Exploring the therapeutic potential of Xiangsha Liujunzi Wan in Crohn's disease: from network pharmacology approach to experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiangsha Liujunzi Wan (LJZW) is a traditional Chinese medicine (TCM) formula containing a variety of traditional Chinese herb components. Its principal components are often used in the treatment of gastrointestinal diseases and contribute to the treatment of Crohn's disease (CD). AIM OF THE STUDY: To explore the therapeutic potential of LJZW in CD through network pharmacology, bioinformatics, molecular docking, and experimental verification. METHODS: The principal bioactive components and corresponding targets of LJZW were ascertained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Potential targets for CD were identified in GeneCards, OMIM, DrugBank, DisGeNET, CTD, and Gene Expression Omnibus (GEO) databases. Intersection targets of LJZW and CD were identified using a Venn diagram and visualized using Cytoscape 3.8.0 to construct a protein-protein interaction (PPI) network. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were employed to assess the function of intersection targets. AutoDockTools and PyMOL were used for molecular docking to recognize the association between the core ingredients of LJZW and the core targets of CD. Subsequently, a series of experiments were conducted for validation. RESULTS: The network pharmacology results indicated that there were 156 bioactive components and 268 corresponding targets for LJZW, 3023 primary relevant targets for CD, and 169 intersection targets for LJZW and CD. The PPI network was employed to identify five hub genes and six clusters. The GO functional analysis indicated that intersection targets are primarily correlated with oxidative stress and inflammatory response. KEGG pathway analysis revealed that these targets were primarily associated with the phosphotylinosital 3 kinase (PI3K)-protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) signaling pathways. The molecular docking results showed that the core ingredients of LJZW had good binding ability with the core targets of CD. A series of experiments demonstrated that LJZW could effectively attenuate TNBS-induced colitis symptoms, inhibit the inflammatory response and protect intestinal barrier function by inhibiting the PI3K-AKT and MAPK signaling pathways, thus preventing and treating CD. CONCLUSION: LJZW has the characteristics of multi-component, multi-target and multi-pathway treatment, which helps to improve the treatment of CD, protect the intestinal barrier, and exert the effect of anti-inflammatory therapy by inhibiting PI3K-AKT and MAPK signaling pathways.

Understanding the molecular pathway of triclosan-induced ADHD-like behaviour: Involvement of the hnRNPA1-PKM2-STAT3 feedback loop.

Triclosan (TCS) is an environmental pollutant. In recent years, there has been increasing level of concern regarding the potential toxicity of TCS in animals and humans, especially its effects on the nervous system. However, whether TCS induces ADHD-like behaviour and the mechanism by which it affects neural function are unclear. The impact of 60 days of continuous exposure to TCS on the behaviour of offspring rats was assessed in this research. According to the results of this study, TCS exposure led to ADHD-like behaviour in offspring rats and activated microglia in the prefrontal cortex (PFC), inducing inflammatory factor release. In vitro studies showed that TCS increased the levels of inflammatory cytokines, including interleukin (IL)-1ß, IL-6 and tumour necrosis factor (TNF)-α, in HMC3 cells. More importantly, we found that TCS regulated the STAT3 pathway by upregulating PKM2 via hnRNPA1. In summary, this study suggested that TCS can induce ADHD-like behaviour in offspring rats and continuously activate HMC3 microglia through the hnRNPA1-PKM2-STAT3 feedback loop, promoting inflammatory cytokine secretion.

Long-life triclosan exposure induces ADHD-like behavior in rats via prefrontal cortex dopaminergic deficiency.

In recent years, exposure to triclosan (TCS) has been linked to an increase in psychiatric disorders. Nonetheless, the precise mechanisms of this occurrence remain elusive. Therefore, this study developed a long-life TCS-exposed rat model, an SH-SY5Y cell model, and an atomoxetine hydrochloride (ATX) treatment model to explore and validate the neurobehavioral mechanisms of TCS from multiple perspectives. In the long-life TCS-exposed model, pregnant rats received either 0 mg/kg (control) or 50 mg/kg TCS by oral gavage throughout pregnancy, lactation, and weaning of their offspring (up to 8 weeks old). In the ATX treatment model, weanling rats received daily injections of either 0 mg/kg (control) or 3 mg/kg ATX via intraperitoneal injection until they reached 8 weeks old. Unlike the TCS model, ATX exposure only occurred after the pups were weaned. The results indicated that long-life TCS exposure led to attention-deficit hyperactivity disorder (ADHD)-like behaviors in male offspring rats accompanied by dopamine-related mRNA and protein expression imbalances in the prefrontal cortex (PFC). Moreover, in vitro experiments also confirmed these findings. Mechanistically, TCS reduced dopamine (DA) synthesis, release, and transmission, and increased reuptake in PFC, thereby reducing synaptic gap DA levels and causing dopaminergic deficits. Additional experiments revealed that increased DA concentration in PFC by ATX effectively alleviated TCS-induced ADHD-like behavior in male offspring rats. These findings suggest that long-life TCS exposure causes ADHD-like behavior in male offspring rats through dopaminergic deficits. Furthermore, ATX treatment not only reduce symptoms in the rats, but also reveals valuable insights into the neurotoxic mechanisms induced by TCS.

The V protein in oncolytic Newcastle disease virus promotes HepG2 hepatoma cell proliferation at the single-cell level.

BACKGROUND: Newcastle disease virus (NDV) is an oncolytic virus that can inhibit cancer cell proliferation and kill cancer cells. The NDV nonstructural V protein can regulate viral replication; however, whether the V protein contributes to NDV oncolysis is unclear. RESULTS: This study revealed that NDV inhibited tumor cell proliferation and that V protein expression promoted the proliferation of HepG2 cells, as determined at the single-cell level. In addition, to identify the regulatory mechanism of the V protein in HepG2 cells, transcriptome sequencing was performed and indicated that the expression/activation of multiple cell proliferation-related genes/signaling pathways were changed in cells overexpressing the V protein. Hence, the MAPK and WNT signaling pathways were selected for verification, and after blocking these two signaling pathways with inhibitors, the V protein promotion of cell proliferation was found to be attenuated. CONCLUSIONS: The results showed that the V protein regulated the proliferation of cancer cells through multiple signaling pathways, providing valuable references for future studies on the mechanism by which the V protein regulates cancer cell proliferation.