Combination Effect of Titrated Extract of Centella asiatica and Astaxanthin in a Mouse Model of Phthalic Anhydride-Induced Atopic Dermatitis

PURPOSE: In our previous study, we demonstrated that both titrated extract of Centella asiatica (TECA) and astaxanthin (AST) have anti-inflammatory effects in a 5% phthalic anhydride (PA) mouse model of atopic dermatitis (AD). The increasing prevalence of AD demands new therapeutic approaches for treating the disease. We investigated the therapeutic efficacy of the ointment form of TECA, AST and a TECA + AST combination in a mouse model of AD to see whether a combination of the reduced doses of 2 compounds could have a synergistic effect. METHODS: An AD-like lesion was induced by the topical application of 5% PA to the dorsal ear and back skin of an Hos:HR-1 mouse. After AD induction, TECA (0.5%), AST (0.5%) and the TECA (0.25%) + AST (0.25%) combination ointment (20 μg/cm2) were spread on the dorsum of the ear or back skin 3 times a week for 4 weeks. We evaluated dermatitis severity, histopathological changes and changes in protein expression by Western blotting for inducible nitric oxide synthase (iNOS), cyclocxygenase (COX)-2, and nuclear factor (NF)-κB activity. We also measured the concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and immunoglobulin E (IgE) in the blood of AD mice by enzyme-linked immunosorbent assay (ELISA). RESULTS: PA-induced skin morphological changes and ear thickness were significantly reduced by TECA, AST and TECA + AST treatments, but these inhibiting effects were more pronounced in the TECA + AST treatment. TECA, AST and the TECA+AST reatments inhibited the expression of iNOS and COX-2; NF-κB activity; and the release of TNF-α, IL-6 and IgE. However, the TECA+AST treatment showed additive or synergistic effects on AD. CONCLUSIONS: Our results demonstrate that the combination of TECA and AST could be a promising therapeutic agent for AD by inhibiting NF-κB signaling.

Streptococcus mutans activates the AIM2, NLRP3 and NLRC4 inflammasomes in human THP-1 macrophages / 国际口腔科学杂志·英文版

Streptococcus mutans (S. mutans), a major aetiologic agent of dental caries, is involved in systemic diseases, such as bacterial endocarditis, if it enters the bloodstream through temporary bacteraemia. Interleukin (IL)-1β, a proinflammatory cytokine, is related to the host defences against pathogens, and its synthesis, maturation, and secretion are tightly regulated by the activation of the inflammasome, an inflammatory signalling complex. This study examined the signalling mechanism of IL-1β secretion and the inflammasome pathway induced by S. mutans to explain the molecular mechanism through which systemic infection by oral streptococci can occur. After infection of THP-1 cells with S. mutans, the expression of inflammasome components was detected using various methods. S. mutans induced IL-1β secretion via caspase-1 activation, and S. mutans-induced IL-1β secretion required absent in melanoma (AIM2), NLR family pyrin domain-containing 3 (NLRP3) and NLR family CARD domain-containing 4 (NLRC4) inflammasome activation. In particular, the S. mutans-induced NLRP3 inflammasome was mediated by adenosine triphosphate (ATP) release, potassium depletion and lysosomal damage. Our study provides novel insight into the innate immune response against S. mutans infection.

Inhibitory Effect of Carnosol on Phthalic Anhydride-Induced Atopic Dermatitis via Inhibition of STAT3

Carnosol is a phenolic antioxidant present in rosemary (Rosmarinus officinalis). It is known for anti-inflammatory effects, analgesic activity and anti-cancer effects. However, no study has been dedicated yet to its effect on atopic dermatitis (AD). Here, we show that carnosol effectively inhibited LPS-induced nitric oxide (NO) generation and expression of inflammatory marker proteins (iNOS and COX-2) in RAW 264.7 cells. In addition, carnosol effectively inhibits the phosphorylation of STAT3 and DNA binding activity in RAW 264.7 cells. Pull down assay and docking model analysis showed that carnosol directly binds to the DNA binding domain (DBD) of STAT3. We next examined the anti-atopic activity of carnosol (0.05 μg/cm²) using 5% Phthalic anhydride (PA)-induced AD model in HR1 mice. Carnosol treatment significantly reduced 5% PA-induced AD like skin inflammation in skin tissues compared with control mice. Moreover, carnosol treatment inhibits the expression of iNOS and COX-2 in skin tissue. In addition, the levels of TNF-α, IL-1β, and Immunoglobulin-E in blood serum was significantly decreased in carnosol treated mice compared with those of 5% PA treated group. Furthermore, the activation of STAT3 in skin tissue was decreased in carnosol treated mice compared with control mice. In conclusion, these findings suggest that carnosol exhibited a potential anti-AD activity by inhibiting pro-inflammatory mediators through suppression of STAT3 activation via direct binding to DBD of STAT3.

Rutin induces autophagy in cancer cells

Rutin (3,3′,4′,5,7-pentahydroxyflavone-3-rhamnoglucoside) is a bioactive flavonoid from the plant kingdom. Rutin has been studied as potential anticancer agent due to its wide range of pharmacological properties including antioxidative, anti-inflammatory and anticancer. Autophagy is a conserved intracellular catabolic pathway to maintain cell homeostasis by formation of autophagosome. Processing of autophagy involves various molecules including ULK1 protein kinase complex, Beclin-1–Vps34 lipid kinase complex, ATG5, ATG12, and LC3 (light chain 3). Cargo-carried autophagosomes fuse with lysosomes resulting in autophagolysosome to eliminate vesicles and degrade cargo. However, the actions of rutin on autophagy are not clearly understood. In this study, we analyzed the effect of rutin on autophagy and inflammation in cancer cell lines. Interestingly, rutin induced autophagy in leukemia (THP-1), oral (CA9-22), and lung (A549) cell lines. TNF-α, key modulator of inflammation, was upregulated by inhibition of rutin-induced autophagy. Taken together, these data indicated that rutin induced autophagy and consequently suppressed TNF-α production.

The pleckstrin homology domain of phospholipase D1 accelerates EGFR endocytosis by increasing the expression of the Rab5 effector, rabaptin-5

Endocytosis is differentially regulated by hypoxia-inducible factor-1alpha (HIF-1alpha) and phospholipase D (PLD). However, the relationship between HIF-1alpha and PLD in endocytosis is unknown. HIF-1alpha is degraded through the prolyl hydroxylase (PHD)/von Hippel-Lindau (VHL) ubiquitination pathway in an oxygen-dependent manner. Here, we show that PLD1 recovers the decrease in epidermal growth factor receptor (EGFR) endocytosis induced by HIF-1alpha independent of lipase activity via the Rab5-mediated endosome fusion pathway. EGF-induced interaction of PLD1 with HIF-1alpha, PHD and VHL may contribute to EGFR endocytosis. The pleckstrin homology domain (PH) of PLD1 itself promotes degradation of HIF-1alpha, then accelerates EGFR endocytosis via upregulation of rabaptin-5 and suppresses tumor progression. These findings reveal a novel role of the PLD1-PH domain as a positive regulator of endocytosis and provide a link between PLD1 and HIF-1alpha in the EGFR endocytosis pathway.

Centella asiatica enhances neurogenesis and protects neuronal cells against H2O2-induced oxidative injury / 동물의과학연구지

Traditionally, Centella asiatica leaf extracts are used to treat neurodegenerative diseases in India. Centella asiatica is reportedly used to enhance memory and treat dementia, but its promoting effect on neural stem cell differentiation has not been studied yet. In the present study, we investigated whether or not Centella asiatica leaf extracts act on neuronal precursor cells and neuronal cell lines to induce neuronal differentiation, neurite outgrowth, and neuroprotection. The neurogenesis-promoting potential of Centella asiatica leaf extracts was determined by differentiation assay on neural stem cells isolated from mouse embryos and PC12 cell lines. To understand the contribution of specific neural cell types towards increase after Centella asiatica treatment, neural stem cells were differentiated into various neural subtypes and checked by Western blotting using neural cell lineage-specific antibody markers. Neuroprotective activity of Centella asiatica was analyzed in PC12 cells exposed to 100 microM of H2O2. Cell growth was analyzed by MTT assay while cell death was analyzed by Western blotting detection of apoptosis-related proteins. Cells treated with Centella asiatica had significantly longer primary and secondary neurites as well as a higher number of neurites per cell compared to control cells. Expression levels of TUBBIII, TH, NF, and BDNF increased upon Centella asiatica treatment, suggesting that Centella asiatica has a neurogenesis-promoting effect. Centella asiatica also inhibited oxidative stress-induced neural cell damage through regulation of apoptosis- and cell cycle-related proteins. Thus, leaf extracts of Centella asiatica might promote neurogenesis, neuroregeneration, and neuroprotection in the context of neurodegenerative diseases.

The Effect of a Discharge Education Program for Readmitted Chemotherapy Patients on Compliance with Sick Role Behavior and Educational Satisfaction

PURPOSE: This study was designed to evaluate the effects of a discharge education program for hospitalized readmitted patients with chemotherapy-in terms of sick role behavior and educational satisfaction. METHODS: The data were collected with a nonequivalent control group non-synchronized design and were analyzed with a nonequivalent control group pre-posttest design. The subjects included 49 patients with cancer, 25 in the experimental group, and 24 in the control group. Data were analyzed with spss win 21, chi2-tests, paired t-tests, and independent t-tests. RESULTS: The experimental group was educated according to their needs at discharge, and they showed higher compliance with sick role behavior. CONCLUSION: To improve compliance with sick role behavior, readmitted hematologic neoplasms chemotherapy patients should receive discharge education according to their needs at the clinic by using an educational manual.

Phospholipase D2 promotes degradation of hypoxia-inducible factor-1alpha independent of lipase activity

Hypoxia-inducible factor-1alpha (HIF-1alpha) is a key transcriptional mediator that coordinates the expression of various genes involved in tumorigenesis in response to changes in oxygen tension. The stability of HIF-1alpha protein is determined by oxygen-dependent prolyl hydroxylation, which is required for binding of the von Hippel-Lindau protein (VHL), the recognition component of an E3 ubiquitin ligase that targets HIF-1alpha for ubiquitination and degradation. Here, we demonstrate that PLD2 protein itself interacts with HIF-1alpha, prolyl hydroxylase (PHD) and VHL to promote degradation of HIF-1alpha via the proteasomal pathway independent of lipase activity. PLD2 increases PHD2-mediated hydroxylation of HIF-1alpha by increasing the interaction of HIF-1alpha with PHD2. Moreover, PLD2 promotes VHL-dependent HIF-1alpha degradation by accelerating the association between VHL and HIF-1alpha. The interaction of the pleckstrin homology domain of PLD2 with HIF-1alpha also promoted degradation of HIF-1alpha and decreased expression of its target genes. These results indicate that PLD2 negatively regulates the stability of HIF-1alpha through the dynamic assembly of HIF-1alpha, PHD2 and VHL.

Enhanced Anti-Cancer Effect of Snake Venom Activated NK Cells on Lung Cancer Cells by Inactivation of NF-kappaB

In the present study, we investigated anti-cancer effect of snake venom activated NK cells (NK-92MI) in lung cancer cell lines. We used snake venom (4 microg/ml) treated NK-92MI cells to co-culture with lung cancer cells. There was a further decrease in cancer cell growth up to 65% and 70% in A549 and NCI-H460 cell lines respectively, whereas 30-40% was decreased in cancer cell growth by snake venom or NK-92MI alone treatment. We further found that the expression of various apoptotic proteins such as that Bax, and cleaved caspase-3 as well as the expression of various death receptor proteins like DR3, DR4 and Fas was also further increased. Moreover, consistent with cancer cell growth inhibition, the DNA binding activity of NF-kappaB was also further inhibited after treatment of snake venom activated NK-92MI cells. Thus, the present data showed that activated NK cells could further inhibit lung cancer cell growth.

Nuclear Factor-kappaB Dependent Induction of TNF-alpha and IL-1beta by the Aggregatibacter actinomycetemcomitans Lipopolysaccharide in RAW 264.7 Cells

Aggregatibacter actinomycetemcomitans is an important pathogen in the development of localized aggressive periodontitis. Lipopolysaccharide (LPS) is a virulent factor of periodontal pathogens that contributes to alveolar bone loss and connective tissue degradation in periodontal disease. Our present study was designed to investigate the cytokine expression and signaling pathways regulated by A. actinomycetemcomitans LPS (Aa LPS). Cytokine gene expression profiling in RAW 264.7 cells was performed by microarray analyses. The cytokine mRNA and protein levels and related signaling pathways induced by Aa LPS were measured by RT-PCR, ELISA and western blotting. Microarray results showed that Aa LPS strongly induced the expression of NF-kappaB, NF-kappaB-related genes, inflammatory cytokines, TNF-alpha and IL-1beta in RAW 264.7 cells. NF-kappaB inhibitor pretreatment significantly reduced the levels of TNF-alpha and IL-1beta mRNA and protein. In addition, the Aa LPS-induced TNF-alpha and IL-1beta expression was inhibited by p38/JNK MAP kinase inhibitor pretreatment. These results show that Aa LPS stimulates TNF-alpha and IL-1beta expression through NF-kappaB and p38/JNK activation in RAW 264.7 cells, suggesting the essential role of this pathway in the pathogenesis of localized aggressive periodontitis.

Effectiveness of a Comprehensive Stress Management Program to Reduce Work-Related Stress in a Medium-Sized Enterprise

OBJECTIVES: To assess the effectiveness of a comprehensive workplace stress management program consisting of participatory action-oriented training (PAOT) and individual management. METHODS: A comprehensive workplace stress management program was conducted in a medium-sized enterprise. The baseline survey was conducted in September 2011, using the Korean Occupational Stress Scale (KOSS) and Worker's Stress Response Inventory (WSRI). After implementing both organizational and individual level interventions, the follow up evaluation was conducted in November 2011. RESULTS: Most of the workers participated in the organizational level PAOT and made Team-based improvement plans. Based on the stress survey, 24 workers were interviewed by a researcher. After the organizational and individual level interventions, there was a reduction of several adverse psychosocial factors and stress responses. In the case of blue-collar workers, psychosocial factors such as the physical environment, job demands, organizational system, lack of rewards, and occupational climate were significantly improved; in the case of white-collar workers, the occupational climate was improved. CONCLUSIONS: In light of these results, we concluded that the comprehensive stress management program was effective in reducing work-related stress in a short-term period. A persistent long-term follow up is necessary to determine whether the observed effects are maintained over time. Both team-based improvement activities and individual interviews have to be sustainable and complementary to each other under the long-term plan.

Eosinophilic Myocarditis Associated with Visceral Larva Migrans Caused by Toxocara Canis Infection

A 41-year-old woman who was diagnosed with myocarditis presented eosinophilia. Since the antibody against Toxocara canis (T. canis) was positive, we diagnosed that she had visceral larva migrans due to T. canis associated with myocarditis. She was treated with oral albendazole and prednisolone for two weeks, eosinophil count and hepatic enzymes were normalized after completion of treatment. This is the first report of myocarditis caused by T. canis infection in Korea.

Blood Cyst of Subvalvular Apparatus of the Mitral Valve in an Adult

Blood cysts of the heart are rare benign tumors, usually involving the cardiac valves. They are found mainly in the first month of life and in children; and are rarely seen in adults. Here, we report a case of a blood cyst on the subvalvular apparatus of the mitral valve, which was incidentally discovered during chest computed tomography in a 47-year-old man. To the best of our knowledge, this is the first reported case of blood cyst of the heart in an adult in Korea.

Newly Identified TLR9 Stimulant, M6-395 Is a Potent Polyclonal Activator for Murine B Cells

BACKGROUND: Toll-like receptors (TLRs) have been extensively studied in recent years. However, functions of these molecules in murine B cell biology are largely unknown. A TLR4 stimulant, LPS is well known as a powerful polyclonal activator for murine B cells. METHODS: In this study, we explored the effect of a murine TLR9 stimulant, M6-395 (a synthetic CpG ODNs) on B cell proliferation and Ig production. RESULTS: First, M6-395 was much more potent than LPS in augmenting B cell proliferation. As for Ig expression, M6-395 facilitated the expression of both TGF-beta1-induced germ line transcript alpha (GLTalpha) and IL-4-induced GLTgamma1 as levels as those by LPS and Pam3CSK4 (TLR1/2 agonist) : a certain Ig GLT expression is regarded as an indicative of the corresponding isotype switching recombination. However, IgA and IgG1 secretion patterns were quite different--these Ig isotype secretions by M6-395 were much less than those by LPS and Pam3CSK4. Moreover, the increase of IgA and IgG1 production by LPS and Pam3CSK4 was virtually abrogated by M6-395. The same was true for the secretion of IgG3. We found that this unexpected phenomena provoked by M6-395 is attributed, at least in part, to its excessive mitogenic nature. CONCLUSION: Taken together, these results suggest that M6-395 can act as a murine polyclonal activator but its strong mitogenic activity is unfavorable to Ig isotype switching.

A Case of Coccidioidal Meningitis / 감염과화학요법

A 35-year-old man with known coccidioidal meningitis developed a severe headache and vomiting during routine treatment. Hydrocephalus was visible on brain imaging, and CSF study revealed pleocytosis, lowering of glucose, and increased intracranial pressure. Dexamethasone and mannitol was used for intracranial pressure control. Intrathecal amphotericin B administration and switching to itraconazole resulted in gradual improvement of symptoms. After 4 months of discontinuing amphotericin B intrathecal administration, the patient developed severe headaches with vomiting, diplopia and tandem gait. Coccidioidal meningitis aggravation was suspected based on brain MRI and CSF studies. Ventriculo-peritoneal shunt insertion was performed for intracranial pressure control and the combined therapy of intrathecal amphotericin B administration and fluconazole was maintained. This combined regimen kept the meningitis stable for 1 month.

Association between Intracellular Infectious Agents and Schizophrenia

OBJECTIVE: A number of studies have reported association between Toxoplasma gondii (T. gondii) and Chlamydia infection and the risk of schizophrenia. The aim of the present study was to compare the prevalence of T. gondii and Chlamydia infection between the schizophrenia and normal control subjects and to compare the clinical features between seropositive and seronegative schizophrenia patients. METHODS: The rate of serum reactivity to T. gondii, Chlamydia trachomatis (C. trachomatis), Chlamydia pneumonia in 96 schizophrenia and 50 control subjects was investigated using enzyme-linked immunosorbent assay and indirect fluorescent antibody technique. The clinical symptoms of the schizophrenia patients were scored with Positive and Negative Syndrome Scale and a comparative analysis was carried out. RESULTS: A significant positive association between immunoglobulin G (IgG) antibodies to T. gondii and C. trachomatis in schizophrenia was found, and the odds ratio of schizophrenia associated with IgG antibody was found to be 3.22 and 2.86, respectively. The Toxoplasma-seropositive schizophrenia patient had higher score on the negative subscale N1 and N7 and general psychopathology subscale G13, while C. trachomatis-seropositive schizophrenia patient had higher score on the general psychopathology subscale G10. CONCLUSION: The results from the present study suggest significant association between T. gondii, C. trachomatis infection and schizophrenia. In future, further studies are needed to elucidate the correlation between the two types of infection and schizophrenia.

Pulmonary Functions and Related Factors in Shipyard Workers / 대한산업의학회지

OBJECTIVES: The purpose of this study was to evaluate the factors which affect pulmonary function in shipyard workers in order to build a body of basic information that can be used to prevent and manage pulmonary disorders in the future. METHODS: We studied the respiratory symptoms, smoking history, chest radiographies, and pulmonary functions of 793 workers associated with two shipyards from April 2009 to July 2009. The workers were subdivided into 3 groups by job type: welders, grinders, and machinist-managers. The data was analyzed according to job type and other possible impact factors. RESULTS: Significant differences among job type were seen with dyspnea and coughing during working hours and in the morning. In pulmonary functions, there were significant differences in forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), peak expiratory flow (PEF), and maximal mid-expiratory flow (MMEF) (except FEV1/FVC%) among job types. Grinders especially showed significantly lower figures in the indices of FEV1, FVC, and MMEF. CONCLUSIONS: Pulmonary function was significantly lower in grinders. Grinders seem to be affected by exposure to a combination of dust particles (silica, lead, and manganese) and irritant gases in the workplace. These results suggested that workers and health officials should work together to adopt technical preventive measures, such as having well- ventilated work areas and appropriate respiratory protective devices.

Incidentally Detected Situs Ambiguous in Adults

Situs ambiguous is rare congenital anomaly in adults. In 2 adult patients who admitted for different cardiac problems, situs ambiguous with polysplenia was detected. A 42-year-old male admitted for radio frequent catheter ablation of atrial fibrillation, and he had left-sided inferior vena cava (IVC), hepatic segment of IVC interruption with hemiazygos continuation, multiple spleens and intestinal malrotation. And in a 52-year-old female case who was hospitalized due to infective endocarditis after implanting pacemaker for sick sinus syndrome, multiple spleens, left-sided stomach, bilateral liver with midline gallbladder, and left-sided IVC were found. Those findings were consistent with situs ambiguous with polysplenia, but their features were distinctive.

Gemcitabine Plus Platinum Combination Chemotherapy for Elderly Patients with Advanced Non-small Cell Lung Cancer: A Retrospective Analysis / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: This study aimed to analyze the efficacy and toxicity of gemcitabine plus platinum chemotherapy for patients aged 70 years or older with advanced non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: We reviewed the records of stage IIIB, IV NSCLC patients or surgically inoperable stage II, IIIA NSCLC patients who were aged 70 years or older when treated with gemcitabine (1,250 mg/m2) plus cisplatin (75 mg/m2) or carboplatin (AUC5) chemotherapy from 2001 to 2010 at Seoul St. Mary's Hospital, Uijeongbu St. Mary's Hospital and St. Vincent's Hospital. Gemcitabine was administered on days 1 and 8, and cisplatin or carboplatin was administered on day 1. Treatments were repeated every 3 weeks for a maximum of 4 cycles. RESULTS: The median age of the 62 patients was 73.5 years (range, 70 to 84 years). Forty-one (66%) patients exhibited comorbidity. The mean number of treatment cycles was 3.9. The compared average relative dose intensity of gemcitabine plus platinum chemotherapy was 84.8%. The median progression-free survival and overall survival (OS) were 5.0 months and 9.4 months, respectively. Reduced Eastern Cooperative Oncology Group (ECOG) performance status (none vs. > or =1) and weight loss ( or =5%) after treatment were found to have a significant effect on OS (p=0.01). CONCLUSION: Gemcitabine plus platinum chemotherapy is an effective treatment option with an acceptable level of toxicity in patients aged 70 years or older with good performance status in advanced NSCLC.

Freezing of Gait Following Hypoxic Brain Injury: Two Cases Reports

Freezing of gait (FOG), which is the most common symptoms in Parkinson's disease, is a unique gait disorder that patients are unable to initiate or continue locomotion. However, the pathophysiology of FOG has been poorly understood. We report two cases, one case is a 26-year old man and the second case is a 65-year old man, who showed FOG following hypoxic brain injuries caused by sudden cardiac arrest and hypovolemic shock, respectively. Brain F-18 FDG-PET images demonstrated the diffuse cortical hypometabolism in case 1 patient, and the decreased metabolism of the subcortical structures in case 2 patient. Two patients showed the typical features of FOG (turning, destination, and tight quarter hesitations combined with kinesia paradoxa) and the abnormal patterns of temporospatial data in kinematic gait analysis. We present two cases of FOG following hypoxic brain injury with reviewing of some literatures.