Lianweng Granules Alleviate Intestinal Barrier Damage via the IL-6/STAT3/PI3K/AKT Signaling Pathway with Dampness-Heat Syndrome Diarrhea.

Dampness-heat syndrome diarrhea (DHSD) is a common clinical disease with a high prevalence but still has no satisfactory therapeutic medicine, so the search for a safe and effective drug candidate is ongoing. This study aims to explore the efficacy and mechanisms of Lianweng granules (LWG) in the treatment of DHSD and to identify the blood transport components of LWG. We assessed the efficacy of LWG in DHSD by various in vivo metrics such as body weight, disease activity index (DAI), histopathologic examination, intestinal barrier function, levels of inflammatory, apoptotic biomarkers, and oxidative stress. We identified the blood components of LWG using ultra-high performance liquid chromatography-mass spectrometry/mass spectrometry (UHPLC-MS/MS), and the resolved key components were used to explore the relevant targets. We next predicted the potential mechanisms of LWG in treating DHSD using network pharmacology and molecular docking based on the relevant targets. Finally, the mechanisms were validated in vivo using RT-qPCR, Western blotting, ELISA, and immunofluorescence and evaluated in vitro using Cell Counting Kit-8 (CCK-8), small interfering RNA, cellular enthusiasm transfer assay (CETSA), and drug affinity response target stability (DARTS). Ninety-one pharmacodynamic components of LWG enter the bloodstream and exert possible therapeutic effects. In vivo, LWG treatment improved body weight, reduced colonic injury and DAI scores, lowered inflammation, oxidative stress, and apoptosis markers, and partially restored intestinal barrier function in DHSD mice. Guided by network pharmacology and molecular docking, it is suggested that LWG may exert therapeutic effects by inhibiting IL-6/STAT3/PI3K/AKT signaling. LWG significantly decreased the expression of IL-6, p-STAT3, p-PI3K, p-AKT, and other proteins. These findings were supported by in vitro experiments, where CETSA, DARTS, and siRNA evidenced LWG's targeting of STAT3. LWG targeted STAT3 to inhibit inflammation, oxidative stress, and apoptosis in the colon, thereby restoring the intestinal barrier function to some extent and exerting a therapeutic effect on DHSD.

PARs in the inflammation-cancer transformation of CRC

Colorectal cancer (CRC) is one of the common malignancies with a global trend of increasing incidence and mortality. There is an urgent need to identify new predictive markers and therapeutic targets for the treatment of CRC. Protease-activated receptors (PARs) are a class of G-protein-coupled receptors, with currently identified subtypes including PAR1, PAR2, PAR3 and PAR4. Increasingly, studies suggest that PARs play an important role in the growth and metastasis of CRC. By targeting multiple signaling pathways may contribute to the pathogenesis of CRC. In this review, we first describe recent studies on the role of PARs in CRC inflammation-cancer transformation, focusing on the important role of PARs in signaling pathways associated with inflammation-cancer transformation, and summarize the progress of research on PARs-targeted drugs (AU)

PARs in the inflammation-cancer transformation of CRC.

Colorectal cancer (CRC) is one of the common malignancies with a global trend of increasing incidence and mortality. There is an urgent need to identify new predictive markers and therapeutic targets for the treatment of CRC. Protease-activated receptors (PARs) are a class of G-protein-coupled receptors, with currently identified subtypes including PAR1, PAR2, PAR3 and PAR4. Increasingly, studies suggest that PARs play an important role in the growth and metastasis of CRC. By targeting multiple signaling pathways may contribute to the pathogenesis of CRC. In this review, we first describe recent studies on the role of PARs in CRC inflammation-cancer transformation, focusing on the important role of PARs in signaling pathways associated with inflammation-cancer transformation, and summarize the progress of research on PARs-targeted drugs.