Presence of chromogranin-derived antimicrobial peptides in plasma during coronary artery bypass surgery and evidence of an immune origin of these peptides

Blood ◽  
2002 ◽  
Vol 100 (2) ◽  
pp. 553-559 ◽  
Author(s):  
Aurélie Tasiemski ◽  
Hamida Hammad ◽  
Franck Vandenbulcke ◽  
Christophe Breton ◽  
Thomas J. Bilfinger ◽  
...  
Keyword(s):  
Artery Bypass ◽  
Antimicrobial Properties ◽  
Microscopic Analysis ◽  
Skin Incision ◽  
Biologically Active ◽  
Chromogranin B ◽  
Positive Role ◽  
Active Peptides

Abstract Chromogranin A (CGA) and chromogranin B (CGB) are acidic proteins stored in secretory organelles of endocrine cells and neurons. In addition to their roles as helper proteins in the packaging of peptides, they may serve as prohormones to generate biologically active peptides such as vasostatin-1 and secretolytin. These molecules derived from CGA and CGB, respectively, possess antimicrobial properties. The present study demonstrates that plasmatic levels of both vasostatin-1 and secretolytin increase during surgery in patients undergoing cardiopulmonary bypass (CPB). Vasostatin-1 and secretolytin, initially present in plasma at low levels, are released just after skin incision. Consequently, they can be added to enkelytin, an antibacterial peptide derived from proenkephalin A, for the panoply of components acting as a first protective barrier against hypothetical invasion of pathogens, which may occur during surgery. CGA and CGB, more commonly viewed as markers for endocrine and neuronal cells, were also found to have an immune origin. RNA messengers coding for CGB were amplified by reverse transcription–polymerase chain reaction in human monocytes, and immunocytochemical analysis by confocal microscopy revealed the presence of CGA or CGB or both in monocytes and neutrophils. A combination of techniques including confocal microscopic analysis, mass spectrometry measurement, and antibacterial tests allowed for the identification of the positive role of interleukin 6 (IL-6) in the secretolytin release from monocytes in vitro. Because IL-6 release is known to be strongly enhanced during CPB, we suggest a possible relationship between IL-6 and the increased level of secretolytin in patients undergoing CPB.

RAS and Leukemia: From Basic Mechanisms to Gene-Directed Therapy

1999 ◽  
Vol 17 (3) ◽  
pp. 1071-1071 ◽  
Author(s):  
Darrin M. Beaupre ◽  
Razelle Kurzrock
Keyword(s):  
Signaling Pathways ◽  
Posttranslational Modification ◽  
Antitumor Agents ◽  
Biologically Active ◽  
Ras Signaling ◽  
Farnesyl Transferase ◽  
Therapeutic Implications ◽  
Farnesyl Transferase Inhibitors

PURPOSE AND DESIGN: The purpose of this review is to provide an overview of the literature linking Ras signaling pathways and leukemia and to discuss the biologic and potential therapeutic implications of these observations. A search of MEDLINE from 1966 to October 1998 was performed. RESULTS: A wealth of data has been published on the role of Ras pathways in cancer. To be biologically active, Ras must move from the cytoplasm to the plasma membrane. Importantly, a posttranslational modification—addition of a farnesyl group to the Ras C-terminal cysteine—is a requisite for membrane localization of Ras. Farnesylation of Ras is catalyzed by an enzyme that is designated farnesyltranferase. Recently, several compounds have been developed that can inhibit farnesylation. Preclinical studies indicate that these molecules can suppress transformation and tumor growth in vitro and in animal models, with little toxicity to normal cells. CONCLUSION: An increasing body of data suggests that disruption of Ras signaling pathways, either directly through mutations or indirectly through other genetic aberrations, is important in the pathogenesis of a wide variety of cancers. Molecules such as farnesyl transferase inhibitors that interfere with the function of Ras may be exploitable in leukemia (as well as in solid tumors) as novel antitumor agents.

scholarly journals DSS1 and ssDNA regulate oligomerization of BRCA2

2020 ◽  
Vol 48 (14) ◽  
pp. 7818-7833 ◽  
Author(s):  
Hang Phuong Le ◽  
Xiaoyan Ma ◽  
Jorge Vaquero ◽  
Megan Brinkmeyer ◽  
Fei Guo ◽  
...  
Keyword(s):  
Replication Fork ◽  
Microscopic Analysis ◽  
Filament Formation ◽  
Electron Microscopic ◽  
Microscopic Imaging ◽  
Cellular Events ◽  
Self Association ◽  
Oligomeric Forms

Abstract The tumor suppressor BRCA2 plays a key role in initiating homologous recombination by facilitating RAD51 filament formation on single-stranded DNA. The small acidic protein DSS1 is a crucial partner to BRCA2 in this process. In vitro and in cells (1,2), BRCA2 associates into oligomeric complexes besides also existing as monomers. A dimeric structure was further characterized by electron microscopic analysis (3), but the functional significance of the different BRCA2 assemblies remains to be determined. Here, we used biochemistry and electron microscopic imaging to demonstrate that the multimerization of BRCA2 is counteracted by DSS1 and ssDNA. When validating the findings, we identified three self-interacting regions and two types of self-association, the N-to-C terminal and the N-to-N terminal interactions. The N-to-C terminal self-interaction of BRCA2 is sensitive to DSS1 and ssDNA. The N-to-N terminal self-interaction is modulated by ssDNA. Our results define a novel role of DSS1 to regulate BRCA2 in an RPA-independent fashion. Since DSS1 is required for BRCA2 function in recombination, we speculate that the monomeric and oligomeric forms of BRCA2 might be active for different cellular events in recombinational DNA repair and replication fork stabilization.

scholarly journals Candida albicans forms biofilms on the vaginal mucosa

Microbiology ◽  
2010 ◽  
Vol 156 (12) ◽  
pp. 3635-3644 ◽  
Author(s):  
M. M. Harriott ◽  
E. A. Lilly ◽  
T. E. Rodriguez ◽  
P. L. Fidel ◽  
M. C. Noverr
Keyword(s):  
Biofilm Formation ◽  
Ex Vivo ◽  
Microscopic Analysis ◽  
Vaginal Mucosa ◽  
First Time ◽  
Established Role ◽  
Type Strains

Current understanding of resistance and susceptibility to vulvovaginal candidiasis challenges existing paradigms of host defence against fungal infection. While abiotic biofilm formation has a clearly established role during systemic Candida infections, it is not known whether C. albicans forms biofilms on the vaginal mucosa and the possible role of biofilms in disease. In vivo and ex vivo murine vaginitis models were employed to examine biofilm formation by scanning electron and confocal microscopy. C. albicans strains included 3153A (lab strain), DAY185 (parental control strain), and mutants defective in morphogenesis and/or biofilm formation in vitro (efg1/efg1 and bcr1/bcr1). Both 3153A and DAY815 formed biofilms on the vaginal mucosa in vivo and ex vivo as indicated by high fungal burden and microscopic analysis demonstrating typical biofilm architecture and presence of extracellular matrix (ECM) co-localized with the presence of fungi. In contrast, efg1/efg1 and bcr1/bcr1 mutant strains exhibited weak or no biofilm formation/ECM production in both models compared to wild-type strains and complemented mutants despite comparable colonization levels. These data show for the first time that C. albicans forms biofilms in vivo on vaginal epithelium, and that in vivo biotic biofilm formation requires regulators of biofilm formation (BCR1) and morphogenesis (EFG1).

scholarly journals Impact of Oxidative Stress and Protein S-Glutathionylation in Aortic Valve Sclerosis Patients with Overt Atherosclerosis

2019 ◽  
Vol 8 (4) ◽  
pp. 552 ◽  
Author(s):  
Vincenza Valerio ◽  
Veronika A. Myasoedova ◽  
Donato Moschetta ◽  
Benedetta Porro ◽  
Gianluca L. Perrucci ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Smooth Muscle Actin ◽  
Artery Bypass ◽  
Protein S ◽  
Aortic Valve Sclerosis ◽  
Cell Adhesion Molecule 1 ◽  
First Time ◽  
Glutathione Homeostasis

Aortic valve sclerosis (AVSc) is characterized by non-uniform thickening of the leaflets without hemodynamic changes. Endothelial dysfunction, also caused by dysregulation of glutathione homeostasis expressed as ratio between its reduced (GSH) and its oxidised form (GSSG), could represent one of the pathogenic triggers of AVSc. We prospectively enrolled 58 patients with overt atherosclerosis and requiring coronary artery bypass grafting (CABG). The incidence of AVSc in the studied population was 50%. The two groups (No-AVSc and AVSc) had similar clinical characteristics. Pre-operatively, AVSc group showed significantly lower GSH/GSSG ratio than No-AVSc group (p = 0.02). Asymmetric dimethylarginine (ADMA) concentration was significantly higher in AVSc patients compared to No-AVSc patients (p < 0.0001). Explanted sclerotic aortic valves presented a significantly increased protein glutathionylation (Pr-SSG) than No-AVSc ones (p = 0.01). In vitro, inhibition of glutathione reductase caused β-actin glutathionylation, activation of histone 2AX, upregulation of α2 smooth muscle actin (ACTA2), downregulation of platelet and endothelial cell adhesion molecule 1 (PECAM1) and cadherin 5 (CDH5). In this study, we showed for the first time that the dysregulation of glutathione homeostasis is associated with AVSc. We found that Pr-SSG is increased in AVSc leaflets and it could lead to EndMT via DNA damage. Further studies are warranted to elucidate the causal role of Pr-SSG in aortic valve degeneration.

scholarly journals In vitro and in vivo evidence for an inflammatory role of the calcium channel TRPV4 in lung epithelium: Potential involvement in cystic fibrosis

2016 ◽  
Vol 311 (3) ◽  
pp. L664-L675 ◽  
Author(s):  
Clémence O. Henry ◽  
Emilie Dalloneau ◽  
Maria-Teresa Pérez-Berezo ◽  
Cristina Plata ◽  
Yongzheng Wu ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Calcium Channel ◽  
Lung Inflammation ◽  
Transient Receptor Potential ◽  
Biologically Active ◽  
Transient Receptor Potential Vanilloid ◽  
Anti Inflammatory

Cystic fibrosis (CF) is an inherited disease associated with chronic severe lung inflammation, leading to premature death. To develop innovative anti-inflammatory treatments, we need to characterize new cellular and molecular components contributing to the mechanisms of lung inflammation. Here, we focused on the potential role of “transient receptor potential vanilloid-4” (TRPV4), a nonselective calcium channel. We used both in vitro and in vivo approaches to demonstrate that TRPV4 expressed in airway epithelial cells triggers the secretion of major proinflammatory mediators such as chemokines and biologically active lipids, as well as a neutrophil recruitment in lung tissues. We characterized the contribution of cytosolic phospholipase A2, MAPKs, and NF-κB in TRPV4-dependent signaling. We also showed that 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids, i.e., four natural lipid-based TRPV4 agonists, are present in expectorations of CF patients. Also, TRPV4-induced calcium mobilization and inflammatory responses were enhanced in cystic fibrosis transmembrane conductance regulator-deficient cellular and animal models, suggesting that TRPV4 is a promising target for the development of new anti-inflammatory treatments for diseases such as CF.

scholarly journals Inhibition of Microglia Activation as a Phenotypic Assay in Early Drug Discovery

2013 ◽  
Vol 19 (1) ◽  
pp. 17-31 ◽  
Author(s):  
Mariana Figuera-Losada ◽  
Camilo Rojas ◽  
Barbara S. Slusher
Keyword(s):  
Drug Discovery ◽  
Nuclear Factor Κb ◽  
Microglia Activation ◽  
Biologically Active ◽  
Therapeutic Drugs ◽  
Mitogen Activated Protein ◽  
Disproportionate Number ◽  
Early Drug

Complex biological processes such as inflammation, cell death, migration, proliferation, and the release of biologically active molecules can be used as outcomes in phenotypic assays during early stages of drug discovery. Although target-based approaches have been widely used over the past decades, a disproportionate number of first-in-class drugs have been identified using phenotypic screening. This review details phenotypic assays based on inhibition of microglial activation and their utility in primary and secondary screening, target validation, and pathway elucidation. The role of microglia, both in normal as well as in pathological conditions such as chronic neurodegenerative diseases, is reviewed. Methodologies to assess microglia activation in vitro are discussed in detail, and classes of therapeutic drugs known to decrease the proinflammatory and cytotoxic responses of activated microglia are appraised, including inhibitors of glutaminase, cystine/glutamate antiporter, nuclear factor κB, and mitogen-activated protein kinases.

503. SUCCESSFUL IN VITRO FERTILIZATION (IVF) AFTER PRIOR FAILED IVF UTILIZING A PROPRIETARY BLEND OF SUPPLEMENTS

2009 ◽  
Vol 21 (9) ◽  
pp. 104
Author(s):  
B. Poursharif ◽  
J. Paden ◽  
B. Acacio
Keyword(s):  
In Vitro Fertilization ◽  
Egg Quality ◽  
Clinical Pregnancy ◽  
Ivf Outcome ◽  
Positive Role ◽  
Vitro Fertilization ◽  
Embryo Fragmentation ◽  
History Of

Background: To date, little is known about the effect of supplements on the outcome of in vitro fertilization (IVF). The data on this matter is limited to measuring the overall pregnancy rate on a population of women who took a specific supplement, and not on IVF patients. Objectives: To demonstrate the positive role of an investigated supplement in the outcome of patients undergoing IVF. Method: 18 women undergoing IVF treatment were placed on a proprietary combination of vitamins and antioxidants designed to encourage blood flow and improve egg quality. The women were selected for this protocol mostly due to prior poor egg quality and/or large amount of embryo fragmentation .The women took supplementation twice daily for 4–12 weeks prior to transfer. The charts of the patients who used the supplements were used to obtain data. Previous failed IVF was defined as negative pregnancy. Successful IVF outcome was determined by positive chemical pregnancy and clinical pregnancy after one attempt. Range and mean was calculated for patient's age and number of failed previous IVF attempts. The previous IVF attempts were performed in different centers without using this supplement in all patients. Results: Eighteen patients used the supplement before and during their IVF cycles. Patient's age ranged from 28 to 44 with mean of 36.4 years. They had on average, 2 prior failed IVF attempts. Seventeen of 18 patients had successful IVF outcome. The failed patient required frozen testicular extraction of sperm (TESE), prior to IVF. Summary: Seventeen of 18 patients who used our supplements had successful IVF. These patients failed an average of 2 previous IVF attempts without using our supplements. Conclusion: Usage of our supplements is associated with improved rates of success in patients undergoing IVF with a history of prior failed IVF attempts. Larger studies need to be conducted.

Anti-angiogenesis Potential of Phytochemicals for the Therapeutic Management of Tumors

2020 ◽  
Vol 26 (2) ◽  
pp. 265-278 ◽  
Author(s):  
Samman Munir ◽  
Asad A. Shah ◽  
Muhammad Shahid ◽  
Muhammad S. Ahmed ◽  
Aqsa Shahid ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Angiogenesis Inhibitors ◽  
Metastatic Potential ◽  
Biologically Active ◽  
Angiogenic Potential ◽  
Recent Developments ◽  
Pharmaceutical Industries ◽  
Pathological Stages

The role of angiogeneses during the growth and progression of tumors is well documented. Likewise, a balance is generally maintained between the cellular proliferation and the apoptosis, therefore, the tumors can persist for years in a dormant phase. During the past few years, many hypotheses have been proposed relating to the importance of tumor angiogenesis for the development and spread of tumors and preventive or therapeutic capacity of angiogenesis inhibitors as a potential target for controlling the growth of cancerous tissue. The antiangiogenic based therapeutic approaches are considered as the most promising method for the control of tumors, as this therapeutic approach is less likely to attain the drug resistance. Further, the tumor vasculature is an important prognostic marker that can independently predict the pathological stages as well as the metastatic potential of tumors. Various biologically active phytochemicals have been extracted from the dietary sources and the plants that have engaged the scientist and pharmaceutical industries around the globe. The antioxidant, antiinflammatory, anti-proliferative and anti-angiogenic potential of these bioactive phytochemicals is evident from the in vitro studies using cell lines and investigations involving the animal models..The present review is focused on the promising role of anti-angiogenesis-based therapies for the management of tumors and the recent developments relating to the interplay of phytochemicals and angiogenesis for the suppression of tumor cells.

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