MHY2251, a New SIRT1 Inhibitor, Induces Apoptosis via JNK/p53 Pathway in HCT116 Human Colorectal Cancer Cells

Sirtuins (SIRTs) belong to the nicotinamide adenine dinucleotide (NAD+)-dependent class III histone deacetylase family. They are key regulators of cellular and physiological processes, such as cell survival, senescence, differentiation, DNA damage and stress response, cellular metabolism, and aging. SIRTs also influence carcinogenesis, making them potential targets for anticancer therapeutic strategies. In this study, we investigated the anticancer properties and underlying molecular mechanisms of a novel SIRT1 inhibitor, MHY2251, in human colorectal cancer (CRC) cells. MHY2251 reduced the viability of various human CRC cell lines, especially those with wild-type TP53. MHY2251 inhibited SIRT1 activity and SIRT1/2 protein expression, while promoting p53 acetylation, which is a target of SIRT1 in HCT116 cells. MHY2251 treatment triggered apoptosis in HCT116 cells. It increased the percentage of late apoptotic cells and the sub-G1 fraction (as detected by flow cytometric analysis) and induced DNA fragmentation. In addition, MHY2251 upregulated the expression of FasL and Fas, altered the ratio of Bax/Bcl-2, downregulated the levels of pro-caspase-8, -9, and -3 proteins, and induced subsequent poly(ADP-ribose) polymerase cleavage. The induction of apoptosis by MHY2251 was related to the activation of the caspase cascade, which was significantly attenuated by pre-treatment with ZVAD-FMK, a pan-caspase inhibitor. Furthermore, MHY2251 stimulated the phosphorylation of c-Jun N-terminal kinase (JNK), and MHY2251-triggered apoptosis was blocked by pre-treatment with SP600125, a JNK inhibitor. This finding indicated the specific involvement of JNK in MHY2251-induced apoptosis. MHY2251 shows considerable potential as a therapeutic agent for targeting human CRC via the inhibition of SIRT1 and activation of JNK/p53 pathway.

Disability Weights for the Korean Burden of Disease Study: Focused on Comparison with Disability Weights in the Australian Burden of Disease Study / 예방의학회지

OBJECTIVE: This study aimed to measure the disability weights for the Korean Burden of Disease study, and to compare them with those adopted in the Australian study to examine the validity and describe the distinctive features. METHODS: The standardized valuation protocol was developed from the Global Burden of Disease (GBD) study and the Dutch Disability Weights study. Disability weights were measured for 123 diseases of the Korean version of Disease Classification by three panels of 10 medical doctors each. Then, overall distribution, correlation coefficients, difference by each disease, and mean of differences by disease group were analyzed for comparison of disability weights between the Korean and Australian studies. RESULTS: Korean disability weights ranged from 0.037 to 0.927. While the rank correlation coefficient was moderate to high (rs=0.68), Korean disability weights were higher than the corresponding Australian ones in 79.7% of the 118 diseases. Of these, war, leprosy, and most injuries showed the biggest differences. On the contrary, many infectious and parasitic diseases comprised the greater part of diseases of which Korean disability weights were lower. The mean of the differences was the highest in injuries of GBD disease groups, and in cardiovascular disease, injuries, and malignant neoplasm of the Korean disease category. CONCLUSION: Korean disability weights were found to be valid on the basis of overall distribution pattern and correlation, and are expected to be used as basic data for broadening the scope of burden of disease study. However, some distinctive features still remain to be explored in following studies.

Periorbital Cerebrospinal Fluid Collection after Orbital Roof Craniotomy and Superolateral Orbital Craniotomy

OBJECTIVE: The aims of this study are to review the incidence of cerebrospinal fluid(CSF) collection complicating the simplified anterior skull base approaches via an eyebrow incision and to identify factors that influence its occurrence and treatment. METHODS: The authors retrospectively analyzed the clinical records and radiologic data of 47 cases(45 patients) who underwent superolateral orbital craniotomy or orbital roof craniotomy via an eyebrow incision at the Eulji Medical Center from September 1998 to August 2002. Forty-three cases were anterior circulation aneurysms and four cases were brain tumors. RESULTS: Significant periorbital CSF collection occurred in 13 cases(11 aneurysms, 2 brain tumors). It was managed with aspiration(8 cases), aspiration and lumbar drainage(2 cases), and dural repair(3 cases). There was no statistically significant difference in operative approaches and patient's characteristics. Periorbital CSF collection occurred in one(16.7%) of six cases using preventive lumbar CSF drainage over two days and in 12 (29.3%) out of 41 cases without it(p>005). CONCLUSION: The authors suggest that careful dissection and water-tight closure of frontal dura, sealing with fibrin glue and compressive dressing of operative wounds are important for the prevention of this complication. However, statistically not significant, preventive lumbar CSF drainage seem to be effective. Aspiration and/or lumbar drainage seem to be sufficient for management of postoperative CSF collection and dural repair could be reserved for refractory cases.

Disability Weights for Diseases in Korea / 예방의학회지

OBJECTIVES: This study aimed to develop an evaluation protocol of disability weights using person trade-off, and to test the reliability of the developed protocol in a Korean context. METHODS: To develop the valuation protocol, the Global Burden of Disease (GBD) and the Dutch studies were replicated and modified. Sixteen indicator conditions were selected from the Korean version of disease classification, which was based on that of the GBD Study, and the person trade-off method referred to the Dutch method. RESULTS: The disability weights were valued in a two step panel study. The first step was a carefully designed group process by three panels, using person trade-off to establish the disability weights for sixteen selected indicator conditions. The second step consisted of interpolation of the remaining diseases, on a disability scale, by the individual members of three panels. The members of three panels were all medical doctors, with sufficient knowledge of the consequences of a broad variety of diseases. The internal consistency of the Korean disability weights was satisfactory. Considerable agreement existed within each panel and among the panels. CONCLUSIONS: It was feasible to use a modified evaluation protocol from those used in GBD and Dutch studies. This would provide a rational basis for an international comparative study of disability weights.

Study of Disability-Adjusted Life Expectancy(DALE) Using National Health Interview Survey in Korea / 예방의학회지

OBJECTIVES: To measure DALE (Disability-Adjusted Life Expectancy) in Korea to find out how long Koreans live in a state of full heath. METHODS: DALE was calculated using the life table of 1999 and the disability prevalence from the National Health Interview Survey (NHIS), which was conducted with a sample of 13,523 households in 1998. The disability prevalence was measured using the annual prevalence of the long-term limitation of activities, which were divided into classes 1, 2, 3, 4, 5 and 6 according to the severity of the limitation. The disability weights were measured for each 6 class by conducting a survey of 16 healthcare professionals. The severity-adjusted disability prevalence was calculated by multiplying the disability prevalence of each class by the disability weights respectively. Healthy life years lost due to disability was calculated by multiplying the life expectancy by the severity-adjusted disability prevalence. Finally DALE was measured as the life expectancy minus healthy life years lost due to disability. RESUJLTS: DALE for 1999, which refers to the expectation of equivalent years of good health, were 72.5, 69.5 and 75.3 years, for total, for males and for females, respectively. The percentages for DALE out of the life expectancy were 95.8, 96.6 and 94.4% for total, for males and for females, respectively. CONCLUSIONS: DALE is a newly developed indicator, which could effectively show the healthy life expectancy of populations. A greater notice and use of DALE would be expected as life expectancies increase and the quality of life changes in Korea.

Study of Disability-Adjusted Life Expectancy(DALE) Using National Health Interview Survey in Korea / 예방의학회지

OBJECTIVES: To measure DALE (Disability-Adjusted Life Expectancy) in Korea to find out how long Koreans live in a state of full heath. METHODS: DALE was calculated using the life table of 1999 and the disability prevalence from the National Health Interview Survey (NHIS), which was conducted with a sample of 13,523 households in 1998. The disability prevalence was measured using the annual prevalence of the long-term limitation of activities, which were divided into classes 1, 2, 3, 4, 5 and 6 according to the severity of the limitation. The disability weights were measured for each 6 class by conducting a survey of 16 healthcare professionals. The severity-adjusted disability prevalence was calculated by multiplying the disability prevalence of each class by the disability weights respectively. Healthy life years lost due to disability was calculated by multiplying the life expectancy by the severity-adjusted disability prevalence. Finally DALE was measured as the life expectancy minus healthy life years lost due to disability. RESUJLTS: DALE for 1999, which refers to the expectation of equivalent years of good health, were 72.5, 69.5 and 75.3 years, for total, for males and for females, respectively. The percentages for DALE out of the life expectancy were 95.8, 96.6 and 94.4% for total, for males and for females, respectively. CONCLUSIONS: DALE is a newly developed indicator, which could effectively show the healthy life expectancy of populations. A greater notice and use of DALE would be expected as life expectancies increase and the quality of life changes in Korea.