Jianpi-Qingchang decoction alleviates ulcerative colitis by modulating endoplasmic reticulum stress-related autophagy in intestinal epithelial cells.

Endoplasmic reticulum stress (ERS)-related autophagy is involved in the occurrence and development of ulcerative colitis (UC). Therefore, regulating ERS-related autophagy is a potential therapeutic target for the treatment of UC. Jianpi-Qingchang (JPQC) decoction, consisting of nine Chinese herbal medicines, is used to treat patients with UC. However, its mechanism of action has not been completely elucidated. Here, we aimed to reveal the therapeutic effects and mechanisms of JPQC in UC. We established a colitis model using dextran sulfate sodium (DSS) and an ERS model using thapsigargin (Tg) and administered JPQC. We systematically examined ERS-related autophagy associated protein expression, inflammatory cytokines, apoptotic cells, and autophagic flux. Moreover, the cellular ultrastructure was observed via transmission electron microscopy (TEM). We found that JPQC reduced disease activity index (DAI) scores, counteracted colonic tissue damage, decreased the number of autophagosomes, inhibited proinflammatory cytokines, enhanced anti-inflammatory cytokines, and dampened ERS-related autophagy associated protein gene expression.

Jianpi Qingchang Decoction Ameliorates Chronic Colitis in Piroxicam-Induced IL-10 Knockout Mice by Inhibiting Endoplasmic Reticulum Stress.

BACKGROUND: Excessive endoplasmic reticulum (ER) stress in intestinal epithelial cells (IEC) may lead to impaired intestinal mucosal barrier function and then participate in the pathogenesis of ulcerative colitis (UC). Jianpi Qingchang decoction (JPQCD) has been shown to have protective effects on UC. However, further studies are needed to determine whether JPQCD regulates PERK/eIF2α/ATF4/CHOP pathways to play a role in treating UC. METHODS: IL-10 -/- mice were randomly assigned into five groups: control, model, low-dose JPQCD (JPQCD L), middle-dose JPQCD (JPQCD M), and high-dose JPQCD (JPQCD H). All groups except for the control group were given model feed containing 200 ppm piroxicam for 10 d to induce colitis. As a comparison, we used wild-type mice that were the progeny of IL-10 +/- matings, bred in the same facility. The control group and wild-type mice were fed with common feed. At the same time, mice in each group were given corresponding drugs by gavage for 14 d. The disease activity index of mice in each group was evaluated daily. Colon tissues of mice were collected, colon length was measured, and pathological changes and ultrastructure of colon epithelial cells were observed. The effects of JPQCD on the PERK/eIF2α/ATF4/CHOP pathways were evaluated by western blotting and reverse transcription-polymerase chain reaction (RT-PCR). The expression of CHOP in colon tissue was detected by tissue immunofluorescence assay. The expression of NF-κB, p-NF-κB p65 protein was analyzed by western blotting; the level of IL-17 in colon tissue was detected by enzyme-linked immunosorbent assay (ELISA) and verified by examining NF-κB and IL-17 mRNA levels by RT-PCR. RESULTS: Compared with the control group, the model group showed significant colitis symptoms and severe colonic tissue damage. The results showed that JPQCD significantly reduced body weight loss, ameliorated disease activity index, and restored colon length in IL-10 -/- mice with piroxicam-induced colitis. Western blotting and RT-PCR showed that the PERK/eIF2α/ATF4/CHOP pathway was activated in colon tissue of model mice, suggesting that the pathway is involved in the pathogenesis of ulcerative colitis (UC) and could become a potential therapeutic target. The JPQCD treatment inhibited the activation of the PERK/eIF2α/ATF4/CHOP pathway, alleviated the ER stress, and played a role in preventing and treating UC. In addition, JPQCD can also downregulate the protein of NF-κB, p-NF-κB p65, downregulate the mRNA expression of NF-κB, and reduce the content of IL-17 and its mRNA expression in colon tissues. CONCLUSION: JPQCD may play a protective role in UC by regulating the PERK/eIF2α/ATF4/CHOP signaling pathway and relieving endoplasmic reticulum stress.

Portulaca oleracea L. Extract Ameliorates Intestinal Inflammation by Regulating Endoplasmic Reticulum Stress and Autophagy.

SCOPE: To investigate the role of endoplasmic reticulum stress (ERS)-induced autophagy in inflammatory bowel disease (IBD) and the intervention mechanism of Portulaca oleracea L. (POL) extract, a medicinal herb with anti-inflammatory, antioxidant, immune-regulating, and antitumor properties, in vitro and in vivo. METHODS AND RESULTS: An IL-10-deficient mouse model is used for in vivo experiments; a thapsigargin (Tg)-stimulated ERS model of human colonic mucosal epithelial cells (HIECs) is used for in vitro experiments. The levels of ERS-autophagy-related proteins are examined by immunofluorescence and Western blot. Cellular ultrastructure is assessed with transmission electron microscopy. POL extract promotes a healing effect on colitis by regulating ERS-autophagy through the protein kinase R-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2α (eIF2α)/Beclin1-microtubule-associated protein light chain 3II (LC3II) pathway. CONCLUSION: Overall, the results of this study further confirm the anti-inflammatory mechanism and protective effect of POL extract and provide a new research avenue for the clinical treatment of IBD.