Polystyrene micro/nanoplastics (MPs/NPs) are globally recognized environmental concerns due to their widespread pollution and detrimental effects on physiological functions. However, the neurotoxic effects and underlying mechanisms of MPs/NPs on brain function in adolescents remain incompletely understood. This study investigated the effects of polystyrene MPs/NPs on neurobehavioral function in adolescent mice, utilizing multi-omic analysis and molecular biology assays to explore potential mechanisms. Following oral exposure of MPs (5 μm) or NPs (0.5 μm) at 0.5 mg/day for 4 weeks, NPs induced more severe cognitive impairment in mice than MPs, as assessed by the Morris water maze and Y-maze tests. This impairment might be associated with the neuron loss and neurogenesis inhibition caused by NPs, while dendritic spine loss mediated by MPs in the hippocampus. Furthermore, analysis of hippocampal transcriptome and Western blotting indicated the potential involvement of the PI3K/AKT pathway in NPs-induced neurotoxicity. Meanwhile, exposure to NPs induced more pronounced disruptions in the hippocampal metabolome and gut microbiota, and strong correlations were observed between changes in hippocampal metabolites and gut bacteria. This study elucidated the toxicity mechanism of MPs and NPs in inducing cognitive impairment in adolescent mice, providing insights into their toxicological impacts and potential strategies for intervention.

20(S)-Ginsenoside Rh2 (GRh2) has been extensively studied for multifaceted health benefits. However, the anti-melanoma effect of GRh2 remains poorly understood. Herein, the anti-melanoma effects and underlying mechanisms of GRh2 were investigated. MTT assays, the EdU staining assay, flow cytometric analysis, the cellular thermal shift assay (CETSA), confocal microscope analysis, molecular docking, molecular dynamics (MD), immunoblotting, a B16F10 cell bearing mouse model were adopted to examine the anti-melanoma effect of mechanism of action of GRh2. In melanoma cells, GRh2 was found to suppress cell proliferation, arrest cell cycle at G0/G1 phase and evoke apoptosis. GRh2 initiated autophagy and inhibited the activity of mTOR, the autophagy negative regulator, in melanoma cells. Repressing autophagy enhanced the anti-melanoma efficacy of GRh2. Molecular docking, MD and CETSA studies revealed that GRh2 stably bound to Src protein (one of the upstream kinases of STAT3). GRh2 suppressed Src and STAT3 activities, thereof prohibiting STAT3 nuclear translocation in melanoma cells. STAT3 over-activation attenuated the cytotoxic, apoptotic and autophagy inductive effects of GRh2. Additionally, GRh2 suppressed B16F10 tumor growth without inducing obvious toxicity in mice. It downregulated phospho-Src, phospho-STAT3, phospho-mTOR and Mcl-1 protein levels, while elevated cleaved-PARP and LC3B-II protein levels in B16F10 tumors. GRh2 exerts anti-melanoma effects through suppressing Src/STAT3 signaling. This study advances our understanding on the anti-melanoma mechanism of GRh2 and indicates that the intake of GRh2 has the potential to retard melanoma progression.

The efficacy of dendritic cell (DC)‐based cancer vaccines is critically determined by the functionalities of in vitro maturated DCs. The maturation of DCs typically relies on chemicals that are cytotoxic or hinder the ability of DCs to efficiently activate the antigen‐specific cytotoxic T‐lymphocytes (CTLs) against tumors. Herein, the maturation chemicals are replaced with extracellular silica nanomatrices, fabricated by glancing angle deposition, to promote in vitro maturation of murine bone marrow‐derived DCs (mBMDCs). The extracellular nanomatrices composed of silica nanozigzags (NZs) enable the generation of mature mBMDCs with upregulated levels of co‐stimulatory molecules, C‐C chemokine receptor type‐7, X‐C motif chemokine recetpor‐1, DC‐specific ICAM‐3 grabbing nonintegrin, and enhanced endocytic capacity. The in vitro maturation is partially governed by focal adhesion kinase (FAK) that is mechanically activated in the curved cell adhesions formed at the DC‐NZ interfaces. The NZ‐maturated mBMDCs can prime the antigen‐specific CTLs into programmed cell death protein‐1 (PD‐1)^lowCD44^high memory phenotypes in vitro and suppress the growth of tumors in vivo. Meanwhile, the NZ‐mediated beneficial effects are also observed in human monocyte‐derived DCs. This work demonstrates that the silica NZs promote the anti‐tumor capacity of in vitro maturated DCs via the mechanoactivation of FAK, supporting the potential of silica NZs being a promising biomaterial for cancer immunotherapy.

Hypothalamic obesity (HO) is a disabling disease caused by central nervous system (CNS) damage due to neurosurgery, trauma, or tumors, especially in hypothalamus. The pathological mechanism of its neural circuits is still unclear, and there is currently no corresponding drug due to the complex etiology. G protein-coupled receptors (GPCRs) regulate neural function in many CNS diseases. Among them, melanocortin 4 receptor (MC4R) regulate metabolism and appetite in the hypothalamus. Setmelanotide, an MC4R agonist, has demonstrated anti-obesity effects in genetic forms of obesity; however, its efficacy and mechanisms in HO remain unexplored. This study explored the potential of treating HO by setmelanotide-targeted activation of MC4R in the paraventricular nucleus (PVN). We established a rat hypothalamic injury model to replicate human HO symptoms, such as hyperphagia (50% increase in food intake), elevated Lee index, and more than 25% weight gain. Immunofluorescence and immunoblot analysis showed that HO disrupted the PVN neuropeptides, leading to the inhibition of MC4R via calmodulin-dependent protein kinase kinase 2 (CaMKK2) and AMP-activated protein kinase (AMPK) signaling. Crucially, administration of setmelanotide restored CaMKK2/AMPK activity, reactivated MC4R neurons, and normalized appetite and feeding behavior during fasting-refeeding and the long-term treatment of obese rats (60% reduction in food intake), ultimately reversing obesity (23% weight loss). These findings underscore the critical role of MC4R dysfunction in hypothalamic injury and highlight the strategies to pharmacologically activate MC4R via CaMKK2/AMPK signaling to restore metabolic homeostasis, proposing a translatable therapeutic agent to manage obesity caused by CNS injury.

Aim of the study: Traditional Chinese Medicine offers a holistic approach that could provide complementary benefits for bipolar disorder treatment. However, the clinical cases in Traditional Chinese Medicine are highly dispersed, creating challenges for translational research. This study employs a novel data-mining-derived approach to identify treatment patterns and active metabolite interactions within these clinical cases.Methods and materials: Bipolar disorder-related targets were determined using DisGeNET and GeneCards databases. Active botanical drugs were extracted from the BATMAN-TCM 2.0 database. All terms for botanical drugs and diseases were confirmed via the Pharmacopoeia of the People’s Republic of China 2020 Edition and Medical Subject Headings. Networks were constructed using Cytoscape, with data analysis performed using Python. MTT cell viability and qRT-PCR analysis were used to perform in vitro experiments on SH-SY5Y neuroblastoma cells.Results: Five key botanical drugs—Glycyrrhizae Radix Et Rhizoma, Poria, Coptidis Rhizoma, Bupleuri Radix, and Polygalae Radix—were identified as core drugs in BD treatment formulas. The botanical drug-metabolite-target network was constructed. In vitro experiments using SH-SY5Y neuroblastoma cells demonstrated dose-dependent effects of palmitic acid (PA) and stearic acid (SA) on cell viability and gene expression. qRT-PCR analysis revealed bidirectional regulation of GABRA1 and ESR1 by these metabolites.Conclusion: Five botanical drugs: Glycyrrhizae Radix Et Rhizoma, Poria, Coptidis Rhizoma, Bupleuri Radix, and Polygalae Radix, were identified as the core botanical drugs in bipolar disorder treatment. The main mechanism of these botanical drugs is their effects on the gamma-aminobutyric acid type A receptor and ESR1.

Enterocytes mediate both nutrient absorption and antimicrobial peptide (AMP) secretion while constantly exposed to osmotic fluctuations. However, the role of volume-regulated anion channel (VRAC), a key osmo-sensitive ion channel, in enterocytes and inflammatory bowel disease (IBD) remains unclear. Here, we show that intestinal epithelial cell (IEC)-specific knockout of LRRC8A, the essential VRAC subunit, exacerbates colitis and inflammation-associated colorectal cancer. VRAC deficiency specifically disrupts enterocyte maturation and zonation, expanding AMP-producing enterocytes while reducing enterocytes responsible for nutrient absorption. Retinoic acid metabolism emerges as the most affected nutrient pathway in VRAC-deficient IECs, with reduced Adh1, Aldh1a2 expression and aldehyde dehydrogenase activity. Supplementation with retinoic acid reversed inflammation caused by VRAC deficiency. Conversely, VRAC deficiency induced gut microbiota dysbiosis, while administration of Lactobacillus species effectively restored microbial balance and alleviated inflammation. This study delineates the role of VRAC in balancing nutrient absorption and antimicrobial defense in enterocytes to safeguard gut homeostasis.