Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell

BACKGROUND: Vascular smooth muscle cell proliferation plays an important role in the development of atherosclerosis. We previously reported that adiponectin, an adipocyte-specific plasma protein, accumulated in the human injured artery and suppressed endothelial inflammatory response as well as macrophage-to-foam cell transformation. The present study investigated the effects of adiponectin on proliferation and migration of human aortic smooth muscle cells (HASMCs). Methods and Results- HASMC proliferation was estimated by [(3)H] thymidine uptake and cell number. Cell migration assay was performed using a Boyden chamber. Physiological concentrations of adiponectin significantly suppressed both proliferation and migration of HASMCs stimulated with platelet-derived growth factor (PDGF)-BB. Adiponectin specifically bound to (125)I-PDGF-BB and significantly inhibited the association of (125)I-PDGF-BB with HASMCs, but no effects were observed on the binding of (125)I-PDGF-AA or (125)I-heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) to HASMCs. Adiponectin strongly and dose-dependently suppressed PDGF-BB-induced p42/44 extracellular signal-related kinase (ERK) phosphorylation and PDGF beta-receptor autophosphorylation analyzed by immunoblot. Adiponectin also reduced PDGF-AA-stimulated or HB-EGF-stimulated ERK phosphorylation in a dose-dependent manner without affecting autophosphorylation of PDGF alpha-receptor or EGF receptor. CONCLUSIONS: The adipocyte-derived plasma protein adiponectin strongly suppressed HASMC proliferation and migration through direct binding with PDGF-BB and generally inhibited growth factor-stimulated ERK signal in HASMCs, suggesting that adiponectin acts as a modulator for vascular remodeling.     

Increased incidence of autoantibodies to interleukin-1a in rheumatoid arthritis with interstitial lung disease

OBJECTIVE: To clarify the clinical significance of autoantibodies (auto-Ab) to interleukin-1alpha (IL-1alpha) in rheumatoid arthritis (RA) with interstitial lung disease (ILD), we examined the IL-1alpha auto-Ab level in serum of patients with RA with/without ILD. METHODOLOGY: We investigated the level of IL-1alpha auto-Ab in serum of 70 patients with RA with/without ILD and 40 control patients (CP). Levels of IL-1alpha auto-Ab were measured by radioimmunoassay, and serum was regarded as IL-1alpha auto-Ab positive at an auto-Ab level of more than 5 ng/mL. RESULTS: Interleukin-1alpha auto-Ab was detected in the serum of 30 out of 70 RA patients (42.9%), and six out of 40 CP (15%) (P < 0.05). Interleukin-1alpha auto-Ab were detected in the serum of 18 out of 32 patients with RA with ILD (56.2%) and 12 out of 38 patients with RA without ILD (31.5%). The positive rate of these autoantibodies in RA with ILD was significantly higher than that in RA without ILD (P < 0.05). Although C-reactive protein, immunoglobulin G, rheumatoid factor and rheumatoid arthritis particle agglutination levels in serum from patients with RA with ILD were not significantly different between the IL-1alpha auto-Ab-positive and -negative groups, the lactate dehydrogenase level (LDH) and AaDO, in the IL-1alpha auto-Ab-positive group were significantly higher than those in the negative group (LDH: P < 0.001, AaDO2: P < 0.05). CONCLUSION: These results suggest that IL-1alpha auto-Ab are generated in response to the immunoinflammatory process of ILD in RA, and these autoantibodies may neutralize and regulate the IL-1alpha activity.     

Prevention of variceal recurrence, bleeding, and death in cirrhosis patients with hypersplenism, especially those with severe thrombocytopenia

BACKGROUND/AIMS: We investigated the impact of different treatments on the prognosis of cirrhosis patients with esophageal varices and thrombocytopenia. METHODOLOGY: This prospective study enrolled 52 cirrhosis patients with esophageal varices and hypersplenism (platelet count < 50,000/mm3). In 26 patients, endoscopic variceal ligation plus partial splenic embolization were performed, while endoscopic variceal ligation alone was done in 26 patients. Endoscopic variceal ligation was repeated until complete eradication of varices was achieved. Partial splenic embolization was performed using the Seldinger method and embolic material was injected until a 60% to 80% reduction of splenic blood flow was achieved. The primary endpoints during the follow-up period included recurrence of varices, variceal bleeding, and death. RESULTS: Comparison of endoscopic variceal ligation plus partial splenic embolization with endoscopic variceal ligation alone by multivariate analysis showed a relative risk ratio of 0.390 (95% CI [0.178-0.854]; p = 0.024) for new varices, 0.191 (95% CI [0.047-0.780]; p = 0.021) for variceal bleeding, and 0.193 (95% CI [0.053-0.699]; p = 0.012) for death. CONCLUSIONS: These results suggest that endoscopic variceal ligation plus partial splenic embolization can prevent variceal recurrence, bleeding, and death in cirrhosis patients with esophageal varices and thrombocytopenia.     

Effect of stretch on improvement of muscular contractures in rats

[Purpose] The purpose of this study was to investigate how a stretching torque affects muscular contractures. [Subjects] The subjects of this study were 48 male Wistar rats. [Methods] Subjects were divided into 4 groups as follows: Group 1 was the control; Group 2 had muscles in continuous fixation; Group 3 had muscles stretched in the direction of dorsiflexion by a spring balancer set at a torque of 0.3N for a period of 30 minutes after continuous fixation; and Group 4 had muscles stretched in the direction of dorsiflexion by a spring balancer set at a torque of 3.0N for a period of 30 minutes after continuous fixation. Joint fixation periods were for 2 and 4-weeks. Ankle joint range of motion and soleus flexibility were analyzed. [Results] For the 2-week joint fixation, soleus flexibility in Group 4 showed an increase compared with that of Group 3. For both fixation periods, range of motion in Group 4 showed an increase compared with that of Group 3. [Conclusion] For both fixation periods, stretching improved joint range of motion. In the 2-week joint fixation, soleus flexibility improved. However, soleus flexibility did not improve in the 4-week joint fixation.Key words: Muscular contracture, Stretching, Muscular flexibility     

ASO Visual Abstract: Fecal Microbes Associated with the Outcomes After Esophagectomy in Patients with Esophageal Cancer

Annals of Surgical Oncology -     

Matrix metalloproteinase 9 (MMP-9) in patients with rheumatoid arthritis

Matrix metalloproteinase 9 (MMP-9) degrades type IV collagen, gelatin, type V collagen and type XI collagen. We measured proMMP-9 and proMMP-9-TIMP-1 complex in sera and joint fluids by sandwich ELISA, and immunohistochemically examined the expression of this enzyme in joint tissues from patients with rheumatoid arthritis (RA). ProMMP-9 was purified from the culture medium of HT 1080 cells by the three steps of chromatography. Purified proMMP-9 and activated MMP-9 by aminophenylmercuric acetate showed two bands of 92 and 67 kDa on gelatin zymography. We raised two monoclonal antibody clones, named 2G9 and 8G7, against proMMP-9. 2G9 and 8G7 reacted with proMMP-9 in western blotting and these clones reacted not only with proMMP-9, but also with proMMP-9-TIMP-1 complex in sandwich ELISA, respectively. The proMMP-9 concentration in 86 sera (749.4±940.2 ng/ml) and 54 joint fluids (4539.9±7681.5 ng/ml) from patients with RA was significantly higher than those of patients with osteoarthritis (15 sera: 139.0±149.6 ng/ml; 16 joint fluids: 655.0±1982.8 ng/ml) and control (37 sera: 266.7±120.4 ng/ml; three joint fluids: 0 ng/ml). The immunohistochemistry with 2G9 monoclonal antibody showed that proMMP-9 were expressed in the neutrophils and the monocytes-macrophages which diffusely infiltrated in the sublining layer of rheumatoid synovium. In addition, the osteoclasts along subchondral bone were also intensively stained. The proMMP-9 concentration in joint fluids from 39 RA patients was positively correlated to the count of proMMP-9 positive cells in RA synovium (r=0.607) and to the score of diffuse infiltrates of lymphocytes (r=0.720). However, it did not show correlation to the stage and the class defined by Steinbrocker and to the other clinical laboratory data. Our results suggest that proMMP-9 actively participates in joint destruction of RA through the expression of neutrophils and monocytes-macrophages and is regulated by lymphocytes.     

Genetic variant of the renin-angiotensin system and prevalence of type 2 diabetes mellitus: a modest but significant effect of aldosterone synthase

Recent genome-wide association studies have identified multiple variants that confer risk of type 2 diabetes mellitus (DM). However, established associations explain only a part of the heritability. Thus, even at the genome-wide association studies era, candidate gene approach should be still useful. Recent interventional studies against the renin-angiotensin system (RAS) showed reduction in new onset of DM, implying the system is involved in the onset. We substantiated the hypothesis that genetic variants of RAS have significant association with prevalence of DM. We enrolled to the study consecutive 782 subjects who had consulted our hospitals for mainly lifestyle related diseases. They consisted of 282 (36.1 %) diabetes cases. Genotypes were assayed with genomic DNA for conventional four genes of the RAS, i.e., angiotensin converting enzyme (ACE) insertion/deletion variant, angiotensinogen (AGT) M235T variant, angiotensin II type I receptor (AT1) A1166C variant, and aldosterone synthase (CYP11B2) C-344T variant. Association between the genetic variants of the RAS and prevalence of type 2 DM was tested. A significant association of DM and CYP11B2 genotype was obtained. There was no significant association between DM and ACE, AGT and AT1 variants. A multivariate logistic regression showed that age, gender, and CYP11B2 genotype were independent factors for association to diabetes, the DM risk of CC/CT to TT being 1.40 (95 % CI 1.04–1.90, p = 0.029). Thus, it is concluded that a genetic variant of the RAS should have a modest but significant impact on the onset of type 2 diabetes mellitus.