Evaluation of Therapeutic Effects of Astaxanthin on Impairments in Salivary Secretion

The involvement of reactive oxygen species (ROS) in the pathophysiology of Sjögren’s syndrome (SS), an autoimmune disorder, and irradiation-induced impairments in salivary secretion has been reported. Meanwhile, the strong antioxidant astaxanthin (Ast) has been suggested to have therapeutic effects on various diseases. In the present study, we examined the ROS scavenging capacity of Ast using a human salivary gland epithelial cell line (HSY) and investigated the effects of Ast on salivary secretion in a mouse model of irradiation-induced salivary gland dysfunction. Furthermore, we performed a clinical study of Ast in six SS patients and six normal individuals, quantifying the volume of saliva secretion and the level of oxidative stress markers in the saliva. Ast partially suppressed hydrogen peroxide-induced ROS in HSY cells. The mouse model demonstrated that the pre-administration of Ast resulted in the suppression of irradiation-induced hyposalivation. Furthermore, the administration of Ast appeared to increase salivary output in both the SS and normal groups. The level of oxidative stress marker, hexanoyl-lysine, in the saliva was reduced after Ast intake. These results suggest that Ast might act as an ROS scavenger, providing benefits to SS patients with impaired salivary secretion

Complement-5 Inhibition Deters Progression of Fulminant Hepatitis to Acute Liver Failure in Murine Models

BACKGROUND & AIMS: Acute liver failure (ALF) is a life-threatening condition with limited treatment alternatives. ALF pathogenesis seemingly involves the complement system. However, no complement-targeted intervention has been clinically applied. In this study, we aimed to investigate the potential of Complement-5 (C5)-targeted ALF treatment. METHODS: ALF was induced in C5-knockout (KO, B10D2/oSn) mice and their wild-type (WT) counterparts (B10D2/nSn) through intraperitoneal lipopolysaccharide (LPS) and d-galactosamine (D-GalN) administration. Thereafter, monoclonal anti-C5 antibody (Ab) or control immunoglobulin was administered intravenously. Furthermore, a selective C5a-receptor (C5aR) antagonist was administered to WT mice to compare its efficacy with that of anti-C5-Ab-mediated total C5 inhibition. We clarified the therapeutic effect of delayed anti-C5-Ab administration after LPS/D-GalN challenge. We also assessed the efficacy of anti-C5-Ab in another ALF model, using concanavalin-A. RESULTS: Liver injury was evident 6 hours after LPS/D-GalN administration. C5-KO and anti-C5-Ab treatment significantly improved overall animal survival and significantly reduced serum transaminase and high-mobility group box-1 release with decreased histological tissue damage. This improvement was characterized by significantly reduced CD41+ platelet aggregation, maintained F4/80+ cells, and less infiltration of CD11+/Ly6-G+ cells with lower cytokine/chemokine expression. Furthermore, C5-KO and anti-C5-Ab downregulated tumor necrosis factor-α production by macrophages before inducing marked liver injury. Moreover, single-stranded-DNA cells and caspase activation were reduced, indicating significant attenuation of apoptosis. Anti-C5-Ab treatment protected the liver more effectively than the C5aR antagonist, and its delayed doses were hepatoprotective. In addition, anti-C5-Ab treatment was effective against concanavalin-A-induced ALF. CONCLUSIONS: C5 inhibition effectively suppresses progression to ALF in mice models of fulminant hepatitis, serving as a new potential treatment strategy for ALF

Double radiofrequency ablation is more extensive with a spherical zone shape compared to single ablation in a pig liver model

Objective : We compared the duration of ablation and the area of coagulation necrosis between a single ablation method (SAM) and a double ablation method (DAM) with a ’multitined expandable’ electrode (LeVeen 2cm) for radiofrequency ablation (RFA) using pig liver. Method : In the SAM group, ablation was completed after the first roll-off. In the DAM group, an additional ablation was performed to achieve a second roll-off. The comparison was made of the time required for roll-off and the extent of coagulation necrosis between the both groups. The Ellipticity index (EI) quantitatively describes the shape of the general RF ablation zone in the axial plane. Results : There was no statistically significant difference in the interval until the first roll-off between both groups (SAM group : 100.7±24.7 seconds vs DAM group : 103.2±37.7 seconds, P=0.43). In the DAM group, the interval from the start of the additional ablation until the second roll-off was 154.0±86.9 seconds, longer than the interval for the first roll-off (P=0.023). The extent of coagulation necrosis was significantly more extensive in the DAM group (axial diameter, mean±SD, 26.2±2.8 mm)×(maximal diameter : 29.3±1.6 mm)× (minimal diameter : 26.5±3.6 mm) compared to the SAM group with (23.0±3.3 mm)×(23.7± 3.1 mm)×(20.0±2.5 mm), respectively. Although there was no statistically significant difference in the EI between both groups, macroscopically, the shape of coagulation necrosis tended to be non-spherical in the SAM group and spherical in the DAM group. Conclusions : The DAM with a ’multitined expandable’ electrode was more extensive with a spherical zone shape compared to the SAM

Complement 5 Inhibition Ameliorates Hepatic Ischemia/reperfusion Injury in Mice, Dominantly via the C5a-mediated Cascade

[Background. ] Hepatic ischemia/reperfusion injury (IRI) is a serious complication in liver surgeries, including transplantation. Complement activation seems to be closely involved in hepatic IRI; however, no complement-targeted intervention has been clinically applied. We investigated the therapeutic potential of Complement 5 (C5)-targeted regulation in hepatic IRI. [Methods. ] C5-knockout (B10D2/oSn) and their corresponding wild-type mice (WT, B10D2/nSn) were exposed to 90-minute partial (70%) hepatic ischemia/reperfusion with either anti-mouse-C5 monoclonal antibody (BB5.1) or corresponding control immunoglobulin administration 30 minutes before ischemia. C5a receptor 1 antagonist was also given to WT to identify which cascade, C5a or C5b-9, is dominant. [Results. ] C5-knockout and anti-C5-Ab administration to WT both significantly reduced serum transaminase release and histopathological damages from 2 hours after reperfusion. This improvement was characterized by significantly reduced CD41+ platelet aggregation, maintained F4/80+ cells, and decreased high-mobility group box 1 release. After 6 hours of reperfusion, the infiltration of CD11+ and Ly6-G+ cells, cytokine/chemokine expression, single-stranded DNA+ cells, and cleaved caspase-3 expression were all significantly alleviated by anti-C5-Ab. C5a receptor 1 antagonist was as effective as anti-C5-Ab for reducing transaminases. [Conclusions. ] Anti-C5 antibody significantly ameliorated hepatic IRI, predominantly via the C5a-mediated cascade, not only by inhibiting platelet aggregation during the early phase but also by attenuating the activation of infiltrating macrophages/neutrophils and hepatocyte apoptosis in the late phase of reperfusion. Given its efficacy, clinical availability, and controllability, C5-targeted intervention may provide a novel therapeutic strategy against hepatic IRI

Historical changes of hospitalization in patients with hepatocellular carcinoma considering for clinical path preparation

We examined the hospitalization time in 346 patients with hepatocellular carcinoma who were treated between January 1991 and March 2002 (486 admissions). A newly introduced IVR CT system and an advanced catheter shortened the mean time from 65.0 (1991) to 35.6 (2001) days in patients who underwent transcatheter arterial embolization (TAE). For patients having TAE combined with percutaneous ethanol infusion (PEI), the mean time was shortened from 156.5 to 48.7 days. In those who underwent PEI, the values were 56.0 and 36.8 days, respectively. In those who underwent radio frequency ablation (RFA), the mean time in 2001 was 25.3 days. Overall, the mean time was shortened from 60.5 to 38.0 days. In particular, the mean time (41.0 days) after 1999, when the IVR CT system and RFA were introduced, was significantly shorter than that before their introduction (58.9 days). Advances in instruments and procedures for TAE have greatly shortened the hospitalization period. In patients who underwent PEI, the rate of decrease in the mean time was small and it is difficult decrease their length of hospital stay ; therefore, RFA may be frequently employed in the future

Rho-associated protein kinase and cyclophilin a are involved in inorganic phosphate-induced calcification signaling in vascular smooth muscle cells

Arterial calcification, a risk factor of cardiovascular events, develops with differentiation of vascular smooth muscle cells (VSMCs) into osteoblast-like cells. Cyclophilin A (CypA) is a peptidyl-prolyl isomerase involved in cardiovascular diseases such as atherosclerosis and aortic aneurysms, and rho-associated protein kinase (ROCK) is involved in the pathogenesis of vascular calcification. CypA is secreted in a ROCK activity-dependent manner and works as a mitogen via autocrine or paracrine mechanisms in VSMCs. We examined the involvement of the ROCK-CypA axis in VSMC calcification induced by inorganic phosphate (Pi), a potent cell mineralization initiator. We found that Pi stimulated ROCK activity, CypA secretion, extracellular signal-regulated protein kinase (ERK) 1/2 phosphorylation, and runt-related transcription factor 2 expression, resulting in calcium accumulation in rat aortic smooth muscle cells (RASMCs). The ROCK inhibitor Y-27632 significantly suppressed Pi-induced CypA secretion, ERK1/2 phosphorylation, and calcium accumulation. Recombinant CypA was found to be associated with increased calcium accumulation in RASMCs. Based on these results, we suggest that autocrine CypA is mediated by ROCK activity and is involved in Pi-induced ERK1/2 phosphorylation following calcification signaling in RASMCs

Influence of an artificial pleural effusion technique on cardio-pulmonary function and autonomic activity

Objective : Percutaneous treatment of hepatocellular carcinoma (HCC) located directly under the diaphragm is problematic because ultrasonic imaging is difficult, and the lung may be injured during the procedure. It has been reported that an infusion of 5% glucose solution into the thoracic cavity enables percutaneous treatment in such cases. However, the safety aspects of this have not been investigated. In this study, variations in heart rate and changes in circulatory and respiratory dynamics were examined during the infusion of artificial pleural effusion directly under the diaphragm in patients with HCC. Method : The subjects were 13 patients with an HCC directly under the diaphragm. About 500 ml of a 5% glucose solution was infused into the thoracic cavity, and mean blood pressure, heart rate, and oxygen saturation were measured. Holter electrocardiography was simultaneously recorded to evaluate autonomic nerve function. To analyze variations in heart rate, the low-frequency waves (LF : 0.04-0.15 Hz), high-frequency waves (HF : 0.15-0.40 Hz, an index of parasympathetic nerve activity), and the LF/HF ratio (index of sympathetic nerve activity) were examined. The above parameters were measured before, during (when infusion of the half the planned volume was complete), and after infusion were compared. Results : No significant changes in the mean blood pressure or heart rate were found. Oxygen saturation was significantly decreased during and after the infusion. The HF value was slightly higher after infusion and the LF value was significantly increased during infusion. The LF/HF ratio was significantly increased during infusion, and this increase persisted after infusion. Conclusions : The infusion of artificial pleural effusion had no effect on circulatory dynamics, but transiently affected respiratory functions. It was also revealed that infusion stimulated the parasympathetic nerves