Modafinil exerts anti-inflammatory and anti-fibrotic effects by upregulating adenosine A2A and A2B receptors.

Adenosine receptor (AR) suppresses inflammation and fibrosis by activating cyclic adenosine monophosphate (cAMP) signaling. We investigated whether altered AR expression contributes to the development of fibrotic diseases and whether A2AAR and A2BAR upregulation inhibits fibrotic responses. Primary human lung fibroblasts (HLFs) from normal (NHLFs) or patients with idiopathic pulmonary fibrosis (DHLF) were used for in vitro testing. Murine models of fibrotic liver or pulmonary disease were developed by injecting thioacetamide intraperitoneally, by feeding a high-fat diet, or by intratracheal instillation of bleomycin. Modafinil, which activates cAMP signaling via A2AAR and A2BAR, was administered orally. The protein amounts of A2AAR, A2BAR, and exchange protein directly activated by cAMP (Epac) were reduced, while collagen and α-smooth muscle actin (α-SMA) were elevated in DHLFs compared to NHLFs. In liver or lung tissue from murine models of fibrotic diseases, A2AAR and A2BAR were downregulated, but A1AR and A3AR were not. Epac amounts decreased, and amounts of collagen, α-SMA, KCa2.3, and KCa3.1 increased compared to the control. Modafinil restored the amounts of A2AAR, A2BAR, and Epac, and reduced collagen, α-SMA, KCa2.3, and KCa3.1 in murine models of fibrotic diseases. Transforming growth factor-ß reduced the amounts of A2AAR, A2BAR, and Epac, and elevated collagen, α-SMA, KCa2.3, and KCa3.1 in NHLFs; however, these alterations were inhibited by modafinil. Our investigation revealed that A2AAR and A2BAR downregulation induced liver and lung fibrotic diseases while upregulation attenuated fibrotic responses, suggesting that A2AAR and A2BAR-upregulating agents, such as modafinil, may serve as novel therapies for fibrotic diseases.

Localized malignant pleural sarcomatoid mesothelioma misdiagnosed as benign localized fibrous tumor.

Localized malignant pleural mesothelioma (LMPM) is a rare tumor with good prognosis by surgical resection. We report an atypical case of malignant pleural sarcomatoid mesothelioma (SM) in an asymptomatic 65-year-old woman, who had no history of exposure to asbestos. She presented with a small pleural mass without pleural effusion and was misdiagnosed as a benign localized fibrous tumor (BLFT) on pathologic examination through a surgical tumor specimen. However, seven months later, the patient returned with serious cancerous symptoms. A large recurrent tumor mass was found within the chest wall invading at the old surgical resection site. SM, a subtype of LMPM, was confirmed with histopathogy and immunohistochemisty. In conclusion, malignant pleural mesothelioma (MPM) can present with typical radiologic finding similar to a BLFT, and has a wide histopathologic presentation in biopsy specimen. A thorough pathologic investigation should be attempted even when a pleural mass resembles benign, localized, and small on radiologic studies.

Discovery of novel peptides targeting pro-atherogenic endothelium in disturbed flow regions -Targeted siRNA delivery to pro-atherogenic endothelium in vivo.

Atherosclerosis occurs preferentially in arterial regions exposed to disturbed blood flow. Targeting these pro-atherogenic regions is a potential anti-atherogenic therapeutic approach, but it has been extremely challenging. Here, using in vivo phage display approach and the partial carotid ligation model of flow-induced atherosclerosis in mouse, we identified novel peptides that specifically bind to endothelial cells (ECs) exposed to disturbed flow condition in pro-atherogenic regions. Two peptides, CLIRRTSIC and CPRRSHPIC, selectively bound to arterial ECs exposed to disturbed flow not only in the partially ligated carotids but also in the lesser curvature and branching point of the aortic arch in mice as well as human pulmonary artery branches. Peptides were conjugated to branched polyethylenimine-polyethylene glycol polymer to generate polyplexes carrying siRNA targeting intercellular adhesion molecule-1 (siICAM-1). In mouse model, CLIRRTSIC polyplexes carrying si-ICAM-1 specifically bound to endothelium in disturbed flow regions, reducing endothelial ICAM-1 expression. Mass spectrometry analysis revealed that non-muscle myosin heavy chain II A (NMHC IIA) is a protein targeted by CLIRRTSIC peptide. Further studies showed that shear stress regulates NMHC IIA expression and localization in ECs. The CLIRRTSIC is a novel peptide that could be used for targeted delivery of therapeutics such as siRNAs to pro-atherogenic endothelium.

Spontaneous pneumothorax as the first manifestation of lung cancer: two case report.

Spontaneous pneumothorax (SP), as the first manifestation of lung cancer, is relatively rare, with reported occurrence rate of between 0.03% and 0.05%. The mechanism of concurrent pneumothorax with lung cancer is not clear, however several theories were proposed, including tumor necrosis mechanism and rupture of the bulla which contains tumor. We herein report two cases of lung cancer, in which the initial manifestations was only limited to SP. Without any radiologic abnormalities preoperatively, wedge resection of bullatous lung and subsequent histologic study followed. Pathologic study revealed the presence of bullatous change of the lung and combined lung cancer.

Detoxification of Glutaraldehyde Treated Porcine Pericardium Using L-arginine & NABH(4).

BACKGROUND: Calcification is the most frequent cause of clinical failure of bioprosthetic tissues fabricated from GA-fixed porcine valves or bovine pericardium. A multi-factorial approach using different mechanisms was recently developed to reduce the calcification of bioprosthetic tissues. The purpose of the present study was to evaluate the synchronized synergism of using L-arginine and NaBH(4), compared with ethanol and L-lysine, in glutaraldehyde treated porcine pericardium from the standpoint of calcification and tissue elasticity. MATERIALS AND METHODS: Porcine pericardium was fixed at 0.625% GA (7 days at room temperature after 2 days at 4℃). An interim step of ethanol (80%; 1 day at room temperature) or L-lysine (0.1 M; 2 days at 37℃) or L-arginine (0.1 M; 2 days at 37℃) was followed by completion of the GA fixation. A final step of NaBH(4) (0.1 M; 2 days at room temperature) was followed. Their tensile strength, thickness, and thermal stability were measured. Treated pericardia were implanted subcutaneously into three-week-old Sprague-Dawley rats for 8 weeks. Calcium content was assessed by atomic absorption spectroscopy and histology. RESULTS: L-arginine and NaBH(4) pretreatment (1.81±0.39 kgf/5 mm p=0.001, 0.30±0.08 mm p<0.001) significantly increased tensile strength and thickness compared with the control (0.53±0.34 kgf/5 mm, 0.10±0.02 mm). In a thermal stability test, L-arginine and NaBH(4) pretreatment (84.25±1.12℃, p=0.023) caused a significant difference from the control (86.25±0.00℃). L-lysine and NaBH(4) pretreatment (183.8±42.6 ug/mg, p=0.804), and L-arginine and NaBH(4) pretreatment (163.3±27.5 ug/mg, p=0.621) did not significantly inhibit calcification compared to the control (175.5±45.3 ug/mg), but ethanol and NaBH(4) pretreatment did (38.5±37.3 ug/mg, p=0.003). CONCLUSION: The combined pretreatment using L-arginine and NaBH(4) after GA fixation seemed to increase the tensile strength and thickness of porcine pericardium, fixed with GA. Additionally, it seemed to keep thermal stability. However it could not decrease the calcification of porcine pericardium fixed with GA. NaBH(4) pretreatment seemed to decrease the calcification of porcine pericardium fixed with GA, but only with ethanol.