesquiterpene lactones, a class of natural compounds abundant in the Asteraceae family, have gained attention owing to their diverse biological activities, and particularly their anti-proliferative effects on human cancer cells. In this study, we systematically investigated the structure-activity relationship of ten sesquiterpene lactones with the aim of elucidating the structural determinants for the STAT3 inhibition governing their anti-proliferative effects. Our findings revealed a significant correlation between the STAT3 inhibitory activity and the anti-proliferative effects of sesquiterpene lactones in MDA-MB-231 breast cancer cell lines.

Carnosine and Retinol Synergistically Inhibit UVB-Induced PGE Synthesis in Human Keratinocytes through the Up-Regulation of Hyaluronan Synthase 2.

Skin aging results from complex interactions of intrinsic and extrinsic factors, leading to structural and biochemical changes such as wrinkles and dryness. Ultraviolet (UV) irradiation leads to the degradation of hyaluronic acid (HA) in the skin, and the with fragmented HA contributes to inflammation. This study revealed that the synergistic combination of carnosine and retinol (ROL) increases HA production in normal human epidermal keratinocytes (NHEKs) by upregulating hyaluronan synthase 2 (HAS2) gene transcription.

Prenylated Chrysin Derivatives as Partial PPARγ Agonists with Adiponectin Secretion-Inducing Activity.

Decreased circulating adiponectin levels are associated with an increased risk of human metabolic diseases. The chemical-mediated upregulation of adiponectin biosynthesis has been proposed as a novel therapeutic approach to managing hypoadiponectinemia-associated diseases. In preliminary screening, the natural flavonoid chrysin () exhibited adiponectin secretion-inducing activity during adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs).

Structure-Activity Relationships of Truncated 1'-Homologated Carbaadenosine Derivatives as New PPARγ/δ Ligands: A Study on Sugar Puckering Affecting Binding to PPARs.

Peroxisome proliferator-activated receptors (PPARs) are associated with the regulation of metabolic homeostasis. Based on a previous report that 1'-homologated 4'-thionucleoside acts as a dual PPARγ/δ modulator, carbocyclic nucleosides - with various sugar conformations were synthesized to determine whether sugar puckering affects binding to PPARs. ()-conformer was synthesized using Charette asymmetric cyclopropanation, whereas ()-conformer was synthesized using stereoselective Simmons-Smith cyclopropanation.

In vitro and in vivo suppression of SARS-CoV-2 replication by a modified, short, cell-penetrating peptide targeting the C-terminal domain of the viral spike protein.

Peptides are promising therapeutic agents for COVID-19 because of their specificity, easy synthesis, and ability to be fine-tuned. We previously demonstrated that a cell-permeable peptide corresponding to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike C-terminal domain (CD) inhibits the interaction between viral spike and nucleocapsid proteins that results in SARS-CoV-2 replication in vitro. Here, we used docking studies to design R-t-Spike CD(D), a more potent short cell-penetrating peptide composed of all D-form amino acids and evaluated its inhibitory effect against the replication of SARS-CoV-2 S clade and other variants.

Computational Prediction of the Phenotypic Effect of Flavonoids on Adiponectin Biosynthesis.

machine learning applications for phenotype-based screening have primarily been limited due to the lack of machine-readable data related to disease phenotypes. Adiponectin, a nuclear receptor (NR)-regulated adipocytokine, is relatively downregulated in human metabolic diseases. Here, we present a machine-learning model to predict the adiponectin-secretion-promoting activity of flavonoid-associated phytochemicals (FAPs).

Hepatic TREM2 macrophages express matrix metalloproteinases to control fibrotic scar formation.

Liver cirrhosis is characterized by the extensive deposition of extracellular matrix such as fibril collagen, causing dysfunction and failure of the liver. Hepatic macrophages play pivotal roles in the transition from inflammatory to restorative properties upon hepatic injury. In particular, scar-associated macrophages (SAMacs) control liver fibrosis with the representative expression of matrix metalloproteinase (MMP).

Discovery of Pan-peroxisome Proliferator-Activated Receptor Modulators from an Endolichenic Fungus, .

Adiponectin-synthesis-promoting compounds possess therapeutic potential to treat diverse metabolic diseases, including obesity and diabetes. Phenotypic screening to find adiponectin-synthesis-promoting compounds was performed using the adipogenesis model of human bone marrow mesenchymal stem cells. The extract of the endolichenic fungus 047215 significantly promoted adiponectin production.

Discovery of PPARγ and glucocorticoid receptor dual agonists to promote the adiponectin and leptin biosynthesis in human bone marrow mesenchymal stem cells.

Adiponectin and leptin are major adipocytokines that control crosstalk between adipose tissue and other organ systems. Hypoadiponectinemia and hypoleptinemia are associated with human metabolic diseases. Compounds with adipocytokine biosynthesis-stimulating activities could be developed as therapeutics against diverse metabolic conditions.

Design, Synthesis, and Biological Activity of l-1'-Homologated Adenosine Derivatives.

On the basis of the previously reported polypharmacological profile of truncated d-1'-homologated adenosine derivatives [J. Med. Chem.

Macrophage-Specific Connexin 43 Knockout Protects Mice from Obesity-Induced Inflammation and Metabolic Dysfunction.

Adipose tissue macrophages are a major immune cell type contributing to homeostatic maintenance and pathological adipose tissue remodeling. However, the mechanisms underlying macrophage recruitment and polarization in adipose tissue during obesity remain poorly understood. Previous studies have suggested that the gap junctional protein, connexin 43 (Cx43), plays a critical role in macrophage activation and phagocytosis.