Gastroesophageal reflux disease (GERD) is a chronic condition of the digestive tract with limited therapeutic options. Bitter taste receptors (TAS2Rs) and transient receptor potential vanilloid-1 (TRPV1) are implicated in modulating inflammatory responses. Berberine (BBR) and evodiamine (EVO) are known to activate TAS2Rs and TRPV1, respectively. However, whether BBR and EVO can ameliorate GERD by targeting TAS2Rs and TRPV1 remains uncertain. This study aims to determine whether BBR and EVO mitigate esophageal injury by targeting TAS2R38 and TRPV1 and to elucidate their underlying molecular mechanisms. A GERD rat model was developed using esophagogastric anastomosis, while GERD in human esophageal epithelial cells (HEECs) was induced via bile acid (BA) exposure. Esophageal pathology was analyzed through hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM). mRNA and protein levels were measured via qRT-PCR, immunofluorescence, immunohistochemistry and Western blot analysis. Small interfering RNA was used to silence TAS2R38 and TRPV1 in HEECs. The activation of TAS2R38 and TRPV1 by BBR and EVO was assessed through Ca²⁺ mobilization assays. Finally, in vivo validation was conducted using U73122 to inhibit TAS2Rs and resiniferatoxin (RTX) to ablate TRPV1. BBR and EVO treatments significantly improved esophageal pathology in GERD rats and reduced BA-induced inflammation in HEECs. Additionally, BBR and EVO suppressed proinflammatory factors expression, upregulated barrier proteins such as E-cadherin and claudin-1, and inhibited the phosphorylation of p65, JNK, and ERK in the MAPK/NF-κB signaling pathways in both in vivo and in vitro models. Furthermore, BBR and EVO, whether individually or in combination, reduced dilated intercellular spaces (DIS), increased desmosome numbers, and modulated macrophage polarization in GERD rats. Knockdown of TAS2R38 and TRPV1 in HEECs notably diminished the stimulatory effects of BBR and EVO. Moreover, the regulation of barrier function and MAPK/NF-κB pathway proteins by BBR and EVO in BA-induced HEECs was abrogated upon TAS2R38 and TRPV1 knockdown. Similarly, U73122 and RTX reversed the effects of BBR and EVO on macrophage polarization and MAPK/NF-κB signaling pathways in vivo. We firstly demonstrate that BBR and EVO alleviate GERD, with enhanced synergistic efficacy observed when used in combination. Mechanistically, BBR and EVO activate the TAS2R38 and TRPV1, respectively, leading to downregulation of phosphorylation in MAPK/NF-κB signaling pathways and modulation of macrophage polarization. These findings offer a novel foundation for the clinical application of BBR and EVO in GERD treatment.

Lipid metabolism is important in various cancers. However, the association between lipid metabolism and uterine corpus endometrial carcinoma (UCEC) is still unclear. In this study, we collected clinicopathologic parameters and the expression of lipid metabolism-related genes (LMRGs) from the Cancer Genome Atlas (TCGA). A lipid metabolism-related risk model was built and verified. The risk score was developed based on 11 selected LMRGs. The expression of 11 LMRGs was confirmed by qRT-PCR in clinical samples. We found that the model was an independent prediction factor of UCEC in terms of multivariate analysis. The overall survival (OS) of low-risk group was higher than that in the high-risk group. GSEA revealed that MAPK signaling pathway, ERBB signaling pathway, ECM receptor interaction, WNT pathway, and TGF-β signaling pathway were enriched in the high-risk group. Low-risk group was characterized by high tumor mutation burden (TMB) and showed sensitive response to immunotherapy and chemotherapy. In brief, we built a lipid metabolism gene expression-based risk signature which can reflect the prognosis of UCEC patients and their response to chemotherapeutics and immune therapy.

Zuojin Pill (ZJP), a traditional Chinese medicinal formula, is widely recognized for its diverse pharmacological properties in the management of gastrointestinal disorders. However, the precise mechanisms underlying its therapeutic effects in gastroesophageal reflux disease (GERD) remain inadequately understood. This study aims to investigate the therapeutic effects of ZJP in GERD and to elucidate the molecular mechanisms involved. The chemical composition of ZJP was characterized using HPLC-Q-Exactive-MS. A rat model of GERD was established through esophagogastric anastomosis, and three different doses of ZJP were administered. Histological changes were assessed via hematoxylin-eosin (H&E) staining, while pro-inflammatory cytokines were quantified to evaluate the anti-inflammatory effects of ZJP. Network pharmacology combined with bioinformatics analysis was employed to predict potential therapeutic targets and signaling pathways of ZJP in GERD. Validation of the mechanisms was conducted through Western blotting, immunofluorescence (IF), transmission electron microscopy (TEM), and immunohistochemistry (IHC). The results demonstrated that ZJP effectively alleviated pathological alterations and reduced pro-inflammatory cytokine levels in esophageal tissues of GERD rats. Western blotting and IF analysis of E-cadherin and claudin-1 confirmed that ZJP enhanced the integrity of the esophageal mucosal barrier. TEM imaging revealed that ZJP restored intercellular space (DIS), increased desmosome density, thereby protecting esophageal tissues from the detrimental effects of GERD. Furthermore, ZJP modulated macrophage polarization in the GERD rat model. Mechanistic investigations indicated that ZJP exerted its therapeutic effects by inhibiting MAPK/NF-κB signaling pathway activation and downregulating the expression of prostaglandin-endoperoxide synthase 2 (PTGS2) and matrix metalloproteinase 2 (MMP2), consistent with predictions from network pharmacology analysis. This study provides comprehensive evidence for the therapeutic efficacy of ZJP in GERD, acting through modulation of inflammation, mucosal barrier integrity, and macrophage polarization. Additionally, ZJP downregulated PTGS2 and MMP2 expression and suppressed the activation of MAPK/NF-κB signaling pathways, underscoring its potential as a therapeutic intervention for GERD.