Arginase Inhibition by Ethylacetate Extract of Caesalpinia sappan Lignum Contributes to Activation of Endothelial Nitric Oxide Synthase

Caesalpinia sappan (C. sappan) is a medicinal plant used for promoting blood circulation and removing stasis. During a screening procedure on medicinal plants, the ethylacetate extract of the lignum of C. sappan (CLE) showed inhibitory activity on arginase which has recently been reported as a novel therapeutic target for the treatment of cardiovascular diseases such as atherosclerosis. CLE inhibited arginase II activity prepared from kidney lysate in a dose-dependent manner. In HUVECs, inhibition of arginase activity by CLE reciprocally increased NOx production through enhancement of eNOS dimer stability without any significant changes in the protein levels of eNOS and arginase II expression. Furthermore, CLE-dependent arginase inhibition resulted in increase of NO generation and decrease of superoxide production on endothelium of isolated mice aorta. These results indicate that CLE augments NO production on endothelium through inhibition of arginase activity, and may imply their usefulness for the treatment of cardiovascular diseases associated with endothelial dysfunction.     

Relationship between chronic kidney disease and risk of coronary heart disease in Korean men

There have been many epidemiological researches of chronic kidney disease (CKD), accompanied by an increase in the incidence of coronary heart disease (CHD). However, as far as we know, little research has been done to examine the extent of the relationship between CKD and CHD as estimated by Framingham risk score (FRS) in Korean men. CKD was defined as either proteinuria or an eGFR of < 60 mL/min per 1.73 m(2). The FRS has been used to predict the 10-yr risk of coronary events and usually divided into three levels of risk < 10% (low), 10%-19% (intermediate) and ≥ 20% (high). We defined FRS ≥ 10% as more-than-a-moderate CHD risk group and FRS ≥ 20% as a high CHD risk group, respectively. After adjusting for covariates, multivariable-adjusted logistic regression analyses showed a strong statistical significant relationship between CKD and high risk of CHD (adjusted OR, 1.95 [95% CI, 1.32-2.87]). Dipstick urinalysis and eGFR can be readily measured in most clinical settings. The measurement of kidney function may represent a relatively inexpensive and efficient way to identify individuals at higher risk for CHD.     

Selection of optimal passage of bone marrow-derived mesenchymal stem cells for stem cell therapy in patients with amyotrophic lateral sclerosis

Mesenchymal stem cells (MSCs) obtained from bone marrow (BM) are currently used as an alternative therapy in amyotrophic lateral sclerosis (ALS) patients. Selection of optimal passages of autologous BM-derived MSCs during long-term in vitro expansion is important for clinical trials in patients with ALS. We isolated and expanded MSCs from the BM of eight ALS patients to analyze the growth kinetics, differentiation potential, cellular surface antigen expression, karyotype modifications and secretion of various cytokines during long-term culture. The morphology and size of the cells changed from small and spindle-like cells to large and polygonal types in later passages. The growth rate of the MSCs was highest in the third passage, followed by a gradual decrease. There were no special modifications of cell surface antigens or the karyotype of the MSCs from the first to the tenth passage. MSCs in the fourth passage were differentiated into adipocytes, osteocytes and chondrocytes. When we analyzed the cultured media of MSCs at the third, fifth, seventh and ninth passages, IL-6, VEGF and IL-8 showed high expression, with more than 50 pg/10,000 cells at these passages; however, their expression progressively decreased with additional passages. In addition, secretion of IL-15, GM-CSF, IL-10, PDGF-bb, G-CSF, IL-1β, basic FGF and IFN-γ gradually decreased over prolonged culture. We suggest that MSCs at earlier passages are more suitable for stem cell therapy in ALS patients because of their stability and more potent anti-inflammatory and neuroprotective properties.     

Early changes in vasoreactivity after simulated microgravity are due to an upregulation of the endothelium-dependent nitric oxide/cGMP pathway

Emerging evidence suggests that nitric oxide (NO) plays a pivotal role in the mechanism of vascular hyporesponsiveness contributing to microgravity-induced orthostatic intolerance. The cellular and enzymatic source of the NO, however, remains controversial. In addition, the time course of the endothelial-dependent contribution remains unstudied. We tested the hypotheses that the change in vasoresponsiveness seen in acute (3-day) hindlimb unweighted (HLU) animals is due to an endothelium-dependent mechanism and that endothelial-dependent attenuation in vasoreactivity is due to endothelial nitric oxide synthase (NOS-3) dependent activation. Vasoreactivity was investigated in rat aortic rings following acute HLU treatment. Dose responsiveness to norepinepherine (NE) was depressed after 3-day HLU [1,338 ± 54 vs. 2,325 ± 58 mg at max (NE), HLU vs. C, P < 0.001]. However, removal of the endothelium restored the vascular contractility to that of C. In addition, 1H-oxadiazole quinoxalin-1-one (ODQ), a soluble guanylyl cyclase inhibitor, restored the reduced vasoconstrictor responses to phenylephrine (PE) seen in 3-day HLU rings (1.30 ± 0.10 vs. 0.53 ± 0.07 g, HLU + ODQ vs. HLU, P = 0.0001). Ca⁺ dependent nitric oxide synthase (NOS) activity was increased, as was vascular NO products as a result of HLU. While NOS-3 expression was not increased in HLU rats, phosphorylation of NOS-3 at serine-1177 (an activator of NOS-3) was increased while phosphorylation of serine-495 (an inactivator of NOS-3) was decreased. These findings demonstrate that changes in vasoresponsiveness in the acute HLU model of microgravity are due to an upregulation of the endothelial-dependent NO/cGMP pathway through NOS phosphorylation.     

Development of isoform-specific monoclonal antibodies against human IL-18 binding protein

Interleukin-18 binding protein (IL-18BP) is a soluble antagonist of IL-18 originally discovered while attempting to isolate a soluble receptor by using IL-18-ligand affinity column. IL-18BP has four isoforms (a, b, c, and d) in humans and two isoforms (c and d) in mice. The human isoforms IL-18BPa and IL-18BPc neutralize IL-18 activity sufficiently at an equimolar ratio; however IL-18BPb and IL-18BPd isoforms lack a complete Ig domain at C-terminus and lose the ability to neutralize IL-18 activity. Mouse IL-18BPc and IL-18BPd isoforms, possessing a similar complete Ig domain, also neutralize the biological activity of mouse IL-18 at an equimolar ratio. Here we expressed recombinant proteins of the active human IL-18BP isoforms and developed monoclonal antibodies (MAbs) against human IL-18BP a and c isoforms. We obtained two MAbs (78-4 and 38-3) of human IL-18BPa and two MAbs (18-7 and 29-6) of human IL-18BPc. The MAb clones 18-7 and 29-6 specifically recognized recombinant IL-18BPc in Western blot analyses and ELISA, whereas the MAb clone 78-4 recognized both isoforms in Western blot analyses, but only human IL-18BPa isoform in ELISA. We developed a sandwich ELISA by using the monoclonal antibody specific to human IL-18BPa isoform. The isoform-specific anti-human IL-18BP MAb may be a useful tool in categorizing a distinct group of patients from various autoimmune diseases related to IL-18BP.     

Palliative chemotherapy preferences and factors that influence patient choice in incurable advanced cancer

OBJECTIVE: To determine the extent of informed decision-making and treatment preference of Korean patients receiving palliative chemotherapy. METHODS: We assessed 138 patients (median age: 58 years; 73% male) with advanced cancer who had received at least one cycle of chemotherapy. General demographic information, the extent of information received, patient preferences for palliative chemotherapy and randomized trials were determined using structured patient interviews. We investigated the survival threshold for justifying toxicity, the factors influencing individual preference for chemotherapy and the attitude of patients towards randomized trials. RESULTS: Before chemotherapy, 72.1% of patients were given information about adverse events of treatment, but only 39.5% were told of alternative treatments. There was significant inter-individual variability in willingness to accept chemotherapy, as well as a wide range of thresholds. Patients reporting higher quality of life were more likely to judge treatment as acceptable. When given the choice for randomization for conventional chemotherapy, investigational agents or supportive care, patients usually refused enrollment into randomized trials. CONCLUSION: Self-assessed quality of life was a significant predictor of stronger preference for chemotherapy. In the palliative setting, good doctor-patient communications and consideration of patients' preferences are necessary for making decisions about proper treatment.     

Prognostic factors for survival of patients with advanced gastric cancer treated with cisplatin-based chemotherapy

Purpose The present study evaluated baseline patient- or tumor-related prognostic factors in patients with advanced gastric adenocarcinoma. Patients and methods A total of 304 consecutive patients with newly diagnosed metastatic or recurrent gastric cancer treated with one or more cycles of cisplatin-based chemotherapy at the Korea Cancer Center Hospital were enrolled in the current study. Results Among the original 304 patients, only 4 patients were alive at the time of this analysis. The median survival for all patients was 7.3 (95% CI, 6.3–8.2) months. Five independent prognostic factors were identified by a multivariate analysis: poor performance status (hazard ratio [HR], 1.46; 95% CI, 1.32–2.92), elevated total bilirubin (HR, 2.04; 95% CI, 1.73–2.35), presence of peritoneal metastasis (HR, 1.73; 95% CI, 1.57–1.90), presence of bone metastasis (HR, 3.11; 95% CI, 2.69–3.53), and more than 1 metastatic site (HR, 1.22; 95% CI, 1.06–1.38). A prognostic index was constructed that divided the patients into a good (n = 162), moderate (n = 82), or poor (n = 60) risk group. The 1-year survival rates for the good, moderate, and poor risk groups were 34.6, 20.7, and 1.7%, respectively, and the survival differences among the groups were highly significant (P < 0.0001). Conclusion Five prognostic factors were identified from patients receiving first-line cisplatin-based chemotherapy for advanced gastric cancer. A simple prognostic index was then developed that produced distinct survival rates among the different risk groups. Therefore, this prognostic model could help clinicians and patients in clinical decision-making and treatment tailoring based on the estimated prognosis.