CTNNB x WNT3A

Jaceosidin (JAC) is a natural flavonoid with anti-oxidant and other pharmacological activities; however, its anti-cancer mechanism remains unclear. We investigated the mechanism of action of JAC in gastric cancer cells. Cytotoxicity and apoptosis assays showed that JAC effectively killed multiple gastric cancer cells and induced apoptosis in human gastric adenocarcinoma AGS cells via the mitochondrial pathway. Network pharmacological analysis suggested that its activity was linked to reactive oxygen species (ROS), AKT, and MAPK signaling pathways. Furthermore, JAC accumulated ROS to up-regulate p-JNK, p-p38, and IκB-α protein expressions and down-regulate the p-ERK, p-STAT3, and NF-κB protein expressions. Cell cycle assay results showed that JAC accumulated ROS to up-regulate p21 and p27 protein expressions and down-regulate p-AKT, CDK2, CDK4, CDK6, Cyclin D1, and Cyclin E protein expressions to induce G0/G1 phase arrest. Cell migration assay results showed JAC accumulated ROS to down-regulate Wnt-3a, p-GSK-3β, N-cadherin, and β-catenin protein expressions and up-regulate E-cadherin protein expression to inhibit migration. Furthermore, N-acetyl cysteine pre-treatment prevented the change of these protein expressions. In summary, JAC induced apoptosis and G0/G1 phase arrest and inhibited migration through ROS-mediated signaling pathways in AGS cells.

N-Nitrosamine disinfection by-products (NAs-DBPs) have been well proven for its role in esophageal carcinogenesis. However, the role of intratumoral microorganisms in esophageal squamous cell carcinoma (ESCC) has not yet been well explored in the context of exposure to NAs-DBPs. Here, the multi-omics integration reveals F. periodonticum (Fp) as "facilitators" is highly enriched in cancer tissues and promotes the epithelial mesenchymal transition (EMT)-like subtype formation of ESCC. We demonstrate that Fp potently drives de novo synthesis of fatty acids, migration, invasion and EMT phenotype through its unique FadAL adhesin. However, N-nitrosomethylbenzylamine upregulates the transcription level of FadAL. Mechanistically, co-immunoprecipitation coupled to mass spectrometry shows that FadAL interacts with FLOT1. Furthermore, FLOT1 activates PI3K-AKT/FASN signaling pathway, leading to triglyceride and palmitic acid (PA) accumulation. Innovatively, the results from the acyl-biotin exchange demonstrate that FadAL-mediated PA accumulation enhances Wnt3A palmitoylation on a conserved cysteine residue, Cys-77, and promotes Wnt3A membrane localization and the translocation of β-catenin into the nucleus, further activating Wnt3A/β-catenin axis and inducing EMT phenotype. We therefore propose a "microbiota-cancer cell subpopulation" interaction model in the highly heterogeneous tumor microenvironment. This study unveils a mechanism by which Fp can drive ESCC and identifies FadAL as a potential diagnostic and therapeutic target for ESCC.

Catalpol, an important compound found in Rehmannia glutinosa (a plant with high nutritional and antidepressant medicinal value), exhibits various biological activities and has the ability to penetrate the blood-brain barrier. Our recent studies revealed a gender difference in the antidepressant activity of Rehmannia glutinosa with females showing better responses than males. Catalpol is likely the key compound responsible for this gender-specific difference, which caters to current clinical observations that the severity and impact of depression are approximately two to three times higher in females than in males. However, the sex-specific mechanism of catalpol's antidepressant effects remains unclear.

Our recent molecular network predictions suggest that the gender-specific antidepressant properties of catalpol primarily involve the regulation of SIRT1-mediated synaptic plasticity and neurogenesis. Building on this, the present study used a well-established chronic unpredictable mild stress model of depression in mice to confirm the sex-specific antidepressant characteristics of catalpol over time and intensity. Furthermore, using SIRT1 inhibitors and activators, behavioral tests, hematoxylin & eosin, Nissl, and Golgi staining, western blotting, immunofluorescence, and real-time PCR, we evaluated the key indicators of depressive behavior, synaptic plasticity, and neurogenesis before and after SIRT1 intervention to comprehensively assess whether the sex-specific antidepressant mechanism of catalpol indeed involves SIRT1-mediated synaptic plasticity and neurogenesis.

The gender-dependent antidepressant effects of catalpol are characterized by a faster onset and stronger effects in females compared to males, with females showing stronger regulation of SIRT1-mediated synaptic plasticity and neurogenesis. Activation of SIRT1 preserved the gender differences in catalpol's effects on depressive behavior, hippocampal synaptic plasticity (including neuronal consolidation, neuronal density, dendritic spines, and PSD95 and SYP gene and protein expression), and neurogenesis (including enhancement of GAP43 and MAP2 expression, activation of c-myc, cyclinD1, Ngn2, and NeuroD1 mRNA levels, and upregulation of the Wnt3a/β-catenin/GSK-3β pathway), while inhibition of SIRT1 abolished these gender differences in the effects of catalpol.

Catalpol exhibits higher antidepressant activity in female mice compared to male mice, and the mechanism underlying this gender difference in antidepressant effects may depend on catalpol's higher sensitivity in improving hippocampal SIRT1-mediated synaptic plasticity and neurogenesis in females. The novelty of this study lies in its first-time revelation of the gender-specific phenotypes, targets, and molecular mechanisms of the antidepressant effects of catalpol.