Bioactive Secondary Metabolites Isolated from the Antarctic Lichen Himantormia lugubris.

Two new depsidones, himantormiones A and B (1 and 2) were isolated and identified from the Antarctic lichen, Himantormia lugubris (Parmeliaceae), with seven known compounds (3-9). The structures of two new compounds (1 and 2) were determined by means of spectroscopic analyses, including 1D and 2D NMR and HR-MS. The isolated compounds were tested for antimicrobial and cytotoxic activities, where himantormione B (2) exhibited inhibitory effect against Staphylococcus aureus with the IC50 value of 7.01±0.85 mM. Compound 2 also exhibited strong cytotoxic activity against HCT116 cells (colon cancer) with the EC50 value of 1.11±0.85 µM, where that of the positive control, 5-fluouracil, was 9.4±1.90 µM.

Bioactive Terphenyls Isolated from the Antarctic Lichen Stereocaulon alpinum.

Three p-terphenyls (2-4)-2-hydroxy-3,5-dimethoxy-p-terphenyl (2), 2-hydroxy-3,6-dimethoxy-p-terphenyl (3), and 2,3,5,6-tetramethoxy-p-terphenyl (4)-were isolated for the first time as natural products along with seven known compounds (1, 5-10) from the Antarctic lichen Stereocaulon alpinum. Structures of the new compounds were elucidated by comprehensive analyses of 1D and 2D NMR and HREIMS experiments. Compound 3 exhibited cytotoxicity against HCT116 cells with the IC50 value of 3.76 ± 0.03 µM and also inhibited NO production in LPS-induced RAW264.7 macrophages with the IC50 value of 22.82 ± 0.015 µM.

Anticancer Activity of 2-O-caffeoyl Alphitolic Acid Extracted from the Lichen, Usnea barbata 2017-KL-10.

Colorectal cancer is one of the life-threatening ailments causing high mortality and morbidity worldwide. Despite the innovation in medical genetics, the prognosis for metastatic colorectal cancer in patients remains unsatisfactory. Recently, lichens have attracted the attention of researchers in the search for targets to fight against cancer. Lichens are considered mines of thousands of metabolites. Researchers have reported that lichen-derived metabolites demonstrated biological effects, such as anticancer, antiviral, anti-inflammatory, antibacterial, analgesic, antipyretic, antiproliferative, and cytotoxic, on various cell lines. However, the exploration of the biological activities of lichens' metabolites is limited. Thus, the main objective of our study was to evaluate the anticancer effect of secondary metabolites isolated from lichen (Usnea barbata 2017-KL-10) on the human colorectal cancer cell line HCT116. In this study, 2OCAA exhibited concentration-dependent anticancer activities by suppressing antiapoptotic genes, such as MCL-1, and inducing apoptotic genes, such as BAX, TP53, and CDKN1A(p21). Moreover, 2OCAA inhibited the migration and invasion of colorectal cancer cells in a concentration-dependent manner. Taken together, these data suggest that 2OCAA is a better therapeutic candidate for colorectal cancer.

RIFLE classification in geriatric patients with acute kidney injury in the intensive care unit.

BACKGROUND: The RIFLE classification is widely used to assess the severity of acute kidney injury (AKI), but its application to geriatric AKI patients complicated by medical problems has not been reported. METHODS: We investigated 256 geriatric patients (≥65 years old; mean age, 74.4 ± 6.3 years) who developed AKI in the intensive care unit (ICU) according to the RIFLE classification. Etiologic, clinical, and prognostic variables were analyzed. RESULTS: They were categorized into RIFLE-R (n = 53), RIFLE-I (n = 102), and RIFLE-F (n = 101) groups. The overall in-hospital mortality was 39.8 %. There were no significant differences in RIFLE category between survivors and non-survivors. Survivors had significantly less needs for a ventilator and vasopressor, and lower number of failing organs. Survivors had higher systolic blood pressure, hemoglobin level, and serum albumin levels. We performed a logistic regression analysis to identify the independent predictors of in-hospital mortality. In a univariate analysis, hypertension, chronic kidney disease, RIFLE classification, number of failing organs, need for a ventilator and vasopressor, systolic blood pressure, hemoglobin level, and serum albumin levels were identified as prognostic factors of in-hospital mortality. However, in a multivariate analysis, hypertension, chronic kidney disease, number of failing organs, and serum albumin levels were independent risk factors, with no significant difference for in-hospital mortality with the RIFLE classification. CONCLUSION: The RIFLE classification might not be associated with mortality in geriatric AKI patients in the ICU. In geriatric patients with AKI, various factors besides severity of AKI should be considered to predict mortality.

Extracellular volume expansion and the preservation of residual renal function in Korean peritoneal dialysis patients: a long-term follow up study.

INTRODUCTION: In chronic peritoneal dialysis patients, preservation of residual renal function (RRF) is a major determinant of patient survival, and maintaining sufficient intravascular volume has been hypothesized to be beneficial for the preservation of RRF. The present study aimed to test this hypothesis using multifrequency bioimpedence analyzer (MFBIA), in Korean peritoneal dialysis patients. METHODS: A total of 129 patients were enrolled in this study. The baseline MFBIA was checked, and the patients were divided into the following two groups: group 1, extracellular water per total body water (ECW/TBW) < median, group 2, ECW/TBW > median. We followed up the patients, and then we analyzed the changes in the urine output (UO) and the solute clearance (weekly uKt/V) in each group. Data associated with patient and technical survivor were collected by medical chart review. The volume measurement was made using Inbody S20 equipment (Biospace, Seoul, Korea). We excluded the anuric patients at baseline. RESULT: The median value of ECW/TBW was 0.396. The mean patient age was 49.74 ± 10.01 years, and 62.1 % of the patients were male; most of the patients were on continuous ambulatory peritoneal dialysis (89.1 %). The mean dialysis vintage was 26.20 ± 28.71 months. All of the patients were prescribed hypertensive medication, and 48.5 % of the patients had diabetes. After 25.47 ± 6.86 months of follow up, ΔUO and Δweekly Kt/V were not significantly different in the two groups as follows: ΔUO (-236.07 ± 185.15 in group 1 vs -212.21 ± 381.14 in group 2, p = 0.756); Δ weekly Kt/v (-0.23 ± 0.43 in group 1 vs -0.29 ± 0.49 in group 2, p = 0.461). The patient and technical survivor rate was inferior in the group 2, and in the multivariable analysis, initial hypervolemia was an independent factor that predicts both of the patient mortality [HR 1.001 (1.001-1.086), p = 0.047] and the technical failure [HR 1.024 (1.001-1.048), p = 0.042]. CONCLUSIONS: Extracellular volume expansion, measured by MFBIA, does not help preserve residual renal function, and is harmful for the technical and patient survival in Korean peritoneal dialysis patients.

Cardiac valve calcification is associated with presence and severity of coronary artery disease in patients with pre-dialysis chronic kidney disease.

BACKGROUND: Cardiac valve calcification is common in chronic kidney disease (CKD) patients. Coronary artery disease (CAD) is the one of major causes for increased cardiovascular mortality in CKD patients. We hypothesized that cardiac valve calcification is associated with the presence and the severity of CAD in pre-dialysis CKD patients. METHODS: This study included 1166 patients who underwent transthoracic echocardiography for assessment of cardiac valve calcification and coronary angiography for assessment of CAD. The patients were divided into two groups according to estimated glomerular filtration rate (eGFR): pre-dialysis CKD group (n = 215, eGFR < 60 ml/min/1.73 m(2)) and non-CKD group (n = 951, eGFR ≥ 60 ml/min/1.73 m(2)). RESULTS: In the pre-dialysis CKD group, subjects with aortic valve calcification (AVC), mitral valve calcification (MVC), and at least one valve calcification had more severe CAD compared with those without AVC, MVC, and any valve calcification. Multivariate analysis showed that pre-dialysis CKD patients who had AVC, MVC, and at least one valve calcification were 3.02 times (P = 0.033), 3.73 times (P = 0.029), and 3.31 times (P = 0.012) more likely to have CAD compared with those without AVC, MVC, and any valve calcification, respectively. However, in the non-CKD group, there was no association between cardiac valve calcification and the severity/presence of CAD. CONCLUSIONS: Cardiac valve calcification is associated with the presence and severity of CAD in pre-dialysis CKD. Assessment of cardiac valve calcification by means of transthoracic echocardiography could be a valuable non-invasive method for CAD risk stratification in pre-dialysis CKD patients.

Pyeloduodenal fistula successfully treated by endoscopic ligation without surgical nephrectomy: case report.

A 74-yr-old woman presented with fever and abdominal discomfort. She was in a septic condition caused by urinary tract infection. Her computed tomogram of the abdomen revealed features of hydronephrosis with ureteral stones in both kidneys. During percutaneous nephrostomies, right pyeloduodenal fistula (PDF) was diagnosed. Elective surgery was originally planned but the patient was in a poor condition to undergo surgery. Instead, 2 times endoscopic clipping and ligation by endoloop were applied with parenteral antibiotics for the fistula lesion. On admission day 30, she was discharged from the hospital after confirmation of no more contrast leakage on fistulography. We reviewed the literature and discuss the etiologies, clinical presentations, diagnosis, and treatment of PDF.

Clinical features of patients with stress-induced cardiomyopathy associated with renal dysfunction: 7 case series in single center.

BACKGROUND: Stress-induced cardiomyopathy (sCMP) is characterized by transient wall-motion abnormalities involving the left ventricular apex and mid-ventricle that are precipitated by emotional or physical stress. As the heart and kidney influence each other's function through bidirectional pathways, sCMP can induce renal dysfunction or be induced by renal dysfunction. This study reviewed the clinical characteristics and outcomes of patients with confirmed sCMP associated with renal dysfunction. METHODS: We conducted a retrospective analysis of the medical records of all patients from our institution who were diagnosed with sCMP from March 2010 to April 2012. Each patient's demographic characteristics, presenting symptoms, triggering events, electrocardiographic characteristics, laboratory data, echocardiographic study findings, cardiac catheterization data, and outcomes were reviewed. RESULTS: Among 30 patients who were diagnosed with sCMP, 7 patients had associated renal dysfunction. Three patients were on maintenance hemodialysis (HD) and 4 patients had acute kidney injury (AKI). Their mean ejection fraction was 35.2% at initial echocardiography, and 57.2% at follow-up echocardiography. Pericardial effusion was detected in all HD patients initially; these patients were treated with intensive HD for suspected under-dialysis status. In patients with AKI, the mean peak serum creatinine was 4.17 mg/dL. Two patients were treated with continuous renal replacement therapy. One patient required maintenance HD, and 1 patient died. Two patients had full renal recovery to their baseline renal function at 7 and 14 days. CONCLUSIONS: Patients with renal dysfunction including those with AKI and those undergoing HD can develop sCMP, renal function must be closely monitored in patients with sCMP. Additionally, it should be considered that patients on HD who develop sCMP may be under-dialyzed.

Decreased renal function is an independent predictor of severity of coronary artery disease: an application of Gensini score.

Coronary artery disease (CAD) is the leading cause of death in patients with chronic kidney disease (CKD).Although many studies have shown a higher prevalence of CAD among these patients, the association between the spectrum of renal dysfunction and severity of CAD remains unclear. In this study, we investigate the association between renal function and the severity of CAD. We retrospectively reviewed the medical records of 1,192 patients who underwent elective coronary angiography (CAG). The severity of CAD was evaluated by Gensini score according to the degree of luminal narrowing and location(s) of obstruction in the involved main coronary artery. In all patients, the estimated glomerular filtration rate (eGFR) was independently associated with Gensini score (ß=-0.27, P < 0.001) in addition to diabetes mellitus (ß=0.07, P = 0.02), hypertension (ß=0.12, P < 0.001), low density lipoprotein (LDL)-cholesterol (ß=0.08, P = 0.003), and hemoglobin (ß=-0.07, P = 0.03) after controlling for other confounding factors. The result of this study demonstrates that decreased renal function is associated not only with the prevalence, but also the severity, of CAD.

Serum cystatin C as a predictor for cardiovascular events in end-stage renal disease patients at the initiation of dialysis.

BACKGROUND: There has been no study to investigate whether cystatin C could predict cardiovascular events in incident dialysis patients. We aimed to delineate the role of serum cystatin C and cystatin C-based estimated glomerular filtration rate (eGFR(cysC)) for prediction of cardiovascular events. METHODS: This study included 66 end-stage renal disease patients who survived for >3 months after the start of dialysis, and serum cystain C levels were measured at the point of dialysis initiation. RESULTS: Serum cystatin C was correlated with blood urea nitrogen (r = 0.537, p < 0.001), serum creatinine (r = 0.480, p < 0.001) and smoking (r = 0.284, p = 0.021). Cystatin C was inversely correlated with age (r = -0.316, p = 0.01) and eGFR(Cr) by modification of diet in renal disease (r = -0.533, p < 0.001). Kaplan-Meier analysis for cardiovascular events revealed that patients in the group with lower cystatin C levels (<4.14 mg/L) had a better event-free survival rate than patients in the group with higher cystatin C levels (≥4.14 mg/L) (p = 0.039). In univariate analysis, cystatin C (hazard ratio (HR) 2.62, p = 0.011) and eGFR(cysC) (HR 0.64, p = 0.004) were significant factors for the prediction of cardiovascular events. After multivariate adjustment, serum cystatin C and eGFR(cysC) were independent determinants of cardiovascular events (HR 3.952, p = 0.001 and HR 0.640, p = 0.004, respectively). CONCLUSION: Serum cystatin C might be an independent marker of cardiovascular events in incident dialysis patients. Furthermore, eGFR(cysC) based on measured serum cystatin C could have a new role in predicting cardiovascular events beyond the estimation of true GFR.

7ß-22 Dihydroxyhopane, Isolated from the Sub-Antarctic Lichen, Inhibits the Viability and Stemness in Glioma Stem Like Cells.

Background: Glioma stem cells (GSCs) have been reported to contribute to tumor initiation and relapse, therapy resistance, and intra-tumoral heterogeneity of glioblastoma multiforme. Therefore, inhibiting GSCs presents a critical therapeutic tactic to suppress the aggressiveness of tumors. Methods: In this study, we examined the effects of 7ß-22 dihydroxyhopane (AP 18), isolated from the sub-Antarctic lichen, Pseudocyphellaria freycinetii. The cytotoxic effect of AP 18 and its effects on cell proliferation were assessed by alamarBlue assay and 5-ethynyl-2'-deoxyuridine (EdU) assay. Real-time confluence analysis was performed with a Celloger automatic live cell imaging system. Western Blotting and 3-D optical diffraction tomography (ODT) imaging were performed to determine whether apoptosis was triggered by AP 18. A Limiting dilution assay and qRT-PCR were performed to investigate the impact of AP 18 on GSC stemness. Results: AP 18 significantly reduced GSCs viability and proliferation, inducing programmed cell death identified by Annexin V/PI staining and had effects on morphologic features determined by 3-D ODT. Interestingly, treatment with AP 18 suppressed stemness features. Conclusion: Taken together, our results suggest that AP 18 might be a potential therapeutic agent to target GSCs.

Lucidumol A, Purified Directly from Ganoderma lucidum, Exhibits Anticancer Effect and Cellular Inflammatory Response in Colorectal Cancer.

Colorectal cancer (CRC) is a deadly disease regardless of sex, and a few therapeutic approaches have been fully developed at advanced stages, even if some strategies have durable clinical benefits, such as immunotherapy and chemotherapy. Ganoderma lucidum has been recognized as an organism that suppresses tumors and inflammation; however, the molecular mechanisms induced by a triterpenoid in Ganoderma lucidum, Lucidumol A, have not yet been fully explored in CRC and inflammatory responses. To this end, we extracted Lucidumol A from Ganoderma lucidum and analyzed its anticancer effect and anti-inflammatory potential in CRC cell lines and RAW264.7 macrophage-derived cell lines, respectively. A series of in vitro experiments including cell survival, wound healing, and migration assays were performed to determine the role of Lucidumol A in the CRC cell line. We also analyzed inflammatory responses using qRT-PCR, Western Blot, and ELISA in RAW 264.7 macrophaged-derived cell lines exposed to various concentrations of Lucidumol A. Lucidumol A efficiently suppressed the metastatic potential of CRC at very low concentrations. Furthermore, significant anti-inflammatory activities were observed in Lucidumol A-treated RAW264.7 cells through modulation of inflammation-associated marker genes and cytokines. In conclusion, Lucidumol A plays an important role in Ganoderma lucidum-dependent tumor suppression and anti-inflammation, suggesting different strategies to treat CRC patients, and other diseases evoked by proinflammatory cytokines, despite the need to explore further its mechanism of action.

High serum and urine neutrophil gelatinase-associated lipocalin levels are independent predictors of renal progression in patients with immunoglobulin A nephropathy.

BACKGROUND/AIMS: Tubulointerstitial injury plays an important role in the progression of immunoglobulin A nephropathy (IgAN), and neutrophil gelatinase-associated lipocalin (NGAL) is among the most sensitive tubular biomarkers. We investigated whether serum or urine NGAL predicts prognosis in patients with IgAN. METHODS: The present study enrolled patients with biopsy-proven IgAN from January 2005 to December 2010, whose serum and urine samples at the time of kidney biopsy were preserved by freezing. We retrospectively reviewed patient clinical data and followed patients until October 2012. Serum and urine NGAL levels were measured using an enzyme-linked immunosorbent assay kit. Renal progression was defined as an estimated glomerular filtration rate decline by > 50% or progression to end-stage renal disease. RESULTS: There were 121 patients enrolled in this study. During the median follow-up period of 41.49 months, renal progression was found in nine patients (7.4%). Serum or urine NGAL alone could not predict renal progression; however, when serum and urine NGAL levels were combined, belonging to the high NGAL group independently predicted renal progression (hazard ratio [HR], 5.56; 95% confidence interval [CI], 1.42 to 21.73; p = 0.014), along with tubular damage graded according to the Oxford classification as T2 (HR, 8.79; 95% CI, 2.01 to 38.51; p = 0.004). In addition, a Kaplan-Meier curve of renal survival showed significantly higher renal progression in patients in the high NGAL group (log rank, p = 0.004). CONCLUSIONS: In patients with IgAN, high serum and urine NGAL levels at the time of kidney biopsy predict renal progression.

Use of Multifrequency Bioimpedance Analysis in Male Patients with Acute Kidney Injury Who Are Undergoing Continuous Veno-Venous Hemodiafiltration.

INTRODUCTION: Fluid overload is a well-known predictor of mortality in patients with acute kidney injury (AKI). Multifrequency bioimpedance analysis (MF-BIA) is a promising tool for quantifying volume status. However, few studies have analyzed the effect of MF-BIA-defined volume status on the mortality of critically ill patients with AKI. This retrospective medical research study aimed to investigate this issue. METHODS: We retrospectively reviewed the medical records of patients with AKI who underwent continuous veno-venous hemodiafiltration (CVVHDF) from Jan. 2013 to Feb. 2014. Female patients were excluded to control for sex-based differences. Volume status was measured using MF-BIA (Inbody S20, Seoul, Korea) at the time of CVVHDF initiation, and volume parameters were adjusted with height squared (H2). Binary logistic regression analyses were performed to test independent factors for prediction of in-hospital mortality. RESULTS: A total of 208 male patients were included in this study. The mean age was 65.19±12.90 years. During the mean ICU stay of 18.29±27.48 days, 40.4% of the patients died. The in-hospital mortality rate increased with increasing total body water (TBW)/H2 quartile. In the multivariable analyses, increased TBW/H2 (OR 1.312(1.009-1.705), p=0.043) and having lower serum albumin (OR 0.564(0.346-0.919, p=0.022) were independently associated with higher in-hospital mortality. When the intracellular water (ICW)/H2 or extracellular water (ECW)/H2 was adjusted instead of the TBW/H2, only excess ICW/H2 was independently associated with increased mortality (OR 1.561(1.012-2.408, p=0.044). CONCLUSIONS: MF-BIA-defined excess TBW/H2 and ICW/H2 are independently associated with higher in-hospital mortality in male patients with AKI undergoing CVVHDF.

Significance of residual renal function for phosphate control in chronic hemodialysis patients.

BACKGROUND: The aim of this study was to compare mineral metabolism between anuric and nonanuric chronic hemodialysis patients, and determine the differences in phosphate control between the two groups. METHODS: A total of 77 chronic hemodialysis patients were enrolled in this cross-sectional study from January 2012 to February 2012. Patient demographics, laboratory findings, medication histories, and vascular calcification scores were collected. We divided the patients into anuric and nonanuric groups according to the residual renal function and then compared their clinical features. Multivariate binary regression analysis was used in each group to determine the independent factors related to phosphate control. RESULTS: The mean patient age was 59.27±13.95 years, and 57.1% of patients were anuric. In anuric patients, dialysis vintage was significantly longer, but the mean Kt/V was not different between groups. Serum phosphate, fibroblast growth factor (FGF)-23, and Ca/P products were significantly higher, and 1,25(OH)2D3 levels were significantly lower in the anuric patients, although the intact parathyroid hormone and 25(OH)D levels were not different. In anuric patients, LnFGF-23 [hazard ratio (HR) 2.894, 95% confidence interval (CI) 1.294-6.474, P=0.010] was an independent factor predictive of phosphate control. However, in the nonanuric patients, glomerular filtration rate (HR 0.409, 95% CI 0.169-0.989, P=0.047) and blood urea nitrogen (HR 1.090, 95% CI 1.014-1.172, P=0.019) were independent factors predictive of phosphate control. CONCLUSION: In chronic hemodialysis patients, preservation of residual renal function is a significant determinant of phosphate control, and the factors associated with phosphate control is different depending on the residual renal function status. In the anuric patients, FGF-23 is most significantly associated with phosphate control; however, glomerular filtration rate and blood urea nitrogen are more important than FGF-23 in the nonanuric HD patients.