渡邉 俊介

Abstract Background Ulcerative colitis (UC) is a chronic inflammatory disease of unknown etiology. Although various new drugs have been developed in recent years, many of them are expensive, generating a demand for inexpensive and useful therapeutic drugs. Ogikenchuto (TJ‐98), an existing Kampo medicine, has been used to treat ulcers and similar conditions for some time. The current study therefore investigated whether TJ‐98 could be a new therapeutic agent for UC, a chronic inflammatory disease. Methods This study used 6‐week‐old female C57BL/6J mice to establish a mouse model of dextran sulfate sodium (DSS)‐induced colitis. We then evaluated the therapeutic effects of tacrolimus and TJ‐98 on colitis based on body weight, intestinal length, intestinal fibrosis, and cytokines. Sirius red staining was used to evaluate intestinal fibrosis, while interleukin‐1 beta (IL‐1β), interleukin‐6 (IL‐6), and tumor necrosis factor‐alpha (TNF‐α) were used to evaluate cytokines involved in inflammation. Results Neither tacrolimus nor TJ‐98 ameliorated weight loss. Although tacrolimus did not remediate intestinal shortening, intestinal fibrosis, or cytokine levels (IL‐1β, IL‐6, and TNF‐α), TJ‐98 did ameliorate intestinal shortening and intestinal fibrosis and decrease IL‐1β levels. Conclusions This study confirmed that TJ‐98 suppressed the inflammation caused by DSS‐induced enteritis and decreased the associated intestinal fibrosis, highlighting its potential as an inexpensive novel therapeutic agent for UC.

BACKGROUND: Focal intestinal perforation (FIP) is a devastating complication of premature birth, and extremely low birth weight (ELBW) infants are at highest risk. This study aimed to evaluate the relationship of the superior mesenteric artery (SMA) and portal vein (PV) blood flow velocities to investigate the association between intestinal blood flow and FIP. In addition, the herbal formula Daikenchuto (TJ-100) is expected to improve intestinal blood flow disorders; therefore, we evaluated its effect. METHODS: We conducted a prospective cohort study of 15 ELBW infants from January 2020 to August 2021. Measured variables included birth weight, 5-minute Apgar score, time of oral feeding initiation, ductus arteriosus (PDA) closure (percent), diastolic and systolic blood pressure, SMA and PV blood flow velocity, and FIP onset data. Fifteen infants were divided into three groups: a non-surgery group (Group I; 6), a surgery group with FIP (Group II; 4), and a TJ-100 administration group (Group III; 5). The main outcome parameters included SMA and PV blood flow velocities with TJ-100. RESULTS: SMA and PV blood flow differed significantly for the SMA of Group I and the SMA and PV of Group III (P < 0.01, P = 0.01, and P = 0.04, respectively). There was a correlation between SMA and PV in Group III (P = 0.03). CONCLUSION: TJ-100 may increase SMA and PV blood flow and improve intestinal blood flow in ELBW infants at risk of FIP. Therefore, the effects of TJ-100 should undergo further study.

BACKGROUND: We previously reported that polyphyllin D, the main component of the traditional herbal medicinal Paris polyphylla, exhibited anticancer effects in vitro against human neuroblastoma cells. The aim of this investigation was to examine in vivo antitumor effects of polyphyllin D. METHODS: Subcutaneous tumors were established in immune-deficient BALB/c nude mice using human neuroblastoma cell lines IMR-32 and LA-N-2. To evaluate the polyphyllin D activity, we used a mouse model of IMR-32 or LA-N-2 cell lines and analyzed subcutaneous tumors. RESULTS: Subcutaneous tumor models were successfully established in mice using two human neuroblastoma cell lines. In the subcutaneous tumor model, porphyrin D was found to suppress tumor volume. We found that polyphyllin D suppressed the number of foci by Ki-67 staining (IMR-32 and LA-N-2; p < 0.01, 0.02, respectively). We found that polyphyllin D induces the RIPK3 expression, while polyphyllin D phosphorylates Ser358 in IMR-32 and Ser358 and Tyr376 in LA-N-2. CONCLUSION: We developed a mouse model of subcutaneous tumors of neuroblastoma and demonstrated for the first time that polyphyllin D has an antitumor effect on neuroblastoma. Polyphyllin D can cause necroptosis depending on the cell type. The new drug can be expected by investigating a method to selectively induce cell death through the analysis of necroptosis.

PURPOSE: We previously reported that polyphyllin D, a main component of the traditional Chinese medicinal herb Paris polyphylla, exhibited anticancer effects in vitro against human neuroblastoma cells. The aims of this investigation was to examine the presence or absence of in vivo anti-metastasis effects of polyphyllin D were to establish a liver metastasis model of neuroblastoma and to evaluate the anti-metastasis effects of polyphyllin D. METHODS: Subcutaneous and intraperitoneal tumors, and metastasis models were established in immune-deficient BALB/c nude and BALB/c Rag-2/Jak3 double-deficient (BRJ) mice using the human neuroblastoma cell lines IMR-32, LA-N-2, or NB-69. For evaluating polyphyllin D activity, we used a mouse model of liver metastasis with the IMR-32 cells line injected through the tail vein. We analyzed the livers number and area of liver tumors in of the phosphate buffer solution- and polyphyllin D-treated groups. RESULTS: Liver metastasis and intraperitoneal dissemination models were successfully established in immune-deficient BRJ mice using the three human neuroblastoma cell lines. In the liver metastasis, the model of IMR-32 cells, we found that polyphyllin D suppressed both the number and total area of metastatic foci the average number of metastatic foci, average focus areas, and number of cleaved caspase-3-positive cells were significantly lower in the polyphyllin D group (p = 0.016, 0.020, 0.043, respectively). CONCLUSIONS: We developed a mouse models of neuroblastoma metastasis and demonstrated for the first time that polyphyllin D has an antitumor effect on neuroblastoma liver metastases.

BACKGROUND: Biliary atresia (BA) is a rare disorder characterized by obstructive jaundice in infants, shortly after birth. Postoperatively, some patients exhibit portal hypertension and progressive liver fibrosis. Splenomegaly is a symptom of portal hypertension. We aimed to investigate splenomegaly as a marker for complications of portal hypertension and the relationship between splenomegaly and liver fibrosis in the long-term native liver (NL). METHODS: Between 1977 and 2018, 71 patients underwent hepaticojejunostomy. We included 54 patients (34 NL group, 20 liver transplant (LT) group) who fulfilled the eligibility criteria. Spleen volume (SV), total bile acids, hyaluronic acid, type IV collagen, and aspartate aminotransferase-to-platelet ratio index (APRi) were measured. Data were analyzed using Student's t-test, regression analysis, and receiver operating characteristic (ROC) curve analysis (P < 0.05). RESULTS: Total bile acids, hyaluronic acid, type IV collagen, and APRi increased in NL patients with a large SV at >25 years. SV and type IV collagen were correlated with NL for >25 years (r = 0.79 [P = 0.006], y = 1.1 - [0.03 × type IV collagen] [P = 0.008]). In the ROC curve analysis, the cutoff value for type IV collagen was 165 ng/mL (P = 0.07). CONCLUSIONS: We suggest that SV as a prognostic index for End-Stage Liver Disease may be useful in biliary atresia. Long-term follow-up is necessary because the clinical course may be favorable in childhood but worsen during adulthood.

Abstract Case Advanced glycation end products (AGEs) associated with diabetes, renal failure, and non‐alcoholic fatty liver disease have recently been receiving attention. The present study aimed to investigate therapeutic effects of Astragali Radix (AR) using skin autofluorescence (SAF) to evaluate AGEs. Treatment group (May 2019 to May 2020) was 18 patients. AR administration period was six months. SAF, body mass index, mean blood pressure, hemoglobin A1c, serum creatinine, estimated glomerular filtration rate (eGFR), aspartate transaminase, and alanine transaminase (ALT) were used. Outcome Significant differences in SAF (P &lt;0.01) and serum creatinine (P = 0.03) were observed in the treatment group. Regression analysis showed that SAF was correlated with serum creatinine and ALT. Conclusion We suggest that AR may improve SAF, serum creatinine, and ALT. Improving AGEs through AR may ameliorate liver function, and eGFR with improvement of serum creatinine. Future studies are necessary to confirm our findings.

BACKGROUND: Disseminated intravascular coagulation (DIC) with Kasabach-Merrit syndrome from a large hepatic hemangioma is life-threatening. We report a case of giant hepatic hemangioma of the newborn with KMS. RESULTS: The patient was born at 37 gestational weeks and 2 days via cesarean section; weight at birth was 2952 g. Congenital duodenal atresia was noted during the fetal period. DIC developed after delivery and a giant liver hemangioma was diagnosed via abdominal CT. The cause of DIC was Kasabach–Merritt syndrome owing to a giant hepatic hemangioma. First, combination therapy of 2 mg/kg/day of prednisolone and 0.2 mg/kg/day of propranolol was initiated form enterostomy. However, the size of the hepatic hemangioma did not alter, as observed via image evaluation. Therefore, 0.3 mg/kg/day of everolimus was administered frorm enterostomy. Subsequently, the size of the hepatic hemangioma was assessed via image evaluation. Although it did not alter, blood flow to the hepatic hemangioma decreased and thrombocytopenia was also suppressed. We performed hepatic lateral segmentectomy, radical operation for duodenal atresia. The pathological diagnosis of the removed tumor was infantile hemangioma. CONCLUSION: We report everolimus may be useful when PSL and propranolol are ineffective.