bluuebunny/crossref_metadata_2025_split huggingface dataset:
Converting the tumor suppressor function of WWOX to tumor promoting by Serine 14 phosphorylation
Authors: Ho Pei‐Chuan , Kuo Hsiang‐Lin , Chang Nan‐Shan 
Published: June 2021

Accumulation of tumor suppressor WWOX with Ser14 phosphorylation has been shown in growing solid tumors and brain lesions with Alzheimer's disease. Functional significance of this regard is unknown. A portion of cytosolic WWOX is recruited to the cell membrane/cytoskeleton by binding hyaluronidase Hyal‐2. Here, we identified a cell surface‐exposed N‐terminal epitope WWOX7‐21 (amino acid #7 to 21), which is in front of the first WW domain. Treatment of breast 4T1 cancer stem cell spheres with the WWOX7‐21 antibody resulted in dramatic inhibition of ceritinib‐mediated cell death (>85% inhibition). Similar results were observed using other therapeutic chemicals. In contrast, when 4T1 stem cell spheres were treated with micromolar levels of synthetic WWOX7‐21 and WWOX7‐11 peptides, 4T1 cells in the spheres became highly susceptible to death by ceritinib. Notably, when pS14‐WWOX7‐11 peptide was used to treat the 4T1 spheres, cells significantly acquired resistance to ceritinib. WWOX7‐21 and WWOX7‐11 peptides caused spleen Z cell expansion and activation by expressing Hyal‐2, Zfra, and Noxa to block 4T1 growth and metastasis in mice. Accordingly, stimulating membrane Hyal‐2 with agonist Hyal‐2 antibody, sonicated hyaluronan and Zfra peptide primed Z cells for activation and blocking cancer growth in vivo. Purified activated Z cells aggressively attacked and caused death of 4T1 stem cells in spheres in vitro, as determined by time‐lapse microscopy. In stark contrast, pSer14‐WWOX7‐21 peptide significantly induced clonal expansion of spleen CD8alpha+ T and CD19+ B cells in vivo and enhanced cancer growth. Together, phosphorylation at Ser14 turns WWOX from tumor suppressor into tumor promoter.Support or Funding InformationMOST, TaiwanThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
MED28 modulates transcription factor FOXM1‐associated migration and invasion in human non‐small cell lung cancer (NSCLC) cells
Authors: Hsieh Nien‐Tsu , Huang Chun‐Yin , Li Chien‐Cheng , Wang I‐Ching , Lee Ming‐Fen 
Published: June 2021

Lung cancer has become a leading cause of cancer deaths worldwide, where non‐small cell lung cancer (NSCLC) accounts for the majority of the diagnosed cases. Increased expression of transcription factor Forkhead Box M1 (FOXM1) is involved in the unfavorable development of several types of cancer, including lung tumor aggressiveness. MED28 exhibits multiple cellular roles, including a Mediator subunit for transcription, an interactor with merlin, Src kinases, Grb2 and cytoskeleton‐associated proteins, which is involved in many cellular signaling pathways. Our laboratory has previously found that MED28 appears to modulate the development of epithelial‐mesenchymal transition and invasion in human NSCLC cells. The objective of the current study is to investigate the potential role of MED28 in FOXM1‐associated tumorigenesis in NSCLC. MED28 expression positively corresponded to both migration and Matrigel invasion events. Inducible expression of FOXM1 not only enhanced NSCLC cell migration and Matrigel invasion but also significantly inhibited siMED28‐mediated suppression of cell invasiveness. Suppression of MED28 reduced the expression of FOXM1 as well as MMP2, a metastasis marker and downstream target of FOXM1. MED28 also regulated the luciferase activity of the MMP2‐reporter gene. Taken together, our data indicate an important connection between MED28 and FOXM1 in the progression of malignancy in NSCLC.Support or Funding InformationThis work was supported by the grants NSC102‐2320‐B‐309‐001‐MY3 and MOST106‐2320‐B‐309‐001‐MY3 to M‐F Lee.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Serotonin Promotes Enterohemorrhagic Escherichia Coli Pathogenesis Through Altered AI‐2 Production by Gut Microbiota
Authors: Menon Rani , Jani Sneha , Riordan Rebekah , Jayaraman Arul 
Published: June 2021

The overall goal of this study is to investigate the cross‐talk between a host metabolite (serotonin), the commensal bacterial community, and a microbial signaling molecule (Autoinducer‐2; AI‐2), in the etiology of Enterohemorrhagic Escherichia coli (EHEC) infections. A broad range of microbial (e.g., AI‐2, indole) and host metabolites (e.g., neuroendocrine hormones such as serotonin and norepinephrine) are present in the GI tract microenvironment and often function together to modulate the virulence of enteric pathogens. Serotonin is of specific interest as it is abundant in the GI tract and has pleiotropic roles on intestinal physiology. While it is well established that serotonin levels increase during inflammation, its impact on the commensal microbiota composition and function, and thereby, on enteric pathogen infections is poorly understood. Here we show that serotonin exposure results in a statistically significant increase (p<0.05) in the production of AI‐2 produced by non‐pathogenic E. coli and EHEC. Serotonin exposure also increased the expression of virulence genes (eaeA, escC, and escV) in EHEC in vitro and this increase depends on the luxS gene that is required for AI‐2 production. Based on these results, we hypothesize that serotonin's effects on EHEC virulence are mediated through AI‐2. Administering serotonin in mice resulted in pronounced dysbiosis of the microbiota composition. Interestingly, approximately 50% of the bacterial communities that showed a significant fold change (p<0.05) at the genus level had representative members with the luxS gene. Significant changes were also observed in the levels of six tryptophan‐derived microbiota metabolites including a reduction in the levels of indole. Together, our results support a model in which an increase in serotonin causes microbiota dysbiosis, increases AI‐2 levels, downregulates the beneficial anti‐inflammatory metabolites, thereby creating a niche favorable for EHEC colonization. Understanding the specific mechanisms underlying the effect of serotonin on the microbial community can lead to the development of new therapeutic approaches for combating enteric infections.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Characterizing nucleic acid association with bacterial membrane vesicles and their transfer to host cells
Authors: Rodriguez Blanca Victoria , Kuehn Meta J. 
Published: June 2021

Numerous studies have shown that extracellular nucleic acids can be secreted by bacteria via membrane vesicles (MVs) which can serve as protected vehicles for nucleic acid transfer into host cells. MVs are known to carry biologically active macromolecules that play a significant role in bacteria‐host cell communication. A potential role for prokaryotic MV‐associated RNA in pathogen‐host interactions was proposed recently but intensive investigation into this hypothesis has not been conducted. It has been revealed that vesicles contain a distinct profile of RNA molecules relative to the parent cell RNA profile of multiple bacterial organisms, thereby suggesting a selective export or protective mechanism for RNAs associated with vesicles. Previous studies have highlighted the immunomodulatory characteristics of RNA produced by the human pathogen Staphylococcus aureus during infection of host immune cells but it is currently unknown whether immunomodulatory RNAs are secreted in association with MVs. As such, we are interested in gaining a thorough understanding of the identity, selection, localization, and host cell interaction of MV‐associated RNAs derived from S. aureus.Using electrophoretic analysis and microscopy imaging approaches, I have found that RNAs are associated with purified MVs produced by S. aureus. By size distribution analysis, I discovered that the MV‐associated RNAs appeared to be <50 nucleotides in length, consistent with previously published reports for MVs produced by other bacteria. When examining the functional roles of MV associated RNA, I discovered that S. aureus MVs induced the production of a cytokine that is typically induced in response to signaling cascades initiated by nucleic acid receptors in cultured macrophage cells. Thus, my results suggest a role for MV‐associated nucleic acids in stimulating a host immune response that could be distal to the site of infection. Based on these findings, I hypothesize that MVs are enriched with nuclease‐protected nucleic acid fragments containing immunostimulatory sequences. Using RNA‐seq and qRT‐PCR of MV RNA cargo, those sequences can be identified. Nuclease protection assays suggest a portion of the nucleic acids associated with the MVs are protected by a location inside the vesicle membrane or by association with vesicle cargo proteins. By screening for the presence and importance of RNA‐binding proteins in the MVs, I can identify mechanisms of RNA selection and protection. This research will uncover mechanisms of RNA association with bacterial MVs and mechanisms of host immune cell modulation by the MV‐associated RNAs.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Legionella Effector RavD Binds Host Phosphoinositide‐3‐phosphate and Contributes to Lysosomal Avoidance
Authors: Neunuebel Ramona 
Published: June 2021

Subversion of phosphoinositide lipids is a key strategy that bacterial pathogens employ to survive within hosts. Due to the importance of phosphoinositides in phagocytosis, bacterial pathogens that infect innate immune cells manipulate these lipids to alter phagosome maturation with the purpose of converting the nascent phagosome into a replication‐permissive niche. The intracellular bacterial pathogen, Legionella pneumophila, the causative agent of a severe pneumonia known as Legionnaires' disease, infects alveolar macrophages where it proliferates within the safety of a vacuole. Upon phagocytosis, L. pneumophila hijacks the nascent phagosome and remodels the cytosolic façade of the phagosomal membrane by stimulating fusion with vesicles derived from the endoplasmic reticulum. This process relies on the function of bacterial effector proteins translocated directly into the host cell via a specialized secretion system. A number of L. pneumophila effector proteins have been shown to bind phosphoinositides either for the purpose of manipulating their metabolism or as a means of targeting specific host membrane compartments. Our preliminary data indicate that many more phosphoinositide‐binding effectors remain to be discovered. Here, we show that the L. pneumophila effector, RavD, is a novel phosphoinositide‐3‐phosphate (PI3P) binding‐protein. We establish that RavD is found on the Legionella‐containing vacuole (LCV) at early stages of infection and harbors its PI3P binding domain within the C terminal region of the protein. In the absence of the ravD gene, the LCV accumulates lysosomal markers at 2 hours post‐infection, consistent with the notion that RavD function is necessary to arrest phagosome maturation.Support or Funding InformationThis work was supported by the University of Delaware Research Foundation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Metabolic Reprogramming of Macrophages Exposed to Pseudomonas aeruginosa Biofilm
Authors: Ammons Mary Cloud Bosworth , Fuchs Amanda , Copie Valerie 
Published: June 2021

Currently, the annual economic cost of chronic wounds exceeds $1 billion in the United States and the incidence of non‐healing wounds is expected to dramatically increase in the next several years due to a Type 2 diabetes epidemic. Several common characteristics typical of chronic wounds include the development of persistent antibiotic‐resistant colonization by microbial biofilms, excessive inflammation, and failure of human cells to respond to reparative stimuli. Pseudomonas aeruginosa is one of the predominant opportunistic pathogens that colonizes greater than 50% of all chronic wounds in the U.S. In an effort to better understand the molecular mechanisms by which P. aeruginosa biofilms interfere with human macrophage responses to pathogens, we have undertaken comprehensive metabolomics studies of activated macrophages. These studies have been designed to probe the metabolic reprogramming of these immune cells as result of exposure to secreted molecules produced by P. aeruginosa biofilms, using an in vitro host‐pathogen co‐culture model. Herein, we present our most recent NMR‐based metabolomics results. This metabolic phenotyping is correlated with fluorescence‐activated cell sorting (FACS) analysis to determine the relationship between metabolic regulation and macrophage immunomodulation (i.e macrophage polarization into pro‐ or anti‐inflammatory M1 or M2 subpopulations, respectively) in response to exposure of macrophages to co‐culture with P. aeruginosa biofilms.Support or Funding InformationA.L.F. was supported by funds provided through a Kopriva Fellowship. A.L.F. and M.C.B.A. are suppported by funds provided by the National Institute of Health (NIH) grant number 1KO1GM103821. M.C.B.A. was also supported by the NIH grant number 1KO1GM103821. NMR spectra were recorded at MSU on a Bruker AVANCE III 600 MHz NMR spectrometer. Funding for this instrument and corresponding upgrade was provided by the NIH SIG program (grant numbers 1S10RR13878 and 1S10RR026659). M.C.B.A. is currently supported by a NIH Grant No. P20GM109007 (National Institute of General Medical Sciences).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
25‐Hydroxycholesterol inhibits viral infection in a liver X receptor dependent manner
Authors: Wei Zhuo 
Published: June 2021

Cholesterol 25‐hydroxylase (CH25H) catalyzes the production of 25‐hydroxycholesterol (25HC), which is an endogenous liver X receptor (LXR) agonist. The recent studies have demonstrated that CH25H is an interferon (IFN)‐induced gene and IFN‐activated 25HC functions as a molecule potently inhibiting viral infection. Previously, besides IFN‐γ, we also identified several LXR‐responsive elements (LXREs) in the CH25H promoter and determined LXR activation induced CH25H expression. Thus, we hypothesized that the LXR‐activated CH25H expression can play an important role in antiviral infection. In this study, we determined that 25HC induced its own production by activating CH25H expression. We further determined that 25HC and synthetic LXR ligands (T0901317/GW3965) inhibited the infection of HSV‐1 as well as MLV‐(VSV)‐GFP in hepatocytes and the infection of HSV‐1 in macrophages in an LXR‐dependent manner. Therefore, genetic deletion of LXRα, LXRβ or CH25H by CRISPR/Cas9 system in HepG2 cells increased cell susceptibility to HSV‐1 infection, and attenuated 25HC or T0901317‐inhibited viral infection. Lacking of IFN‐γ expression also attenuated, but not blocked, LXR‐induced CH25H expression and LXR‐inhibited HSV‐1 infection. 25HC can be further metabolized to 25‐hydroxycholesterol‐3‐sulfate (25HC3S) by sterol sulfotransferase‐2B1b (SULT2B1b). We observed that SULT2B1b moderately reduced the antiviral actions of 25HC based on the determination that 25HC3S was a weaker inhibitor of HSV‐1 infection than 25HC. In summary, our study demonstrates 25HC/T0901317 inhibits viral infection in an LXR‐dependent manner.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Reverse Correlation between Body Mass Index and Post‐Transplant Hypertension by a New Diagnostic Criteria
Authors: Tantisattamo Ekamol , Vutthikraivit Possawat , Ratanasrimetha Praveen 
Published: June 2021

IntroductionObesity is associated with hypertension (HTN). Recent new diagnostic criteria for HTN with systolic blood pressure (SBP) and diastolic blood pressure of >130 and >80 mmHg, respectively associated with body mass index (BMI) in kidney transplant recipients is unknown.MethodsSystolic hypertension (SHTN) and diastolic hypertension (DHTN) after 1‐month post‐transplantation is determined by old and new diagnostic criteria. A time‐to‐events of developing post‐transplant SHTN and DHTN associated with pre‐transplant BMI are compared between HTN defined by old and new criteria by using Cox proportional hazard regression analysis.ResultsSeventy kidney transplant recipients are reviewed and followed for 96 months. Mean age was 52.7±1.4 years (mean±SEM) and 59% are males. Half of the study population is White, and 34% and 16% are Black and others, respectively. Mean pre‐transplant BMI is 27.64±0.67 kg/m2. At 1‐month post‐transplant, a mean pre‐transplant SBP and DBP are 130.91±2.14 and 77.71±1.51 mmHg, respectively. With an old diagnostic criterion for HTN, 70% have SHTN but up to 90% have SHTN diagnosed by the new criteria. At 96‐month post‐transplant, obese patients has 15% lower risk for SHTN diagnosed with the old criterion (Hazard ratio (HR) 0.850; 95% CI 0.473 – 1.529; p‐value 0.588); whereas, these patients have 2.3% greater risk for SHTN by new criteria (HR 1.023; 95% CI 0.601 – 1.741; p‐value 0.934) [figure 1]. For DHTN, obese patients have 23.7% decreased risk for DHTN diagnosed with the old criterion (HR 0.763; 95% CI 0.394 – 1.478; p‐value 0.422), and also have 14.9% lower risk for DHTN by new criteria (HR 0.851; 95% CI 0.496 – 1.461; p‐value 0.559) [figure 2].ConclusionThe incidence of SHTN and DHTN are increased with the new diagnostic criterion for HTN. The new criteria appear to have the reverse effect on the association between BMI and SHTN, but not DHTN. Further studies related to SHTN are required to elucidate the outcomes of SHTN after kidney transplantation.Support or Funding InformationNoneThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Expression Differences of Cyclin Dependent Kinase Inhibitors In Aged and Young Pancreatic Beta Cells
Authors: Aitken Talon J. , Grover Samuel G. , Booren Parker L. , Tessem Jeffery Sivert 
Published: June 2021

The number of people affected by diabetes is continually rising, affecting over 400 million people worldwide. The insulin secreting pancreatic beta cells are essential to control proper glucose absorption and storage in insulin sensitive peripheral tissue. Both Type 1 and Type 2 diabetes are characterized by decreased functional beta cell mass and, consequently, decreased insulin production. One potential intervention is the use of beta cell transplantation from cadaveric donors. A major impediment to greater application of this treatment is the scarcity of transplant ready beta cells. Increasing the amount of functional beta cells will lead to increased insulin production and better management or a possible treatment strategy for the disease. Various genes have been defined that can induce beta cell replication. A major caveat of these findings, however, is that these factors induce replication in young beta cells and not aged beta cells. Given that the majority of beta cells that will be used for transplant will come from aged donors, it is imperative to understand why aged beta cells are refractory to these proliferative mechanisms. We aimed to determine why aged beta cells do not replicate as well as young beta cells. We hypothesized that one reason for why aged beta cells are refractory to genes that induce proliferation is greater expression of cell cycle inhibitors. The cell cycle is tightly regulated by cyclin‐dependent kinases. Cells also produce proteins known as cyclin‐dependent kinase inhibitors(CDKI's), which bind to cyclin dependent kinases, effectively shutting down cell proliferation. Here we demonstrate the expression of the INK4 and Cip/Kip family of CDKI's by mRNA, protein and histological expression in 5 week old and 5 month old primary rat beta cells. These results begin to define the functional changes that result in the inability of aged beta cells to replicate.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Synergistic Anti‐adipogenic Effect of 3,3′‐diindolylmethane and Capsaicin in 3T3‐L1 Adipocytes
Authors: Lee Jihye , Lee Seong‐Ho 
Published: June 2021

3,3′‐diindolylmethane is a metabolite of indole‐3‐carbinole abundant in cruciferous vegetables and capsaicin is an active component of chili pepper that belongs to Capsicum. Recently we reported that 3,3′‐diindolylmethane repressed fat accumulation via AMPK‐dependent manner in differentiated adipocytes and C. elegans. Based on our previous findings that 3,3′‐diindolylmethane and capsaicin possess synergistic anti‐cancer activity, the current study was conducted to explore if 3,3′‐diindolylmethane in combination with capsaicin synergistically suppresses adipogenesis using differentiated 3T3‐L1 adipocytes. Co‐treatment of 3,3′‐diindolylmethane and capsaicin significantly reduced triglycerides accumulation and expression of adipogenic marker proteins (PPARγ and C/EBPα). Combinational treatment of 3,3′‐diindolylmethane and capsaicin also modulated expression of several apoptosis‐ and cell cycle‐regulating proteins. Multiple mechanisms appear to be involved in synergistic anti‐adipogenic effect by combinational use of 3,3′‐diindolylmethane and capsaicin.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.