Volker Briken

Loyola University Maryland, Baltimore, Maryland, United States

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Publications (48)327.61 Total impact

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    ABSTRACT: Approximately, 40-70% of active pharmaceutical ingredients (API) are severely limited by their extremely poor aqueous solubility and consequently there is a high demand for excipients that can be used to formulate clinically relevant doses of these drug candidates. Here, proof-of-concept studies demonstrate the potential of our recently discovered acyclic cucurbit[n]uril-type molecular container Motor1 (M1) as a solubilizing agent for insoluble drugs. M1 did not induce significant rates of mutations in various Salmonella typhimurium test strains during the Ames test, suggesting low genotoxicity. M1 also has low risk of causing cardiac toxicity in humans since it did not inhibit the human Ether-à-go-go-Related Gene channel as tested on transfected CHO cell lines via patch clamp analysis. Albendazole (ABZ) is a widely used anti-helminthic agent but that has also shown promising efficacy against cancerous cells in vitro. However, due to its low aqueous solubility (2.7 micromolar) and poor pharmacokinetics, ABZ is clinically limited as an anti-cancer agent. Here we investigated the potential of M1 as a solubilizing excipient for ABZ formulation. A pharmacokinetic study indicated that ABZ escapes the peritoneal cavity resulting in 78% absolute bioavailability while its active intermediate metabolite, albendazole sulfoxide, achieved 43% absolute bioavailability. The daily dosing of 681 mg/kg M1 complexed with 3.2 mg/kg of ABZ for 14 days did not result in significant weight loss or pathology in Swiss Webster mice. In vivo efficacy studies using this M1•ABZ inclusion complex showed significant decreases in tumor growth rates and increases in survival of mice bearing SK-OV-3 xenograft tumors. In conclusion, we provide substantial new evidence demonstrating that M1 is a safe and efficient excipient that enables in vivo parenteral delivery of poorly water-soluble APIs.
    No preview · Article · Jan 2016 · Molecular Pharmaceutics
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    ABSTRACT: Many intracellular pathogens cause disease by subverting macrophage innate immune defense mechanisms. Intracellular pathogens actively avoid delivery to or directly target lysosomes, the major intracellular degradative organelle. In this article, we demonstrate that activator of G-protein signaling 3 (AGS3), an LPS-inducible protein in macrophages, affects both lysosomal biogenesis and activity. AGS3 binds the Gi family of G proteins via its G-protein regulatory (GoLoco) motif, stabilizing the Gα subunit in its GDP-bound conformation. Elevated AGS3 levels in macrophages limited the activity of the mammalian target of rapamycin pathway, a sensor of cellular nutritional status. This triggered the nuclear translocation of transcription factor EB, a known activator of lysosomal gene transcription. In contrast, AGS3-deficient macrophages had increased mammalian target of rapamycin activity, reduced transcription factor EB activity, and a lower lysosomal mass. High levels of AGS3 in macrophages enhanced their resistance to infection by Burkholderia cenocepacia J2315, Mycobacterium tuberculosis, and methicillin-resistant Staphylococcus aureus, whereas AGS3-deficient macrophages were more susceptible. We conclude that LPS priming increases AGS3 levels, which enhances lysosomal function and increases the capacity of macrophages to eliminate intracellular pathogens.
    No preview · Article · Dec 2015 · The Journal of Immunology
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    ABSTRACT: The synthesis of acyclic cucurbit[n]uril dendrimers G1-G3 that bear four dendrons on their aromatic sidewalls via thiolate SN2 chemistry is reported. G1-G3 are polycationic and can bind to pEGFP plasmid DNA as shown by dynamic light scattering (DLS), gel electrophoresis, and scanning electron microscopy (SEM). The gene delivery ability of G1-G3 is presented.
    No preview · Article · Nov 2015 · Organic Letters
  • Swati Shah · Joe R Cannon · Catherine Fenselau · Volker Briken
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    ABSTRACT: The ESX-5 secretion system of Mycobacterium tuberculosis (Mtb) is important for bacterial virulence and the secretion of the large PE/PPE protein family that constitutes 10% of the Mtb genome. A four-gene region of ESX-5 is duplicated three times in the Mtb genome but the function of these duplicates is unknown. Here we investigated one of these duplicates, the esxI, esxJ, ppe15 and pe8 (ESX-5a) region. ESX-5a deletion mutant in the model system, M. marinum (Mm) background was deficient in the secretion of some members of the PE/PPE family of proteins. Surprisingly, we also identified other proteins that are not members this family, thus expanding the range ESX-5 secretion substrates. In addition, we demonstrate that ESX-5a is important for virulence of Mm in the zebrafish model. Furthermore, we show the role of the Mtb ESX-5a region in inflammasome activation but not in host cell death induction, which is different from the Mtb ESX-5 system. In conclusion, the ESX-5a region is non-redundant with its ESX-5 paralog and is necessary for secretion of a specific subset of proteins in Mtb and Mm that are important for bacterial virulence of Mm. Our findings point to a role for the three ESX-5 duplicate regions in the selection of substrates for secretion via ESX-5 and hence they provide the basis for a refined model of the molecular mechanism of this type VII secretion system. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    No preview · Article · Aug 2015 · Infection and immunity
  • Lalitha Srinivasan · Sarah Ahlbrand · Volker Briken
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    ABSTRACT: Mycobacterium tuberculosis (Mtb) has coevolved with humans for tens of thousands of years. It is thus highly adapted to its human host and has evolved multiple mechanisms to manipulate host immune responses to its advantage. One central host pathogen interaction modality is host cell death pathways. Host cell apoptosis is associated with a protective response to Mtb infection, whereas a necrotic response favors the pathogen. Consistently, Mtb inhibits host cell apoptosis signaling but promotes induction of programmed necrosis. The molecular mechanisms involved in Mtb-mediated host cell death manipulation, the consequences for host immunity, and the potential for therapeutic and preventive approaches will be discussed.
    No preview · Article · Jun 2014 · Cold Spring Harbor Perspectives in Medicine
  • Liping Cao · Gaya Hettiarachchi · Volker Briken · Lyle Isaacs
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    ABSTRACT: Stay on target: The cucurbit[7]uril derivative 1, which bears a covalently attached biotin targeting ligand allows for the efficient delivery of oxaliplatin as its 1⋅oxaliplatin complex to cancer cells resulting in enhanced cytotoxicity relative to oxaliplatin alone.
    No preview · Article · Nov 2013 · Angewandte Chemie International Edition
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    Volker Briken · Sarah E Ahlbrand · Swati Shah
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    ABSTRACT: The production of IL-1β during the infection with Mycobacterium tuberculosis (Mtb) is important for successful host immune defense. In macrophages and dendritic cells the host cell inflammasome is crucial for generation of secreted IL-1β in response to Mtb infections. In these cell types Mtb infection only activates the NLRP3-inflammasome. New reports demonstrate that nitric oxide has an important function in the negative regulation of the NLRP3-inflammasome to reduce tissue damage during Mtb infections. The type I interferon, IFN-β, is induced after Mtb infections and can also suppress NLRP3-inflammasome activation. In contrast, IFN-β increases activity of the AIM2-inflammasome after infection with intracellular pathogens such as Francisella tularensis and Listeria monocytogenes. Recent results demonstrate that non-tuberculous mycobacteria but not virulent Mtb induce the AIM2-inflammasome in an IFN-β dependent matter. Indeed, Mtb inhibits AIM2-inflammasome activation via its ESX-1 secretion system. This novel immune evasion mechanism may help Mtb to allow the induction of low levels of IFN-β to suppress the NLRP3-inflammasome without activating the AIM2-inflammasome.
    Preview · Article · Oct 2013 · Frontiers in Cellular and Infection Microbiology
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    ABSTRACT: Mycobacterium tuberculosis extracellular DNA gains access to the host cell cytosol via the ESX-1 secretion system. It is puzzling that this extracellular DNA of M. tuberculosis does not induce activation of the absent in melanoma 2 (AIM2) inflammasome because AIM2 recognizes cytosolic DNA. In this study, we show that nonvirulent mycobacteria such as Mycobacterium smegmatis induce AIM2 inflammasome activation, which is dependent on their strong induction of IFN-β production. In contrast, M. tuberculosis, but not an ESX-1-deficient mutant, inhibits the AIM2 inflammasome activation induced by either M. smegmatis or transfected dsDNA. The inhibition does not involve changes in host cell AIM2 mRNA or protein levels but led to decreased activation of caspase-1. We furthermore demonstrate that M. tuberculosis inhibits IFN-β production and signaling, which was partially responsible for the inhibition of AIM2 activation. In conclusion, we report a novel immune evasion mechanism of M. tuberculosis that involves the ESX-1-dependent, direct or indirect, suppression of the host cell AIM2 inflammasome activation during infection.
    Preview · Article · Aug 2013 · The Journal of Immunology
  • Gaya Hettiarachchi · Da Ma · Duc Nguyen · Lyle Isaacs · Volker Briken

    No preview · Article · Aug 2013 · Cancer Research
  • Volker Briken
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    ABSTRACT: The topic of host cell death response upon Mycobacterium tuberculosis (Mtb) infection has been a controversial one [1]. Recent findings demonstrate that one of the important confounding factors was most likely the fact that while Mtb inhibits host cell apoptosis induction early during the infection it clearly induces a necrotic form of cell death during later infection stages [2, 3]. This bi-phasic intracellular lifestyle in regard to host cell death manipulation is emerging as a common theme shared with other facultative and obligate intracellular bacterial pathogens such as Chlamydia and Legionella [4-6]. Accordingly, the list of discovered bacterial proteins involved in host cell apoptosis inhibition is growing [7, 8]. At the same time it is clearly beneficial for the resistance of the host to overcome the bacterial apoptosis block during the early stage of the infection [9-11]. Hence, host cell components have evolved to recognize intracellular pathogens and mediate host cell apoptosis induction if necessary [12]. There have been several reviews on the various aspects of the host cell death response upon Mtb infection [1, 3, 13-15]. Thus in this chapter I will focus on the pathogen side of the equation and describe the tremendous progress that has been made in the identification and characterization of Mtb genes involved in manipulation of host cell death pathways.
    No preview · Article · Mar 2013 · Advances in Experimental Medicine and Biology
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    Volker Briken
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    ABSTRACT: The uptake of apoptotic cells by phagocytes is defined as efferocytosis. In this issue of Cell Host & Microbe, Martin et al. (2012) and Yang et al. (2012) report that macrophage- and neutrophil-mediated efferocytosis of apoptotic cells containing mycobacteria is an innate antibacterial effector mechanism.
    Preview · Article · Sep 2012 · Cell host & microbe
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    ABSTRACT: Interleukin-1β (IL-1β) is important for host resistance against Mycobacterium tuberculosis (Mtb) infections. The response of the dendritic cell inflammasome during Mtb infections has not been investigated in detail. Here we show that Mtb infection of bone marrow-derived dendritic cells (BMDCs) induces IL-1β secretion and that this induction is dependent upon the presence of functional ASC and NLRP3 but not NLRC4 or NOD2. The analysis of cell death induction in BMDCs derived from these knock-out mice revealed the important induction of host cell apoptosis but not necrosis, pyroptosis or pyronecrosis. Furthermore, NLRP3 inflammasome activation and apoptosis induction were both reduced in BMDCs infected with the esxA deletion mutant of Mtb demonstrating the importance of a functional ESX-1 secretion system. Surprisingly, caspase-1/11-deficient BMDCs still secreted residual levels of IL-1βand IL-18 upon Mtb infection which was abolished in cells infected with the esxA Mtb mutant. Altogether we demonstrate the partially caspase-1/11-independent, but NLRP3- and ASC-dependent IL-1β secretion in Mtb-infected BMDCs. These findings point towards a potential role of DCs in the host innate immune response to mycobacterial infections via their capacity to induce IL-1β and IL-18 secretion.
    Full-text · Article · Jul 2012 · PLoS ONE
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    ABSTRACT: The solubility characteristics of 40-70% of new drug candidates are so poor that they cannot be formulated on their own, so new methods for increasing drug solubility are highly prized. Here, we describe a new class of general-purpose solubilizing agents-acyclic cucurbituril-type containers-which increase the solubility of ten insoluble drugs by a factor of between 23 and 2,750 by forming container-drug complexes. The containers exhibit low in vitro toxicity in human liver, kidney and monocyte cell lines, and outbred Swiss Webster mice tolerate high doses of the container without sickness or weight loss. Paclitaxel solubilized by the acyclic cucurbituril-type containers kills cervical and ovarian cancer cells more efficiently than paclitaxel alone. The acyclic cucurbituril-type containers preferentially bind cationic and aromatic drugs, but also solubilize neutral drugs such as paclitaxel, and represent an attractive extension of cyclodextrin-based technology for drug solubilization and delivery.
    Full-text · Article · Apr 2012 · Nature Chemistry
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    ABSTRACT: Mycobacterium tuberculosis promotes its replication by inhibiting the apoptosis of infected macrophages. A proapoptotic M. tuberculosis mutant lacking nuoG, a subunit of the type I NADH dehydrogenase complex, exhibits attenuated growth in vivo, indicating that this virulence mechanism is essential. We show that M. tuberculosis also suppresses neutrophil apoptosis. Compared to wild-type, the nuoG mutant spread to a larger number of lung phagocytic cells. Consistent with the shorter lifespan of infected neutrophils, infection with the nuoG mutant resulted in fewer bacteria per infected neutrophil, accelerated bacterial acquisition by dendritic cells, earlier trafficking of these dendritic cells to lymph nodes, and faster CD4 T cell priming. Neutrophil depletion abrogated accelerated CD4 T cell priming by the nuoG mutant, suggesting that inhibiting neutrophil apoptosis delays adaptive immunity in tuberculosis. Thus, pathogen modulation of apoptosis is beneficial at multiple levels, and enhancing phagocyte apoptosis promotes CD4 as well as CD8 T cell responses.
    Full-text · Article · Jan 2012 · Cell host & microbe
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    Volker Briken · David M Mosser

    Preview · Article · Nov 2011 · Journal of leukocyte biology
  • Gaya Hettiarachchi · Da Ma · Duc Nguyen · Lyle Isaacs · Volker Briken

    No preview · Article · Jul 2011 · Cancer Research

  • No preview · Article · Jan 2011 · Cancer Research
  • Daniel C. Stein · Volker Briken
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    ABSTRACT: Post-translational modifications of proteins represent an additional mechanism of generating surface variability in bacteria. Glycosylation of proteins, long thought to be unique to Eukarya, have now been demonstrated in both Bacteria and Archaea. Glycosylation of proteins can substantially influence and modulate protein structure and function and appears to be involved in the fine tuning of cell-cell recognition and signaling. However, while the eukaryotic glycosylation pathways are relatively well defined, little is known of the process in bacteria. Investigations are just beginning to unravel the biological implications of this modification. Bacteria are capable of forming both protein-attached N-glycans and O-glycans. These glycans are quite diverse. Variation in expression of genes that encode the sugar transferases allows the organism rapidly to adapt to changing environments, with the importance of these adaptive responses in human pathogens only now beginning to be understood. Antigenic variation of glycosylated molecules can occur at two levels the on-off switch where a molecule is either glycosylated or not, or the genetic substitution of the genes of one glycosylation pathway for another. This chapter reviews selected examples of bacterial glycosylation, with specific emphasis on the biological outcomes of the variable glycosylation.
    No preview · Chapter · Dec 2010
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    ABSTRACT: This essay describes how the use of a concept inventory has enhanced professional development and curriculum reform efforts of a faculty teaching community. The Host Pathogen Interactions (HPI) teaching team is composed of research and teaching faculty with expertise in HPI who share the goal of improving the learning experience of students in nine linked undergraduate microbiology courses. To support evidence-based curriculum reform, we administered our HPI Concept Inventory as a pre- and postsurvey to approximately 400 students each year since 2006. The resulting data include student scores as well as their open-ended explanations for distractor choices. The data have enabled us to address curriculum reform goals of 1) reconciling student learning with our expectations, 2) correlating student learning with background variables, 3) understanding student learning across institutions, 4) measuring the effect of teaching techniques on student learning, and 5) demonstrating how our courses collectively form a learning progression. The analysis of the concept inventory data has anchored and deepened the team's discussions of student learning. Reading and discussing students' responses revealed the gap between our understanding and the students' understanding. We provide evidence to support the concept inventory as a tool for assessing student understanding of HPI concepts and faculty development.
    Full-text · Article · Dec 2010 · CBE life sciences education
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    ABSTRACT: The HIV pandemic raised the potential for facultative-pathogenic mycobacterial species like, Mycobacterium kansasii, to cause disseminating disease in humans with immune deficiencies. In contrast, non-pathogenic mycobacterial species, like M. smegmatis, are not known to cause disseminating disease even in immunocompromised individuals. We hypothesized that this difference in phenotype could be explained by the strong induction of an innate immune response by the non-pathogenic mycobacterial species. A comparison of two rapid-growing, non-pathogenic species (M. smegmatis and M. fortuitum) with two facultative-pathogenic species (M. kansasii and M. bovis BCG) demonstrated that only the non-pathogenic bacteria induced strong apoptosis in human THP-1 cells and murine bone marrow-derived macrophages (BMDM) and dendritic cells (BMDD). The phospho-myo-inositol modification of lipoarabinomannan (PI-LAM) isolated from non-pathogenic species may be one of the cell wall components responsible for the pro-inflammatory activity of the whole bacteria. Indeed, PI-LAM induces high levels of apoptosis and IL-12 expression compared to the mannosyl modification of LAM isolated from facultative-pathogenic mycobacteria. The apoptosis induced by non-pathogenic M. smegmatis was dependent upon caspase-3 activation and TNF secretion. Consistently, BALB/c BMDM responded by secreting large amounts of TNF upon infection with non-pathogenic but not facultative-pathogenic mycobacteria. Interestingly, C57Bl/6 BMDM do not undergo apoptosis upon infection with non-pathogenic mycobacteria despite the fact that they still induce an increase in TNF secretion. This suggests that the host cell signaling pathways are different between these two mouse genotypes and that TNF is necessary but not sufficient to induce host cell apoptosis. These results demonstrate a much stronger induction of the innate immune response by non-pathogenic versus facultative-pathogenic mycobacteria as measured by host cell apoptosis, IL-12 and TNF cytokine induction. These observations lend support to the hypothesis that the strong induction of the innate immune response is a major reason for the lack of pathogenicity in fast-growing mycobacteria.
    Full-text · Article · Sep 2010 · BMC Microbiology

Publication Stats

2k Citations
327.61 Total Impact Points

Institutions

  • 2008-2015
    • Loyola University Maryland
      • Department of Biology
      Baltimore, Maryland, United States
  • 2007-2015
    • University of Maryland, College Park
      • Department of Cell Biology & Molecular Genetics
      CGS, Maryland, United States
  • 2010
    • Max Planck Institute of Molecular Cell Biology and Genetics
      Dresden, Saxony, Germany
  • 2000-2006
    • Albert Einstein College of Medicine
      • Department of Microbiology & Immunology
      New York City, New York, United States
  • 1998-2002
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
    • Institut de Génétique Moléculaire de Montpellier
      Montpelhièr, Languedoc-Roussillon, France
  • 1997
    • Institut Curie
      Lutetia Parisorum, Île-de-France, France