Sphingosine-1-phosphate promotes liver fibrosis in metabolic dysfunction-associated steatohepatitis.

AIM: Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most prevalent liver diseases and is characterized by steatosis and the accumulation of bioactive lipids. This study aims to understand the specific lipid species responsible for the progression of liver fibrosis in MASH. METHODS: Changes in bioactive lipid levels were examined in the livers of MASH mice fed a choline-deficient diet (CDD). Additionally, sphingosine kinase (SphK)1 mRNA, which generates sphingosine 1 phosphate (S1P), was examined in the livers of patients with MASH. RESULTS: CDD induced MASH and liver fibrosis were accompanied by elevated levels of S1P and increased expression of SphK1 in capillarized liver sinusoidal endothelial cells (LSECs) in mice. SphK1 mRNA also increased in the livers of patients with MASH. Treatment of primary cultured mouse hepatic stellate cells (HSCs) with S1P stimulated their activation, which was mitigated by the S1P receptor (S1PR)2 inhibitor, JTE013. The inhibition of S1PR2 or its knockout in mice suppressed liver fibrosis without reducing steatosis or hepatocellular damage. CONCLUSION: S1P level is increased in MASH livers and contributes to liver fibrosis via S1PR2.

Anti-acid treatment for ulcerated early gastric cancer may be a treatment option avoiding unnecessary gastrectomy: a cohort study.

Diagnosing the invasion depth of ulcerated early gastric cancer is usually inaccurate, especially for endoscopists in primary care clinics who are often not experts in this area. In reality, many patients with open ulcers who can be treated with endoscopic submucosal dissection (ESD) are referred for surgery. Materials and methods: Twelve patients with ulcerated early gastric cancer who were treated with proton pump inhibitors, including vonoprazan, and underwent ESD were included in the study. Conventional endoscopic and narrow-band images were evaluated by five board-certified endoscopists (two physicians: A, B, and three gastrointestinal surgeons: C, D, and E). They assessed the invasion depth, and the results were compared with the pathologic diagnosis. Results: The accuracy of the invasion depth diagnosis was 38.3%. According to the pretreatment diagnosis of invasion depth, gastrectomy was recommended for 41.7% (5/12) of the cases. However, histological examination revealed that additional gastrectomy was required in only one case (8.3%). Thus, in four out of five patients unnecessary gastrectomy could be avoided. Post-ESD mild melena occurred in only one case, and there was no case of perforation. Conclusion: Antiacid treatment contributed to avoid unnecessary gastrectomy in four out of five patients for whom gastrectomy was indicated based on an inaccurate pretreatment diagnosis of the invasion depth.

Transit analysis of thyroid antibodies in graves' disease following painless thyroiditis: a case report.

Graves' disease and painless thyroiditis induce hyperthyroidism and are manifestations of an immunological disorder; however, their clinical entities differ. This case report illustrates a possible interrelation between the pathogenesis of these two disorders. A 34-year-old woman presented with palpitations, fatigue, and shortness of breath and was initially diagnosed with painless thyroiditis, which spontaneously normalized within 2 months. Within the euthyroid state, there were atypical alterations in thyroid autoantibodies, namely, activation of the thyroid stimulating hormone receptor antibody and inactivation of thyroid peroxidase and thyroglobulin antibodies. Ten months later, her hyperthyroidism recurred, with this second incidence deemed to be related to Graves' disease. Our patient had two types of painless thyroiditis with no successive hyperthyroidism, followed by Graves' disease, with her clinical manifestation transitioning from painless thyroiditis to Graves' disease over a 20-month period. Future studies are needed to elucidate the mechanisms and relationship between painless thyroiditis and Graves' disease.

Non-traumatic False Cyst of the Spleen: A Case Report and Review of the Literature.

False cysts have no cellular lining and usually originate from past abdominal trauma. We herein report a 23-year-old woman with an asymptomatic splenic false cyst. She had no history of abdominal trauma. Abdominal computed tomography showed a cystic lesion without internal structure. In contrast, magnetic resonance imaging and ultrasonography revealed an inhomogeneous internal structure without fluid/debris level. Although the images were not typical of a splenic false cyst, the surgically excised mass histologically showed a splenic false cyst (no epithelial element). Non-traumatic splenic false cysts are rare and show nonspecific clinical findings and symptoms. The recommended treatment is splenectomy.

Malignant melanoma in the stomach treated with endoscopic submucosal dissection: a case report.

The initial appearance of malignant melanoma localized in the stomach has never been reported previously. We encountered a patient with gastric melanoma in the stomach, which was histologically confirmed to be confined to the mucosa. Case Presentation: The patient, when in her 40s, had undergone surgery for malignant melanoma of the left heel. However, there were no detailed records of pathological findings. The patient had a 4-mm black elevated lesion in her stomach observed on esophagogastroduodenoscopy after the eradication of Helicobacter pylori. A year later, esophagogastroduodenoscopy showed that the lesion had increased to 8 mm. A biopsy was performed, but no malignancy was found; the patient continued to be followed up. Esophagogastroduodenoscopy performed at the 2-year follow-up revealed that the melanotic lesion had increased to 15 mm, and biopsy was performed and revealed a malignant melanoma. Clinical Discussion: Endoscopic submucosal dissection was performed for gastric malignant melanoma. The margin of the resected malignant melanoma was negative; vascular and lymphatic invasions were not observed, and the lesion was confined to the mucosa. Conclusion: We suggest that even if the first biopsy of a melanotic lesion shows no evidence of malignancy, the lesion should be closely monitored. This is the first reported case of endoscopic submucosal dissection of localized gastric malignant melanoma confined to the mucosa.

Cases of Rapid Hepatitis B Surface Antigen Reduction after COVID-19 Vaccination.

Objective One of the therapeutic goals for chronic infection with hepatitis B virus is the clearance of hepatitis B surface antigen (HBsAg) from the blood, as a high load of HBsAg has been proposed to induce antigen-specific immunotolerance. To achieve HBsAg reduction, Pegylated interferon and nucleos (t) ide analogs are used to treat chronic hepatitis B. Following the coronavirus disease 2019 (COVID-19) outbreak, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has rapidly spread worldwide, and vaccination with mRNA COVID-19 vaccines has been conducted since 2021 in Japan. We experienced three clinical cases in which HBsAg levels rapidly decreased after injection of the COVID-19 vaccine without any incentive. Method To examine whether the vaccine administration was involved in the HBsAg reduction, the number of patients with chronic hepatitis B showing a change in the HBsAg levels during the period before the commencement of the COVID-19 vaccination program in Japan (i.e. until the end of 2020; pre-vaccination-program period) was compared to the number of those who showed a change in HBsAg levels after the initiation of the program (i.e. 2021 onwards; post-vaccination-program period). Results The number of patients whose HBsAg levels was reduced by >50% per year was prominent after the initiation of the vaccination program. Although the involvement of vaccination in HBsAg reduction was not statistically proven (p=0.0532), the result suggests that the administration of COVID-19 vaccines may have been involved in HBsAg reduction in patients with chronic hepatitis B. Conclusion COVID-19 vaccines may be involved in HBsAg reduction.

Gel immersion endoscopic mucosal resection in early gastric cancer with bleeding: A case report.

Gel immersion endoscopy was developed by Yano for the treatment of bleeding. In this case, we performed gel immersion endoscopic mucosal resection to treat a bleeding gastric cancer. An 80-year-old man, with chronic renal failure and on aspirin treatment for ischemic heart disease, underwent endoscopic treatment for multiple early gastric cancers on the anterior and posterior walls of the pyloric ring. An endoscopic submucosal dissection was performed for gastric cancer on the anterior wall; however, the removal of the cancer on the posterior wall was complicated by tumor prolapse and bleeding. Gel formulation (VISCOCLEAR® Otsuka Pharmaceutical Factory, Inc., Tokushima, Japan) was used to immerse the bleeding tumor and subsequently facilitate the endoscopic mucosal resection. Various factors, such as the use of antithrombotic medication and underlying renal disease, can increase the risk of bleeding during endoscopic gastric cancer resection. If bleeding persists, the resection margin becomes obscured. Gel formulations, such as VISCOCLEAR®, can be applied to control bleeding and improve visibility. In this case, gel immersion was useful for endoscopic mucosal resection of the bleeding tumor. The use of gel immersion endoscopic resection should be considered for the treatment of early gastric cancer, however further cases should be evaluated.

Iron chelator deferasirox inhibits NF-κB activity in hepatoma cells and changes sorafenib-induced programmed cell deaths.

OBJECTIVE: The improvements of antitumor effects and tolerability on chemotherapy for advanced hepatocellular carcinoma (HCC) are warranted. Here, we aimed to elucidate the mechanism of the combining effect of tyrosine kinase inhibitor sorafenib (SOR) and iron chelator deferasirox (DFX) in human hepatoma cell lines, HepG2 and Huh-7. METHODS: The types of programmed cell deaths (PCDs); necrosis/necroptosis and apoptosis, were evaluated by flow cytometry and fluorescent microscopy. Human cleaved caspase-3 was analyzed by ELISA for apoptosis. GSH assay was used for ferroptosis. PCDs inhibition was analyzed by adding apoptosis inhibitor Z-VAD-FMK, ferroptosis inhibitor ferrostatin-1, necroptosis inhibitor necrosulfonamide, respectively. The expression of NF-κB was quantified by Western blotting. RESULTS: In SOR monotherapy, cleaved caspase-3 expression was increased in all concentrations, confirming the result that SOR induces apoptosis. In SOR monotherapy, GSH/GSSG ratio was decreased on concentration-dependent, showing that SOR also induced ferroptosis. Lipid Peroxidation caused by SOR, corresponding to ferroptosis, was suppressed by DFX. In fluorescence microscopy of SOR monotherapy, apoptosis was observed at a constant rate on all concentrations, while necroptosis and ferroptosis were increased on high concentration. In sorafenib and deferasirox combinations, sub G1 phase increased additively. In SOR and DFX combinations, the cytotoxic effects were not suppressed by ferrostatin-1, but suppressed by Z-VAD-FMK and necrosulfonamide. In each monotherapy, and SOR + DFX combinations, the expression of NF-κB in nucleus was suppressed. Regarding PCD by SOR and DFX combination, ferroptosis was suppressed and both apoptosis and necroptosis became dominant. CONCLUSION: Suppression of NF-κB is possibly involved in the effect of DFX. As a result, SOR and DFX combination showed additive antitumor effects for HCC through the mechanism of programed cell deaths and NF-kB signal modification.

Localizing spontaneously hemostatic colonic diverticular bleeding using VISCOCLEAR gel: A case report.

Colonic diverticular bleeding is the most common type of gastrointestinal bleeding. We report a case of an 82-year-old man with a chief complaint of melena. Enhanced computed tomography showed multiple diverticula, and water-assisted colonoscopy could not help identify the diverticulum responsible for bleeding. We injected VISCOCLEAR, a novel gel formulation, into the digestive tract endoscopically and successfully localized the bleeding point. Moreover, the use of VISCOCLEAR secured a clear visual field with reduced glare, as seen in the digital endoscopic image. Subsequently, we performed hemostatic clipping. The course after the endoscopic treatment was unremarkable. In this case, we could identify the exposed bleeding vessels in the diverticulum using VISCOCLEAR and perform hemostatic clipping. We intend to evaluate the effectiveness of VISCOCLEAR further by analyzing a series of cases.

Eosinophilic esophagitis induced by sublingual immunotherapy with cedar pollen: a case report.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease associated with eosinophilic infiltration of the esophageal mucosa mostly due to exposure to allergens. However, the causes and pathogenesis of EoE are not fully understood. We encountered a case of EoE that was triggered by sublingual immunotherapy (SLIT) for cedar pollen allergy. A 40-year-old man who was treated with Japanese cedar pollen tablet SLIT for cedar pollen allergy developed heartburn 3 weeks after the initiation of the treatment. He took vonoprazan for the heartburn, but the heartburn did not improve. Then, esophagogastroduodenoscopy was performed; it revealed longitudinal furrows and white spots on the esophageal mucosa, decreased vascular permeability, and erosions. Consequently, the patient was diagnosed with EoE. Heartburn and chest discomfort disappeared 1 week after the discontinuation of Japanese cedar pollen tablet SLIT, and the patient tested positive for drug allergy to Japanese cedar pollen tablet SLIT. In this study, we found that if heartburn persists during SLIT for cedar pollen allergy, and does not improve on administration of vonoprazan or proton pump inhibitors, EoE should be suspected. In addition, the occurrence of EoE due to drug allergy is indicated.

Cronkhite-Canada Syndrome Successfully Treated by Corticosteroids before Presenting Typical Ectodermal Symptoms.

Cronkhite-Canada syndrome (CCS) is a rare disease characterized by diffuse gastrointestinal polyposis with chronic diarrhea and ectodermal change, but its etiology is unknown. We present a case at the age of 26 years complaining of epigastralgia and weight loss. Endoscopic examination revealed extensive diffuse polypoid lesions of the stomach and the terminal ileum, all of which showed hyperplastic polyps pathologically. There were no polypoid lesions in his colon. He has no family history of diffuse gastrointestinal polyposis. Diffuse gastrointestinal hyperplastic polyposis without any hereditary association led us to suspect this case as CCS although he did not show chronic diarrhea and any ectodermal symptoms such as onychodystrophy, alopecia, and hyperpigmentation. After initiation of a corticosteroid therapy, his epigastralgia disappeared and he gained appetite and weight, accompanied by normalization of serum albumin levels. Endoscopic examination 1 year after initiation of corticosteroid therapy revealed a decrease in the number of gastric polyposis and those inflammations. This rare young case may suggest that early therapeutic intervention with corticosteroids could improve the prognosis of CCS, preventing not only malnutrition but also appearance of several ectodermal symptoms.

Effects of vonoprazan on gastric PH and clinical course after gastric ESD: A retrospective and prospective study.

BACKGROUND: Vonoprazan has been more widely used for artificial ulcers after endoscopic submucosal dissection (ESD) for early gastric cancer; however, no reports have examined intragastric pH during ESD. The present study aimed to measure gastric pH at the time of ESD and the clinical course afterwards for patients treated with vonoprazan the night before undergoing ESD. MATERIALS AND METHODS: We examined medication status regarding gastric acid secretion and antithrombotic drugs, post-ESD bleeding as a perioperative complication, and the timing of upper gastrointestinal endoscopy after ESD and ulcer healing in 156 patients who underwent gastric ESD at our hospital from January 2014 to December 2019. The gastric pH was measured at the time of ESD after administration of 20 mg vonoprazan on the night before gastric ESD. RESULTS: There were 14 cases of post-ESD bleeding in patients treated with proton-pump inhibitors (PPIs), including oozing during second-look endoscopy compared to only 1 case of bleeding with vonoprazan administration (p < 0.05). Vonoprazan was also associated with better post-ESD ulcer healing than PPIs. Gastric pH during ESD after vonoprazan administration on the night before gastric ESD was ≥6.96 in all 11 patients. CONCLUSION: Post-ESD bleeding was reduced, and ulcer healing was improved in patients treated with vonoprazan the night before their procedure. Our results suggest high gastric pH during ESD due to vonoprazan administration may be beneficial for hemostasis and ulcer healing following ESD.

Effectiveness and safety of tumor site marking with near-infrared fluorescent clips in colorectal laparoscopic surgery: A case series study.

BACKGROUND: In colorectal laparoscopic surgery, accuracy of tumor marking has been an important but not fully resolved issue. The tattoo marking technique or intraoperative endoscopy have been used but they either carry the risk of accidental intestinal puncture or require either longer operation times, a skilled endoscopist and/or intraoperative colon insufflation. We supposed that tumor site marking with the near-infrared fluorescent clips, ZEOCLIP FS clips (Zeon Medical Co., Ltd., Tokyo, Japan) might overcome disadvantages of both tattoo marking and intraoperative endoscopy-based tumor localization methods. This is the first report on the case series using near-infrared fluorescent marking clip. We summarize the early results in 30 patients, who underwent colorectal laparoscopic surgery; we focus particularly on effectiveness and safety of the method. MATERIALS AND METHODS: Thirty consecutive patients, who underwent laparoscopic surgery for colorectal cancer after previous endoscopic ZEOCLIP FS placement were enrolled from May 2019 till October 2019. The primary endpoint was the rate of intraoperative clip detection and the secondary endpoints were: the rate of adverse effects, percentage of slipped clips and usefulness of plain abdominal radiography to preoperatively confirm the clip retention. Locations of fluorescent clips were identified with a full-color fluorescence laparoscope. All operations and clip placements were performed by the same senior surgeon with sufficient experience in both procedures. RESULTS: Fluorescent clips could be detected in 94.1% of tumor lesions. Three (2.1%) clips dropped before surgery. Plain abdominal radiography was sufficient to assess clip retention in all cases. No adverse effects related to either clip placement or clip detection were observed. CONCLUSION: The ZEOCLIP FS could be easily detected from the serosal side of the intestinal tract when placed 1-2 days before surgery. Fluorescent clip-guided laparoscopy may be considered a safe and effective method for localization of colorectal tumor sites. The Research Registry UIN: researchregistry5400.

A novel fluorescent marking clip for laparoscopic surgery of colorectal cancer: A case report.

INTRODUCTION: In laparoscopic surgery, marking of tumor location has been gaining importance. Tattoo marking has been often used but the technique carries the risk of accidental peritoneal scattering or other organ injury. We have been involved in the development of a novel fluorescent clip for marking tumor sites and supposed that its usage would reduce risks related to other marking methods. CASE PRESENTATION: A 52-year-old man was diagnosed with sigmoid colon cancer and polyp, and was scheduled for laparoscopic sigmoidectomy. On the day before operation, fluorescent clips (ZEOCLIP FS: Zeon Medical co, Ltd, Tokyo) were endoscopically placed around the tumor and polyp sites, 4 clips for each lesion attached every 90 degrees within the colonic lumen, respectively. During the operation, locations of the fluorescent clips were easily confirmed using a full-color fluorescent laparoscope, VISION SENSE (Medtronic Co., U.S.). Curative operation was performed accordingly with the preoperative pathological and radiological findings. The postoperative course was uneventful. DISCUSSION: Locations of intraluminally placed fluorescent clips were clearly and easily recognized through the serosal layer of the intestinal wall using a fluorescent laparoscope. Complications related to dye scattering or intestinal wall/other organ perforation were not observed suggesting that future incorporation of this tumor site marking technique into laparoscopic surgery might be beneficial. CONCLUSION: The fluorescent marking clips were easily placed and recognized with a fluorescent laparoscope. This method is expected to be safe and risks of accidental puncture related to tattoo marking method can be reduced or almost eliminated.

Inactivation of cysteine and serine proteases by singlet oxygen.

The reaction of singlet oxygen with individual proteins is less well understood than that with other biological molecules. The inhibition of caspase 3 by singlet oxygen appears to involve the modification of a catalytic cysteine residue, since the reactivity of the sulfhydryl with alkylating agents decreased after singlet oxygen treatment. In addition to three cysteine proteases, two serine proteases were also found to be inhibited by singlet oxygen with a similar dose dependency, while an aspartate protease and a metalloprotease were not affected. The carbonyl content of these enzymes was elevated as the result of treatment with singlet oxygen. The catalytic center in serine proteases and cysteine proteases, in which catalytic reactions are based on similar mechanisms involving nucleophilic catalysis assisted by histidine as a general acid/base, can be expected to be modified by singlet oxygen and undergo inactivation.

Suppression of the pro-apoptotic function of cytochrome c by singlet oxygen via a haem redox state-independent mechanism.

Stimuli for apoptotic signalling typically induce release of cyt c (cytochrome c) from mitochondria. Cyt c then initiates the formation of the apoptosome, comprising Apaf-1 (apoptotic protease-activating factor 1), caspase-9 and other cofactors. The issue of whether the redox state of the haem in cyt c affects the initiation of the apoptotic pathway is currently a subject of debate. In a cell-free reconstitution system, we found that only oxidized cyt c was capable of activating the caspase cascade. Oxidized cyt c was reduced by the physiological reductants cysteine and glutathione, after which it was unable to activate the caspase cascade. It is thus likely that cyt c with oxidized haem is in a conformation capable of interaction with Apaf-1 and forming apoptosomes. When either oxidized or reduced cyt c was treated with submillimolar concentrations of endoperoxide, which affected less than 3% of the redox state of haem, the ability of the oxidized cyt c to activate the caspase cascade was abolished. Higher amounts of singlet oxygen were required to affect the optical spectral change of haem, suggesting that the suppressed pro-apoptotic function of oxidized cyt c is a mechanism that is separate from the redox state of haem. Oxidative protein modification of cyt c by singlet oxygen was evident, on the basis of elevated contents of carbonyl compounds. Our data suggest that singlet oxygen eliminates the pro-apoptotic ability of oxidized cyt c not via the reduction of haem, but via the modification of amino acid residues that are required for apoptosome formation.