Downregulation of OATP2B1 by proinflammatory cytokines leads to 5-ASA hyposensitivity in Ulcerative colitis.

5-Aminosalicylic acid (5-ASA) is a first-line agent in both remission and maintenance therapy for ulcerative colitis (UC). However, the mucosal concentration of 5-ASA was significantly lower in patients with severe histological inflammation, which further led to a poor response to 5-ASA treatment. Our study aimed to clarify the mechanism of 5-ASA uptake into colonic epithelial cells and to further explore the reason for the decreased colonic mucosal 5-ASA concentration in UC patients. Our results demonstrated that the colonic 5-ASA concentration was notably reduced in DSS-induced colitis mice and inversely correlated with colonic inflammation. 5-ASA was not a substrate of carnitine/organic cation transporter 1/2 (OCTN1/2) or multidrug resistance protein 1 (MDR1), whereas organic anion transporting polypeptide 2B1 (OATP2B1) and sodium-coupled monocarboxylate transporter 1 (SMCT1) mediated the uptake of 5-ASA, with a greater contribution from OATP2B1 than SMCT1. Inhibitors and siRNAs targeting OATP2B1 significantly reduced 5-ASA absorption in colonic cell lines. Moreover, OATP2B1 expression was dramatically downregulated in colon tissues from UC patients and dextran sodium sulfate (DSS)-induced colitis mice, and was also negatively correlated with colonic inflammation. Mechanistically, mixed proinflammatory cytokines downregulated the expression of OATP2B1 in a time- and concentration-dependent manner through the hepatocyte nuclear factor 4 α (HNF4α) pathway. In conclusion, OATP2B1 was the pivotal transporter involved in colonic 5-ASA uptake, which indicated that inducing OATP2B1 expression may be a strategy to promote 5-ASA uptake and further improve the concentration and anti-inflammatory efficacy of 5-ASA in UC.

A case report of gastrointestinal stromal tumor of the duodenum.

INTRODUCTION: Gastrointestinal stromal tumors (GISTs) rarely occur in the duodenum, and only a few cases have been reported. Its clinical manifestations are not specific, and the imaging examination results are not typical, so a preoperative diagnosis is difficult. Pathologic examinations and genetic testing after surgical resection are the main diagnostic methods. Here, a case of duodenal stromal tumor complicated by gastrointestinal perforation is reported. A 57-year-old man presented with paroxysmal abdominal pain and bloating for 7 days. Contrast-enhanced computed tomography of the abdomen revealed a large mass (10 cm in diameter) in the right upper abdomen, which was considered neoplastic. The mass was anterior and inferior to the head of the pancreas, and medial to the mesenteric vessels. The tumor surrounded the descending and horizontal parts of the duodenum, and it ruptured into the lumen of the descending duodenum. After the patient underwent tumor resection, we found a rupture of the descending duodenal opening. After that, duodenal fistula drainage, gastrostomy, jejunostomy, small intestinal adhesion release and abdominal irrigation drainage were performed. Immunohistochemical staining results were as follows: CD34 (-), desmin (-), S-100 (-), CD117 (9.7) (+), DoG-1 (+), SDHB (+), Ki-67 (+5%). Based on these results, the lesion was finally diagnosed as duodenal GIST. The patient underwent surgical resection without targeted therapy and recovered well. DISCUSSION: Duodenal stromal tumors often present with gastrointestinal bleeding and other clinical symptoms, requiring urgent surgery. Complete resection of the tumor is an effective surgical method. Extended resection does not prolong survival. However, surgical treatment should be determined according to the size and location of the tumor and its relationship to the pancreas. This highly malignant duodenal stromal tumor was >10 cm, accompanied by gastrointestinal perforation and necrosis. Surgical resection was required while protecting the organ function.