Month: May 2019

KLF4 was downregulated in ovarian cancers compared to controls and that KLF4 did not affect cell proliferation but increased the Bcl-2/Bax ratio and inhibited apoptosis. In contrast, we found that KLF4 inhibits the proliferation of SKOV3 cells in colony formation and MTT assays. The discrepancy may be caused by the low transfection efficiency in that study compared to our highly efficient inducible lentiviral transduction. We also found that KLF4 inhibits cell proliferation in Lithium citrate OVCAR3 cells. Our data demonstrate that KLF4 inhibits cell proliferation, migration, and invasion, hence it functions as a tumor suppressor in both SKOV3 and OVCAR3 cells. KLF4 can have a dual effect either as an oncogene or a tumor suppressor in breast cancer cells. To compare the actions of KLF4 in MCF7 breast cancer with that in ovarian cancer cells, we performed similar experiments using the same lentiviral Tet-on inducible vector-transduced in MCF7 cells. We found that KLF4 inhibits MCF7 cell proliferation. Our finding is similar to the results shown in MCF10A cells by Yori et al.. Yu et al., however, showed that KLF4 functions as an oncogene in MCF7 cells, which is opposite to our finding. The morphology in KLF4 expressing SKOV3 cells in the presence of Dox was clearly altered from control cells without Dox at the different time points ; however, we did not observe obvious morphological alteration in OVCAR3 cells following induction of KLF4 expression. One of reasons causing this phenomenon is that KLF4 also induced cell apoptosis in ovarian cancer cells based on our unpublished data. The morphological differences may be caused by the different responses to KLF4 induced apoptosis in both cell lines. In both SKOV3 and OVCAR3 cells the epithelial cell marker gene E-cadherin was upregulated, and the mesenchymal marker genes vimentin and Ascomycin snail2 were downregulated following induction of KLF4 overexpression. Altogether, these data suggest that KLF4 primarily promoted MET in ovarian cancer cells. The expression of EMT associated marker genes in ovarian cancer cells are similar to what we observed in MCF7 breast cancer cells, although the endogenous expression of vimentin in MCF7 was not detectable in KLF4-overexpressing or control cells. This may be caused by low endogenous expression level of vimentin in MCF7 cells. Our data support the hypothesis that KLF4 is a key regulator promoting MET and inhibiting EMT in ovarian and breast cancer cells. Previous studies showed that KLF4 binds to the promoter regions of E-cadherin and snail2, thus can activate the expression of E-cadherin or repress the expression of snail2 in fibroblasts and several cancer cell lines. The expression of epithelial cell marker E-cadherin is required for stem cell reprogramming. KLF4 facilitates the MET process by activating E-cadherin expression. In ovarian cancer cells, we observed a KLF4dependent upregulation of E-cadherin and a downregulation of vimentin and snail2. Our data indicate that KLF4 transcriptionally binds to the promoters of E-cadherin, thus leading to the activation of E-cadherin expression in ovarian cancer cells. The EMT or MET is tightly regulated by multiple signaling pathways. Several studies have shown that multiple signaling pathways, including WNT, Notch, NFkB, and TGFb, are involved in EMT or MET transition in cancers. Previous studies also showed that TGFb promotes EMT in ovarian cancer cells. However, there are no related studies on describing the mechanism how KLF4 is involved in EMT and interacts with those pathways in ovarian cancer cells.

In comparison, the rats underwent bariatric surgery had relatively higher proportions of smooth muscle fibers in the cavernosal tissue. This appears to indicate that bariatric surgery could potentially reduce cavernosal fibrosis in the setting of diabetes. Through these findings, bariatric surgery seems to improve glucose homeostasis with biochemical factors, thus leading to structural and functional improvements in the corpus cavernosum and resulting in improved erectile dysfunction. The limitations of this pilot study included firstly the relatively small sample size and lack of metabolic parameters. As the purpose of this experiment was to identify the structural and functional background of bariatric surgery in cases of diabetes, we did not perform metabolic evaluations such as testosterone and lipid Etidronate profiles. In future studies, evaluation of these metabolic parameters can be further investigated. Second, the lack of physical measurement, except that of body weight, means that the results of this study cannot be generalized to human studies because obesity is closely correlated to BMI and abdominal circumference. Further evaluation with a larger sample size and metabolic parameter evaluation would be needed. A conventional drug treatment model with a positive control would be needed to clarify the effect of bariatric surgery. Third, the baseline information of histological/expression study were not evaluated. With baseline information for evaluating the pre- and post-operative changes in histological and expression study, the exact effect of bariatric surgery on erectile tissue might be more elucidated. Though this experiment focused on the comparison of the effect of bariatric surgery on erectile dysfunction in a T2DM rat model, the lack of baseline information of histological and biochemical is limitation of this study. In a future study, the limitations including baseline data should be evaluated to understand the exact effect of bariatric surgery on erectile tissue. The gram-negative bacterium Bordetella pertussis, the causative agent of whooping cough, accounted for high mortality rates among infants in the pre-vaccine era. Whole cell and acellular Indinavir sulfate vaccines have drastically decreased the number of cases. However, recently resurgence of pertussis in the vaccinated population has been observed in the USA and in European countries. Currently pertussis is still endemic, ranking in the top-ten of vaccine preventable diseases worldwide, according to the WHO. Next to improved diagnostics and public awareness, also strain adaptation and waning immunity are thought to be responsible for this increase in disease cases. Thus, a call for vaccines with improved efficacy is evident. As a main feature of the innate immune response upon B. pertussis infection in mice the recognition of lipopolysaccharide by TLR4 has been acknowledged. This activation of TLR4 by B. pertussis leads to up-regulation of cytokine gene expression and recruitment of neutrophils into the lungs. It was found in animal models that B. pertussis infection results in formation of T-helper 1 and Th17 cells. Since immunity induced by natural infections provides faster clearance upon reinfection and is longer lasting compared to both acellular and whole cell pertussis vaccination, immune mechanisms induced upon infection or vaccination have been compared. In human and murine studies, immunization with whole cell or acellular pertussis vaccines results predominantly in a Th1 or a Th2 response, respectively.

They recognize “pathogen-associated molecular patterns ” which are structurally conserved molecules derived from microbes and are distinguishable from host molecules, and activate the innate immune responses. Till now, more than 13 members of the TLR family have been identified in mammals. To define the expression profile of TLRs and their pathogenic roles will improve our understanding of RA. In this study, we systemically detected the expression of TLRs in RA, and revealed their roles in perpetuating the persistent inflammation. In this study, we revealed the distinct expression pattern of TLRs in RA. These receptors, particularly TLR2, TLR3, and TLR4 played crucial roles in the production of inflammatory cytokines, MMPs, and VEGF by RASF. More important, ligation of these TLRs expressed by RASF promoted inflammatory Th1 and Th17 responses. Thus TLRs contribute not only to the initiation but also to the perpetuation of the inflammation in RA which would be served as new therapeutic targets for the disease. One of the most significant characteristics of RA is the intensive inflammation that is out of control. Managing to control the inflammation could prevent the Oxysophocarpine disease progression, which would be the optimal strategy for RA therapy. One direct strategy is targeting the pathogenic inflammatory cytokines. Indeed, inhibitors of TNF-a have greatly advanced the management of RA, dramatically decreasing signs and symptoms of the diseases. At present, at least three agents are available which differ in pharmacokinetics and ability to bind lymphotoxin, crosslink membrane-bound TNF and induce apoptosis. Recently, IL-6 has also been proved to be a therapeutic target for RA. IL-6R monoclonal antibody tocilizumab showed promising perspective in treating RA patients. Biological reagents targeting other inflammatory cytokines would appear in the following studies. However, RA is a complicated disease involving many inflammatory cytokines. So, targeting the upstream sources of the inflammation would demonstrate better efficacy for RA therapy. Nonetheless, how the inflammation in RA is initiated, propagated, and maintained remains controversial. Infection has long been speculated to be an underlying factor contributing to RA pathogenesis. Indeed, peptidoglycan, bacterial and viral DNA as well as viral RNA were proved to be present in RA patient inflamed joints. These PAMPs would activate the corresponding TLRs, inducing robust inflammatory mediator production. In addition, endogenous heat shock protein, fibrinogen, hyaluronan, and double stranded RNA from apoptotic cells also exist in RA joints. These “danger-associated molecular patterns ” could also provoke TLRs to induce inflammation. In this study, we proved that peptidoglycan, ploy, LPS, and CpGcould activate RASF to induce vigorous inflammatory mediator production. This suggests that TLRs serve as an important contributor to the initiation and propagation of the inflammatory responses in RASF, which would eventually exacerbate the inflammation in RA. In addition, in the current study, we showed for the first time that TLR activation exacerbated RASF-mediated inflammatory Th1 and Th17 responses. Th1 cells are considered to be the conventional pathogenic cells in RA, because RA is thought to be a Th1-biased disease with Th1/Th2 imbalance. Recently, attention has increasingly focused on the role of Th17 cells, a subset that produces IL-17A, 17F, 21, and 22 and TNF-a. IL17A, which Clofentezine synergizes with TNF-a.