Novel SIRT Inhibitor, MHY2256, Induces Cell Cycle Arrest, Apoptosis, and Autophagic Cell Death in HCT116 Human Colorectal Cancer Cells

We examined the anticancer effects of a novel sirtuin inhibitor, MHY2256, on HCT116 human colorectal cancer cells to investigate its underlying molecular mechanisms. MHY2256 significantly suppressed the activity of sirtuin 1 and expression levels of sirtuin 1/2 and stimulated acetylation of forkhead box O1, which is a target protein of sirtuin 1. Treatment with MHY2256 inhibited the growth of the HCT116 (TP53 wild-type), HT-29 (TP53 mutant), and DLD-1 (TP53 mutant) human colorectal cancer cell lines. In addition, MHY2256 induced G0/G1 phase arrest of the cell cycle progression, which was accompanied by the reduction of cyclin D1 and cyclin E and the decrease of cyclin-dependent kinase 2, cyclin-dependent kinase 4, cyclin-dependent kinase 6, phosphorylated retinoblastoma protein, and E2F transcription factor 1. Apoptosis induction was shown by DNA fragmentation and increase in late apoptosis, which were detected using flow cytometric analysis. MHY2256 downregulated expression levels of procaspase-8, -9, and -3 and led to subsequent poly(ADP-ribose) polymerase cleavage. MHY2256-induced apoptosis was involved in the activation of caspase-8, -9, and -3 and was prevented by pretreatment with Z-VAD-FMK, a pan-caspase inhibitor. Furthermore, the autophagic effects of MHY2256 were observed as cytoplasmic vacuolation, green fluorescent protein-light-chain 3 punctate dots, accumulation of acidic vesicular organelles, and upregulated expression level of light-chain 3-II. Taken together, these results suggest that MHY2256 could be a potential novel sirtuin inhibitor for the chemoprevention or treatment of colorectal cancer or both.

YJI-7 Suppresses ROS Production and Expression of Inflammatory Mediators via Modulation of p38MAPK and JNK Signaling in RAW 264.7 Macrophages

Chalcone, (2E)-1,3-Diphenylprop-2-en-1-one, and its synthetic derivatives are known to possess anti-oxidative and anti-inflammatory properties. In the present study, we prepared a novel synthetic chalcone compound, (E)-1-(4-hydroxyphenyl)-3-(2-(trifluoromethoxy)phenyl)prop-2-en-1-one name (YJI-7), and investigated its inhibitory effects on endotoxin-stimulated production of reactive oxygen species (ROS) and expression of inflammatory mediators in macrophages. We demonstrated that treatment of RAW 264.7 macrophages with YJI-7 significantly suppressed lipopolysaccharide (LPS)-stimulated ROS production. We also found that YJI-7 substantially decreased NADPH oxidase activity stimulated by LPS, indicating that YJI-7 regulates ROS production via modulation of NADPH oxidase in macrophages. Furthermore, YJI-7 strongly inhibited the expression of a number of inflammatory mediators in a gene-selective manner, suggesting that YJI-7 possesses potent anti-inflammatory properties, as well as anti-oxidative activity. In continuing experiments to investigate the mechanisms that could underlie such biological effects, we revealed that YJI-7 suppressed phosphorylation of p38MAPK and JNK stimulated by LPS, whereas no significant effect on ERK was observed. Furthermore, LPS-stimulated production of ROS, activation of NADPH oxidase and expression of inflammatory mediators were markedly suppressed by treatment with selective inhibitor of p38MAPK (SB203580) and JNK (SP600125). Taken together, these results demonstrated that YJI-7, a novel synthetic chalcone derivative, suppressed LPS-stimulated ROS production via modulation of NADPH oxidase and diminished expression of inflammatory mediators, at least in part, via down-regulation of p38MAPK and JNK signaling in macrophages.

The Association between 10-Year Atherosclerotic Cardiovascular Diseases Risk Score Calculated Using 2013 American College of Cardiology/American Heart Association Guidelines and Serum 25-Hydroxyvitamin D Level among Aged 40–79 Years in Korea: The Sixth / 가정의학회지

BACKGROUND: We examined the relationship between 10-year predicted atherosclerosis cardiovascular disease (ASCVD) risk score and 25-hydroxyvitamin D in Koreans aged 40–79 years. METHODS: A population-based, cross-sectional design was used from data based on the Korea National Health and Nutrition Examination Survey 2014. RESULTS: A total of 1,134 healthy Koreans aged 40–79 years were included. A positive relationship between serum 25-hydroxyvitamin D level and ASCVD score was shown in women (β=0.015) after adjusting for central obesity, physical activity, and supplement intake. The chances of being in the moderate to high risk (risk group, ASCVD score ≥5%) with vitamin D sufficiency (serum 25-hydroxyvitamin D ≥20 ng/mL) was 1.267-fold (95% confidence interval, 1.039–1.595) greater than the chance of being included in the group with vitamin D deficiency (serum 25-hydroxyvitamin D < 20 ng/mL) after adjustments in women. CONCLUSION: Our research indicated a significantly positive association between 25-hydroxyvitamin D and ASCVD score. Further detailed studies to evaluate this correlation are needed.

Depression and Quality of Life in Patients with Systemic Lupus Erythematosus

OBJECTIVE: The objective of this study is to examine the prevalence of depression and its related factors including quality of life, brain-derived neurotrophic factor (BDNF), and vitamin D in patients with systemic lupus erythematosus (SLE). METHODS: Depression was assessed using the center for epidemiologic studies depression (CES-D) scale. Disease activity, disease-related organ damage, the EuroQol-5 dimensions (EQ-5D), sociodemographic features, and laboratory tests including serum vitamin D level were surveyed. Serum BDNF was measured using an enzyme-linked immunosorbent assay. RESULTS: Depression was observed in 22.8% of 180 SLE patients (n=41). Patients with marital status of single/divorced/separated/widowed, a higher patient global assessment (PGA) score, and extreme pain/discomfort showed significant association with depression. The EQ-5D index showed negative correlation with CES-D score (r=-0.56, p<0.05). In each EQ-5D dimension, depression showed significant association with moderate to severe problems in self-care and usual activities, and extreme pain/discomfort. Serum BDNF levels were not associated with depression (p=0.75) but associated with SLE disease activity index (SLEDAI; r=-0.21, p<0.05). Serum vitamin D levels were not associated with depression (p=0.60) but showed negative correlation with SLEDAI (r=-0.23, p<0.05) and mean glucocorticoid dose over the previous 3 months (r=-0.21, p<0.05) after adjustment for use of vitamin D supplement. CONCLUSION: Depression was prevalent in patients with SLE and was associated with low quality of life, and a higher PGA but not with SLEDAI. Serum BDNF and vitamin D levels were not associated with depression but showed snegative correlation with SLEDAI.

Extraglandular Manifestations in Korean Patients with Primary Sjogren's Syndrome

OBJECTIVES: To investigate the clinical findings upon initial diagnosis and extraglandular manifestations in Korean patients with primary Sjogren's syndrome (pSS). METHODS: We collected clinical and laboratory data from 238 pSS patients enrolled at Seoul National University Hospital, Seoul National University Bundang Hospital and Seoul Medical Center from March 2011 to December 2014. All patients met the American-European Consensus Group criteria for pSS. RESULTS: Upon initial diagnosis, sicca symptoms (xerophthalmia or xerostomia) as the chief complaint were only observed in 129 (54.2%) pSS patients, while extraglandular manifestation was more common as the chief complaint in male patients or those with younger age (<40 years) than female or older patients (both p<0.05). Extraglandular manifestations were found in 178 (74.8%) patients, with musculoskeletal manifestations being most common (53.8%). Peripheral neuropathy in pSS patients was associated with Raynaud phenomenon and elevated serum total immunoglobulin G (IgG) levels (both p<0.05). Serum beta2-microglobulin (beta2-M) levels were significantly correlated with European League against Rheumatism (EULAR) Sjogren's syndrome disease activity index, erythrocyte sedimentation rate and serum total IgG (all p<0.001), and were higher in patients with extraglandular manifestations than those without (p<0.05). Serum C3 levels were decreased in patients with extraglandular manifestation, compared to those without (p<0.05). Malignant lymphoma was found in Korean pSS patients (1.7%) and associated with elevated serum beta2-M levels (p<0.0001). CONCLUSION: Extraglandular manifestations were common in pSS patients and may be a diagnostic tool for male or younger pSS patients. Serum beta2-M levels can be useful markers for monitoring pSS patients.

Tophaceous Gout Misidentified as Inflammatory Polyp in External Auditory Canal

Gout is an inflammatory disorder in which urate crystals are deposited in the joints or soft tissues causing severe inflammation and pain. Urate crystals usually deposit in the joints, and sometimes in the extra-articular sites. A 67-year-old woman visited the otolaryngology clinic due to otalgia and discharge from the ear. She had experienced recurrent arthritis in the left second metatarsophalangeal joint from five years ago. She visited the otolaryngology clinic of our university hospital due to persistent inflammation in the ear canal despite treatment with antibiotics. An otoscopic examination showed a polyp-like mass near the eardrum. Computed tomography scan of temporal bone showed thickening of the eardrum and increased soft tissue density in the external ear canal. On histologic examination the polyp was finally found to be a urate crystal mass. She is now in a good state with urate lowering therapy. We report on a Korean case of tophaceous gout in the external ear canal that was misidentified as an inflammatory polyp.

A Case of Shewanella algae Bacteremia Accompanying Cellulitis in Both Legs of a Patient on Hemodialysis: Case Report and Literature Review

We report a fatal case of Shewanella algae bacteremia accompanied by cellulitis in both legs of a chronic renal failure patient who had not been exposed to sea water or raw fish. A 47-year-old male on hemodialysis was admitted to our clinic due to pain in both legs accompanied by a febrile sensation that started 2 days prior to his visit. A blood culture specimen revealed S. algae, a rare human opportunistic pathogen. In spite of early and appropriate antimicrobial treatment, the patient died of septic shock on the second day of his hospital stay. Recently, serious infections caused by Shewanella species have been reported in increasing frequency. Hepatobiliary diseases have been proposed as predisposing factors, not only for infection by this organism, but also for fatality. However, we should be aware of the significance of S. algae in patients with renal insufficiency, especially those on maintenance hemodialysis. Herein, we report our case with review relevant literature.

Evans syndrome following long-standing Hashimoto's thyroiditis and successful treatment with rituximab / 대한혈액학회지

We report a case of a 51-year-old woman with Evans syndrome (autoimmune hemolytic anemia and primary immune thrombocytopenia) and hypothyroidism. She was previously diagnosed with Hashimoto's thyroiditis in 1994 (age, 35) and autoimmune hemolytic anemia (AIHA) 3 years ago. She was treated with oral prednisolone. After a period, in which the anemia waxed and waned, there was an abrupt development of thrombocytopenia (nadir 15x10(9)/L) that coincided with the tapering off of prednisolone after 3 years of administration. Because her thrombocytopenia was refractory to prednisolone, we administered rituximab (375 mg/m2 weekly) for 4 weeks. Two weeks after the completion of the rituximab treatment, her platelet count was up to 92x10(9)/L. No intermittent peaking of thyroid stimulating hormone occurred after rituximab treatment was initiated. Evans syndrome and autoimmune thyroiditis might share common pathophysiological mechanisms. This notion supports the use of rituximab in a patient suffering from these disorders.

Clinical Features of Hospitalized Patients with Community Acquired Pneumonia during 2009 Influenza A (H1N1) Pandemic / 대한구급학회지

BACKGROUND: A new influenza A(H1N1) virus emerged and spread globally in 2009, and the rapid progression of pneumonia often required ICU care. We describe the cause analysis and clinical aspects of community acquired pneumonia during the period of the pandemic H1N1 influenza A. METHODS: We reviewed the medical records of 48 adult cases of community acquired pneumonia in which patients were admitted to a public health hospital in Seoul from August to November in 2009. The patients had confirmed H1N1 influenza A based on RT-PCR assay. RESULTS: Thirteen cases of the 48 (27.1%) were 2009 H1N1 RT-PCR positive patients and three (6.3%) of these cases were mixed viral and bacterial pneumonia patients. The mean age was younger and the PSI score was lower in H1N1 patients. Chest radiographic findings of ground glass opacity and interstitial marking were remarkable in H1N1 patients. Major complication events with ICU care or death occurred in 23.1% of the H1N1 positive group and 48.6% of the H1N1 negative group (p=0.202). The major complication group of H1N1 patients had a higher PSI score, lower platelet count, higher CRP and higher mixed bacterial co-infection. CONCLUSIONS: If patients were younger and showed a radiologic finding of interstitial marking or ground glass opacity, we could consider H1N1 influenza as the cause of community acquired pneumonia. A high PSI score, thrombocytopenia, increased CRP and bacterial co-infection were predictable factors of major complication.

The Clinical Implication of MAGE Gene Detection in Bronchial Washing Fluid in Routine Practice / 결핵및호흡기질환

BACKGROUND: Melanoma antigen genes (MAGE) are expressed in many human malignant cells and are silent in normal tissues other than in testis and in placenta. But MAGE expression in benign lung diseases, such as pulmonary tuberculosis or cases with severe inflammation, needs further evaluation to overcome false-positive findings. We evaluated detection rates of the melanoma antigen genes (MAGE) RT-nested PCR in bronchoscopic washing samples from patients with benign lung disease, as well as in patients with malignancies. METHODS: Bronchial washing fluid from 122 patients was used for cytological examination and MAGE gene detection using RT-nested-PCR of common A1-6 mRNA. We compared the results from the RT-nested PCR and the pathologic or bacteriologic diagnosis. We also analyzed the expression rate and false positive rate of MAGE gene. RESULTS: Among 122 subjects, lung cancer was diagnosed in 23 patients and benign lung disease was diagnosed in 99 patients. In patients with lung cancer, the positive rate of MAGE expression was 47.8% (11/23) and in benign lung disease group, the expression rate was 14.1% (14/99). Among benign lung disease group, the expression rate of MAGE gene (25.0%) in patients with pulmonary tuberculosis (11/44) was especially high. CONCLUSION: MAGE A1-6 RT-nested PCR of bronchial washing fluid can be used as a complementary method in lung cancer, but that test results in a high false positive rate in tuberculosis patients.