Discovery of Novel Bicyclic Pyrazoles as Potent PIP5K1C Inhibitors.

Phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) is generated by phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) from phosphatidylinositol 4-phosphate (PI4P). Structurally diverse and selective inhibitors against PIP5Ks are required to further elucidate the therapeutic potential for PIP5K inhibition, although the effects of PIP5K inhibition on various diseases and their symptoms, such as cancer and chronic pain, have been reported. Our medicinal chemistry efforts led to novel and potent PIP5K1C inhibitors. Compounds 30 and 33 not only showed potent activity but also demonstrated low total clearance in mice and high levels of kinase selectivity. These compounds might serve as tools to further elucidate the complex biology and therapeutic potential of PIP5K inhibition.

Feasibility and Safety of Super Energy-dense Oral Nutritional Supplementation in Postoperative Gastric Cancer Patients.

BACKGROUND/AIM: Ensuring that postoperative gastric cancer patients receive sufficient oral nutritional supplementation (ONS) to prevent body weight loss (BWL) is a serious challenge. The present pilot study evaluated the feasibility and safety of small, frequent sip feeds (SIP) with super energy-dense ONS (SED ONS; 4 kcal/ml) in postoperative gastric cancer patients. PATIENTS AND METHODS: Patients received 400 kcal/day of SED ONS in four, daily, 25 ml SIP for 12 weeks after gastrectomy. The primary outcome was the percentage of postoperative weight change. The expected mean weight change was 90% (10% standard deviation). A sample population of 14 patients, sufficient for a 95% confidence interval with a 10% margin of error, was enrolled. RESULTS: The mean weight change for patients receiving SIP with SED ONS was 93.8%. The mean SED ONS intake was 348 kcal/day. Thirteen patients consumed more than 200 kcal/day of SED ONS. One patient with a mean intake of 114 kcal/day had undergone total gastrectomy followed by adjuvant chemotherapy. CONCLUSION: Small, frequent SIP with SED ONS was found to be feasible and safe in postoperative gastric cancer patients. A multicenter randomized controlled trial is warranted to determine whether SIP with SED ONS is effective in preventing BWL.

Laparoscopically assisted percutaneous endoscopic gastrostomy performed for remnant stomach in patient with amyotrophic lateral sclerosis: a case report.

BACKGROUND: Although percutaneous endoscopic gastrostomy (PEG) offers better access to the gastrointestinal system, in patients with previous abdominal surgery, PEG can be unsuccessful. Laparoscopically assisted percutaneous endoscopic gastrostomy (LAPEG) is indicated for such patients. However, patients with amyotrophic lateral sclerosis (ALS) may be more susceptible to anesthesia-related complications than other patients, requiring the indications for LAPEG, along with perioperative management, to be considered carefully. CASE PRESENTATION: A 70-year-old, male patient with ALS was referred to our hospital for a gastrostomy for progressive dysphagia. He had undergone an open distal gastrectomy for gastric ulcer perforation in his twenties. Upper gastrointestinal endoscopy denied the transillumination sign and focal finger invagination. Because the risk of respiratory complications caused by general anesthesia was not considered serious, the decision was made to perform a LAPEG. Under careful, intraoperative airway management and neuromuscular monitoring, adhesiolysis was performed to increase mobility of the remnant stomach. A gastrostomy tube was inserted through the abdominal wall and into the remnant stomach under laparoscopic and endoscopic guidance. The patient was discharged in stable condition on postoperative day 3 without any respiratory complications. CONCLUSIONS: LAPEG was able to be performed in a patient with ALS with a previous gastrectomy. A perioperative team comprised of neurologists, endoscopists, surgeons, anesthesiologists, and nurses who are fully conversant with ALS must be assembled to deal with potentially complex medical issues related to the procedure and anesthetic and perioperative management.

Surgery for acute abdomen in adult patients with severe motor and intellectual disabilities.

Purpose: The present study aimed to examine the characteristics, outcomes, and problems related to surgery for acute abdomen in adult patients with severe motor and intellectual disabilities (MID). Methods: The clinical records of 35 adult patients with severe MID who received emergency surgery for acute abdomen between 2011 and 2020 were reviewed. Results: The median duration from onset to surgery was 48 hours. There were 2 cases of in-hospital mortality (5.7%), and all the patients underwent surgery more than 72 hours after onset. The in-hospital mortality rate was significantly higher in patients who received surgery later than 72 hours after onset. Bowel obstruction was the most common disease among the acute abdomen cases (71.4%) and most often involved volvulus of the small bowel and cecum. Of the patients with bowel obstruction with severe MID, 72.0% had abdominal distention, 16.0% had abdominal pain, and 4.0% had vomiting. The median duration from onset to surgery was significantly longer in the patients with bowel obstruction with severe MID than in those without severe MID (24 hours vs. 16 hours). Conclusion: Acute abdomen in patients with severe MID was often due to bowel obstruction caused by volvulus. Because patients with severe MID have few symptoms, they are susceptible to adverse surgical outcomes associated with a prolonged duration from onset to surgery.

Impact of super energy-dense oral nutritional supplementation (SED ONS) on glycemic variability and food intake postoperatively in gastric cancer patients.

PURPOSE: Adherence to oral nutritional supplements (ONS) to prevent weight loss after gastrectomy is problematic. The present study evaluated the impact of super energy-dense ONS (SED ONS; 4 kcal/mL) on glycemic change and energy intake after gastrectomy. METHODS: Gastrectomy patients were placed on continuous glucose monitoring for a 3-day observation period after food intake had been stabilized postoperatively. In addition, they were given 0, 200, and 400 kcal/day of SED ONS on Days 1, 2, and 3, respectively. The primary outcome was the area under the curve < glucose 70 mg/dL (AUC < 70). The secondary outcomes were other indices of glucose fluctuation and the amount of food and SED ONS intake. RESULTS: Seventeen patients were enrolled. The AUC < 70 did not differ significantly with or without SED ONS over the observation period. SED ONS did not cause postprandial hypoglycemia and prevented nocturnal hypoglycemia. The mean dietary intake did not change significantly during the observation period, and the total energy intake increased significantly according to the amount of SED ONS provided. CONCLUSION: SED ONS after gastrectomy increased the total energy intake without dietary reduction and it did not result in hypoglycemia.

A case of late postoperative intra-abdominal hemorrhage developing 13 months after laparoscopic sleeve gastrectomy.

A 29-year-old male patient underwent laparoscopic sleeve gastrectomy (LSG) for morbid obesity and was discharged without any complications. Thirteen months later, he visited the emergency room with epigastric pain. A few hours before onset, he had had a larger-than-usual meal and vomited afterwards. Enhanced abdominal computed tomography revealed a hematoma 127 × 63 mm in diameter around the stomach. Angiography revealed no extravasation or pseudoaneurysm. Upper gastrointestinal endoscopy found no ulcers or abnormality of the stapler line scar from the LSG. The patient's vital signs were stable, and his hemoglobin had not fallen below the previous day's value. Conservative treatment was therefore chosen. The patient was discharged in stable condition after 11 days of hospitalization. However, the exact source of the hemorrhage was unable to be detected on the imaging findings. In view of his clinical course and the hematoma location, omental vessels were suspected of being the source of the hemorrhage.

Liver retraction using an L-shaped retractor during sleeve gastrectomy.

PURPOSE: The Nathanson liver retractor (NLR) and the snake liver retractor (SLR) are commonly used in bariatric surgery and their use is associated with some disadvantages. We developed an L-shaped liver retractor (LLR) and herein evaluated its efficacy and safety. METHODS: The present retrospective study enrolled patients undergoing sleeve gastrectomy in our department between June 2014 and December 2020. The patients were divided into three groups according to the liver retractor used (LLR, SLR or NLR) for a comparative analysis of the efficacy and safety of the devices. The procedural time (PT) of each retractor type, defined as the time from retractor insertion to liver fixation, was compared. RESULTS: In total, 140 patients successfully underwent laparoscopic sleeve gastrectomy. The LLR, SLR and NLR were used in 37, 91, and 12 of these patients, respectively. The PT for the LLR was the shortest. AST/ALT elevation was significantly more frequent in the NLR group than in the SLR group and tended to be less frequent in the LLR group in comparison to the NLR group (p = 0.09). The length of hospital stay in the NLR group was significantly longer in comparison to the LLR group. CONCLUSION: Our study suggested that the LLR was superior to the conventional liver retractors used in sleeve gastrectomy.

A case of disseminated carcinomatosis of the bone marrow from gastric cancer developing rapidly after a gastrectomy.

BACKGROUND: Disseminated carcinomatosis of the bone marrow (DCBM) is often associated with disseminated intravascular coagulation (DIC) and a poor prognosis. Moreover, the timing of the diagnosis varies. We presented herein the first report of a case of DCBM from gastric cancer that developed rapidly after a gastrectomy. CASE PRESENTATION: A 42-year-old male patient was referred to us for gastric cancer. Preoperative laboratory tests were normal. Abdominal computed tomography (CT) revealed no obvious bone metastasis, and he underwent a laparoscopic distal gastrectomy. On postoperative day (POD) 1, laboratory data indicated severe thrombocytopenia. Postoperative bleeding requiring reoperation was found. Afterwards, he complained of lower back pain. His ALP and LDH gradually became elevated. On POD 8, DIC was diagnosed. CT and bone scintigraphy showed multiple, widespread bone metastases. Based on these findings, DCBM from gastric cancer was diagnosed. Systemic chemotherapy was started on POD 12. The DIC subsided during the first course, and he was discharged on POD 21. The patient died of tumor progression 7 months later. CONCLUSION: When thrombocytopenia is observed immediately after a gastrectomy for gastric cancer, the possibility of DCBM should be considered.

Intratumoral pseudoaneurysm within a liver metastasis of gastric cancer: a case report.

BACKGROUND: Intrahepatic artery pseudoaneurysms are mostly iatrogenic and result from hepatobiliary interventions. The incidence of intrahepatic artery pseudoaneurysms within liver tumors without prior intervention is extremely rare. We presented herein the first report of a case of an intratumoral pseudoaneurysm within a liver metastasis of gastric cancer without any prior intervention during chemotherapy. CASE PRESENTATION: A 59-year-old male patient underwent a distal gastrectomy and D2 lymph node dissection for gastric cancer. He was treated in the emergency room for right abdominal pain following the 4th cycle of nivolumab administration as second-line chemotherapy after adjuvant chemotherapy with S-1 and first-line chemotherapy for a liver metastasis of gastric cancer with ramucirumab plus paclitaxel. CT showed a 72-mm metastatic liver tumor containing a 9-mm pseudoaneurysm and fluid collection around the hepatic edge. Intrahepatic artery pseudoaneurysm within the metastatic liver tumor was diagnosed, with the surrounding fluid indicating potential, active bleeding. An emergency angiography confirmed the presence of a pseudoaneurysm in the intrahepatic artery, which was embolized using microcoils. The contributory causes of the intratumoral pseudoaneurysm were assumed to be the following: (1) tumor necrosis leading to encasement, erosion of the vessel wall, and subsequent arterial wall weakening; and (2) inhibition of vascular endothelial growth by ramucirumab resulting in a vessel wall breach and pseudoaneurysm formation. CONCLUSION: It is necessary to recognize that pseudoaneurysms can arise within a metastatic liver tumor during chemotherapy.

Rescue Levodopa/Carbidopa Intestinal Gel for Secondary Deep Brain Stimulation Failure.

OBJECTIVE: The long-term efficacy of deep brain stimulation (DBS) for motor fluctuations in advanced Parkinson's disease (PD) has been well established; however, motor fluctuations may recur over time despite multiple adjustments of DBS settings and medications. METHODS: We conducted a retrospective chart review of three patients for whom levodopa-carbidopa intestinal gel (LCIG) was additionally administered as a rescue therapy for secondary DBS failure due to the recurrence of motor fluctuations. RESULTS: The three patients had advanced PD with a disease duration of 14-19 years, and had undergone DBS for motor fluctuations refractory to standard medical management. LCIG was administered to the patients because of symptom recurrence years after DBS and provided complementary effects in all patients. CONCLUSION: The cases presented here show that rescue LCIG therapy may be a complementary treatment option for patients with post-DBS advanced PD who have a recurrence of troublesome motor complications.

Hemi-double stapling technique performed with a transorally inserted anvil for esophagojejunostomy in the surgical treatment of gastric cancer.

INTRODUCTION: A transorally inserted anvil has been developed to facilitate the creation of a stapled anastomosis without the need for a purse string to secure the anvil into place during laparoscopic total gastrectomy (LTG). We describe a hemi-double stapling technique and application of a transorally inserted anvil for esophagojejunostomy during LTG, and we report the results of a retrospective study in which we examined the feasibility and safety of this method. We also describe the key technical details of the method. METHODS: Our anastomotic method has four chief features: (a) the esophagus is cut at a slant, and its left cut end is cut and punched for the hemi-double stapling technique; (b) the anvil and circular stapler are connected, placing the distal jejunum in cranial traction; (c) a single layer of sutures is used to correct dog-earing and overlapping, and these points are completely closed with Lembert sutures; and (d) the jejunal limb is fixed to the duodenal stump to prevent kinking of the jejunal limb and to decrease tension on the anastomosis. RESULTS: This method has been used in 53 patients thus far. LTG with Roux-en-Y reconstruction was successful in all patients, and there was no need for conversion to open surgery. The mean operative time was 313 minutes, and the mean blood loss was 106 mL. The mean postoperative hospital stay was 18 days. There was no anastomotic leakage or stenosis. CONCLUSION: Hemi-double stapling technique with a transorally inserted anvil for LTG can be performed safely and easily and safely. It can also product good outcomes.

Right inferior phrenic artery pseudoaneurysm after a laparoscopic gastrectomy: a case report.

BACKGROUND: Ruptured pseudoaneurysms are a rare complication of gastrectomy, but when they do develop, they are often fatal. We presented herein the first report of a case of pseudoaneurysm arising from the right inferior phrenic artery (RIPA) after a laparoscopic gastrectomy. CASE PRESENTATION: A 61-year-old male patient underwent a laparoscopic distal gastrectomy and D1+ lymph node dissection with Roux-en-Y reconstruction for early gastric cancer. He was discharged on postoperative day (POD) 9 without any complications, such as anastomotic or pancreatic leakage. On POD 19, he was referred to the emergency room for upper abdominal pain. Enhanced abdominal computed tomography revealed a 60 × 70 mm hematoma, indicating intra-abdominal bleeding and a 10-mm pseudoaneurysm in the RIPA. Selective digital subtraction angiography confirmed the presence of a pseudoaneurysm in the RIPA, which was embolized using multiple microcoils. Thereafter, no clinical signs were observed, and the patient was discharged from the hospital 15 days after angiography without any recurrence of bleeding. We hypothesized that the cause of the pseudoaneurysm was mechanical vascular injury due to the thermal spread of the ultrasonically activated devices (USADs) during lymphatic node dissection. CONCLUSION: Given the thermal spread of USADs, safe and appropriate lymph node dissection based on precise anatomical knowledge is crucial to preventing postoperative pseudoaneurysms.

[A Case of Advanced Gastric Cancer with Pathological Complete Response after Chemotherapy(S-1/Cisplatin)].

A 68-year-old female patient presented with advanced gastric cancer and multiple hepatic tumors. Upper GI endoscopy showed a type 3 lesion in the posterior wall of the gastric body. Abdominal computed tomography revealed multiple liver metastases, and staging laparoscopy identified peritoneal dissemination. She was diagnosed with clinical Stage Ⅳ gastric cancer(cT3N2M1H1). She received 3 courses of combined chemotherapy containing S-1 and cisplatin. The therapeutic response was PR. We performed total gastrectomy with D2 lymph node dissection and splenectomy. Histopathological examination revealed no residual cancer cells, indicating pCR. She continued S-1 adjuvant chemotherapy and has remained free from recurrence for 18 months.

Technique and outcome of percutaneous endoscopic transgastric jejunostomy for continuous infusion of levodopa-carbidopa intestinal gel for treatment of Parkinson's disease.

Objective: A new method of drug delivery via the small bowel, continuous infusion of levodopa-carbidopa intestinal gel (LCIG), for patients with advanced Parkinson's disease (PD) has been developed and shown to improve patients' quality of life. Levodopa is infused directly and continuously into the proximal jejunum via a percutaneous endoscopic transgastric jejunostomy (PEG-J) tube that is connected to a portable infusion pump. The aim of this study was to evaluate the safety and outcomes of our PEG-J technique performed in advance of LCIG therapy in patients with advanced PD. Material and methods: We reviewed the cases of 37 patients who underwent PEG-J for LCIG therapy at our hospital between November 2016 and May 2018. Pull-through percutaneous endoscopic gastrostomy (PEG) and gastropexy were performed in all patients. The J-tube was inserted through the PEG tube and placed beyond the ligament of Treitz endoscopically under fluoroscopic guidance. After two weeks, the gastropexy sutures were removed. Results: PEG-J with placement of the tube beyond the ligament of Treitz was successful in all 37 patients. Median procedure time was 26.4 min. Median hospital stay after the procedure was 16 days. Median follow-up with the PEG-J tube in place was 11 months. There were five procedure-related complications (13.5%) and 13 device-related complications (35.1%). There was no death related to the procedure. Conclusions: Our PEG-J technique can be performed safely in patients with advanced PD, and favorable outcomes have been achieved to date.

Comparative study of outcomes of Roux-en-Y reconstruction and Billroth â reconstruction performed after radical distal gastrectomy.

BACKGROUND: Billroth Ⅰ (BⅠ) reconstruction and Roux-en-Y (RY) reconstruction are both commonly performed after distal gastrectomy (DG). We conducted a retrospective study to evaluate which is the better option. METHODS: Included in our study were 162 patients who, between April 2011 and October 2015, underwent DG followed by BⅠ reconstruction (n = 93) or RY reconstruction (n = 69). All patients were followed up for at least 1 year. We compared perioperative outcomes, postoperative complications, gastrointestinal (GI) symptoms, endoscopic findings, and nutritional status between the 2 groups of patients. RESULTS: Patient characteristics did not differ between the 2 groups, with the exception of the incidence of gastric body tumors, which was significantly higher in the RY group (73.9% vs. 19.4%; p < 0.001). Operation time was significantly longer in the RY reconstruction group (p < 0.001). There was no significant between-group difference in the grades of GI dysfunction (p = 0.122).The endoscopically determined RGB (Residual food, Gastritis, Bile reflux)scores were significantly better in the RY reconstruction group than in the BI reconstruction group (p = 0.027, p < 0.001,p < 0.001,respectively).There was also no significant between-group difference in the change (1-year postoperative value/preoperative value) in body weight, body mass index, serum albumin concentration, or total cholesterol concentration (p = 0.484,p = 0.613,p = 0.760,p = 0.890, respectively). CONCLUSIONS: RY reconstruction appears not to be advantageous over BⅠ reconstruction in terms of GI function or nutritional status 1 year after surgery. RY reconstruction does appear to be superior in terms of preventing bile reflux but takes more operation time.

Aqueous Extract of Glucoraphanin-Rich Broccoli Sprouts Inhibits Formation of Advanced Glycation End Products and Attenuates Inflammatory Reactions in Endothelial Cells.

We have previously shown that sulforaphane not only inhibits formation of advanced glycation end products (AGEs) but also exerts anti-inflammatory effects on AGE-exposed human umbilical vein endothelial cells (HUVECs) and AGE-injected rat aortae. Here we examined the effects of aqueous extract of glucoraphanin-rich broccoli sprouts on formation of AGEs and then investigated whether the extract could attenuate inflammatory or oxidative stress reactions in tumor necrosis factor-alpha (TNF-α)- or AGE-exposed HUVECs. Fresh broccoli sprouts were homogenized in phosphate-buffered saline and filtered through a gauze. After centrifugation, clear extract was obtained. AGE formation was measured by enzyme-linked immunosorbent assay. Gene expression was evaluated by real-time reverse transcription-polymerase chain reaction. Reactive oxygen species (ROS) generation were measured using a fluorescent dye. Five percent broccoli sprout extract inhibited the formation of AGEs, reduced basal gene expressions of monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1,) and receptor for AGEs (RAGE), and upregulated endothelial nitric oxide synthase (eNOS) mRNA levels in HUVECs. TNF-α upregulated MCP-1, ICAM-1, and RAGE mRNA levels in HUVECs, all of which were attenuated by the treatment with 1% broccoli sprout extract. Pretreatment of 1% broccoli sprout extract prevented the ROS generation in HUVECs evoked by AGEs. The present study demonstrates that sulforaphane-rich broccoli sprout extract could inhibit the AGE-RAGE axis and exhibit anti-inflammatory actions in HUVECs. Supplementation of sulforaphane-rich broccoli sprout extract may play a protective role against vascular injury.

Augmented rectangle technique for Billroth I anastomosis in totally laparoscopic distal gastrectomy for gastric cancer.

BACKGROUND: Billroth I reconstruction is a means of anastomosis that is widely performed after surgical resection for distal gastric cancer. Interest has grown in totally laparoscopic gastrectomy, and several methods for totally laparoscopic performance of Billroth I reconstruction have been reported. However, the methods are cumbersome, and postoperative complications such as twisting at the site of anastomosis and obstruction due to stenosis have arisen. We developed an augmented rectangle technique (ART) by which the anastomosis is created laparoscopically with the use of three automatic endoscopic linear staplers, and the resulting anastomotic opening is wide and less likely to become twisted or stenosed. The technical details of our ART-based Billroth I anastomosis are presented herein along with results of the procedure to date. METHODS: The technique was applied in 160 patients who underwent totally laparoscopic distal gastrectomy for gastric cancer between December 2013 and August 2017. Clinicopathological data, surgical data, and postoperative outcomes were analyzed. RESULTS: During surgery, there were no troubles associated with gastrointestinal reconstruction and there was no transition to laparotomy. There were no postoperative complications, including suture failure and stenosis, associated with the gastrointestinal reconstruction, and the average postoperative hospital stay was 12 days. CONCLUSION: Totally laparoscopic ART-based Billroth I reconstruction is both feasible and safe. We expect this technique to contribute to the spread of safe totally laparoscopic surgery for gastric cancer.

Triple-stapled quadrilateral anastomosis: a new technique for creation of an esophagogastric anastomosis.

BACKGROUND: Esophagogastric anastomosis performed after esophagectomy is technically complex and often the source of postoperative complications. The best technique for this anastomosis remains a matter of debate. We describe a new all-stapled side-to-side anastomosis, which we refer to as triple-stapled quadrilateral anastomosis (TRIQ), that can be performed after minimally invasive surgery, and we report results of a retrospective evaluation of postoperative outcomes among the 60 patients in whom this anastomosis has been performed thus far. METHODS: The anastomosis is created by apposition of the posterior walls of the esophagus and stomach. A linear stapler is applied to create a V-shaped posterior anastomotic wall. The anterior wall is closed in a gentle chevron-like shape with the use of 2 separate linear staplers, resulting in a wide quadrilateral anastomosis. The anastomosis is then wrapped with a greater omentum flap. RESULTS: The patient group comprised 48 men and 12 women with a mean age of 67.8 years. Neoadjuvant chemotherapy was performed in 43 of these patients. Neither the thoracoscopic or laparoscopic procedure was converted to open surgery in any patient. The median operation time was 474 min (range 680-320 min). The intraoperative blood loss volume was 104.4 mL (range 240-30 mL). There were no anastomosis-related complications above Clavien-Dindo grade II. CONCLUSIONS: TRIQ can be performed easily and safely, and good short-term outcome can be expected.

Methylglyoxal-derived hydroimidazolone-1 evokes inflammatory reactions in endothelial cells via an interaction with receptor for advanced glycation end products.

OBJECTIVE: Glyceraldehyde-derived advanced glycation end products contribute to vascular inflammation in diabetes. However, what advanced glycation end product structure could evoke inflammatory reactions remains unknown. We examined whether and how methylglyoxal-derived hydroimidazolone 1, one of the advanced glycation end products formed from glyceraldehyde, elicits inflammatory reactions in human umbilical vein endothelial cells. MATERIALS AND METHODS: Glyceraldehyde-advanced glycation end products-aptamer was prepared using a systemic evolution of ligands by exponential enrichment. The binding affinities of methylglyoxal-derived hydroimidazolone 1 to receptor for advanced glycation end products or advanced glycation end product-aptamer were measured with a quartz crystal microbalance. Intracellular reactive oxygen species generation and THP-1 cell adhesion were evaluated using fluorescent probes. Gene expression was analysed by reverse transcription polymerase chain reaction. RESULTS: Methylglyoxal-derived hydroimidazolone 1 bound to receptor for advanced glycation end products and advanced glycation end product-aptamer with a dissociation constant ( Kd) of 56.7 µM and 1.51 mM, respectively. Methylglyoxal-derived hydroimidazolone 1 at 100 µg/mL significantly increased reactive oxygen species generation in human umbilical vein endothelial cells, which were attenuated by anti-receptor for advanced glycation end products antibody or advanced glycation end product-aptamer. In all, 100 µg/mL methylglyoxal-derived hydroimidazolone 1 significantly increased receptor for advanced glycation end products and intercellular adhesion molecule-1 messenger RNA levels in, and THP-1 cell adhesion to, human umbilical vein endothelial cells, all of which were blocked by anti-receptor for advanced glycation end products antibody. CONCLUSION: Our present results indicate that methylglyoxal-derived hydroimidazolone 1 evokes inflammatory reactions in human umbilical vein endothelial cells via receptor for advanced glycation end products, although apparently limited to supraphysiological levels of methylglyoxal-derived hydroimidazolone 1. Methylglyoxal-derived hydroimidazolone 1 is a distinct advanced glycation end product structure that could mediate harmful effects of methylglyoxal and glyceraldehyde-mediated glycation processes.

N-butanol extracts of Morinda citrifolia suppress advanced glycation end products (AGE)-induced inflammatory reactions in endothelial cells through its anti-oxidative properties.

BACKGROUND: Advanced glycation end products (AGEs), senescent macroprotein derivatives formed during a normal aging process and acceleratedly under diabetic conditions, play a role in atherosclerotic cardiovascular disease. AGEs cause endothelial cell (EC) damage, an initial trigger for atherosclerosis through the interaction with a receptor for AGEs (RAGE). We have previously shown that n-butanol extracts of Morinda citrifolia (noni), a plant belonging to the family Rubiaceae, block the binding of AGEs to RAGE in vitro. In this study, we examined the effects of n-butanol extracts of noni on reactive oxygen species (ROS) generation and inflammatory reactions on AGE-exposed human umbilical vein ECs (HUVECs). METHODS: HUVECs were treated with 100 µg/ml AGE-bovine serum albumin (AGE-BSA) or non-glycated BSA in the presence or absence of 670 ng/ml n-butanol extracts of noni for 4 h. Then ROS generation and inflammatory and gene expression in HUVECs were evaluated by dihydroethidium staining and real-time reverse transcription-polymerase chain reaction analyses, respectively. THP-1 cell adhesion to HUVECs was measured after 2-day incubation of AGE-BSA or BSA in the presence or absence of 670 ng/ml n-butanol extracts of noni. RESULTS: N-butanol extracts of noni at 670 ng/ml significantly inhibited the AGE-induced ROS generation and RAGE, intercellular adhesion molecule-1 and plasminogen activator inhibitor-1 gene expressions in HUVECs. AGEs significantly increased monocytic THP-1 cell adhesion to HUVECs, which was also prevented by 670 ng/ml n-butanol extracts of noni. CONCLUSIONS: The present study demonstrated for the first time that N-butanol extracts of noni could suppress the AGE-induced inflammatory reactions in HUVECs through its anti-oxidative properties via blocking of the interaction of AGEs with RAGE. Inhibition of the AGE-RAGE axis by n-butanol extracts of noni may be a novel nutraceutical strategy for the treatment of cardiovascular disease.