Stasis and Inflammation in Varicose Vein Development: An Interleukin-Mediated Process from Intima to Media.

INTRODUCTION: This study investigated the combination of venous stasis and inflammation in varicose vein development. METHODS: The study included patients with primary varicose veins operated using high ligation and stripping of greater saphenous vein. All of them showed reflux at sapheno-femoral junction on preoperative Doppler ultrasound. Mesenteric veins from early or advanced gastric cancer specimens were used as control group. Inflammatory mediators expressed in the venous wall were measured via immunohistochemistry and compared between the two groups. RESULTS: Thirty-five (59.3%) men and 24 women with a mean age of 52.8 years (range, 23-77 years) were included and 29 (49.2%) patients had edema or skin changes according to Clinical-Etiology-Anatomy-Pathophysiology (CEAP) classification and reporting standards for chronic venous disorders. The expression of interleukin 6 (IL-6) and transforming growth factor ß1 (TGF-ß1) in intima and those of IL-6 in media of greater saphenous veins increased, with statistically significant differences between the two groups (p < 0.001). IL-6 in media and TGF-ß1 levels in intima were independent predictors of varicose veins (adjusted odds ratios 74.62 and 66.69, respectively). CONCLUSION: Elevated venous pressure represented by reflux on Doppler ultrasound and increased expression of inflammatory cytokines including IL-6 in media and TGF-ß1 in intima are associated with the development of varicose veins.

Molecular epidemiology and virulence factors of group B Streptococcus in South Korea according to the invasiveness.

BACKGROUND: Group B Streptococcus (GBS) causes invasive infections in newborns and elderly individuals, but is a noninvasive commensal bacterium in most immunocompetent people. Recently, the incidence of invasive GBS infections has increased worldwide, and there is growing interest in the molecular genetic characteristics of invasive GBS strains. Vaccines against GBS are expected in the near future. Here, we aimed to analyze the molecular epidemiology of GBS according to the invasiveness in South Korea. METHODS: We analyzed GBS isolates collected and stored in two hospitals in South Korea between January 2015 and December 2020. The invasiveness of these isolates was determined via a retrospective review of clinical episodes. Totally, 120 GBS isolates from 55 children and 65 adults were analyzed. Serotype and sequence type (ST) were determined using multiplex polymerase chain reaction (PCR) and multilocus sequence typing, respectively. Fourteen virulence factor-encoding genes of GBS were analyzed using multiplex PCR. RESULTS: Forty one (34.2%) were invasive infection-related GBS isolates (iGBS). The most frequently detected serotype was III (39/120, 32.5%), and it accounted for a high proportion of iGBS (21/41, 51.2%). The most frequent ST was ST19 (18/120, 15.0%), followed by ST2 (17/120, 14.2%). Serotype III/ST17 was predominant in iGBS (12/41, 29.3%), and all 17 ST2 strains were noninvasive. The distribution of most of the investigated virulence factors was not significantly related to invasiveness; noteworthily, most of the serotype III/ST17 iGBS carried pilus island (PI) 2b (10/12, 83.3%), and the prevalence of fbsB was significantly low compared with noninvasive GBS isolates (P = 0.004). Characteristically, the combination of bca(+)-cspA(+)-pavA(+)-fbsB(-)-rib(+)-bac(-) was predominant in iGBS (24.4%, 10/41). CONCLUSIONS: Serotype III/ST17 GBS carrying PI-2b was frequently detected in iGBS. There was no significant association between invasiveness and the pattern of virulence factors; however, a specific combination of virulence factors was predominant in iGBS.

Fitness costs of Tn1546-type transposons harboring the vanA operon by plasmid type and structural diversity in Enterococcus faecium.

BACKGROUND: This study analyzed the genetic traits and fitness costs of vancomycin-resistant Enterococcus faecium (VREfm) blood isolates carrying Tn1546-type transposons harboring the vanA operon. METHODS: All E. faecium blood isolates were collected from eight general hospitals in South Korea during one-year study period. Antimicrobial susceptibility testing and vanA and vanB PCR were performed. Growth rates of E. faecium isolates were determined. The vanA-positive isolates were subjected to whole genome sequencing and conjugation experiments. RESULTS: Among 308 E. faecium isolates, 132 (42.9%) were positive for vanA. All Tn1546-type transposons harboring the vanA operon located on the plasmids, but on the chromosome in seven isolates. The plasmids harboring the vanA operon were grouped into four types; two types of circular, nonconjugative plasmids (Type A, n = 50; Type B, n = 46), and two types of putative linear, conjugative plasmids (Type C, n = 16; Type D, n = 5). Growth rates of vanA-positive E. faecium isolates were significantly lower than those of vanA-negative isolates (P < 0.001), and reduction in growth rate under vancomycin pressure was significantly larger in isolates harboring putative linear plasmids than in those harboring circular plasmids (P = 0.020). CONCLUSIONS: The possession of vanA operon was costly to bacterial hosts in antimicrobial-free environment, which provide evidence for the importance of reducing vancomycin pressure for prevention of VREfm dissemination. Fitness burden to bacterial hosts was varied by type and size of the vanA operon-harboring plasmid.

Butin Protects Keratinocytes From Particulate Matter 2.5 and Ultraviolet B-Mediated Damages.

BACKGROUND: Butin is a naturally occurring compound with a wide range of medicinal properties, including anti-inflammatory, anti-arthritic, and antioxidant properties. Particulate matter 2.5 (PM2.5) and ultraviolet B (UVB) radiation contribute to skin cell damage via the induction of oxidative stress. METHODS: This study sought to assess the protective effects of butin against damage triggered by PM2.5 and UVB in human HaCaT keratinocytes. Assessments were performed to evaluate cell viability, apoptosis, and cellular component damage. RESULTS: Butin exhibited its protective ability via the inhibition of PM2.5-induced reactive oxygen species generation, lipid peroxidation, DNA damage, protein carbonylation, and mitochondrial damage. Butin reduced the PM2.5-induced c-Fos and phospho-c-Jun protein levels as well as mitogen-activated protein kinase. Furthermore, butin mitigated PM2.5- and UVB-induced apoptosis. CONCLUSION: Butin had the potential as a pharmaceutical candidate for treating skin damage caused by PM2.5 and UVB exposure.

Multilaboratory Evaluation of the MALDI-TOF Mass Spectrometry System, MicroIDSys Elite, for the Identification of Medically Important Filamentous Fungi.

With the increasing number of fungal infections and immunocompromised patients, rapid and accurate fungal identification is required in clinical microbiology laboratories. We evaluated the applicability of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) system, MicroIDSys Elite (ASTA Corp., South Korea) for the identification of medically important filamentous fungi. A total of 505 strains comprising 37 genera and 90 species collected from 11 Korean hospitals were sent to the microbiology laboratory of International St. Mary's Hospital. All isolates were tested using MicroIDSys Elite, and data were analyzed using the MoldDB v.1.22 database (ASTA). Correct identification rates were compared with the multigene sequencing results. MicroIDSys Elite correctly identified 86.5% (437/505) and 88.9% (449/505) of all tested isolates at the species and genus level, respectively. About 98.2% of Aspergillus isolates were identified at the species level, including cryptic and rare species of A. calidoustus, A. tamarii, A. lentulus, A. versicolor and A. aculeatus. MicroIDSys Elite identified 75.0% of basidiomycetes, including Schizophyllum commune, and 84.3% of the dermatophytes. It also distinguished Sprothrix globosa at the species level. The mean scores of total isolates corresponding to correct species identification were significantly higher than those obtained for genus-level identification (253.5 ± 50.7 vs. 168.6 ± 30.3, P < 0.001). MicroIDSys Elite showed high accuracy for the identification of filamentous fungi, including cryptic and rare Aspergillus species. It is suitable for use in clinical laboratories as a rapid and efficient tool for clinical mold identification. Further evaluations are recommended for MicroIDSys Elite as a rapid and efficient tool for the identification of medically important filamentous fungi.

Impact of vanA-Positive Enterococcus faecium Exhibiting Diverse Susceptibility Phenotypes to Glycopeptides on 30-Day Mortality of Patients with a Bloodstream Infection.

This study was performed to evaluate the impacts of vanA positivity of Enterococcus faecium exhibiting diverse susceptibility phenotypes to glycopeptides on clinical outcomes in patients with a bloodstream infection (BSI) through a prospective, multicenter, observational study. A total of 509 patients with E. faecium BSI from eight sentinel hospitals in South Korea during a 2-year period were enrolled in this study. Risk factors of the hosts and causative E. faecium isolates were assessed to determine associations with the 30-day mortality of E. faecium BSI patients via multivariable logistic regression analyses. The vanA gene was detected in 35.2% (179/509) of E. faecium isolates; 131 E. faecium isolates exhibited typical VanA phenotypes (group vanA-VanA), while the remaining 48 E. faecium isolates exhibited atypical phenotypes (group vanA-atypical), which included VanD (n = 43) and vancomycin-variable phenotypes (n = 5). A multivariable logistic regression indicated that vanA positivity of causative pathogens was independently associated with the increased 30-day mortality rate in the patients with E. faecium BSI; however, there was no significant difference in survival rates between the patients of the vanA-VanA and vanA-atypical groups (log rank test, P = 0.904). A high 30-day mortality rate was observed in patients with vanA-positive E. faecium BSIs, and vanA positivity of causative E. faecium isolates was an independent risk factor for early mortality irrespective of the susceptibility phenotypes to glycopeptides; thus, intensified antimicrobial stewardship is needed to improve the clinical outcomes of patients with vanA-positive E. faecium BSI.

Antimicrobial resistance in South Korea: A report from the Korean global antimicrobial resistance surveillance system (Kor-GLASS) for 2017.

At the end of 2015, a global action plan on antimicrobial resistance (AMR) was proposed by the World Health Organization, and the Global AMR Surveillance System (GLASS) was subsequently initiated. The Centers for Disease Control and Prevention of South Korea established a customized AMR surveillance system for South Korea, called Kor-GLASS, in early 2016. A pilot phase of Kor-GLASS was operated from May to December 2016 with six sentinel hospitals, and phase I of Kor-GLASS started in January 2017 with eight sentinel hospitals. Previous surveillance data for overestimated AMR due to duplicate isolation of drug-resistant pathogens were corrected and error-free AMR data were compared with those from other countries. One-half (53.2%, 377/708) of Staphylococcus aureus blood strains exhibited resistance to cefoxitin, indicating methicillin-resistant S. aureus. Resistance to ampicillin in Enterococcus faecalis blood strains was rare (0.6%, 1/175), while the resistance rate to penicillin was 26.3% (46/175). Resistance to vancomycin (34.0%, 98/288) and teicoplanin (18.8%, 98/288) was frequently observed in Enterococcus faecium strains. The resistance rate of Escherichia coli strains to cefotaxime was 32.4% (574/1772), and that of Klebsiella pneumoniae strains was 26.1% (181/693). The resistance rates of Pseudomonas aeruginosa strains to imipenem and meropenem were 19.5% (29/149) and 18.1% (27/149), respectively. And 92.1% (187/203) of Acinetobacter baumannii strains were resistant to both imipenem and meropenem. The high incidence of bacteremia caused by major AMR pathogens among hospitalized patients especially in intensive care units emphasized the importance of hospital infection control and the need to improve the crowded hospitalization system in South Korea. The isolation rate of the Salmonella spp. is decreasing, reflecting the current socio-economic status of South Korea. The proportions of bacterial species in the blood strains were similar to those in other Asian countries with similar lifestyles.

Severe Fever with Thrombocytopenia Syndrome Virus Infection, South Korea, 2010.

Severe fever with thrombocytopenia syndrome (SFTS) was reported in China in 2009 and in South Korea in 2012. We found retrospective evidence of SFTS virus infection in South Korea in 2010, suggesting that infections in South Korea occurred before previously reported and were more concurrent with those in China.

Ceftaroline Resistance by Clone-Specific Polymorphism in Penicillin-Binding Protein 2a of Methicillin-Resistant Staphylococcus aureus.

A total of 281 nonduplicated Staphylococcus aureus blood isolates were collected from January to May 2017 from eight hospitals in South Korea to investigate the epidemiological traits of ceftaroline resistance in methicillin-resistant S. aureus (MRSA). Cefoxitin-disk diffusion tests and the mecA gene PCR revealed that 56.6% (159/281) of the S. aureus isolates were MRSA, and most belonged to ST5 (50.3%, 80/281) and ST72 (41.5%, 66/281). Of the MRSA isolates, 44.0% (70/159) were nonsusceptible to ceftaroline (MIC ≥ 2 mg/liter), whereas all of the methicillin-susceptible S. aureus isolates were susceptible to the drug. Eight amino acid substitutions in penicillin-binding protein 2a (PBP2a), including four (L357I, E447K, I563T, and S649A) in the penicillin-binding domain (PBD) and four (N104K, V117I, N146K, and A228V) in the non-PBD (nPBD) of PBP2a, were associated with ceftaroline resistance. The accumulation of substitutions in PBP2a resulted in the elevation of ceftaroline MICs: one substitution at 1 to 2 mg/liter, two or three substitutions at 2 to 4 mg/liter, and five substitutions at 4 or 16 mg/liter. Ceftaroline resistance in MRSA might be the result of clone-specific PBP2a polymorphism, along with substitutions both in PBD and nPBD, and the elevated ceftaroline MICs were associated with the substitution sites and accumulation of substitutions.

Clinical Characteristics of Macrolide-Resistant Mycoplasma pneumoniae from Children in Jeju.

Mycoplasma pneumoniae is the major pathogen of community-acquired pneumonia in children. The prevalence of macrolide-resistant M. pneumoniae (MRMP) is important owing to the limited alternative therapies for children. We analyzed 111 M. pneumoniae obtained from 107 children admitted for lower respiratory tract infection at Jeju National University Hospital between 2010 and 2015. Macrolide resistance of M. pneumoniae was searched for using polymerase chain reaction (PCR) and sequencing. Of 107 clinical M. pneumoniae, 11 (10.3%) carried macrolide resistance mutations in the 23S rRNA gene. All macrolide resistance mutations were A2063G transitions. We found an acquired A2063G mutation of M. pneumoniae from a patient during macrolide treatment. Patients' characteristics and clinical severity did not differ between those with MRMP and macrolide-sensitive M. pneumoniae, with the exception of frequent pleural effusion in the MRMP group. The prevalence of MRMP (10.3%) in Jeju Island was relatively lower than those of surrounding countries in East Asia. Previous antimicrobial usage and timing of diagnostic test should be considered when determining of macrolide resistance of M. pneumoniae.

Porphyromonas gingivalis causing brain abscess in patient with recurrent periodontitis.

We report an extremely rare case of Porphyromonas gingivalis causing brain abscess in a patient with recurrent periodontitis. The patient presented with right-sided homonymous hemianopsia and right hemiparesis. Emergent surgical drainage was performed and antibiotics were administered. P. gingivalis was identified from the anaerobic culture of the abscess. The clinical course of the patient improved with full recovery of the neurologic deficit.

Three cases of postoperative septic arthritis caused by Mycobacterium conceptionense in the shoulder joints of immunocompetent patients.

Mycobacterium conceptionense is a species member of Mycobacterium fortuitum complex, a potential pathogen of increasing clinical importance among opportunistic infections. This species causes a wide spectrum of cutaneous and extracutaneous diseases. In this report, we describe three patients who underwent shoulder surgery with postoperative joint infection by M. conceptionense.

Rosmarinic Acid Inhibits Ultraviolet B-Mediated Oxidative Damage via the AKT/ERK-NRF2-GSH Pathway In Vitro and In Vivo.

Rosmarinic acid (RA) is a phenolic ester that protects human keratinocytes against oxidative damage induced by ultraviolet B (UVB) exposure, however, the mechanisms underlying its effects remain unclear. This study aimed to elucidate the cell signaling mechanisms that regulate the antioxidant activity of RA and confirm its cyto-protective role. To explore the signaling mechanisms, we used the human keratinocyte cell line HaCaT and SKH1 hairless mouse skin. RA enhanced glutamate-cysteine ligase catalytic subunit (GCLC) and glutathione synthetase (GSS) expression in HaCaT cells in a dose- and time-dependent manner. Moreover, RA induced nuclear factor erythroid-2-related factor 2 (NRF2) nuclear translocation and activated the signaling kinases protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Treatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, the ERK inhibitor U0126, and small interfering RNA (siRNA) gene silencing suppressed RA-enhanced GCLC, GSS, and NRF2 expression, respectively. Cell viability tests showed that RA significantly prevented UVB-induced cell viability decrease, whereas the glutathione (GSH) inhibitors buthionine sulfoximine, LY294002, and U0126 significantly reduced this effect. Moreover, RA protected against DNA damage and protein carbonylation, lipid peroxidation, and apoptosis caused by UVB-induced oxidative stress in a concentration-dependent manner in SKH1 hairless mouse skin tissues. These results suggest that RA protects against UVB-induced oxidative damage by activating AKT and ERK signaling to regulate NRF2 signaling and enhance GSH biosynthesis. Thus, RA treatment may be a promising approach to protect the skin from UVB-induced oxidative damage.

Antimicrobial susceptibility of stenotrophomonas maltophilia isolates from Korea, and the activity of antimicrobial combinations against the isolates.

The aim of this study was to determine antimicrobial susceptibility of recent clinical Stenotrophomonas maltophilia isolates from Korea, and to compare the activity levels of several combinations of antimicrobials. A total of 206 non-duplicate clinical isolates of S. maltophilia was collected in 2010 from 11 university hospitals. Antimicrobial susceptibility testing was performed using the Clinical Laboratory Standards Institute agar dilution method. In vitro activity of antimicrobial combinations was tested using the checkerboard method. The susceptibility rates to trimethoprim-sulfamethoxazole and minocycline were 96% and 99%, respectively. The susceptibility rate to levofloxacin was 64%. All of four antimicrobial combinations showed synergy against many S. maltophilia isolates. A combination of trimethoprim-sulfamethoxazole plus ticarcillin-clavulanate was most synergistic among the combinations. None of the combinations showed antagonistic activity. Therefore, some of the combinations may be more useful than individual drugs in the treatment of S. maltophilia infection. Further clinical studies are warranted to validate our in vitro test results.

Associations of leptin receptors and miRNA polymorphisms with susceptibility to hypertension.

Leptin receptors (LEPR) are located in the central nervous system and other tissues including adipocytes and endothelial cells, where they play a key role in mediating the effects of leptin. MicroRNA (miR/miRNA)-27a and miR-155 have been shown to play an important role in the regulation of LEPR expression and are differentially expressed in various diseases. Therefore, the present study analyzed potential associations of LEPR deletion/insertion (Del/Ins), miR-27aA>G (rs895819) and miR-155T>A (rs767649) polymorphisms with a predisposition to hypertension (HTN). Genotyping was performed by a PCR-restriction fragment length polymorphism assay. Frequencies of LEPR Del/Ins and miRNA gene polymorphisms in patients diagnosed with HTN (n=232) and randomly selected healthy controls (n=247) were assessed. The present study found that Del/Ins and Ins/Ins genotypes and the Ins allele of the LEPR Del/Ins polymorphism were associated with a decreased risk of HTN compared with controls, whereas the miR-27aA>G rs895819 polymorphism was associated with an increased risk of HTN. Combined genotype and allele analyses for LEPR Del/Ins and two miRNA polymorphisms revealed an association with an increased risk or a decreased risk of HTN. Furthermore, stratification analysis revealed that HTN risk factors were associated with waist circumference (WC) and high-density lipoprotein cholesterol (HDL-C) values in LEPR Del/Ins polymorphism. They were also associated with body mass index, WC, triglyceride and HDL-C values in miR-27aA>G polymorphism. The present study revealed a combined effect of LEPR Del/Ins and miR-27aA>G polymorphisms on the risk of HTN in Koreans, suggesting that these gene polymorphisms could be potential markers for predicting HTN risk.

Emergence of NDM-1-producing Pseudomonas aeruginosa Sequence Type 773 Clone: Shift of Carbapenemase Molecular Epidemiology and Spread of 16S rRNA Methylase Genes in Korea.

Imipenemase (IMP)-6-producing Pseudomonas aeruginosa sequence type (ST) 235 is a dominant clone of carbapenemase-producing P. aeruginosa (CPPAE) in Korea. As part of the Antimicrobial Resistance Surveillance System in Korea, we found an increase in the carbapenem resistance rate of P. aeruginosa isolates from blood cultures and a shift in the molecular epidemiology of CPPAE. A total of 212 non-duplicated P. aeruginosa blood isolates were obtained from nine general hospitals and two nursing homes. Twenty-four isolates were identified as CPPAE. We observed the emergence of the NDM-1 P. aeruginosa ST 773 clone (N=10), mostly from Gyeongsang Province. The IMP-6 ST 235 clone (N=11) was detected in all provinces. CPPAE isolates showed very high resistance rates to amikacin, and all NDM-1 P. aeruginosa strains carried rmtB. This is the first nationwide surveillance of the recently emerged NDM-1-producing P. aeruginosa ST773 clone in Korea. Continuous surveillance is necessary to prevent the infection and transmission of carbapenem- and amikacin-resistant P. aeruginosa in Korea.

Serotype Distribution and Antimicrobial Resistance of Streptococcus pneumoniae Causing Invasive Pneumococcal Disease in Korea Between 2017 and 2019 After Introduction of the 13-Valent Pneumococcal Conjugate Vaccine.

Background: Streptococcus pneumoniae is a serious pathogen causing various infections in humans. We evaluated the serotype distribution and antimicrobial resistance of S. pneumoniae causing invasive pneumococcal disease (IPD) after introduction of pneumococcal conjugate vaccine (PCV)13 in Korea and investigated the epidemiological characteristics of multidrug-resistant (MDR) isolates. Methods: S. pneumoniae isolates causing IPD were collected from 16 hospitals in Korea between 2017 and 2019. Serotyping was performed using modified sequential multiplex PCR and the Quellung reaction. Antimicrobial susceptibility tests were performed using the broth microdilution method. Multilocus sequence typing was performed on MDR isolates for epidemiological investigations. Results: Among the 411 S. pneumoniae isolates analyzed, the most prevalent serotype was 3 (12.2%), followed by 10A (9.5%), 34 (7.3%), 19A (6.8%), 23A (6.3%), 22F (6.1%), 35B (5.8%), 11A (5.1%), and others (40.9%). The coverage rates of PCV7, PCV10, PCV13, and pneumococcal polysaccharide vaccine (PPSV)23 were 7.8%, 7.8%, 28.7%, and 59.4%, respectively. Resistance rates to penicillin, ceftriaxone, erythromycin, and levofloxacin were 13.1%, 9.2%, 80.3%, and 4.1%, respectively. MDR isolates accounted for 23.4% of all isolates. Serotypes 23A, 11A, 19A, and 15B accounted for the highest proportions of total isolates at 18.8%, 16.7%, 14.6%, and 8.3%, respectively. Sequence type (ST)166 (43.8%) and ST320 (12.5%) were common among MDR isolates. Conclusions: Non-PCV13 serotypes are increasing among invasive S. pneumoniae strains causing IPD. Differences in antimicrobial resistance were found according to the specific serotype. Continuous monitoring of serotypes and antimicrobial resistance is necessary for the appropriate management of S. pneumoniae infections.

Capsaicin sensitizes TRAIL-induced apoptosis through Sp1-mediated DR5 up-regulation: involvement of Ca(2+) influx.

Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various malignant cells, several cancers including human hepatocellular carcinoma (HCC) exhibit potent resistance to TRAIL-induced cell death. The aim of this study is to evaluate the anti-cancer potential of capsaicin in TRAIL-induced cancer cell death. As indicated by assays that measure phosphatidylserine exposure, mitochondrial activity and activation of caspases, capsaicin potentiated TRAIL-resistant cells to lead to cell death. In addition, we found that capsaicin induces the cell surface expression of TRAIL receptor DR5, but not DR4 through the activation Sp1 on its promoter region. Furthermore, we investigated that capsaicin-induced DR5 expression and apoptosis are inhibited by calcium chelator or inhibitors for calmodulin-dependent protein kinase. Taken together, our data suggest that capsaicin sensitizes TRAIL-mediated HCC cell apoptosis by DR5 up-regulation via calcium influx-dependent Sp1 activation.

Involvement of heme oxygenase-1 in Korean colon cancer.

Heme oxygenase-1 (HO-1) catabolizes heme into carbon monoxide, biliverdin, and free iron which mediate its protective effect against oxidative stress. The aim of the present study was to determine the expression level and activity of HO-1 in Korean colon cancer tissues and cell lines. HO-1 protein expression was higher (>1.5-fold) in tumor tissues than in adjacent normal tissues in 14 of 20 colon cancer patients, and HO-1 protein expression was closely correlated with HO-1 enzyme activity in cancer tissues. Immunohistochemical data confirmed that HO-1 protein was expressed at a higher level in colon cancer tissues than in normal mucosa. Furthermore, HO-1 mRNA and protein expression and enzyme activity were higher in the colon cancer cell lines Caco-2, SNU-407, SNU-1033, HT-29, and SW-403 than in the normal fetal human colon cell line FHC. Treatment with the HO-1 inhibitor zinc protoporphyrin decreased the viability of colon cancer cell lines. These data indicate that HO-1 may serve as a clinically useful biomarker of colon cancer and as a target for anticolon cancer drugs.

(1S,2S,3E,7E,11E)-3,7,11,15-Cembratetraen-17,2-olide, a cembrenolide diterpene from soft coral Lobophytum sp., inhibits growth and induces apoptosis in human colon cancer cells through reactive oxygen species generation.

We observed that (1S,2S,3E,7E,11E)-3,7,11,15-Cembratetraen-17,2-olide (LS-1), marine cembrenolide diterpene, inhibited growth and induced apoptosis in colon cancer cells via a reactive oxygen species (ROS) dependent mechanism. Treatment of HT-29 cells with LS-1 resulted in ROS generation, which was accompanied by disruption of mitochondrial membrane potential, cytosolic release of cytochrome c, sub-G1 peak accumulation, activation of Bid, caspase-3, -8, and -9, and cleavage of poly(ADP-ribose) polymerase (PARP) along with the suppressive expression of B cell lymphoma-2 (Bcl-2). All these effects were significantly blocked on pretreatment with the ROS inhibitor N-acetylcysteine (NAC), indicating the involvement of increased ROS in the proapoptotic activity of LS-1. Moreover, we showed that LS-1 induced the phosphorylation of c-Jun N-terminal kinase (JNK) and dephosphorylation of p38, extracellular signal-regulated kinase (ERK), Akt, Src and signal transducer and activator of transcription (STAT)3, which were effectively attenuated by NAC. In addition, the expressions of antioxidant catalase and glutathione peroxidase were abrogated by treatment using LS-1 with or without NAC. These findings reveal the novel anticancer efficacy of LS-1 mediated by the induction of apoptosis via ROS generation in human colon cancer cells.