Papaverine identified as an inhibitor of high mobility group box 1/receptor for advanced glycation end-products interaction suppresses high mobility group box 1-mediated inflammatory responses.

The interaction of high mobility group box 1 (HMGB1), which is secreted from immune and dying cells during cellular infection and injury, and receptor for advanced glycation end-products (RAGE) appears to be critical for acute and chronic inflammatory disorders. Here we designed a unique cyclic ß-hairpin peptide (Pepb2), which mimics the predicted RAGE-binding domain of HMGB1. Pepb2 competitively inhibited HMGB1/RAGE interaction. We then identified papaverine as a Pepb2 mimetic by in silico 3D-structural similarity screening from the DrugBank library. Papaverine was found to directly inhibit HMGB1/RAGE interaction. It also suppressed the HMGB1-mediated production of pro-inflammatory cytokines, IL-6 and TNF-α, in mouse macrophage-like RAW264.7 cells and bone marrow-derived macrophages. In addition, papaverine attenuated mortality in cecal ligation puncture-induced sepsis model mice. Taken together, these findings indicate that papaverine could become a useful therapeutic against HMGB1/RAGE-mediated sepsis and other inflammatory diseases.

Characterization of a novel microRNA, miR-188, elevated in serum of muscular dystrophy dog model.

MicroRNAs (miRNAs) are non-coding small RNAs that regulate gene expression at the post-transcriptional level. Several miRNAs are exclusively expressed in skeletal muscle and participate in the regulation of muscle differentiation by interacting with myogenic factors. These miRNAs can be found at high levels in the serum of patients and animal models for Duchenne muscular dystrophy, which is expected to be useful as biomarkers for their clinical conditions. By miRNA microarray analysis, we identified miR-188 as a novel miRNA that is elevated in the serum of the muscular dystrophy dog model, CXMDJ. miR-188 was not muscle-specific miRNA, but its expression was up-regulated in skeletal muscles associated with muscle regeneration induced by cardiotoxin-injection in normal dogs and mice. Manipulation of miR-188 expression using antisense oligo and mimic oligo RNAs alters the mRNA expression of the myogenic regulatory factors, MRF4 and MEF2C. Our results suggest that miR-188 is a new player that participates in the gene regulation process of muscle differentiation and that it may serve as a serum biomarker reflecting skeletal muscle regeneration.

Accelerometric outcomes of motor function related to clinical evaluations and muscle involvement in dystrophic dogs.

Duchenne muscular dystrophy (DMD) is an X-linked muscle disorder characterized by primary muscle degeneration. Patients with DMD reveal progressive muscle weakness leading to ambulatory dysfunction. Novel outcome measures are needed for more sensitive evaluation of therapeutic effects in clinical trials. Multiple parameters of acceleration and angular velocity are used as efficient indicators to quantify the motion of subjects, and these parameters have been recently applied for evaluation of motor function in DMD. In the present study, we evaluated gait in a dystrophic dog model, CXMDJ, by measuring three-axial acceleration and angular velocity over the course of months. Hybrid sensors were placed on the dorsal thoracic and lumbar regions of dogs to detect a wide range of acceleration (±8 G) and angular velocity (±1000 degrees per second). Multiple parameters showed lower values in dystrophic dogs compared to wild-type (WT) dogs, and declined over the course of months. Acceleration magnitude (AM) at the thoracic region in dystrophic dogs was prominently lower compared with WT dogs, even at the age of 2 months, the onset of muscle weakness, whereas AM at the lumbar region drastically declined throughout the disease course. The angular velocity index in the vertical direction in the lumbar region increased in dystrophic dogs, suggesting waddling at the girdle. These parameters also accordingly decreased with exacerbation of clinical manifestations and a decrease in spontaneous locomotor activity. The AM of dystrophic dogs was analyzed with magnetic resonance imaging to look for a correlation with crus muscle involvement. Results showed that acceleration and angular velocity are multifaceted kinematic indices that can be applied to assess outcomes in clinical trials for hereditary neuromuscular disorders including DMD.

Intra- and postoperative radiation therapy for an alpha-fetoprotein-producing pancreatic carcinoma.

We describe an alpha-fetoprotein (AFP)-producing pancreatic cancer irradiated intra- and postoperatively. A 64-year-old man with a hypoechic lesion in the pancreatic head and body was referred to us. On admission, his serum AFP level was markedly elevated (441 ng/ml). Computed tomography showed a 65 x 35 mm diameter tumor in the pancreatic head and body. The tumor periphery was enhanced with contrast medium. Angiography revealed faint tumor staining. After laparotomy, curative resection was impossible, because several arteries were embedded in the metastatic lymph nodes. Core needle biopsy was performed. The tumor was irradiated intraoperatively (25 Gy; area, 8 cm(2)). The diagnosis was moderately to poorly differentiated pancreatic adenocarcinoma. Immunohistochemical staining revealed AFP-positive cytoplasm in some cancer cells. The tumor shrunk significantly (longest axis, from 65 to 30 mm) after postoperative external beam radiation therapy (total, 40 Gy). The serum AFP level fell dramatically (from 441 to 2.5 ng/ml). However, distal gastrectomy for postradiation gastric ulceration was required. The patient did well without tumor regrowth or signs of liver or lymph node metastases 1 year 10 months after his first operation. In conclusion, we treated a rare AFP-producing pancreatic cancer with radiotherapy, which was effective. However, care is needed to avoid external beam radiation-induced gastrointestinal ulceration.

Management of unresectable hilar bile duct cancer--preoperative diagnosis, treatment selection, and clinical outcome.

BACKGROUND/AIMS: Hilar bile duct cancer progresses slowly but easily invades the nearby portal vein or hepatic artery. Thus, in some cases, curative resection is impossible, so we need to determine the best non-surgical treatments for this tumor. METHODOLOGY: We classified 98 patients with hilar bile duct cancer into 3 categories: a non-surgical group (34 cases), an exploratory laparotomy group (9 cases), and a surgical resection group (55 cases). Survival rates were examined in the light of clinical factors. RESULTS: In the non-surgical group, extensive vessel invasion was the most common reason for unresectability (13 cases), with broad biliary extension the second most common (11 cases). In the exploratory laparotomy group the most common reason for unresectability was severe vessel invasion (6 cases). Cumulative 1- and 2-year survival rates for patients with unresectable tumors without distant metastasis were 26.9% and 7.2%, respectively. One- and 2-year survival rates for patients with unresectable tumors and with total bilirubin of less than 2 mg/dL on discharge were 36.8% and 9.8%, respectively. The 1-year survival rate with placement of an expandable metallic stent was as high as 55.6%; without the stent it was 7.1% (P = 0.005). Radiation therapy gave a better prognosis than did no radiation (P = 0.01). CONCLUSIONS: Portal and arterial invasion were the principal reasons for unresectability. Use of an expandable metallic stent or radiation therapy, and a total bilirubin level of less than 2 mg/dL on discharge, were factors that enhanced survival in unresectable cases, but distant metastasis, dissemination, and poor general condition or liver function were negative factors for survival.