Search results for: Th1/ Th2 cytokine expression

Authors: Han-Qin Zheng, Yi-Fan Chiang-Hsieh, Chia-Hung Chien, Wen-Chi Chang

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As the most important non-vascular plants, algae have many research applications, including high species diversity, biofuel sources, adsorption of heavy metals and, following processing, health supplements. With the increasing availability of next-generation sequencing (NGS) data for algae genomes and transcriptomes, an integrated resource for retrieving gene expression data and metabolic pathway is essential for functional analysis and systems biology in algae. However, gene expression profiles and biological pathways are displayed separately in current resources, and making it impossible to search current databases directly to identify the cellular response mechanisms. Therefore, this work develops a novel AlgaePath database to retrieve gene expression profiles efficiently under various conditions in numerous metabolic pathways. AlgaePath, a web-based database, integrates gene information, biological pathways, and next-generation sequencing (NGS) datasets in Chlamydomonasreinhardtii and Neodesmus sp. UTEX 2219-4. Users can identify gene expression profiles and pathway information by using five query pages (i.e. Gene Search, Pathway Search, Differentially Expressed Genes (DEGs) Search, Gene Group Analysis, and Co-Expression Analysis). The gene expression data of 45 and 4 samples can be obtained directly on pathway maps in C. reinhardtii and Neodesmus sp. UTEX 2219-4, respectively. Genes that are differentially expressed between two conditions can be identified in Folds Search. Furthermore, the Gene Group Analysis of AlgaePath includes pathway enrichment analysis, and can easily compare the gene expression profiles of functionally related genes in a map. Finally, Co-Expression Analysis provides co-expressed transcripts of a target gene. The analysis results provide a valuable reference for designing further experiments and elucidating critical mechanisms from high-throughput data. More than an effective interface to clarify the transcript response mechanisms in different metabolic pathways under various conditions, AlgaePath is also a data mining system to identify critical mechanisms based on high-throughput sequencing.

Keywords: next-generation sequencing (NGS), algae, transcriptome, metabolic pathway, co-expression

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Authors: Kathy Stein, Mariola Lysson, Anja Schmidt, Beatrix Schumak, Sabine Specht, Hicham Bouabe, Jürgen Heesemann, Axel Roers, Joerg C. Kalff, Sven Wehner

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Objective: Postoperative ileus (POI) is a common complication of abdominal surgery. Monocyte infiltration is a hallmark of POI. The polarization of macrophages/monocytes in this process is not well understood. We aimed to investigate if and how M2 macrophage/monocyte differentiation is involved in POI pathogenesis. Design: POI was induced by intestinal manipulation (IM). C57Bl/6, CCR2-/-, IL-10 reporter (ITIB), IL-10-/- and LysMcre/IL-10fl/fl mice underwent IM. At various points in time leukocyte influx, gene and protein expression of cytokines, chemokines and M2 differentiation markers and intestinal motility were analyzed. Results: IM induced the postoperative expression of the M2 markers Arginase-1 and YM-1, predominantly in F4/80+Ly6C+ monocytes. Gene expression analyses indicated an IL-10-dependent, IL-4-independent M2 polarization of these monocytes. IL-10 dependency of M2 differentiation was confirmed in IL-10 deficient mice. Leukocytes, in the order of infiltrating monocytes, neutrophils, and resident macrophages were the main IL-10 producers during POI. IL-10 producing monocytes as well as M2 marker expression were almost absent in CCR2-deficient mice. However, postoperative IL-10 expression was not altered in CCR2-/- mice. The loss of M2 polarized monocytes neither protected CCR2-/- mice from nor affected resolution of POI. In contrast, IL-10 deficiency reduced postoperative neutrophil numbers and ameliorated POI. IL-10Ra expression was strongly induced in neutrophils but not in monocytes. Conclusion: We conclude that IL-10 counteracts POI resolution by activating IL-10Ra-expressing neutrophils in the late phase of disease while IL-10-dependent M2 differentiation is not pivotal to POI manifestation and resolution.

Keywords: interleukin-10, macrophages, neutrophils, postoperative ileus

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Authors: Badawia Ibrahim, Iman Hussein, Samar El Sheikh, Fatma Abou Elkasem, Hazem Abo Ismael

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Background: Response of breast carcinoma to neoadjuvant chemotherapy (NAC) varies regarding many factors including hormonal receptor status. Breast cancer is a heterogenous disease with different outcomes, hence a need arises for new markers predicting the outcome of NAC especially for the triple negative group when estrogen, progesterone receptors and Her2/neu are negative. FOXP3 is a promising target with unclear role. Aim: To examine the value of FOXP3 expression in locally advanced triple negative breast cancer tumoral cells as well as tumor infiltrating lymphocytes (TILs) and to elucidate its relation to the extent of NAC response. Material and Methods: Forty five cases of immunohistochemically confirmed to be triple negative breast carcinoma were evaluated for NAC (Doxorubicin, Cyclophosphamide AC x 4 cycles + Paclitaxel x 12 weeks, patients with ejection fraction less than 60% received Taxotere or Cyclophosphamide, Methotrexate, Fluorouracil CMF) response in both tumour and lymph nodes status according to Miller & Payne's and Sataloff's systems. FOXP3 expression in tumor as well as TILs evaluated in the pretherapy biopsies was correlated with NAC response in breast tumor and lymph nodes as well as other clinicopathological factors. Results: Breast tumour cells showed FOXP3 positive cytoplasmic expression in (42%) of cases. High FOXP3 expression percentage was detected in (47%) of cases. High infiltration by FOXP3+TILs was detected in (49%) of cases. Positive FOXP3 expression was associated with negative lymph node metastasis. High FOXP3 expression percentage and high infiltration by FOXP3+TILs were significantly associated with complete therapy response in axillary lymph nodes. High FOXP3 expression in tumour cells was associated with high infiltration by FOXP3+TILs. Conclusion: This result may provide evidence that FOXP3 marker is a good prognostic and predictive marker for triple negative breast cancer (TNBC) indicated for neoadjuvant chemotherapy and can be used for stratifications of TNBC cases indicated for NAC. As well, this study confirmed the fact that the tumour cells and the surrounding microenvironment interact with each other and the tumour microenvironment can influence the treatment outcomes of TNBC.

Keywords: breast cancer, FOXP3 expression, prediction of neoadjuvant chemotherapy effect, triple negative

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Authors: Nadia A. Mohamed, Mehrevan M. Abdel-Moniem

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Zingiber officinale (ginger) has been cultivated for medicinal purposes due to their various proprieties both in vitro and in vivo, so we designed to evaluate the ginger’s potential effect on nephrin m RNA expression in cisplatin-induced nephrotoxic rats. Method: Forty male albino rats were divided into group I was injected (IP) with one ml saline, group II(cisplatin) injected (IP) with a single dose of 12 mg/kg cisplatin, group III (ginger) received (PO) 310 mg/kg for 30 successive days, and group IV(cisplatin and ginger) rats received ginger extract (310 mg/kg) daily for 20 successive days (PO), and then on day 20 of ginger extract administration each rat was injected(IP) with a single dose of 12 mg/kg cisplatin. The blood was sampled to assess urea, creatinine (SC), while the levels of malondialdehyde (MDA), nitric oxide (NO) and paraoxonase (PON1) were measured in kidney tissue homogenate. Expression of urinary nephrin gene (nephrin mRNA) was detected using qRT-PCR. Results: Treatment with ginger significantly decreased the levels of kidney function parameters as well as MDA and NO elevated by cisplatin injection, while PON1 was significantly reduced in the cisplatin group. However, the protection of male rats with ginger significantly increased the levels of nephrin gene expression and PON1 compared with the cisplatin-treated group. Our results generated a proposal on the ameliorating effect of ginger on nephrin mRNA gene expression reduction in cisplatin-induced nephrotoxicity.

Keywords: nephrin mRNA, ginger, cisplatin, nephrotoxicity

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Authors: Hanan Mohamed Abd Elmoneim, Rawan Saleh AlJawi, Razan Saleh AlJawi, Aseel Abdullah AlMasoudi , Zyad Adnan Turkistani, Anas Abdulkarim Alkhoutani , Ohood Musaed AlJuhani , Hanan Attiyah AlZahrani

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Background Esophageal cancer is the eighth most common cancer worldwide. More than 90% of esophageal cancers are either squamous cell carcinoma or adenocarcinoma. Squamous dysplasia is a precancerous lesion for squamous cell carcinoma and Barrett's esophagus is the precancerous lesion for adenocarcinoma. Gastro-esophageal reflux disease (GERD) is the initiation factor for Barrett's esophagus. Cyclooxygenase-2 (COX-2) is a key enzyme in arachidonic metabolism. It appears to play an important role in gastrointestinal carcinogenesis. COX-2 activity may be a potential target for the prevention of cancer progression by selective COX-2 inhibitors, which decrease proliferation and increase apoptosis. Objectives To assess COX-2 expression in premalignant and malignant esophageal epitheliums changes and detect its roles in progression of these lesions. Materials and Methods We analyzed the expression of COX-2 immunohistochemically in 40 esophageal biopsies utilizing the streptavidin-biotin-peroxidase complex method on archival formalin fixed-paraffin embedded blocks. Histopathologically, 17 (42.5%) of cases were non-malignant cases which included GERD, Barrett's esophagus and squamous dysplasia. The malignant cases were 23 (57.5%) squamous cell carcinoma, adenocarcinoma and undifferentiated carcinoma. Results In non-malignant cases 7 (41.2%) out of 17 cases had high COX-2 expression. In squamous cell carcinoma 10 (83.3%) out of 12 cases had high COX-2 expression. The expression of COX-2 was high in all 9 (100%) cases of adenocarcinoma. COX-2 expression is significantly increased (P=0.005 and P=0.0001) in squamous cell carcinoma and adenocarcinoma respectively. There was a significant difference in COX-2 immunoreactivity between malignant and non-malignant lesions (P=0.0003). Conclusion COX-2 is responsible for the progression of esophageal diseases from benign to malignant. We recommend that COX-2 immunohistochemistry should be done routinely for premalignant and malignant esophageal lesions as selective COX-2 inhibitors will be helpful in the treatment. Further studies on molecular and genetic basis of COX-2 expression are needed to unmask its role and relation to progression of esophageal lesions.

Keywords: Cox-2, Esophageal adinocarcinoma, Esophageal squamous cell carcinoma, Immunohistochemistry.

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Authors: Rasoul Eslami, Reza Gharakhanlou

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NT-4/5 and TrkB have been proposed to be involved in the coordinated adaptations of the neuromuscular system to elevated level of activity. Despite the persistence of this neurotrophin and its receptor expression in adult skeletal muscle, little attention has been paid to the functional significance of this complex in the mature neuromuscular system. Therefore, the purpose of this research was to study the effect of one session of resistance exercise on mRNA expression of NT4/5 and TrkB proteins in slow and fast muscles of Wistar Rats. Male Wistar rats (10 mo of age, preparation of Pasteur Institute) were housed under similar living conditions in cages (in groups of four) at room temperature under a controlled light/dark (12-h) cycle with ad libitum access to food and water. A number of sixteen rats were randomly divided to two groups (resistance exercise (T) and control (C); n=8 for each group). The resistance training protocol consisted of climbing a 1-meter–long ladder, with a weight attached to a tail sleeve. Twenty-four hours following the main training session, rats of T and C groups were anaesthetized and the right soleus and flexor hallucis longus (FHL) muscles were removed under sterile conditions via an incision on the dorsolateral aspect of the hind limb. For NT-4/5 and TrkB expression, quantitative real time RT-PCR was used. SPSS software and independent-samples t-test were used for data analysis. The level of significance was set at P < 0.05. Data indicate that resistance training significantly (P<0.05) decreased mRNA expression of NT4/5 in soleus muscle. However, no significant alteration was detected in FHL muscle (P>0.05). Our results also indicate that no significant alterations were detected for TrkB mRNA expression in soleus and FHL muscles (P>0.05). Decrease in mRNA expression of NT4/5 in soleus muscle may be as result of post-translation regulation following resistance training. Also, non-alteration in TrkB mRNA expression was indicated in probable roll of P75 receptor.

Keywords: neurotrophin-4/5 (NT-4/5), TrkB receptor, resistance training, slow and fast muscles

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Authors: Sayed Ali Garossi, Azar Heidarizadi, Shahla Mohammad Ganji

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Context: Colorectal cancer is the second type of cancer-related mortality globally. Expression of cas8 (caspase 8) is closely connected to growth and metastasis of colorectal cancer.Cas8/Rip1 plays a vital role in the apoptosis pathway and resistance to chemotherapy. The aim of the present study is to investigate the pattern of gene expression in colorectal cancer and compare the differences using Real-Time PCR to find a potential biomarker candidate for colorectal cancer. Methodology: This study conducted real-time PCR to evaluate gene expression of Cas8 in colorectal cancer patients. The gene-specific primer sequences exon–exon junction was designed by OLIGO7 software for the expression of the gene under investigation. Forty-six patient samples without any chemotherapy were selected, including tumoral tissue and adjacent normal tissue samples. The age of the patients was 50 and the size of the tumors was 5.5 cm. The categories were before and after age 50. Findings: Here, we found that Caspase 8 was overexpressed in CRC tissues compared to corresponding adjacent colon tissues (Cas8: 5.2 vs. 1 ratio); high expression of Cas8 was associated with poor overall survival and independent risk factors for the prognosis of CRC patients. Conclusion: In conclusion, our study pioneered the reporting of high Casp8 expression as a predictor of poor prognosis and chemical resistance in CRC patients.Cas8 overexpression suppressed Cas 8 / Rip1-dependent apoptosis and activated the proliferation of tumor cells by activating necroptosis. The necroptosis pathway has also emerged as a new approach to anti-tumor in cancer treatment.

Keywords: Cas8, necroptosis, apoptosis, Real-Time PCR

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Authors: Sarocha Vivatvakin, Thanaporn Ratchataswan, Thiratest Leesutipornchai, Komkrit Ruangritchankul, Somboon Keelawat, Virachai Kerekhanjanarong, Patnarin Mahattanasakul, Saknan Bongsebandhu-Phubhakdi

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In this globalization era, much attention has been drawn to various molecular biomarkers, which may have the potential to predict the progression of cancer. Epidermal growth factor receptor (EGFR) is the classic member of the ErbB family of membrane-associated intrinsic tyrosine kinase receptors. EGFR expression was found in several organs throughout the body as its roles involve in the regulation of cell proliferation, survival, and differentiation in normal physiologic conditions. However, anomalous expression, whether over- or under-expression is believed to be the underlying mechanism of pathologic conditions, including carcinogenesis. Even though numerous discussions regarding the EGFR as a prognostic tool in head and neck cancer have been established, the consensus has not yet been met. The aims of the present study are to assess the correlation between the level of EGFR expression and demographic data as well as clinicopathological features and to evaluate the ability of EGFR as a reliable prognostic marker. Furthermore, another aim of this study is to investigate the probable pathophysiology that explains the finding results. This retrospective study included 30 squamous cell laryngeal carcinoma patients treated at King Chulalongkorn Memorial Hospital from January 1, 2000, to December 31, 2004. EGFR expression level was observed to be significantly downregulated with the progression of the laryngeal cancer stage. (one way ANOVA, p = 0.001) A statistically significant lower EGFR expression in the late stage of the disease compared to the early stage was recorded. (unpaired t-test, p = 0.041) EGFR overexpression also showed the tendency to increase recurrence of cancer (unpaired t-test, p = 0.128). A significant downregulation of EGFR expression was documented in advanced stage laryngeal cancer. The results indicated that EGFR level correlates to prognosis in term of stage progression. Thus, EGFR expression might be used as a prevailing biomarker for laryngeal squamous cell carcinoma prognostic prediction.

Keywords: downregulation, epidermal growth factor receptor, immunohistochemistry, laryngeal squamous cell carcinoma

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Authors: Mohamed A. Dkhil, Denis Delic, Saleh Al-Quraishy

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Coccidiosis causes considerable economic loss in the poultry industry. The current study aimed to investigate the response of goblet cells as well as the induced tissue damage during Eimeria papilata infection. Mice were infected with sporulated E. papillata oocyts. On day 5 post-infection, the fecal output was determined. Also, the jejunum was prepared for the histological, histochemical and molecular studies. Our results revealed that the intestinal coccidian infection with E. papillata induced a marked goblet cell hypoplasia and depleted mucus secretion. Also, the infection was able to alter the jejuna architecture and increased the apoptotic cells inside the villi. In addition, the real time PCR results indicated that, the inflammatory cytokines TNF-α, iNOS, IFN-y and IL-1β were significantly up-regulated. In contrast, the mRNA expression patterns of IL-6 in response to E. papillata infection did not differ significantly between control and infected mice. Moreover, the mRNA expression of TLR4 was significantly up-regulated, whereas the expression of MUC2 is significantly down-regulated upon infection. Further studies are required to understand the regulatory mechanisms of goblet cells related genes.

Keywords: goblet cells, Eimeria papillata, mice, jejunum

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Authors: Jae Young Song, In-Ohk Ouh, Seyeon Park, Byeong Sul Kang, Soo Dong Cho, In-Soo Cho

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Canine parvovirus (CPV) is a major pathogen of diarrhea disease in dogs. CPV type 2 has three of antigenic variants such as 2a, 2b, and 2c. CPV constructs a small non-enveloped, icosahedral capsid that contains single-stranded DNA. It has capsids that two largely overlapping virion proteins (VP), VP1 (82 kDa), and VP2 (65 kDa). Baculoviruses are insect pathogens that regulate insect populations in nature and are being successfully used to control insect pests. The proteins produced in the baculovirus-expression system are used for instance for functional studies, vaccine preparations, or diagnostics. The vaccines produced by baculovirus-expression system showed elicitation of antibodies. The recombinant baculovirus infected SF9 cells showed broken shape. The recombinant VP2 proteins from cell pellet or supernatant were confirmed by western blotting. The result showed that the recombinant VP2 protein bands were appeared at 65 kDa molecular weight in both cell pellet and supernatant of infected SF9 cell. These results indicated that the recombinant baculovirus infected SF9 cell express the recombinant VP2 protein successfully. In addition, the expressed recombinant VP2 protein is secreted from cell to supernatant. The baculovirus expression system can be used to produce the VP2 protein of CPV 2c. In addition, the secretion property of the expression of VP2 protein may decrease the cost of production, because it can be skipped the cell breaking step. The produced VP2 protein could be used for vaccine and the agent of diagnostic tests. This study provides the foundation of the production of CPV 2c vaccine and the diagnostic agent.

Keywords: baculovirus, canine parvovirus 2c, dog, Korea

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Authors: Rahul Mohite, Lahcen Ouarbya

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This paper focuses on the interplay between humans and computer systems and the ability of these systems to understand and respond to human emotions, including non-verbal communication. Current emotion recognition systems are based solely on either facial or verbal expressions. The limitation of these systems is that it requires large training data sets. The paper proposes a system for recognizing human emotions that combines both speech and emotion recognition. The system utilizes advanced techniques such as deep learning and image recognition to identify facial expressions and comprehend emotions. The results show that the proposed system, based on the combination of facial expression and speech, outperforms existing ones, which are based solely either on facial or verbal expressions. The proposed system detects human emotion with an accuracy of 86%, whereas the existing systems have an accuracy of 70% using verbal expression only and 76% using facial expression only. In this paper, the increasing significance and demand for facial recognition technology in emotion recognition are also discussed.

Keywords: facial reputation, expression reputation, deep gaining knowledge of, photo reputation, facial technology, sign processing, photo type

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Authors: Seok Woo Chang

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Aim: Capseal I and Capseal II are calcium silicate and calcium phosphate based experimental root canal sealer. The aim of this study was to evaluate the biocompatibility and mineralization potential of Capseal I and Capseal II. Materials and Methods: The biocompatibility and mineralization-related gene expression (alkaline phosphatase (ALP), bone sialoprotein (BSP), and osteocalcin (OCN)) of Capseal I and Capseal II were compared using methylthiazol tetrazolium assay and reverse transcription-polymerization chain reaction analysis, respectively. The results were analyzed by Kruskal-Wallis test. P-value of < 0.05 was considered significant. Result: Both Capseal I and Capseal II were favorable in biocompatibility and influenced the messenger RNA expression of ALP and BSP. Conclusion: Within the limitation of this study, Capseal is biocompatible and have mineralization promoting potential, and thus could be a promising root canal sealer.

Keywords: biocompatibility, mineralization-related gene expression, Capseal I, Capseal II

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Authors: F. Polito, M. Cucinotta, A. Conti, C. Lo Giudice, C. Tomasello, F. Angileri, D. La Torre, M. Aguennouz

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Glioblastoma multiforme (GBM) is the most aggressive form of brain tumors, with an extremely poor prognosis. Telomeres lenght is associated with tumor progression in several type of human cancers and telomere elongation is a common molecular feature of advanced malignancies. Among the telomeric shelterin proteins PTOP is required for telomeric protein complex assembly, telomerase recruitment and activity, and telomere length regulation through a PTOP-telomerase interaction. Previous studies suggest that PTOP upregulation is involved in radioresistance and telomere lengthening in colorectal cancer cells. Moreover, in human osteosarcoma cells PTOP deletion led to telomere shortening, increased apoptosis and radiation sensitivity enhancement. However, to date, little is known about the role of PTOP in progression of glioma cancers. In light of this background aim of the study is to investigate the expression of PTOP in different grades of human glioma and its correlation with the pathological grade of gliomas, grades of malignancy, proliferative activity and apoptosis. Fifteen Low Grade Astrocytomas (LGA), 18 Anaplastic Astrocytomas (AA) and 26 Glioblastoma Multiforme (GBM) samples were analyzed. Three samples of normal brain tissue (NBT) were used as controls. The expression levels of PTOP, h-TERT, BIRC1 and cyclin D1 were determined by real time PCR and/or western blot. Results obtained shows that PTOP expression in glioma tissues is tightly correlated with clinical grade ( p < 0.01 ). No correlation was found between PTOP expression and other clinicopathologic parameters. The expression of PTOP was positively correlated with the expression of hTERT and TERF1. Furthermore PTOP positively correlates with cyclin D1 and negatively correlates with the expression of BIRC1. Our findings indicate that PTOP might play key role in the progression of glioma regulating telomerase activity and likely through regulation of cell cycle and apoptosis. In conclusion results obtained prompted us to speculate that PTOP might represents a potential molecular bio marker and a therapeutic target for the treatment of glioblastoma tumors.

Keywords: glioblastoma, PTOP, telomere, brain tumors

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Authors: Amin Pashaye Amiri

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Freedom of information, according to which the public has a right to have access to government-held information, is largely considered as a tool for improving transparency and accountability in governments, and as a requirement of self-governance and good governance. So far, more than ninety countries have recognized citizens’ right to have access to public information. This recognition often took place through the adoption of an act referred to as “freedom of information act”, “access to public records act”, and so on. A freedom of information act typically imposes a positive obligation on a government to initially and regularly release certain public information, and also obliges it to provide individuals with information they request. Such an act usually allows governmental bodies to withhold information only when it falls within a limited number of exemptions enumerated in the act such as exemptions for protecting privacy of individuals and protecting national security. Some steps have been taken at the national and international level towards the recognition of freedom of information as a human right. Freedom of information was recognized in a few countries as a part of freedom of expression, and therefore, as a human right. Freedom of information was also recognized by some international bodies as a human right. The Inter-American Court of Human Rights ruled in 2006 that Article 13 of the American Convention on Human Rights, which concerns the human right to freedom of expression, protects the right of all people to request access to government information. The European Court of Human Rights has recently taken a considerable step towards recognizing freedom of information as a human right. However, in spite of the measures that have been taken, public access to government information is not yet widely accepted as an international human right. The paper will consider the degree to which freedom of information has been recognized as a human right, and study the possibility of widespread recognition of such a human right in the future. It will also examine the possible benefits of such recognition for the development of the human right to free expression.

Keywords: freedom of information, freedom of expression, human rights, government information

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Authors: Sintija Miļuna, Ričards Melderis, Loreta Briuka, Dagnija Rostoka, Ingus Skadiņš, Juta Kroiča

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Objectives Smokeless tobacco products in Latvia become more available and favorable to young adults, especially students and athletes like hockey and floorball players. The aim of the research was to detect visual mucosal changes in the oral cavity in smokeless tobacco users and to evaluate pro - inflammatory and anti - inflammatory cytokine (IL-6, IL-1, IL-8, TNF Alpha) levels in saliva from smokeless tobacco users. Methods A smokeless tobacco group (n=10) and a control group (non-tobacco users) (n=10) were intraorally examined for oral lesions and 5 ml of saliva were collected. Saliva was analysed for Il-6, IL-1, Il-8, TNF Alpha using ELISA Sigma-Aldrich. For statistical analysis IBM Statistics 27 was used (Mann - Whitney U test, Spearman’s Rank Correlation coefficient). This research was approved by the Ethics Committee of Rīga Stradiņš University No.22/28.01.2016. This research has been developed with financing from the European Social Fund and Latvian state budget within the project no. 8.2.2.0/20/I/004 “Support for involving doctoral students in scientific research and studies” at Rīga Stradiņš University. Results IL-1, IL-6, IL-8, TNF Alpha levels were higher in the smokeless tobacco group (IL-1 83.34 pg/ml vs. 74.26 pg/ml; IL-6 195.10 pg/ml vs. 6.16 pg/ml; IL-8 736.34 pg/ml vs. 285.26 pg/ml; TNF Alpha 489.27 pg/ml vs. 200.9 pg/ml), but statistically there is no difference between control group and smokeless tobacco group (IL1 p=0.190, IL6 p=0.052, IL8 p=0.165, TNF alpha p=0.089). There was statistical correlation between IL1 and IL6 (p=0.023), IL6 and TNF alpha (p=0.028), IL8 and IL6 (p=0.005). Conclusions White localized lesions were detected in places where smokeless tobacco users placed sachets. There is a statistical correlation between IL6 and IL1 levels, IL6 and TNF alpha levels, IL8 and IL6 levels in saliva. There are no differences in the inflammatory cytokine levels between control group and smokeless tobacco group.

Keywords: smokeless tobacco, Snus, inflammatory biomarkers, oral lesions, oral pathology

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Authors: Hsiu-Tsu Cho

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Collective efficacy refers to a group’s sense of its capacity to complete a task successfully or to reach objectives. Little effort has been expended on investigating the relationship between the emotion expression of a leader and collective efficacy. In this study, we examined the impact of the different emotions and emotion expression of a group leader on collective efficacy and explored whether the emotion–expressive effects differed under conditions of negative and positive emotions. A total of 240 undergraduate and graduate students recruited using Facebook and posters at a university participated in this research. The participants were separated randomly into 80 groups of four persons consisting of three participants and a confederate. They were randomly assigned to one of five conditions in a 2 (pride vs. guilt) × 2 (emotion expression of group leader vs. no emotion expression of group leader) factorial design and a control condition. Each four-person group was instructed to get the reward in a group competition of solving the five-disk Tower of Hanoi puzzle and making decisions on an investment case. We surveyed the participants by employing the emotional measure revised from previous researchers and collective efficacy questionnaire on a 5-point scale. To induce an emotion of pride (or guilt), the experimenter announced whether the group performance was good enough to have a chance of getting the reward (ranking the top or bottom 20% among all groups) after group task. The leader (confederate) could either express or not express a feeling of pride (or guilt) following the instruction according to the assigned condition. To check manipulation of emotion, we added a control condition under which the experimenter revealed no results regarding group performance in maintaining a neutral emotion. One-way ANOVAs and post hoc pairwise comparisons among the three emotion conditions (pride, guilt, and control condition) involved assigning pride and guilt scores (pride: F(1,75) = 32.41, p < .001; guilt: F(1,75) = 6.75, p < .05). The results indicated that manipulations of emotion were successful. A two-way between-measures ANOVA was conducted to examine the predictions of the main effects of emotion types and emotion expression as well as the interaction effect of these two variables on collective efficacy. The experimental findings suggest that pride did not affect collective efficacy (F(1,60) = 1.90, ns.) more than guilt did and that the group leader did not motivate collective efficacy regardless of whether he or she expressed emotion (F(1,60) = .89, ns.). However, the interaction effect of emotion types and emotion expression was statistically significant (F(1,60) = 4.27, p < .05, ω2 = .066); the effects accounted for 6.6% of the variance. Additional results revealed that, under the pride condition, the leader enhanced group efficacy when expressing emotion, whereas, under the guilt condition, an expression of emotion could reduce collective efficacy. Overall, these findings challenge the assumption that the effect of expression emotion are the same on all emotions and suggest that a leader should be cautious when expressing negative emotions toward a group to avoid reducing group effectiveness.

Keywords: collective efficacy, group leader, emotion expression, pride, guilty

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Authors: Sekou Kangoye, Alexis Todoskoff, Mihaela Barreau

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Modified Condition/Decision Coverage (MC/DC) is a structural coverage criterion that aims to prove that all conditions involved in a Boolean expression can influence the result of that expression. In the context of automotive, MC/DC is highly recommended and even required for most security and safety applications testing. However, due to complex Boolean expressions that often embedded in those applications, generating a set of MC/DC compliant test cases for any of these expressions is a nontrivial task and can be time consuming for testers. In this paper we present an approach to automatically generate MC/DC test cases for any Boolean expression. We introduce novel techniques, essentially based on binary trees to quickly and optimally generate MC/DC test cases for the expressions. Thus, the approach can be used to reduce the manual testing effort of testers.

Keywords: binary trees, MC/DC, test case generation, nontrivial task

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Authors: Laura Kahn, Paul Rodrigues, Onur Savas, Shannon Hahn

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An empirical understanding of an individual's personality expression can have a profound impact on organizations seeking to strengthen team performance and improve employee retention. A team's personality composition can impact overall performance. Creating a tiered information framework that leverages proxies for a user's social context and lexical and linguistic content provides insight into location-specific personality expression. We leverage the layered framework to examine domain-specific, psychological, and lexical cues within social media posts. We apply DistilBERT natural language transfer learning models with real world data to examine the relationship between Big Five personality expressions of people in Science, Technology, Engineering and Math (STEM) fields.

Keywords: big five, personality expression, social media analysis, workforce development

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Authors: Lalita Subedi, Jae Kyoung Chae, Yong Un Park, Cho Kyo Hee, Lee Jae Hyuk, Kang Min Cheol, Sun Yeou Kim

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Neuroinflammation may mediate the relationship between low levels of estrogens and neurodegenerative disease. Estrogens are neuroprotective and anti-inflammatory in neurodegenerative disease models. Due to the long term side effects of estrogens, researches have been focused on finding an effective phytoestrogens for biological activities. Daidzein present in soybeans and its active metabolite equol (7-hydroxy-3-(4'-hydroxyphenyl)-chroman) bears strong antioxidant and anticancer showed more potent anti-inflammatory and neuroprotective role in neuroinflammatory model confirmed its in vitro activity with molecular mechanism through NF-κB pathway. Three major CNS cells Microglia (BV-2), Astrocyte (C6), Neuron (N2a) were used to find the effect of equol in inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), MAPKs signaling proteins, apoptosis related proteins by western blot analysis. Nitric oxide (NO) and prostaglandin E2 (PGE2) was measured by the Gries method and ELISA, respectively. Cytokines like tumor necrosis factor-α (TNF-α) and IL-6 were also measured in the conditioned medium of LPS activated cells with or without equol. Equol inhibited the NO production, PGE-2 production and expression of COX-2 and iNOS in LPS-stimulated microglial cells at a dose dependent without any cellular toxicity. At the same time Equol also showed promising effect in modulation of MAPK’s and nuclear factor kappa B (NF-κB) expression with significant inhibition of the production of proinflammatory cytokine like interleukin -6 (IL-6), and tumor necrosis factor -α (TNF-α). Additionally, it inhibited the LPS activated microglia-induced neuronal cell death by downregulating the apoptotic phenomenon in neuronal cells. Furthermore, equol increases the production of neurotrophins like NGF and increase the neurite outgrowth as well. In conclusion the natural daidzein metabolite equol are more active than daidzein, which showed a promising effectiveness as an anti-neuroinflammatory and neuroprotective agent via downregulating the LPS stimulated microglial activation and neuronal apoptosis. This work was supported by Brain Korea 21 Plus project and High Value-added Food Technology Development Program 114006-4, Ministry of Agriculture, Food and Rural Affairs.

Keywords: apoptosis, equol, neuroinflammation, phytoestrogen

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Authors: Jin Hwan Cheong, Mina Hwang, Myung Hoon Han, Je Il Ryu, Young ha Oh, Seong Ho Koh, Wu Duck Won, Byung Jin Ha

Abstract:

Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) has been reported to play critical roles in the proliferation of various cancer cells. However, the roles of LGR5 in brain tumors and the specific intracellular signaling proteins directly associated with it remain unknown. Expression of LGR5 was first measured in normal brain tissue, meningioma, and pituitary adenoma of humans. To identify the downstream signaling pathways of LGR5, siRNA-mediated knockdown of LGR5 was performed in SH-SY5Y neuroblastoma cells followed by proteomics analysis with 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE). In addition, the expression of LGR5-associated proteins was evaluated in LGR5-inꠓhibited neuroblastoma cells and in human normal brain, meningioma, and pituitary adenoma tissue. Proteomics analysis showed 12 protein spots were significantly different in expression level (more than two-fold change) and subsequently identified by peptide mass fingerprinting. A protein association network was constructed from the 12 identified proteins altered by LGR5 knockdown. Direct and indirect interactions were identified among the 12 proteins. HSP 90-beta was one of the proteins whose expression was altered by LGR5 knockdown. Likewise, we observed decreased expression of proteins in the hnRNP subfamily following LGR5 knockdown. In addition, we have for the first time identified significantly higher hnRNP family expression in meningioma and pituitary adenoma compared to normal brain tissue. Taken together, LGR5 and its downstream sigꠓnaling play critical roles in neuroblastoma and brain tumors such as meningioma and pituitary adenoma.

Keywords: LGR5, neuroblastoma, meningioma, pituitary adenoma, hnRNP

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Authors: M. J. Pourvaghar, M. E. Bahram

Abstract:

Obesity and overweight is one of the most common metabolic disorders in industrialized countries and in developing countries. One consequence of pathological obesity is cardiovascular disease and metabolic syndrome. Chemerin is an adipocyne that plays a role in the regulation of the adipocyte function and the metabolism of glucose in the liver and musculoskeletal system. Most likely, chemerin is involved in obesity-related disorders such as type 2 diabetes and cardiovascular disease. Aerobic exercises reduce the level of chemerin and cause macrophage penetration into fat cells and inflammatory factors. Several efforts have been made to clarify the cellular and molecular mechanisms of hypertrophy and muscular atrophy. Myostatin, a new member of the TGF-β family, is a transforming growth factor β that its expression negatively regulates the growth of the skeletal muscle; and the increase of this hormone has been observed in conditions of muscular atrophy. While in response to muscle overload, its levels decrease after the atrophy period, TGF-β is the most important cytokine in the development of skeletal muscle. Myostatin plays an important role in muscle control, and animal and human studies show a negative role of myostatin in the growth of skeletal muscle. Separation of myostatin from Golgi begins on the ninth day of the onset period and continues until birth at all times of muscle growth. Higher levels of myostatin are found in obese people. Resistance training for 10 weeks could reduce levels of plasma myostatin.

Keywords: chemerin, myostatin, obesity, physical activity

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Authors: Merry Meryam Martgrita, Marselina Irasonia Tan

Abstract:

One of several aggresive cancer is cancer that overexpress c-erbB2 receptor along with the expression of estrogen receptor. Components of extracellular matrix play an important role to increase cancer cells proliferation, migration and invasion. Both components can affect cancer development by regulating the signal transduction pathways in cancer cells. In recent research, SKOV-3 ovarian cancer cell line, that overexpress c-erbB2 receptor was cultured on type IV collagen and treated with estradiol-17β, to reveal the role of both components on RNA and protein level of c-erbB2 receptor. In this research we found a modulation phenomena of increasing and decreasing of c-erbB2 RNA level and a stabilisation phenomena of c-erbB2 protein expression due to estradiol-17β and type IV collagen. It seemed that estradiol-17β has an important role to increase c-erbB2 transcription and the stability of c-erbB2 protein expression. Type IV collagen has an opposite role. It blocked c-erbB2 transcription when it bound to integrin receptor in SKOV-3 cells.

Keywords: c-erbB2, estradiol-17β, SKOV-3, type IV collagen

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Authors: Parinaz Tavakoli Zaniani, Dimitrios Balomenos

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Mitochondrial reactive oxygen species (mROS) play a crucial role in macrophage pro-inflammatory activation, although a detailed understanding of the mechanism and kinetics by which mROS drive signaling molecules is still lacking. In general, it is thought that NF-κB activation drives mROS and general ROS production. Here, We performed a detailed kinetic analysis of mROS production during macrophage activation. We found early mROS generation after LPS (lipopolysaccharide) stimulation. Remarkably as early as 5 minutes, mROS signaling promoted initial NF-κB, MAPK activation and pro-inflammatory cytokine production, as established through inhibition or quenching of mROS. On the contrary, NF-κB inhibition had no effect on mROS production. Our findings point to a mechanism by which mROS increase TRAF-6 ubiquitination and, thus NF-κB activity. mROS inhibition reduced LPS-induced lethality in an in vivo septic shock model by controlling pro-inflammatory cytokine production. Overall, our research provides novel insights into the role of mROS as a primary messenger in the pathway of macrophage and as a regulator of inflammatory responses. We found that early mROS production promotes initial NF-κB, and MAPK activation by regulating TRAF-6 ubiquitination and that mROS inhibition can reduce LPS-induced inflammatory cytokines and lethality in a septic shock model. These findings might lead to novel immunotherapeutic strategies targeting early mROS production and control of extreme inflammation in the context of sepsis and other inflammatory diseases.

Keywords: mitochondria, reactive oxygen species, nuclear factor κB, lipopolysaccharide, macrophages

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Authors: Xuan Li, Xiaobing Cui, Nan Meng, Shuangshuang Guo, Lingling Wang

Abstract:

Objective: To investigate the influence of Paeonol on diabetic nephropathy progression in streptozocin (STZ) -induced diabetic rats. Method Male Wistar rats were injected STZ 30mg.kg-1 combined with Freund's complete adjuvant (CFA) 0.1mL/rat once a week for three weeks. The diabetic rats were treated with Paenol for 13 weeks. At the end of the experiments, the rats were anesthetized. Serum and the kidney were collected. Serum superoxide dismutase (SOD) activity, malondialdehyde (MDA), blood urea nitrogen (BUN), creatinine (Cr) and total cholesterol (Chol) level were detected; kidney paraffin sections were prepared and HE and PAS staining sections were used to evaluate the pathology changes of the kidney. Immunohistochemical analysis was used to observe the expression of VEGF and fibernectin expression in the kidney. Result The blood glucose level remained over 16mmol. L-1 for 13 weeks and the ECM accumulated in the diabetic kidney apparently. Paeonol treatment increased serum SOD activity, however, MDA, BUN, Cr, and Chol level was decreased by paeonol treatment. VEGF and fibernectin expression were increased significantly in the DN rats and paeonol treatment ameliorated the overexpression. Conclusion: paeonol prevented the progression of DN.

Keywords: paeonol, STZ, diabetic nephropathy, fibernectin expression, kidney paraffin sections

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Authors: Md. M. Hossain, Regan Roat, Jenica Christopherson, Colette Free, Zhiguang Guo

Abstract:

Long noncoding RNA (lncRNA) mediated post-transcriptional gene regulation, and their epigenetic landscapes have been shown to be involved in many human diseases. However, their regulation in diabetes through governing islet’s β-cell function and survival needs to be elucidated. Due to the technical and ethical constraints, it is difficult to study their role in β-cell function and survival in human under in vivo condition. In this study, humanized mice have been developed through transplanting human pancreatic islet under the kidney capsule of NOD.SCID mice and induced β-cell death leading to diabetes condition to study lncRNA mediated regulation. For this, human islets from 3 donors (3000 IEQ, purity > 80%) were transplanted under the kidney capsule of STZ induced diabetic NOD.scid mice. After at least 2 weeks of normoglycecemia, lymphocytes from diabetic NOD mice were adoptively transferred and islet grafts were collected once blood glucose reached > 200 mg/dl. RNA from human donor islets, islet grafts from humanized mice with either adoptive lymphocyte transfer (ALT) or PBS control (CTL) were ribodepleted; barcoded fragment libraries were constructed and sequenced on the Ion Proton sequencer. lncRNA expression in isolated human islets, islet grafts from humanized mice with and without induced β-cell death and their regulation in human islets function in vitro under glucose challenge, cytokine mediated inflammation and induced apoptotic condition were investigated. Out of 3155 detected lncRNAs, 299 that highly expressed in islets were found to be significantly downregulated and 224 upregulated in ALT compared to CTL. Most of these are found to be collocated within 5 kb upstream and 1 kb downstream of 788 up- and 624 down-regulated mRNAs. Genomic Regions Enrichment of Annotations Analysis revealed deregulated and collocated genes are related to pancreas endocrine development; insulin synthesis, processing, and secretion; pancreatitis and diabetes. Many of them, that found to be located within enhancer domains for islet specific gene activity, are associated to the deregulation of known islet/βcell specific transcription factors and genes that are important for β-cell differentiation, identity, and function. RNA sequencing analysis revealed aberrant lncRNA expression which is associated to the deregulated mRNAs in β-cell function as well as in molecular pathways related to diabetes. A distinct set of candidate lncRNA isoforms were identified as highly enriched and specific to human islets, which are deregulated in human islets from donors with different BMIs and with type 2 diabetes. These RNAs show an interesting regulation in cultured human islets under glucose stimulation and with induced β-cell death by cytokines. Aberrant expression of these lncRNAs was detected in the exosomes from the media of islets cultured with cytokines. Results of this study suggest that the islet specific lncRNAs are deregulated in human islet with β-cell death, hence important in diabetes. These lncRNAs might be important for human β-cell function and survival thus could be used as biomarkers and novel therapeutic targets for diabetes.

Keywords: β-cell, humanized mouse, pancreatic islet, LncRNAs

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Authors: Lola T. Alimkhodjaeva, Lola T. Zakirova, Soniya S. Ziyavidenova

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Background: Breast cancer occupies the first place among the cancer in women in the world. It is urgent today to study the role of molecular markers which are capable of predicting the dynamics and outcome of the disease. The aim of this study is to define the prognostic value of the content of estrogen receptor (ER), progesterone receptor (PgR), and amplification of HER-2 / neu oncoprotein by studying 3 and 5-year overall and relapse-free survival in 470 patients with primary operable and 280 patients with locally–advanced breast cancer. Materials and methods: Study results of 3 and 5-year overall and relapse-free survival, depending on the content of RE, PgR in primary operable patients showed that ER positive (+) and PgR (+) survival was 100 (96.2%) and 97.3 (94.6%), for ER negative (-) and PgR (-) - 69.2 (60.3%) and 65.4 (57.7%), for ER positive (+) and negative PgR (-) 87.4 (80.1%) and 81.5 (79.3%), for ER negative (-) and positive PgR (+) - 97.4 (93.4%) and 90.4 (88.5%), respectively. Survival results depended also on the level of HER-2 / neu expression. In patients with HER-2 / neu negative the survival rates were as follows: 98.6 (94.7%) and 96.2 (92.3%). In group of patients with the level of HER-2 / neu (2+) expression these figures were: 45.3 (44.3%) and 45.1 (40.2%), and in group of patients with the level of HER-2 / neu (3+) expression - 41.2 (33.1%) and 34.3 (29.4%). The combination of ER negative (-), PgR (-), HER-2 / neu (-) they were 27.2 (25.4%) and 19.5 (15.3%), respectively. In patients with locally-advanced breast cancer the results of 3 and 5-year OS and RFS for ER (+) and PgR (+) were 76.3 (69.3%) and 62.2 (61.4%), for ER (-) and RP (-) 29.1 (23.7%) and 18.3 (12.6%), for ER (+) and PgR (-) 61.2 (47.2%) and 39.4 (25.6%), for ER (-) and PgR (+) 54.3 (43.1%) and 41.3 (18.3%), respectively. The level of HER-2 / neu expression also affected the survival results. Therefore, in HER-2/ neu negative patients the survival rate was 74.1 (67.6%) and 65.1 (57.3%), with the level of expression (2+) 20.4 (14.2%) and 8.6 (6.4%), with the level of expression (3+) 6.2 (3.1%) and 1.2 (1.5%), respectively. The combination for ER, PgR, HER-2 / neu negative was 22.1 (14.3%) and 8.4 (1.2%). Conclusion: Thus, the presence of steroid hormone receptors in breast tumor tissues at primary operable and locally- advanced process as the lack of HER-2/neu oncoprotein correlates with the highest rates of 3- and 5-year overall and relapse-free survival. The absence of steroid hormone receptors as well as of HER-2/neu overexpression in malignant breast tissues significantly degrades the 3- and 5-year overall and relapse-free survival. Tumors with ER, PgR and HER-2/neu negative have the most unfavorable prognostics.

Keywords: breast cancer, estrogen receptor, oncoprotein, progesterone receptor

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Authors: Shima Mahmoudi, Babak Pourakbari, Setareh Mamishi, Mostafa Teymuri, Majid Marjani

Abstract:

Although cytokine analysis has greatly contributed to the understanding of tuberculosis (TB) pathogenesis, data on cytokine profiles that might distinguish progression from latency of TB infection are scarce. Since PE/PPE proteins are known to induce strong humoral and cellular immune responses, the aim of this study was to evaluate the diagnostic potential of interleukin-2 (IL-2) as biomarker after specific antigen stimulation with PE35 and PPE68 for the discrimination of active and latent tuberculosis infection (LTBI). The production of IL-2 was measured in the antigen-stimulated whole-blood supernatants following stimulation with recombinant PE35 and PPE68. All the patients with active TB and LTBI had positive QuantiFERON-TB Gold in Tube test. The level of IL-2 following stimulation with recombinant PE35 and PPE68 were significantly higher in LTBI group than in patients with active TB infection or control group. The discrimination performance (assessed by the area under ROC curve) for IL-2 following stimulation with recombinant PE35 and PPE68 between LTBI and patients with active TB were 0.837 (95%CI: 0.72-0.97) and 0.75 (95%CI: 0.63-0.89), respectively. Applying the 12.4 pg/mL cut-off for IL-2 induced by PE35 in the present study population resulted in sensitivity of 78%, specificity of 78%, PPV of 78% and NPV of 100%. In addition, a sensitivity of 81%, specificity of 70%, PPV of 67% and 87% of NPV was reported based on the 4.4 pg/mL cut-off for IL-2 induced by PPE68. In conclusion, peptides of the antigen PE35 and PPE68, absent from commonly used BCG strains, stimulated strong IL-2- positive T cell responses in patients with LTBI. This study confirms IL-2 induced by PE35 and PPE68 as a sensitive and specific biomarker and highlights IL-2 as new promising adjunct markers for discriminating of LTBI and Active TB infection.

Keywords: IL-2, PE35, PPE68, tuberculosis

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Authors: Amtul Jamil Sami

Abstract:

Apis mellifera is an insect of immense economic importance lives on rich carbohydrate diet including cellulose, nectar, honey and pollen. The carbohydrate metabolism in A mellifera has not been understood fully, as there are no data available, on the functional expression of cellulase gene. The cellulose hydrolyzing enzyme is required for the digestion of pollen cellulose wall, to release the important nutrients (amino acids, minerals, vitamins etc.) from the pollen. A dissection of Apis genome had revealed that there is one gene present for the expression of endo-beta-1,4-glucanase, for cellulose hydrolysis. In the presented work, functional expression of endo-beta-1,4 glucanase gene is reported. Total soluble proteins of the honey bee were isolated and were tested cellulose hydrolyzing enzyme activity, using carboxy-methyl cellulose, as a substrate. A mellifera proteins were able to hydrolyze carboxy-methyl cellulose, confirming its endo- type mode of action. Endo beta-1,4 glucanase enzyme was only present in the gut tissues, no activity was detected in the salivary glands. The pH optima of the enzyme were in the acidic pH range of 4-5-5-0, indicating its metabolic role in the acidic stomach of A mellifera. The reported enzyme is unique, as endo-beta- 1,4 glucanase was able to generate non reducing sugar, as an end product. The results presented, are supportive to the information that the honey bee is capable of producing its novel endo-beta-1,4 glucanase. Further it could be helpful, in understanding, the carbohydrate metabolism in A mellifera.

Keywords: honey bees, Endo-beta 1, 4- glucanase, Apis mellifera, functional expression

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Authors: Hyun Lim, Dong Sook Min, Han Eul Yun, Kil Tae Kim, Ya Nan Sun, Young Ho Kim, Hyun Pyo Kim

Abstract:

Matrix metalloproteinase (MMP)-13 has an important role for degrading cartilage materials under inflammatory conditions such as arthritis. Since the 70% ethanol extract of Acanthopanax koreanum inhibited MMP-13 expression in IL-1β-treated human chondrocyte cell line, SW1353, two major constituents including acanthoic acid and impressic acid were initially isolated from the same plant materials and their MMP-13 down-regulating capacity was examined. In IL-1β-treated SW1353 cells, acanthoic acid and impressic acid significantly and concentration-dependently inhibited MMP-13 expression at 10 – 100 μM and 0.5 – 10 μM, respectively. The potent one, impressic acid, was found to inhibit MMP-13 expression by blocking the phosphorylation of signal transducer and activator of transcription-1/-2 (STAT-1/-2) and activation of c-Jun and c-Fos among cellular signaling pathway involved, but did not affect the activation of mitogen-activated protein kinases (MAPKs) and nuclear transcription factor-κB (NF-κB). Further, impressic acid was also found to inhibit the expression of MMP-13 mRNA (47.7% inhibition at 10 μM), the glycosaminoglycan release (42.2% reduction at 10 μM) and proteoglycan loss in IL-1-treated rabbit cartilage explants culture. For a further study, 21 impressic acid derivatives were isolated from the same plant materials and their suppressive activities against MMP-13 expression were examined. Among the derivatives, 3α-hydroxy-lup-20(29)-en-23-oxo,28-oic acid, (20R)-3α-hydroxy-29-dimethoxylupan-23,28-dioic acid, acankoreoside F and acantrifoside A clearly down-regulated MMP-13 expression, but impressic acid being most potent. All these results suggest that impressic acid, 3α-hydroxy-lup-20(29)-en-23-oxo,28-oic acid, (20R)-3α-hydroxy-29-dimethoxylupan-23,28-dioic acid, acankoreoside F, acantrifoside A and A. koreanum may have a potential for therapeutic agents to prevent cartilage degradation possibly by inhibiting matrix protein degradation.

Keywords: acanthoic acid, Acanthopanax koreanum, cartilage, impressic acid, matrix metalloproteinase

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Authors: Yen-Hao Su, Wan-Chun Tang, Ya-Wen Cheng, Peik Sia, Chi-Chen Huang, Yi-Chao Lee, Hsin-Yi Jiang, Ming-Heng Wu, I-Lu Lai, Jun-Wei Lee, Kuen-Haur Lee

Abstract:

There is a wide range of drugs and combinations under investigation and/or approved over the last decade to treat colorectal cancer (CRC), but the 5-year survival rate remains poor at stages II–IV. Therefore, new, more efficient drugs still need to be developed that will hopefully be included in first-line therapy or overcome resistance when it appears, as part of second- or third-line treatments in the near future. In this study, we revealed that heat shock protein 90 (Hsp90) inhibitors have high therapeutic potential in CRC according to combinative analysis of NCBI's Gene Expression Omnibus (GEO) repository and chemical genomic database of Connectivity Map (CMap). We found that second generation Hsp90 inhibitor, NVP-AUY922, significantly down regulated the activities of a broad spectrum of kinases involved in regulating cell growth arrest and death of NVPAUY922-sensitive CRC cells. To overcome NVP-AUY922-induced upregulation of survivin expression which causes drug insensitivity, we found that combining berberine (BBR), a herbal medicine with potency in inhibiting survivin expression, with NVP-AUY922 resulted in synergistic antiproliferative effects for NVP-AUY922-sensitive and -insensitive CRC cells. Furthermore, we demonstrated that treatment of NVP-AUY922-insensitive CRC cells with the combination of NVP-AUY922 and BBR caused cell growth arrest through inhibiting CDK4 expression and induction of microRNA-296-5p (miR-296-5p)-mediated suppression of Pin1–β-catenin–cyclin D1 signaling pathway. Finally, we found that the expression level of Hsp90 in tumor tissues of CRC was positively correlated with CDK4 and Pin1 expression levels. Taken together, these results indicate that combination of NVP-AUY922 and BBR therapy can inhibit multiple oncogenic signaling pathways of CRC.

Keywords: berberine, colorectal cancer, connectivity map, heat shock protein 90 inhibitor

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