Comparison between hangeshashinto and dexamethasone for IL-1α and ß-defensin 1 production by human oral keratinocytes.

OBJECTIVE: Human ß-defensin 1 (hBD-1) is a antimicrobial peptide that is constantly secreted by oral tissues. Hangeshashinto (HST), a traditional Japanese medicine, has been reported to be effective against stomatitis. This study aimed to clarify the profile of HST by comparing the system of production of interleukin-1α (IL-1α) and hBD-1 in human oral mucosal epithelial cells with dexamethasone (DEX), a steroid used for the treatment of stomatitis. METHODS: Human oral keratinocytes (HOK) were treated with HST, DEX, or HST components (baicalein, baicalin, berberine, and glycyrrhizin) for 24 h, and subsequently cultured for 24 h with or without Pam3CSK4 or lipopolysaccharide (LPS). The cell supernatants, total RNA, and intracellular proteins were collected, and changes in IL-1α and hBD-1 protein production and gene expression were evaluated using ELISA and RT-PCR. The phosphorylation of NF-kB and the cell proliferative ability of HOK were evaluated by western blotting and XTT assay, respectively. RESULTS: DEX (0.01-10 µM) significantly suppressed IL-1α and hBD-1 production induced by either Pam3CSK4 or LPS, and also decreased cell growth. In contrast, HST inhibited Pam3CSK4- and LPS-induced IL-1α production at a concentration range of 12.5-100 µg/mL without affecting the cell proliferative capacity and hBD-1 production of HOK. Baicalein and baicalin, which are flavonoid ingredients of HST, showed anti-IL-1α production. CONCLUSION: HST may be useful as a therapeutic agent for stomatitis and other inflammatory diseases of the oral cavity.

Histological differentiation between sporadic and colitis-associated intestinal cancer in a nationwide study: A propensity-score-matched analysis.

BACKGROUND AND AIM: Colitis-associated intestinal cancer (CAC) can develop in patients with inflammatory bowel disease; however, the malignant grade of CAC may differ from that of sporadic colorectal cancer (CRC). Therefore, we compared histological findings distinct from cancer stage between CAC and sporadic CRC to evaluate the features of CAC. METHODS: We reviewed the clinical and histological data collected from a nationwide database in Japan between 1983 and 2020. Patient characteristics were compared to distinguish ulcerative colitis (UC), Crohn's disease (CD), and sporadic CRC. Comparisons were performed by using all collected data and propensity score-matched data. RESULTS: A total of 1077 patients with UC-CAC, 297 with CD-CAC, and 136 927 with sporadic CRC were included. Although the prevalence of well or moderately differentiated adenocarcinoma (Tub1 and Tub2) decreased according to tumor progression for all diseases (P < 0.01), the prevalence of other histological findings, including signet ring cell carcinoma, mucinous carcinoma, poorly differentiated adenocarcinoma, or squamous cell carcinoma, was significantly higher in CAC than in sporadic CRC. Based on propensity score-matched data for 982 patients with UC and 268 with CD, the prevalence of histological findings other than Tub1 and Tub2 was also significantly higher in those with CAC. At pT4, mucinous carcinoma occurred at a significantly higher rate in patients with CD (45/86 [52.3%]) than in those with sporadic CRC (13/88 [14.8%]) (P < 0.01). CONCLUSION: CAC, including early-stage CAC, has a higher malignant grade than sporadic CRC, and this difference increases in significance with tumor progression.

Intestinal hypomotility due to longitudinal enterotomy can be alleviated by transverse closure.

BACKGROUND: Heineke-Mikulicz (HM) strictureplasty is commonly used to treat short stenoses in Crohn's disease. However, the degree to which intestinal motility is maintained remains unclear. We compared the peristalsis and transport capacity of the sutured intestines with HM configuration and transverse (TS) and longitudinal (LS) incisions. METHODS: The intestinal diameter, intraluminal pressure, and bead transit time of each sutured group were compared with that of the non-treatment (NT) group in the isolated proximal colon of rats. Propulsive contractions were induced using hydroxy-?-sanshool (HAS), a constituent of Japanese pepper. RESULTS: There was no change in the intestinal diameter between HM, TS, and NT groups ; however, it was significantly narrowed at the suture site and its distal side in the LS group. After HAS administration, the intestinal diameter at the suture site in the HM group was higher than that in the LS group. The intraluminal pressure was higher and the transit time was shorter in the HM group compared to those in the LS group. CONCLUSIONS: The HM configuration, which widens the incision site and distal diameter and shortens the cut surface of the circular muscle in the longitudinal direction, may help maintain basal and HAS-induced intestinal peristalsis and motility. J. Med. Invest. 70 : 180-188, February, 2023.

Crohn's Disease-Associated Anorectal Cancer Has a Poor Prognosis With High Local Recurrence: A Subanalysis of the Nationwide Japanese Study.

INTRODUCTION: Colorectal cancer (CRC) is one of the major life-threatening complications in patients with Crohn's disease (CD). Previous studies of CD-associated CRC (CD-CRC) have involved only small numbers of patients, and no large series have been reported from Asia. The aim of this study was to clarify the prognosis and clinicopathological features of CD-CRC compared with sporadic CRC. METHODS: A large nationwide database was used to identify patients with CD-CRC (n = 233) and sporadic CRC (n = 129,783) over a 40-year period, from 1980 to 2020. Five-year overall survival (OS), recurrence-free survival (RFS), and clinicopathological characteristics were investigated. The prognosis of CD-CRC was further evaluated in groups divided by colon cancer and anorectal cancer (RC). Multivariable Cox regression analysis was used to adjust for confounding by unbalanced covariables. RESULTS: Compared with sporadic cases, patients with CD-CRC were younger; more often had RC, multiple lesions, and mucinous adenocarcinoma; and had lower R0 resection rates. Five-year OS was worse for CD-CRC than for sporadic CRC (53.99% vs 71.17%, P < 0.001). Multivariable Cox regression analysis revealed that CD was associated with significantly poorer survival (hazard ratio 2.36, 95% confidence interval: 1.54-3.62, P < 0.0001). Evaluation by tumor location showed significantly worse 5-year OS and RFS of CD-RC compared with sporadic RC. Recurrence was identified in 39.57% of CD-RC cases and was mostly local. DISCUSSION: Poor prognosis of CD-CRC is attributable primarily to RC and high local recurrence. Local control is indispensable to improving prognosis.

Integrated analysis of effect of daisaikoto, a traditional Japanese medicine, on the metabolome and gut microbiome in a mouse model of nonalcoholic fatty liver disease.

Dysregulation of lipid metabolism and diabetes are risk factors for nonalcoholic fatty liver disease (NAFLD), and the gut-liver axis and intestinal microbiome are known to be highly associated with the pathogenesis of this disease. In Japan, the traditional medicine daisaikoto (DST) is prescribed for individuals affected by hepatic dysfunction. Herein, we evaluated the therapeutic potential of DST for treating NAFLD through modification of the liver and stool metabolome and microbiome by using STAM mice as a model of NAFLD. STAM mice were fed a high-fat diet with or without 3 % DST for 3 weeks. Plasma and liver of STAM, STAM with DST, and C57BL/6J ("Normal") mice were collected at 9 weeks, and stools at 4, 6, and 9 weeks of age. The liver pathology, metabolome and stool microbiome were analyzed. DST ameliorated the NAFLD activity score of STAM mice and decreased the levels of several liver lipid mediators such as arachidonic acid and its derivatives. In normal mice, nine kinds of family accounted for 94.1 % of microbiome composition; the total percentage of these family was significantly decreased in STAM mice (45.6 %), and DST administration improved this imbalance in microbiome composition (65.2 %). In stool samples, DST increased ursodeoxycholic acid content and altered several amino acids, which were correlated with changes in the gut microbiome and liver metabolites. In summary, DST ameliorates NAFLD by decreasing arachidonic acid metabolism in the liver; this amelioration seems to be associated with crosstalk among components of the liver, intestinal environment, and microbiome.

Distinct effects of TU-100 (daikenchuto) on long-lasting dysbiosis in the small intestine in patients with colorectal cancer and inflammatory bowel disease.

The profile of the human small intestinal microbiota remains to be uncovered primarily due to sampling difficulties. Ileostomy provides the intestinal luminal contents as ileostomy effluents (IE) that offer opportunity for performing extensive analyses of nutrients, gastrointestinal fluids, metabolites, and microbiome. In the present study, we evaluated changes in the microbiome, pH, and bacterial short-chain fatty acids (SCFAs) in IE obtained from patients who had undergone ileostomy following surgical resection of colon cancer and inflammatory bowel disease (IBD). We enrolled 11 patients who varied in the duration of ileostomy from 3 days to >5 years after surgery and had no inflammation in the small intestine. The analyses suggested that IE from patients previously having IBD had less diversity and greater intraday and interday fluctuations, and increased pH and decreased levels of propionic acid and acetic acid than those in IE from patients previously having cancer. Furthermore, correlation analysis suggested a possible effect of the intestinal microbiome on luminal pH, presumably via SCFA production. The present study suggested that inflammation in the colon may induce long-term dysbiosis in the small intestine even after removal of diseased parts of the colon. Moreover, pharmaceutical-grade Japanese traditional medicine daikenchuto (TU-100) was found to have beneficial effects on postoperative bowel dysfunction and the human small intestinal microbiota. Taken together, these results suggest the necessity of a direct remedy for dysbiosis and the treatment of gastrointestinal lesions to achieve favorable outcomes for chronic gastrointestinal disorders.

Surgical Techniques and Risk of Postoperative Recurrence in CD: A Game Changer?

BACKGROUND: Since its first description, the role of surgery in Crohn's disease (CD) has always been controversial; in fact, it has been mainly considered as a gastroenterological disease for long time. Nevertheless, despite great advances in medical therapy, up to 70-80% of patients with CD will require surgery in their lifetime and up to 30% of them will undergo repeated surgeries due to recurrences. For these reasons, the idea of surgery as a tool in the therapeutic armamentarium to consider even in the early stage of the disease has progressively spread in the last decades, even corroborated by reports showing how primary surgery is able to definitively treat around half of the patients at long-term follow-up. More surgeons are nowadays more and more involved in developing techniques to reduce recurrences that have always been considered as part of the natural history of the disease so far. SUMMARY: In this review, we will go through the role of surgery in the management of CD, showing the potential benefits of an early surgical approach as well as the impact of surgical research in the natural history of the disease. From this standpoint, we will show the role of different anastomotic configurations, emphasizing how more and more data are definitively establishing the impact of the novel Kono-S anastomosis in reducing endoscopic and surgical recurrence. Mesentery-based surgery is a novel and appealing surgical perspective, but more data are required. KEY MESSAGES: Surgery has demonstrated to be a crucial tool in the therapeutic armamentarium for the management of CD. Early surgery and novel surgical techniques, such as the Kono-S anastomosis, may have an impact on the natural history of the disease, including the possibility to prevent recurrences.

Effects of Goshajinkigan (TJ-107) for oxaliplatin-induced peripheral neurotoxicity using the functional assessment of cancer therapy/gynecologic oncology group 12-item neurotoxicity questionnaire in a Phase II, multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: The aim of the present study was to evaluate the efficacy of TJ-107 for oxaliplatin-induced peripheral neurotoxicity in prospective, multi-institutional, randomized, double-blind, placebo-controlled Phase II trials using the functional assessment of cancer therapy/gynecologic oncology group 12-item neurotoxicity questionnaire (FACT-GOG-NTX-12). PATIENTS AND METHODS: The patients who were registered to the Goshajinkigan oxaliplatin neurotoxicity evaluation study (UMIN000002211) were analyzed. A NTX-12 from the validated FACT/GOG-NTX-12 was assessed before treatment and at the end of every 2 cycles. RESULTS: The comparisons of the median scores for TJ-107 and the placebo at 8 and 26 weeks were as follows: numbness or tingling in the hands (P = 0.5820), numbness or tingling in the feet (P = 0.3236), feeling of discomfort in the hands (P = 0.8219), feeling of discomfort in the feet (P = 0.5361), joint pain or muscle cramps (P = 0.1974), feeling weak all over (P = 0.2771), trouble hearing (P = 0.2832), ringing or buzzing in ears (P = 0.1031), trouble buttoning buttons (P = 0.1653), trouble feeling the shape of small objects when held in hand (P = 0.2919), trouble walking (P = 0.5406), and pain in the hands or feet when exposed to cold temperatures (P = 0.1872). CONCLUSION: There might be no clinically significant difference between the use of TJ-107 and the severity and quality of life for patients treated with oxaliplatin.

High Ligation of the Inferior Mesenteric Artery Induces Hypoperfusion of the Sigmoid Colon Stump During Anterior Resection.

Background: Anastomotic leakage (AL) after colorectal surgery is associated with insufficient vascular perfusion of the anastomotic ends. This study aimed to evaluate the effect of high vs. low ligation of the ileocolic artery and inferior mesenteric artery, respectively, on the vascular perfusion of the bowel stumps during ileocecal resection (ICR) and anterior rectal resection (AR). Methods: We retrospectively evaluated patients who underwent ICR or AR between 2016 and 2020. Real-time indocyanine green fluorescence angiography was performed to measure the fluorescence time (FT) as a marker of the blood flow in the proximal and distal stumps before anastomosis. Results: Thirty-four patients with lower right-sided colon cancer underwent laparoscopic ICR. Forty-one patients with rectosigmoid colon or rectal cancer underwent robotic high AR (HAR) (n = 8), robotic low AR (LAR) (n = 6), laparoscopic HAR (n = 8), or laparoscopic LAR (n = 19). The FT was similar in the ileal and ascending colon stumps (p = 1.000) and did not differ significantly between high vs. low ligation of the ileocolic artery (p = 0.934). The FT was similar in the sigmoid colon and rectal stumps (p = 0.642), but high inferior mesenteric artery ligation significantly prolonged FT in the sigmoid colon during AR compared with low ligation (p = 0.004), indicating that the high ligation approach caused significant hypoperfusion compared with low ligation. The AL rate was similar after low vs. high ligation. Conclusions: Low vascular perfusion of the bowel stumps may not be an absolute risk factor for AL. High inferior mesenteric artery ligation could induce sigmoid colon stump hypoperfusion during anterior rectal resection.

Bowel obstruction and perforation secondary to barbed suture after minimally invasive inguinal hernia repair: report of two cases and literature review.

BACKGROUND: Laparoscopic transabdominal preperitoneal patch (TAPP) is now commonly used in the repair of inguinal hernia. Barbed suture can be a fast and effective method of peritoneal closure. We report two rare cases of small bowel obstruction and perforation caused by barbed suture after TAPP. CASES: Patient 1 is a 45-year-old man who underwent laparoscopic repair of a right inguinal hernia. Barbed suture was used to close the peritoneal defect. At 47 days after the operation, he was diagnosed with a small bowel obstruction caused by an elongated tail of the barbed suture. Emergency laparoscopic exploration was performed for removal of the embedded suture and detorsion of the volvulus. The second patient is a 50-year-old man who was admitted with a small bowel perforation one week after TAPP herniorrhaphy. Emergency exploration revealed that the tail of the barbed suture had pierced the small intestine, causing a tiny perforation. After cutting and releasing the redundant tail of the barbed suture, the serosal and muscular defect was closed with 2 absorbable single-knot sutures. Both patients have recovered well. Finally, we searched the PubMed database and reviewed the literature on the effectiveness and safety of barbed suture for TAPP. CONCLUSIONS: Surgeons should understand the characteristics of barbed suture and master the technique of peritoneum closure during TAPP in order to reduce the risk of bowel obstruction and perforation.

Intestinal hypoperfusion in patients with Crohn's disease revealed by intraoperative indocyanine green fluorescence imaging.

BACKGROUND: Anastomotic leakage has been reported as an independent risk factor for surgical recurrence at the anastomotic site in patients with Crohn's disease. An inadequate blood supply may contribute to this leakage. Real-time indocyanine green angiography has been useful for confirming vascular perfusion of the intestines. The aim of this study was to evaluate the use of intraoperative indocyanine green angiography to detect vascular perfusion of the intestines during ileocaecal resection in patients with Crohn's disease and colon cancer. MATERIALS AND METHODS: We retrospectively evaluated the medical records of 26 consecutive patients with colon cancer arising in the caecum or ascending colon and 3 consecutive patients with Crohn's disease without a history of disease-related surgery. The patients in the 2 cohorts had undergone ileocaecal resection at Tokushima University Hospital between January 2018 and January 2021. After ileocaecal resection, blood flow was evaluated in ileal (oral) and colon (anal) stapled stumps by indocyanine green fluorescence angiography. The fluorescence time was defined as the time from indocyanine green injection and flush of the injection route to the point when the stump showed the strongest fluorescent signal in the monitor. RESULTS: The fluorescence time for the ileal and colon stumps in patients with Crohn's disease was 43.3 ± 8.8 s each and was significantly longer than the fluorescence time in the patients with colon cancer (29.4 ± 6.5 s and 29.6 ± 6.8 s, respectively) (P < 0.05). CONCLUSION: Intraoperative indocyanine green fluorescence imaging is safe and reproducible for assessing intestinal perfusion prior to anastomosis in patients with colon cancer and Crohn's disease.

Laparoscopic surgical treatment for hydrocele of canal of Nuck: A case report and literature review.

BACKGROUND: Hydrocele of canal of Nuck (HCN) is a rare disease in adult female. The diagnosis and treatment of HCN is still a challenge for surgeons. CASE PRESENTATION: A 56-year-old female presented with recent onset of occasional pain during exercise and an asymptomatic left groin swelling. Ultrasonography results were suspicious for left inguinal hernia incarceration and computed tomography (CT) scan showed no intestinal obstruction, which was considered as HCN. Laparoscopic hydrocelectomy of the HCN and a routine laparoscopic hernia repair via the transabdominal preperitoneal (TAPP) approach were performed. Postoperative pathology showed no malignant lesions or endometriosis. CONCLUSIONS: The preoperative diagnosis of HCN is extremely important. Surgeons should choose appropriate surgical methods for different anatomical HCNs based on the preoperative diagnosis.

Laparoscopic assisted hydrocelectomy of the canal of Nuck: a case report.

BACKGROUND: Accurate diagnosis and complete resection of hydrocele of canal of Nuck (HCN) is still a challenge for surgeons. CASE PRESENTATION: A 28-year-old woman presented with a suspected inguinal hernia due to swelling in her right groin and was introduced for surgical treatment. Computed tomography scan revealed local cyst formation in the right groin and eliminated intestinal incarceration. In order to further confirm the diagnosis, we used laparoscopic exploration; after excluding a combined hernia, HCN was surgically removed using a conventional anterior peritoneal approach and a mesh patch repair was not needed. Postoperative pathology results showed no endometriosis or malignancy. CONCLUSIONS: Laparoscopic assisted anterior approach provides both an accurate intraoperative diagnosis and a quick complete resection of HCN; it is the preferred treatment for women of childbearing age with pure HCN.

A multicenter phase II trial of preoperative chemoradiotherapy with S-1 plus oxaliplatin and bevacizumab for locally advanced rectal cancer.

BACKGROUND: We clarified the safety and efficacy of preoperative chemoradiotherapy for locally advanced rectal cancer using a multidrug regimen (S-1 + oxaliplatin + bevacizumab). METHODS: This multicenter phase II trial involved 47 patients with locally advanced rectal cancer. All patients received S-1 orally (80 mg/m2/day on days 1-5, 8-12, 15-19, and 22-26) and infusions of oxaliplatin (50 mg/m2 on days 1, 8, 15, and 22) and bevacizumab (5 mg/kg on days 1 and 15). The total radiation dose was 40 Gy delivered in daily fractions of 2 Gy via the four-field technique. The primary endpoint was the pathological complete response rate. The secondary endpoints were safety (incidence of adverse events) and clinical response, relapse-free survival, overall survival, local recurrence, R0 resection, downstaging, and treatment completion rates. RESULTS: All 47 patients received chemoradiotherapy, and 44 patients underwent curative resection. Two patients refused surgery and selected a watch-and-wait strategy. The pathological complete response rate was 18.2% in patients who underwent curative resection. The clinical response rate was 91.3% in 46 patients. Concerning hematotoxicity, there was one grade 4 adverse event (2.1%) and seven grade 3 events (14.9%). Diarrhea was the most frequent non-hematotoxic event, and the grade 3 event rate was 25.5%. CONCLUSIONS: Although preoperative chemoradiotherapy for patients with locally advanced rectal cancer using the S-1 + oxaliplatin + bevacizumab regimen did not achieve the expected pathological complete response rate, this regimen led to an improved clinical response rate.

The Japanese Extracted Herbal Medicine Daikenchuto Increases the Contractile Activity of the Internal Anal Sphincter Muscle in Conscious Dogs.

OBJECTIVES: This study aimed to elucidate the effect of the extract of daikenchuto (DKT), a Japanese Kampo medicine, on the contractile activity of the internal anal sphincter in conscious dogs. METHODS: Force transducers were attached to the serosal surface of the rectum and the internal anal sphincter of male beagle dogs. In addition, the contractile activity of the rectum and the internal anal sphincter was continuously measured until 6 h after DKT administration via telemetry in the conscious state. The DKT dose was 1.5 g/body, and the administration route was intrarectal in the expectation of a direct effect on the rectoanal region. DKT was re-administered to the same animal after drug withdrawal, and the plasma concentrations of hydroxy-α-sanshool (HAS) and hydroxy-ß-sanshool (HBS) before and after administration were measured. RESULTS: After DKT administration, the contractile activity of the internal anal sphincter immediately increased, peaked at 10 min, continued for ≥1 h, and had almost disappeared after 4 h. Rectal contraction differed from that of the internal anal sphincter, with no significant contraction observed. HAS and HBS were found in the plasma of animals administered with DKT and persisted up to 2 h after the administration. CONCLUSIONS: This is the first report on in vivo telemetry demonstrating that DKT exhibited contractile effects on the dog's internal anal sphincter. The increased anal pressure and improvement of fecal incontinence symptoms observed in previous clinical studies may have been based on this sphincter contraction.

Surgical Treatment for Crohn's Disease: A Role of Kono-S Anastomosis in the West.

More than 80% of patients with Crohn's disease (CD) will require surgical intervention during their lifetime, with high rates of anastomotic recurrence and stenosis necessitating repeat surgery. Current data show that pharmacotherapy has not significantly improved the natural history of postoperative clinical and surgical recurrence of CD. In 2003, antimesenteric hand-sewn functional end-to-end (Kono-S) anastomosis was first performed in Japan. This technique has yielded very desirable outcomes in terms of reducing the incidence of anastomotic surgical recurrence. The most recent follow-up of these patients showed that very few had developed surgical recurrence. This new approach is superior to stapled functional end-to-end anastomosis because the stumps are sutured together to create a stabilizing structure (a "supporting column"), serving as a supportive backbone of the anastomosis to help prevent distortion of the anastomotic lumen due to disease recurrence and subsequent clinical symptoms. This technique requires careful mesenteric excision for optimal preservation of the blood supply and innervation. It also results in a very wide anastomotic lumen on the antimesenteric side. The Kono-S technique has shown efficacy in preventing surgical recurrence and the potential to become the new standard of care for intestinal CD.

[A Case Report of Impaired Consciousness in a Patient after Receiving the Fourth Dose of Fentanyl Sublingual Tablet].

Oral transmucosal fentanyl has been indicated for the management of breakthrough pain in patients with cancer. Fentanyl sublingual tablets(FST)have been approved for use in Japan since 2013. However, the optimal use of FSTs has not been well-elucidated. In this case, a 73-year-old man with rectal cancer and third lumbar vertebral metastasis was treated with 100 µg FST and 12.5 µg/h fentanyl patch every day for the management of cancer-related breakthrough pain. After receiving the fourth dose of FST, the patient was unconscious for 2 days. However, his respiration was stable. This case shows that due care should be taken while administering FSTs to patients, specifically geriatric patients with bone metastasis and hypoalbuminemia.

Author Correction: The Japanese herbal medicine Hangeshashinto enhances oral keratinocyte migration to facilitate healing of chemotherapy-induced oral ulcerative mucositis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Weak acids induce PGE2 production in human oesophageal cells: novel mechanisms underlying GERD symptoms.

The role of weak acids with pH values in the range of 4-7 has been implicated in the symptoms of gastroesophageal reflux disease (GERD). Prostaglandin E2 (PGE2) is associated with heartburn symptom in GERD patients; however, the precise productive mechanisms remain unclear. In this study, we revealed that exposure to weak acids increases PGE2 production with a peak at pH 4-5, slightly in human normal oesophageal cells (Het-1A), and robustly in oesophageal squamous carcinoma cells (KYSE-270). Release of PGE2 from the oesophageal mucosa was augmented by weak acid treatment in rat. Chenodeoxycholic acid (CDCA), a bile acid, upregulated cyclooxygenase-2 (COX-2) expression in Het-1A and KYSE-270 and induced PGE2 production in KYSE-270 cells. Weak acid-induced PGE2 production was significantly inhibited by cytosolic phospholipase A2 (cPLA2), ERK, and transient receptor potential cation channel subfamily V member 4 (TRPV4), a pH-sensing ion channel, inhibitors. Hangeshashinto, a potent inhibitor of COX-2, strongly decreased weak acid- and CDCA-induced PGE2 levels in KYSE-270. These results indicated that weak acids induce PGE2 production via TRPV4/ERK/cPLA2 in oesophageal epithelial cells, suggesting a role in GERD symptoms like heartburn. Interventions targeting pH values up to 5 may be necessary for the treatment of GERD.