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.

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.

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.

[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.

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.

RAGE-aptamer Attenuates the Growth and Liver Metastasis of Malignant Melanoma in Nude Mice.

Epidemiological studies have suggested the link between cumulative diabetic exposure and cancer. Interaction of advanced glycation end products (AGEs) with their receptor (RAGE) may contribute to the phenomenon. We examined here the effects of DNA aptamer raised against RAGE (RAGE-aptamer) on growth and liver metastasis of G361 melanoma in nude mice. Malignant melanoma cells were intradermally injected into the upper flank region of nude mice, which received continuous administration of RAGE-aptamer (38.4 pmol/day/g body weight) or vehicle intraperitoneally by an osmotic pump up to 42 days. RAGE-aptamer significantly reduced levels of 8-hydroxy-2'-deoxy-guanosine, AGEs, RAGE, proliferating nuclear antigen, cyclin D1, vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1), and CD31 and Mac-3, respective markers of endothelial cells and macrophages in tumors of nude mice and suppressed the proliferation and liver metastasis of malignant melanoma. Furthermore, RAGE-aptamer attenuated the AGE-induced oxidative stress generation, proliferation, and VEGF and MCP-1 gene expression in both G361 melanoma cells and endothelial cells. The present findings suggest that RAGE-aptamer could attenuate melanoma growth and liver metastasis in nude mice by suppressing the tumor angiogenesis and macrophage infiltration via inhibition of the AGE-RAGE system. RAGE-aptamer may be a novel therapeutic tool for the treatment of malignant melanoma.

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.

[A Study of Preoperative Chemotherapy with S-1 plus Cisplatin for Advanced Gastric Cancer].

We studied the effects of preoperative chemotherapy with S-1 plus cisplatin for advanced gastric cancer. There were 16 patients who underwent radical surgery with neoadjuvant chemotherapy between 2000 and 2015. The indications for this were advanced gastric cancer with bulky N2 or N3 lymph nodes, or stage above T4a. Seven patients (43%) showed adverse events, all of which were tumors above Grade 3. Response evaluation showed PR in 13 cases (81%). The histopathological evaluation was Grade 0 in 8 patients (50%) and Grade 1a or above in 8 (50%). Death from recurrence within a year occurred in 4 cases, and 7 patients survived with no recurrence for over 5 years. All cases of survivors with no recurrence had a histopathological evaluation of Grade 1 or above. Three cases (75%) with recurrence and death within a year all had with Grade 0 tumors. We concluded that neoadjuvant chemotherapy with S-1 plus cisplatin was effective for advanced gastric cancer and that histopathological evaluation was invaluable for accurate prognosis.

[A Case of Gemcitabine Refractory Lung Metastasis after Distal Pancreatectomy for Pancreatic Cancer, Effectively Treated with S -1 as Second Line Chemotherapy].

A 64-year-old man was diagnosed with pancreatic cancer by abdominal computed tomography (CT). The examination showed a pancreatic tail cancer and a distal pancreatectomy was performed in 2010. Histopathologically, this tumor was a moderately-differentiated tubular adenocarcinoma. He received gemcitabine adjuvant chemotherapy for a year. In 2012, a chest CT scan revealed 4 nodules in the lower left lobe. We diagnosed gemcitabine-refractory lung metastases after distal pancreatectomy for pancreatic cancer. S-1 chemotherapy was administered as a second line chemotherapy for metastatic pancreatic cancer. After 2 courses of this regimen, the lung metastases were reduced. After 6 courses, a clinical complete response was obtained. Four years and 6 months after the operation, the patient is well without any signs of recurrence, and S-1 chemotherapy is still ongoing.

[A Case of Advanced Gastric Cancer with Peritoneal Dissemination Effectively Treated with S-1 and Docetaxel Combination Chemotherapy].

A 72-year-old man underwent surgery for advanced gastric cancer. Systemic chemotherapy was started, using a regimen of S-1/CDDP for 4 courses, followed by 8 courses of S-1. Three years and 8 months after the surgery, abdominal CT demonstrated ascites, and the serum CA19-9 level was abnormally high (1,165.1 U/mL). Adenocarcinoma cells were found in the ascites. Treatment with S-1/docetaxel (DOC) was started. After 10 courses, the ascites disappeared and the serum CA19-9 value returned to normal. Four years and 7 months after the operation, the patient has been in good health, with no signs of recurrence.

[A Case of Advanced Gastric Cancer with Long-Term Survival after Chemotherapy with Combined S-1 and CPT-11].

Here, we report a 54-year-old man diagnosed with type 3 advanced gastric cancer who underwent a total gastrectomy and splenectomy plus D2 lymphadenectomy. The pathologic diagnosis was Stage Ⅳ (T3N0H0P0CY1M1). Sixteen courses of combined S-1/CPT-11 chemotherapy were completed, at which time the CPT-11 was discontinued because of malaise, and S-1 alone was continued for a year. The patient is well and has been recurrence-free for 7 years. Thus, he is considered a long- term survivor who was treated with combination S-1/CPT-11 chemotherapy.

[A Case of Colon Cancer with Multiple Liver Metastases Successfully Treated with Capecitabine/Oxaliplatin plus Bevacizumab].

A 69-year-old woman was diagnosed with descending colon cancer with multiple liver metastases, and a left hemicolectomy was performed. The patient was treated with capecitabine/oxaliplatin (CapeOX) plus bevacizumab (Bmab). After 5 courses of chemotherapy, the number and size of liver metastases remarkably reduced, and after the 12th course, because of peripheral neuropathy, a "stop-and-go"fashion of administering oxaliplatin (L-OHP) was initiated. After 14 courses, the liver metastases had disappeared. After the 33rd course of L-OHP treatment, the patient started receiving capecitabine therapy. The patient is recurrence-free 3 years after surgery, 14 months after achieving a complete response (CR). We report a case of long-term CR after surgery for descending colon cancer with multiple liver metastases, followed by a "stop-and-go" method of administering L-OHP or CapeOX plus Bmab therapy.

[Two Cases of Liver Metastasis from Pancreatic Cancer with a Complete Response Owing to Chemotherapy].

Case 1: The patient was a 42-year-old man who was diagnosed with intraductal papillary-mucinous carcinoma with liver metastasis. After S-1+gemcitabine and S-1 chemotherapy, the liver metastasis had disappeared and we performed a pancreaticoduodenectomy( PD). Case 2: The patient was a 70-year-old woman who was diagnosed with pancreatic cancer with liver metastasis. After gemcitabine chemotherapy, the liver metastasis had disappeared and we performed a PD. The prognosis of pancreatic cancer is dismal compared to other types of cancer, and for a Stage Ⅳb cancers, the 5-year survival rate is reported to be approximately 3%. We report 2 cases of liver metastases from pancreatic cancer that disappeared in response to chemotherapy. Both patients underwent primary tumor resection after chemotherapy and experienced long-term survival.

Glucagon-like peptide-1 receptor agonist inhibits asymmetric dimethylarginine generation in the kidney of streptozotocin-induced diabetic rats by blocking advanced glycation end product-induced protein arginine methyltranferase-1 expression.

Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in diabetic nephropathy. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, contributes to diabetic nephropathy. We have found that glucagon-like peptide-1 (GLP-1) inhibits the AGE-induced inflammatory reactions in endothelial cells. However, effects of GLP-1 on the AGE-RAGE-ADMA axis are unknown. This study examined the effects of GLP-1 on reactive oxygen species (ROS) generation, gene expression of protein arginine methyltransfetase-1 (PRMT-1), an enzyme that mainly generates ADMA, and ADMA levels in human proximal tubular cells. Streptozotocin-induced diabetic rats received continuous i.p. infusion of 0.3 µg of vehicle or 1.5 µg of the GLP-1 analog exendin-4 per kilogram of body weight for 2 weeks. We further investigated whether and how exendin-4 treatment reduced ADMA levels and renal damage in streptozotocin-induced diabetic rats. GLP-1 inhibited the AGE-induced RAGE and PRMT-1 gene expression, ROS, and ADMA generation in tubular cells, which were blocked by small-interfering RNAs raised against GLP-1 receptor. Exendin-4 treatment decreased gene expression of Rage, Prmt-1, Icam-1, and Mcp-1 and ADMA level; reduced urinary excretions of 8-hydroxy-2'-deoxyguanosine and albumin; and improved histopathologic changes of the kidney in diabetic rats. Our present study suggests that GLP-1 receptor agonist may inhibit the AGE-RAGE-mediated ADMA generation by suppressing PRMT-1 expression via inhibition of ROS generation, thereby protecting against the development and progression of diabetic nephropathy.

Advanced glycation end products potentiate citrated plasma-evoked oxidative and inflammatory reactions in endothelial cells by up-regulating protease-activated receptor-1 expression.

Advanced glycation end products (AGEs) and receptor RAGE interaction contribute to endothelial cell damage in diabetes. Several thrombogenic abnormalities are also involved in diabetic vascular complications. However, the pathological role of thrombin and protease-activated receptor-1 (PAR-1) system in AGE-induced endothelial cell (EC) damage remains unclear. In this study, we investigated the effects of rivaroxaban, an inhibitor of factor Xa on 3% citrated human plasma-evoked reactive oxygen species (ROS) generation and RAGE, monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule-1 (ICAM-1) gene expression in AGE-exposed ECs. We further examined whether FR171113, an inhibitor of PAR-1 blocked the plasma-induced EC damage and if AGEs increased PAR-1 expression in ECs. Human citrated plasma stimulated ROS generation and RAGE, MCP-1 and ICAM-1 expression in ECs, all of which were potentiated by the treatment with AGEs. Rivaroxaban or FR171113 significantly inhibited these derangements in plasma- or plasma plus AGE-exposed ECs. Moreover, AGEs significantly increased the PAR-1 levels in ECs. The present study suggests that citrated plasma could induce oxidative and inflammatory reactions in ECs via the activation of thrombin-PAR-1 system and that AGEs could potentiate the plasma-evoked EC damages via up-regulation of PAR-1. Blockade of the crosstalk between AGE-RAGE axis and coagulation system by rivaroxaban might be a novel therapeutic target for thromboembolic disorders in diabetes.

Switching to multiple daily injection therapy with glulisine improves glycaemic control, vascular damage and treatment satisfaction in basal insulin glargine-injected diabetic patients.

BACKGROUND: Basal and bolus insulin therapy is required for strict blood control in diabetic patients, which could lead to prevention of vascular complications in diabetes. However, the optimal combination regimen is not well established. METHODS: Fifty-nine diabetic patients (49 type 1 and 10 type 2; 52.9 ± 13.3 years old) whose blood glucose levels were uncontrolled (HbA1c > 6.2%) by combination treatment of basal insulin glargine with multiple daily pre-meal injections of bolus short-acting insulin [aspart (n = 19), lispro (n = 37) and regular human insulin (n = 3)] for at least 8 weeks were enrolled in this study. We examined whether glycaemic control and vascular injury were improved by replacement of short-acting insulin with glulisine. Patient satisfaction was assessed with Diabetes Treatment Satisfaction Questionnaire. RESULTS: Although bolus and basal insulin doses were almost unchanged before and after replacement therapy, switching to glulisine insulin for 24 weeks significantly decreased level of HbA1c , advanced glycation end products (AGEs), soluble receptor for AGEs (sRAGE), monocyte chemoattractant protein-1 (MCP-1) and urinary albumin excretion. In multiple stepwise regression analysis, change in MCP-1 values from baseline (ΔMCP-1) was a sole determinant of log urinary albumin excretion. ΔAGEs and ΔsRAGE were independently correlated with each other. The relationship between ΔMCP-1 and ΔsRAGE was marginally significant (p = 0.05). Replacement of short-acting insulin by glulisine significantly increased Diabetes Treatment Satisfaction Questionnaire scores. CONCLUSIONS: Our present study suggests that combination therapy of glargine with multiple daily pre-meal injections of glulisine might show superior efficacy in controlling blood glucose, preventing vascular damage and improving treatment satisfaction in diabetic patients.

[A case of gastric cancer with N2 lymph node metastasis and pancreatic invasion effectively treated with docetax-el/S-1 as a neoadjuvant chemotherapy].

A 74-year-old man was diagnosed with advanced gastric cancer(cStage III B). Laparotomy showed N2 lymph node metastasis and pancreatic invasion. Radical resection appeared impossible and was thus not performed. Chemotherapy consisting of a combination of S-1(80mg/m 2, 2-week administration and 1-week rest), and docetaxel(40mg/m2day 1)was administered with the expectation of tumor downstaging. A partial response(PR)was obtained after five courses of this regimen in which the primary lesion and lymph node swelling remarkably improved. Total gastrectomy, splenectomy, partial colectomy, and D2 lymph node dissection were then performed. Pathological analysis revealed very few cancer cells in the primary lesion and that the lymph nodes had become scarred and fibrotic. The histological appearance was judged to be grade 2 and the final diagnosis was T1N0H0P0CY0M0, fStage I A, curability A. Currently, more than 6 years and 4 months after the operation, the patient is alive without any evidence of recurrence. Thus, docetaxel/S-1 combination therapy was an effective neoadjuvant chemotherapy for this case of advanced gastric cancer.

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.

Advanced glycation end products evoke endothelial cell damage by stimulating soluble dipeptidyl peptidase-4 production and its interaction with mannose 6-phosphate/insulin-like growth factor II receptor.

BACKGROUND: Advanced glycation end products (AGEs) and receptor RAGE interaction play a role in diabetic vascular complications. Inhibition of dipeptidyl peptidase-4 (DPP-4) is a potential therapeutic target for type 2 diabetes. However, the role of DPP-4 in AGE-induced endothelial cell (EC) damage remains unclear. METHODS: In this study, we investigated the effects of DPP-4 on reactive oxygen species (ROS) generation and RAGE gene expression in ECs. We further examined whether an inhibitor of DPP-4, linagliptin inhibited AGE-induced soluble DPP-4 production, ROS generation, RAGE, intercellular adhesion molecule-1 (ICAM-1) and plasminogen activator inhibitor-1 (PAI-1) gene expression in ECs. RESULTS: DPP-4 dose-dependently increased ROS generation and RAGE gene expression in ECs, which were prevented by linagliptin. Mannose 6-phosphate (M6P) and antibodies (Ab) raised against M6P/insulin-like growth factor II receptor (M6P/IGF-IIR) completely blocked the ROS generation in DPP-4-exposed ECs, whereas surface plasmon resonance revealed that DPP-4 bound to M6P/IGF-IIR at the dissociation constant of 3.59 x 10⁻5 M. AGEs or hydrogen peroxide increased soluble DPP-4 production by ECs, which was prevented by N-acetylcysteine, RAGE-Ab or linagliptin. Linagliptin significantly inhibited the AGE-induced ROS generation, RAGE, ICAM-1 and PAI-1 gene expression in ECs. CONCLUSIONS: The present study suggests that AGE-RAGE-induced ROS generation stimulates the release of DPP-4 from ECs, which could in turn act on ECs directly via the interaction with M6P/IGF-IIR, further potentiating the deleterious effects of AGEs. The blockade by linagliptin of positive feedback loop between AGE-RAGE axis and DPP-4 might be a novel therapeutic target for vascular injury in diabetes.