MS-5, a Naphthalene Derivative, Induces Apoptosis in Human Pancreatic Cancer BxPC-3 Cells by Modulating Reactive Oxygen Species

Pancreatic cancer is one of the most fatal cancers with a poor prognosis. Standard chemotherapies have proven largely ineffective because of their toxicity and the development of resistance. Therefore, there is an urgent need to develop novel therapies. In this study, we investigated the antitumor activity of MS-5, a naphthalene derivative, on BxPC-3, a human pancreatic cancer cell line. We observed that MS-5 was cytotoxic to BxPC-3 cells, as well as inhibited the growth of cells in a concentration- and time- dependent manner. Flow cytometry analysis revealed that the percentage of annexin V-positive cells increased after MS-5 treatment. We also observed cleavage of caspases and poly (ADP-ribose) polymerase, and downregulation of Bcl-xL protein. Flow cytometry analysis of intracellular levels of reactive oxygen species (ROS) and mitochondrial superoxide suggested that MS-5 induced the generation of mitochondrial superoxide while lowering the overall intracellular ROS levels. Thus, MS-5 may be potential candidate for pancreatic cancer treatment.

Domperidone Exerts Antitumor Activity in Triple-Negative Breast Cancer Cells by Modulating Reactive Oxygen Species and JAK/STAT3 Signaling

The lack of molecular targets hampers the treatment of triple-negative breast cancer (TNBC). In this study, we determined the cytotoxicity of domperidone, a dopamine D2 receptor (DRD2) antagonist in human TNBC BT-549 and CAL-51 cells. Domperidone inhibited cell growth in a dose- and time-dependent manner. The annexin V/propidium iodide staining showed that domperidone induced apoptosis. The domperidone-induced apoptosis was accompanied by the generation of mitochondrial superoxide and the down-regulation of cyclins and CDKs. The apoptotic effect of domperidone on TNBC cells was prevented by pre-treatment with Mito-TEMPO, a mitochondria-specific antioxidant. The prevention of apoptosis with Mito-TEMPO even at concentrations as low as 100 nM, implies that the generation of mitochondrial ROS mediated the domperidone-induced apoptosis. Immunoblot analysis showed that domperidone-induced apoptosis occurred through the down-regulation of the phosphorylation of JAK2 and STAT3.Moreover, domperidone downregulated the levels of D2-like dopamine receptors including DRD2, regardless of their mRNA levels. Our results support further development of DRD2 antagonists as potential therapeutic strategy treating TNBC.

TM4SF4 and LRRK2 Are Potential Therapeutic Targets in Lung and Breast Cancers through Outlier Analysis / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#To find biomarkers for disease, there have been constant attempts to investigate the genes that differ from those in the disease groups. However, the values that lie outside the overall pattern of a distribution, the outliers, are frequently excluded in traditional analytical methods as they are considered to be ‘some sort of problem.’ Such outliers may have a biologic role in the disease group. Thus, this study explored new biomarker using outlier analysis, and verified the suitability of therapeutic potential of two genes (TM4SF4 and LRRK2). @*Materials and Methods@#Modified Tukey’s fences outlier analysis was carried out to identify new biomarkers using the public gene expression datasets. And we verified the presence of the selected biomarkers in other clinical samples via customized gene expression panels and tissue microarrays. Moreover, a siRNA-based knockdown test was performed to evaluate the impact of the biomarkers on oncogenic phenotypes. @*Results@#TM4SF4 in lung cancer and LRRK2 in breast cancer were chosen as candidates among the genes derived from the analysis. TM4SF4 and LRRK2 were overexpressed in the small number of samples with lung cancer (4.20%) and breast cancer (2.42%), respectively. Knockdown of TM4SF4 and LRRK2 suppressed the growth of lung and breast cancer cell lines. The LRRK2 overexpressing cell lines were more sensitive to LRRK2-IN-1 than the LRRK2 under-expressing cell lines @*Conclusion@#Our modified outlier-based analysis method has proved to rescue biomarkers previously missed or unnoticed by traditional analysis showing TM4SF4 and LRRK2 are novel target candidates for lung and breast cancer, respectively.

Recent Trends in Cyclic Peptides as Therapeutic Agents and Biochemical Tools

Notable progress has been made in the therapeutic and research applications of cyclic peptides since our previous review. New drugs based on cyclic peptides are entering the market, such as plecanatide, a cyclic peptide approved by the United States Food and Drug Administration in 2017 for the treatment of chronic idiopathic constipation. In this review, we discuss recent developments in stapled peptides, prepared with the use of chemical linkers, and bicyclic/tricyclic peptides with more than two rings. These have widespread applications for clinical and research purposes: imaging, diagnostics, improvement of oral absorption, enzyme inhibition, development of receptor agonist/antagonist, and the modulation of protein-protein interaction or protein-RNA interaction. Many cyclic peptides are expected to emerge as therapeutics and biochemical tools.

MS-5, a Naphthalene Derivative, Induces the Apoptosis of an Ovarian Cancer Cell CAOV-3 by Interfering with the Reactive Oxygen Species Generation

Reactive oxygen species (ROS) are widely generated in biological processes such as normal metabolism and response to xenobiotic exposure. While ROS can be beneficial or harmful to cells and tissues, generation of ROS by diverse anti-cancer drugs or phytochemicals plays an important role in the induction of apoptosis. We recently identified a derivative of naphthalene, MS-5, that induces apoptosis of an ovarian cell, CAOV-3. Interestingly, MS-5 induced apoptosis by down-regulating the ROS. Cell viability was evaluated by water-soluble tetrazolium salt (WST-1) assay. Apoptosis was evaluated by flow cytometry analysis. Intracellular ROS (H₂O₂), mitochondrial superoxide, mitochondrial membrane potential (MMP) and effect on cycle were determined by flow cytometry. Protein expression was assessed by western blotting. The level of ATP was measured using ATP Colorimetric/Fluorometric Assay kit. MS-5 inhibited growth of ovarian cancer cell lines, CAOV-3, in a concentration- and time-dependent manner. MS-5 also induced G1 cell cycle arrest in CAOV-3 cells, while MS-5 decreased intracellular ROS generation. In addition, cells treated with MS-5 showed the decrease in MMP and ATP production. In this study, we found that treatment with MS-5 in CAOV-3 cells induced apoptosis but decreased ROS level. We suspect that MS-5 might interfere with the minimum requirements of ROS for survival. These perturbations appear to be concentration-dependent, suggesting that MS-5 may induce apoptosis by interfering with ROS generation. We propose that MS-5 may be a potent therapeutic agent for inducing apoptosis in ovarian cancer cell through regulation of ROS.

Chrysophanic Acid Induces Necrosis but not Necroptosis in Human Renal Cell Carcinoma Caki-2 Cells

BACKGROUND: Chrysophanic acid, also known as chrysophanol, has a number of biological activities. It enhances memory and learning abilities, raises superoxide dismutase activity, and has anti-cancer effects in several model systems. According to previous reports, chrysophanic acid-induced cell death shares features of necrotic cell death. However, the molecular and cellular processes underlying chrysophanic acid-induced cell death remain poorly understood. METHODS: Chrysophanic acid-induced cell death was monitored by cell viability assay and Annexin V-propidium iodide (PI) staining of renal cell carcinoma Caki-2 cells. The induction of intracellular reactive oxygen species (ROS) by chrysophanic acid and the suppression of ROS by anti-oxidants were evaluated by 2',7'-dichlorofluorescin diacetate staining. The expression and phosphorylation of proteins that are involved in apoptosis and necroptosis were detected by immunoblotting. RESULTS: The extent of chrysophanic acid-induced cell death was concentration and time dependent, and dead cells mainly appeared in the PI-positive population, which is a major feature of necrosis, upon fluorescence-activated cell sorting analysis. Chrysophanic acid-induced cell death was associated with the generation of intracellular ROS, and this effect was reversed by pretreatment with N-acetyl cysteine. Chrysophanic acid-induced cell death was not associated with changes in apoptotic or necroptotic marker proteins. CONCLUSIONS: The cell death induced by chrysophanic acid resembled neither apoptotic nor necroptotic cell death in human renal cell carcinoma Caki-2 cells.

Scrotal Erythema Associated with Sorafenib Therapy in a Patient with Hepatocellular Carcinoma / 대한피부과학회지

Sorafenib is an oral, multi-targeted tyrosine kinase inhibitor with anti-angiogenic and anti-proliferative activity. It is approved for the treatment of unresectable hepatocellular and advanced renal carcinomas. Cutaneous toxicity is relatively common in patients receiving sorafenib. The most frequent cutaneous side effect is the hand-foot syndrome. Other adverse skin reactions include facial erythema, acral erythema, erythema multiforme, subungual splinter hemorrhage, stomatitis, and alopecia. In Korea, two cases of scrotal and perianal dermatitis after sorafenib therapy were reported. We report a 54-year-old male patient with a 2-week history of scrotal eczema who had been treated for chronic hepatitis type B, liver cirrhosis, and hepatocellular carcinoma. After 2 weeks of oral sorafenib (800 mg/day) administration, thick, scaly patches appeared on his scrotum. A skin biopsy specimen from these lesions revealed superficial dermal perivascular lymphocytic and neutrophilic infiltration, and dilatation of the lymphatics in the superficial dermis. The lesions improved after treatment with a topical and systemic steroid for 2 weeks. Herein, we report a rare case of scrotal erythema associated with sorafenib.

Treatment of Patients with Refractory Atopic Dermatitis Sensitized to House Dust Mites by Using Sublingual Allergen Immunotherapy

Even though atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, its treatment remains a challenge in clinical practice, with most approaches limited to symptomatic, unspecific anti-inflammatory, or immunosuppressive treatments. Many studies have shown AD to have multiple causes that activate complex immunological and inflammatory pathways. However, aeroallergens, and especially the house dust mite (HDM), play a relevant role in the elicitation or exacerbation of eczematous lesions in many AD patients. Accordingly, allergen-specific immunotherapy has been used in AD patients with the aim of redirecting inappropriate immune responses. Here, we report three cases of refractory AD sensitized to HDM who were treated with sublingual immunotherapy.

Antiangiogenic Therapy Impedes Infiltration by CD4+ and CD8+ Cells Into an Early Colon Tumor

BACKGROUND: While the majority of angiogenesis studies have focused on the late stages of cancer, the emergence of neovascularization in colon tumorigenesis has been observed an earlier stage than expected. Recent reports implied that early angiogenesis might be a defense mechanism to stimulate the natural clearance of microadenomas during colon tumorigenesis. However, little is known about how early angiogenesis affects the natural clearance of tumors. METHODS: Spontaneous colon tumors were developed in adenomatous polyposis coli conditional knockout mice with Cre recombinase adenovirus administration. Vascular endothelial growth factor (VEGF) antagonist, DC101, was administrated to determine the effect of early angiogenesis and then infiltration of immune cells into tumor and concentration of cytokines were evaluated. RESULTS: The continuous administration of the VEGF receptor 2 antagonist DC101 in the mouse models impeded the infiltration by CD4+ and CD8+ cells into the tumor region. Furthermore, the administration of the VEGF antagonist decreased the amounts of anti-tumoral cytokines such as interleukin (IL)-6 and IL-10. CONCLUSIONS: We revealed that newly formed vessels during tumorigenesis can be channels for particular anti-tumoral immune cells. Our results may confer insight for the clinical development of an efficient antiangiogenic therapeutic manual and a timely chemoprevention to suppress tumor growth.

Foreign Body Reaction to Injectable Hyaluronic Acid: Late Granuloma Formation

No abstract available.

Concomitant Impact of High-Sensitivity C-Reactive Protein and Renal Dysfunction in Patients with Acute Myocardial Infarction

PURPOSE: The present study aimed to investigate the impact of high-sensitivity C-reactive protein (hs-CRP) and renal dysfunction on clinical outcomes in acute myocardial infarction (AMI) patients. MATERIALS AND METHODS: The study involved a retrospective cohort of 8332 patients admitted with AMI. The participants were divided into 4 groups according to the levels of estimated glomerular filtration rate (eGFR) and hs-CRP: group I, no renal dysfunction (eGFR > or =60 mL.min(-1).1.73 m(-2)) with low hs-CRP (< or =2.0 mg/dL); group II, no renal dysfunction with high hs-CRP; group III, renal dysfunction with low hs-CRP; and group IV, renal dysfunction with high hs-CRP. We compared major adverse cardiac events (MACE) over a 1-year follow-up period. RESULTS: The 4 groups demonstrated a graded association with increased MACE rates (group I, 8.8%; group II, 13.8%; group III, 18.6%; group IV, 30.1%; p<0.001). In a Cox proportional hazards model, mortality at 12 months increased in groups II, III, and IV compared with group I [hazard ratio (HR) 2.038, 95% confidence interval (CI) 1.450-2.863, p<0.001; HR 3.003, 95% CI 2.269-3.974, p<0.001; HR 5.087, 95% CI 3.755-6.891, p<0.001]. CONCLUSION: High hs-CRP, especially in association with renal dysfunction, is related to the occurrence of composite MACE, and indicates poor prognosis in AMI patients.

Clinical Availability of Component-Resolved Diagnosis Using Microarray Technology in Atopic Dermatitis

BACKGROUND: Various allergens play a role in the elicitation or exacerbation of eczematous skin lesions in atopic dermatitis (AD), and much research effort has been focused on improving diagnostic tests to identify causative allergens. OBJECTIVE: The purpose of this study was to evaluate the diagnostic effectiveness of a newly introduced microarray-based specific immunoglobulin E detection assay, ImmunoCAP ISAC, for use in AD patients. METHODS: The serum samples of 25 AD patients were tested by using ISAC and a multiple allergen simultaneous test-enzyme immunoassay (MAST-EIA). In addition, 10 of the 25 patients underwent skin prick testing (SPT). The positive reaction rates to allergens in each test and the agreements, sensitivities, and specificities of ISAC and MAST-EIA were evaluated versus the SPT results. RESULTS: For ISAC versus SPT, the overall results were as follows: sensitivity, 90.0%; specificity, 98.2%; positive predictive value (PPV), 90.0%; and negative predictive value (NPV), 98.2%. The total agreement and kappa value for ISAC versus SPT were 96.9% and 0.882, respectively. For MAST-EIA versus SPT, the sensitivity was 80.0%, specificity 92.7%, PPV 66.7%, and NPV 96.2%. The total agreement and kappa value for MAST-EIA versus SPT were 90.8% and 0.672, respectively. The overall agreement between the ISAC and MAST-EIA results was 88%. CONCLUSION: The ISAC results in AD correlated well with the SPT results, and compared favorably to the MAST-EIA results. This study demonstrates the potential of ISAC as a convenient allergic diagnostic method in AD patients.

Gross Hematuria Associated with Genitourinary Tuberculosis / 전남의대학술지

A 27-year-old man presented to the emergency department with sudden onset of massive gross hematuria and urinary retention. Contrast-enhanced computed tomography imaging showed uneven, dilated calices and a narrowing of the renal pelvis in the left kidney; in addition, a large hematoma was noted in the urinary bladder. An emergency cystoscopy was performed following detection of the hematoma and blood clots were removed. A lesional biopsy, a tuberculosis (TB) culture, and urine cytology showed positive results for Mycobacterium tuberculosis. The clinical manifestations of genitourinary tuberculosis are nonspecific and are usually detected at a chronic stage. In conclusion, we report an unusual cause of acute kidney injury associated with a subacute stage of genitourinary tuberculosis that caused mucosal erosion and bleeding in the bladder.

Multiple Intradermal Soft Tissue Perineuriomas of the Digit / 대한피부과학회지

Perineurioma is a rare benign peripheral nerve sheath tumor, composed uniformly of perineurial cells. Soft tissue perineurioma primarily arises within the subcutaneous tissue of extremities and trunk as a painless solitary nodule, and should be distinguished from dermatofibroma, neurofibroma, dermatofibrosarcoma protuberans, meningioma and so on. A 25 year-old female is presented with three small asymptomatic papules on the third left finger which were found 3 years ago. Punch biopsy was performed on all of the papules. Microscopic examination demonstrated well-demarcated tumor within dermis, and proliferation of spindle cells with wavy nuclei and elongated bipolar cytoplasmic process, arranged in a whorled pattern. According to immunohistochemical analysis, the tumor cell showed positivity for epithelial membrane antigen, but negativity for S-100 protein, factor XIIIa, CD34, and smooth muscle actin. The diagnosis of soft tissue perineurioma was being made. We report this rare case of perineurioma presented as multiple papules localized within dermis of the digit.

Percutaneous Coronary Intervention for Acute Myocardial Infarction in Elderly Patients with Renal Dysfunction: Results from the Korea Acute Myocardial Infarction Registry

This study aimed to evaluate the effects of percutaneous coronary intervention (PCI) on short- and long-term major adverse cardiac events (MACE) in elderly (>75 yr old) acute myocardial infarction (AMI) patients with renal dysfunction. As part of Korea AMI Registry (KAMIR), elderly patients with AMI and renal dysfunction (GFR<60 mL/min) received either medical (n=439) or PCI (n=1,019) therapy. Primary end point was in-hospital death. Secondary end point was MACE during a 1 month and 1 yr follow-up. PCI group showed a significantly lower incidence of in-hospital death (20.0% vs 14.3%, P=0.006). Short-term and long-term MACE rates were higher in medical therapy group (31.9% vs 19.0%; 57.7% vs 31.3%, P<0.001), and this difference was mainly attributed to cardiac death (29.3% vs 17.6%; 51.9% vs 25.0%, P<0.001). MACE-free survival time after adjustment was also higher in PCI group on short-term (hazard ratio, 0.67; confidence interval, 0.45-0.98; P=0.037) and long-term follow-up (hazard ratio, 0.61, confidence interval, 0.45-0.83; P=0.002). In elderly AMI patients with renal dysfunction, PCI therapy yields favorable in-hospital and short-term and long-term MACE-free survival.

Proteinuria as a Risk Factor for Mortality in Patients with Colorectal Cancer

PURPOSE: We investigated the effects of proteinuria and renal insufficiency on all-cause mortality in patients with colorectal cancer, with special emphasis on cancer staging and cancer-related deaths. MATERIALS AND METHODS: We retrospectively studied a cohort of patients with colorectal cancer. In protocol 1, patients were classified into four groups based on the operability of cancer and proteinuria: group 1, early-stage cancer patients (colorectal cancer stage < or =3) without proteinuria; group 2, early-stage cancer patients with proteinuria; group 3, advanced-stage cancer patients without proteinuria (colorectal cancer stage=4); and group 4, advanced-stage cancer patients with proteinuria. In protocol 2, patients were classified into four similar groups based on cancer staging and renal insufficiency (eGFR <60 mL/min/1.73 m2). Between January 1, 1998 and December 31, 2009, 3379 patients were enrolled in this cohort and followed until May 1, 2012 or until death. RESULTS: The number of patients with proteinuria was 495 (14.6%). The prevalence of proteinuria was higher in advanced-stage cancer (n=151, 22.3%) than in early-stage cancer patients (n=344, 12.7%). After adjusting for age, gender and other clinical variables, the proteinuric, early-stage cancer group was shown to be associated with an adjusted hazard ratio of 1.67 and a 95% confidence interval of 1.38-2.01, compared with non-proteinuric early-stage cancer patients. However, renal insufficiency was not associated with colorectal cancer mortality. CONCLUSION: Proteinuria is an important risk factor for cancer mortality, especially in relatively early colorectal cancer.

Increased Phosphorylation of PI3K/Akt/mTOR in the Obstructed Kidney of Rats with Unilateral Ureteral Obstruction / 전남의대학술지

The present study aimed to investigate changes in the mammalian target of rapamycin (mTOR) signaling pathway in the obstructed kidney of rats with unilateral ureteral obstruction (UUO). Male Sprague-Dawley rats were unilaterally obstructed by ligation of the left proximal ureter for 7 days. Control rats were treated in the same way except that no ligature was made. The expression levels of phosphorylated phosphatidylinositol 3-kinase (PI3K), Akt, and mTOR were determined in the kidney by semiquantitative immunoblotting. The protein expression levels of transforming growth factor (TGF)-beta1, Bax, and Bcl-2 were also determined in the kidney. The phosphorylation of PI3K, Akt, and mTOR was increased in the kidney of ureteral obstruction rats compared with the control. In the obstructed kidney, the protein expression of TGF-beta1 and Bax was also increased, whereas Bcl-2 expression was decreased. In conclusion, the phosphorylation of PI3K/Akt/mTOR was increased in the obstructed kidney of rats with UUO.

Effects of Tamoxifen in Deoxycorticosterone Acetate-salt Hypertensive Nephropahty

BACKGROUND: The present study was designed to evaluate the possible renoprotective effects of tamoxifen in deoxycorticosterone acetate (DOCA)-salt hypertensive (DSH) rats and its role in inflammation and fibrosis in the kidney. METHODS: Male Sprague-Dawley rats, weighing 180 to 200 g, were used. All rats underwent unilateral nephrectomy. One week later, one group of rats (n = 8) was implanted with DOCA strips (200 mg/kg) and another group of rats (n = 8) was implanted with DOCA strips with co-treated with tamoxifen (10 mg/kg) through gavage feeding. Rats that did not implanted DOCA strips served as controls (n = 6). Two weeks later, the systolic blood pressure (SBP) was measured by tail-cuff method. The protein expression of transforming growth factor-beta (TGF-beta), Smad, alpha-smooth muscle actin (alpha-SMA), E-cadherin, ED-1, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) was determined in the kidney by immunoblotting. The mRNA expression of tumor necrosis factor-alpha (TNF-alpha), monocyte chemotactic protein-1 (MCP-1), and vascular cell adhesion molecule-1 (VCAM-1) was determined by real-time polymerase chain reaction. RESULTS: In DSH rats, SBP was increased, which was not affected by tamoxifen treatment. Serum creatinine level was comparable in DSH rats compared with controls, which was not affected by tamoxifen treatment. In DSH rats, the protein expression of TGF-beta, Smad 2/3, Smad 4, alpha-SMA, ED-1, COX-2, iNOS was increased compared with controls, and these changes were attenuated by tamoxifen treatment except that of TGF-beta. The mRNA expression of TNF-alpha, MCP-1, and VCAM-1 was increased, and expression of MCP-1 and VCAM-1 was counteracted by tamoxifen treatment. CONCLUSIONS: Tamoxifen is effective in preventing the progression of nephropathy in DSH rats, the mechanism of which is associated with anti-inflammation and anti-fibrotic effects.

Serratia marcescens Peritonitis in a Diabetic Patient Receiving Continuous Ambulatory Peritoneal Dialysis

We report a case of Serratia marcescens peritonitis in a 45-year-old man with insulin-dependent diabetes mellitus undergoing continuous ambulatory peritoneal dialysis (CAPD). The patient presented with abdominal pain and cloudy dialysate. Empiric antibiotic therapy was initiated intraperitoneally with cefazolin and ceftazidime for 5 days. Cultures of the dialysate revealed S. marcescens, and the treatment was subsequently changed to gentamicin and ceftazidime. Oral ciprofloxacin was also added. The patient's abdominal pain and the dialysate white blood cell (WBC) count, however, did not improve. The indwelling CAPD catheter was therefore removed. This is an unusual case report in the Korean literature of S. marcescens peritonitis in a patient receiving CAPD.

Acute Kidney Injury in Patients with Sepsis and Septic Shock: Risk Factors and Clinical Outcomes

PURPOSE: The aim of this study was to investigate clinical characteristics and risk factors of acute kidney injury (AKI) in patients with sepsis and septic shock. Additionally, we explored whether the severity of AKI affects on the clinical outcomes. MATERIALS AND METHODS: Data were collected retrospectively in a single center. Among 5680 patients who visited emergency department from January to December 2010, 992 patients with sepsis and septic shock were enrolled. Patients were divided into two groups, patients who developed AKI or not, to compare the baseline characteristics, and laboratory and physiologic data. Patients with AKI were subdivided according to its stages for survival analysis. RESULTS: AKI was developed in 57.7% of patients. Multivariable logistic regression analysis revealed that development of septic AKI was associated with older age, pre-existing chronic kidney disease, use of angiotensin converting enzyme inhibitor or angiotensin receptor blocker, presence of shock, positive blood culture results, and low white blood cell and platelet counts. Hospital mortality was higher in AKI group. Crude Kaplan-Meier survival curves demonstrated reduced 30-day survival rate was significantly associated with the severity of acute kidney injury. CONCLUSION: The development of septic AKI was associated with poor clinical outcomes. Furthermore, the severity of AKI was associated with increased mortality.