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  1. Article: Exosomes in Cancer Progression and Therapy Resistance: Molecular Insights and Therapeutic Opportunities.

    Wandrey, Madita / Jablonska, Jadwiga / Stauber, Roland H / Gül, Désirée

    Life (Basel, Switzerland)

    2023  Volume 13, Issue 10

    Abstract: The development of therapy resistance still represents a major hurdle in treating cancers, leading to impaired treatment success and increased patient morbidity. The establishment of minimally invasive liquid biopsies is a promising approach to improving ...

    Abstract The development of therapy resistance still represents a major hurdle in treating cancers, leading to impaired treatment success and increased patient morbidity. The establishment of minimally invasive liquid biopsies is a promising approach to improving the early diagnosis, as well as therapy monitoring, of solid tumors. Because of their manifold functions in the tumor microenvironment, tumor-associated small extracellular vesicles, referred to as exosomes, have become a subject of intense research. Besides their important roles in cancer progression, metastasis, and the immune response, it has been proposed that exosomes also contribute to the acquisition and transfer of therapy resistance, mainly by delivering functional proteins and RNAs, as well as facilitating the export of active drugs or functioning as extracellular decoys. Extensive research has focused on understanding the molecular mechanisms underlying the occurrence of resistance and translating these into strategies for early detection. With this review, we want to provide an overview of the current knowledge about the (patho-)biology of exosomes, as well as state-of-the-art methods of isolation and analysis. Furthermore, we highlight the role of exosomes in tumorigenesis and cancer treatment, where they can function as therapeutic agents, biomarkers, and/or targets. By focusing on their roles in therapy resistance, we will reveal new paths of exploiting exosomes for cancer diagnosis and treatment.
    Language English
    Publishing date 2023-10-09
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2662250-6
    ISSN 2075-1729
    ISSN 2075-1729
    DOI 10.3390/life13102033
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Taspase1 Facilitates Topoisomerase IIβ-Mediated DNA Double-Strand Breaks Driving Estrogen-Induced Transcription.

    Oelschläger, Lisa / Stahl, Paul / Kaschani, Farnusch / Stauber, Roland H / Knauer, Shirley K / Hensel, Astrid

    Cells

    2023  Volume 12, Issue 3

    Abstract: The human protease Taspase1 plays a pivotal role in developmental processes and cancerous diseases by processing critical regulators, such as the leukemia proto-oncoprotein MLL. Despite almost two decades of intense research, Taspase1's biology is, ... ...

    Abstract The human protease Taspase1 plays a pivotal role in developmental processes and cancerous diseases by processing critical regulators, such as the leukemia proto-oncoprotein MLL. Despite almost two decades of intense research, Taspase1's biology is, however, still poorly understood, and so far its cellular function was not assigned to a superordinate biological pathway or a specific signaling cascade. Our data, gained by methods such as co-immunoprecipitation, LC-MS/MS and Topoisomerase II DNA cleavage assays, now functionally link Taspase1 and hormone-induced, Topoisomerase IIβ-mediated transient DNA double-strand breaks, leading to active transcription. The specific interaction with Topoisomerase IIα enhances the formation of DNA double-strand breaks that are a key prerequisite for stimulus-driven gene transcription. Moreover, Taspase1 alters the H3K4 epigenetic signature upon estrogen-stimulation by cleaving the chromatin-modifying enzyme MLL. As estrogen-driven transcription and MLL-derived epigenetic labelling are reduced upon Taspase1 siRNA-mediated knockdown, we finally characterize Taspase1 as a multifunctional co-activator of estrogen-stimulated transcription.
    MeSH term(s) Humans ; Chromatography, Liquid ; DNA ; DNA Topoisomerases, Type II ; Estrogens ; Tandem Mass Spectrometry
    Chemical Substances DNA (9007-49-2) ; DNA Topoisomerases, Type II (EC 5.99.1.3) ; Estrogens ; taspase1, human (EC 3.4.22.-)
    Language English
    Publishing date 2023-01-18
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells12030363
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The Magic Triangle in Oral Potentially Malignant Disorders: Vitamin D, Vitamin D Receptor, and Malignancy.

    Khamis, Aya / Salzer, Lara / Schiegnitz, Eik / Stauber, Roland H / Gül, Désirée

    International journal of molecular sciences

    2023  Volume 24, Issue 20

    Abstract: OPMDs (oral potentially malignant disorders) are a group of disorders affecting the oral mucosa that are characterized by aberrant cell proliferation and a higher risk of malignant transformation. Vitamin D (VitD) and its receptor (VDR) have been ... ...

    Abstract OPMDs (oral potentially malignant disorders) are a group of disorders affecting the oral mucosa that are characterized by aberrant cell proliferation and a higher risk of malignant transformation. Vitamin D (VitD) and its receptor (VDR) have been extensively studied for their potential contributions to the prevention and therapeutic management of various diseases and neoplastic conditions, including oral cancer. Observational studies suggest correlations between VitD deficiency and higher cancer risk, worse prognosis, and increased mortality rates. Interestingly, emerging data also suggest a link between VitD insufficiency and the onset or progression of OPMDs. Understanding the role of the VitD-VDR axis not only in established oral tumors but also in OPMDs might thus enable early detection and prevention of malignant transformation. With this article, we want to provide an overview of current knowledge about OPMDs and VitD and investigate their potential association and ramifications for clinical management of OPMDs.
    MeSH term(s) Humans ; Vitamin D ; Receptors, Calcitriol/genetics ; Precancerous Conditions/pathology ; Mouth Diseases ; Mouth Neoplasms/pathology ; Vitamins ; Vitamin D Deficiency/complications
    Chemical Substances Vitamin D (1406-16-2) ; Receptors, Calcitriol ; Vitamins
    Language English
    Publishing date 2023-10-11
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms242015058
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Cloning Strategy for HDAC1/HDAC2 Hybrid Protein Expression in Mammalian Cells.

    Gül, Désirée / Olf, Sandra / Hagemann, Jan / Stauber, Roland H / Krämer, Oliver H

    Methods in molecular biology (Clifton, N.J.)

    2022  Volume 2589, Page(s) 401–409

    Abstract: Dynamic deacetylation of non-histone proteins by histone deacetylases (HDACs) is a key regulator of protein functions, interactions, and turnover. Among class I HDACs, human HDAC1 and HDAC2 share more than 80% global homology at the amino acid level. ... ...

    Abstract Dynamic deacetylation of non-histone proteins by histone deacetylases (HDACs) is a key regulator of protein functions, interactions, and turnover. Among class I HDACs, human HDAC1 and HDAC2 share more than 80% global homology at the amino acid level. However, despite the high redundancy, there are examples for differential substrate specificities of HDAC1 and HDAC2. Until now it remains quite unclear how specific and overlapping functions of HDAC1/HDAC2 are regulated in different contexts. Here, we describe molecular cloning techniques for the generation of HDAC1/HDAC2 hybrid proteins, HDAC1/HDAC2 mutants lacking known interaction domains, and HDAC1/HDAC2 hybrid proteins with interchanged N-terminal domains. These proteins are tools for the analysis of specific protein interactions and functions in mammalian cells.
    MeSH term(s) Animals ; Humans ; Histone Deacetylase 2/genetics ; Histone Deacetylase 2/metabolism ; Histone Deacetylase 1/genetics ; Histone Deacetylase 1/metabolism ; Histone Deacetylases/metabolism ; Amino Acids ; Cloning, Molecular ; Mammals/metabolism
    Chemical Substances Histone Deacetylase 2 (EC 3.5.1.98) ; Histone Deacetylase 1 (EC 3.5.1.98) ; Histone Deacetylases (EC 3.5.1.98) ; Amino Acids ; HDAC1 protein, human (EC 3.5.1.98) ; HDAC2 protein, human (EC 3.5.1.98)
    Language English
    Publishing date 2022-10-18
    Publishing country United States
    Document type Journal Article
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-2788-4_26
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: The Apoptosis Inhibitor Protein Survivin Is a Critical Cytoprotective Resistor against Silica-Based Nanotoxicity.

    Breder-Bonk, Christina / Docter, Dominic / Barz, Matthias / Strieth, Sebastian / Knauer, Shirley K / Gül, Désirée / Stauber, Roland H

    Nanomaterials (Basel, Switzerland)

    2023  Volume 13, Issue 18

    Abstract: Exposure to nanoparticles is inevitable as they become widely used in industry, cosmetics, and foods. However, knowledge of their (patho)physiological effects on biological entry routes of the human body and their underlying molecular mechanisms is still ...

    Abstract Exposure to nanoparticles is inevitable as they become widely used in industry, cosmetics, and foods. However, knowledge of their (patho)physiological effects on biological entry routes of the human body and their underlying molecular mechanisms is still fragmented. Here, we examined the molecular effects of amorphous silica nanoparticles (aSiNPs) on cell lines mimicking the alveolar-capillary barrier of the lung. After state-of-the-art characterization of the used aSiNPs and the cell model, we performed cell viability-based assays and a protein analysis to determine the aSiNP-induced cell toxicity and underlying signaling mechanisms. We revealed that aSiNPs induce apoptosis in a dose-, time-, and size-dependent manner. aSiNP-induced toxicity involves the inhibition of pro-survival pathways, such as PI3K/AKT and ERK signaling, correlating with reduced expression of the anti-apoptotic protein Survivin on the protein and transcriptional levels. Furthermore, induced Survivin overexpression mediated resistance against aSiNP-toxicity. Thus, we present the first experimental evidence suggesting Survivin as a critical cytoprotective resistor against silica-based nanotoxicity, which may also play a role in responses to other NPs. Although Survivin's relevance as a biomarker for nanotoxicity needs to be demonstrated in vivo, our data give general impetus to investigate the pharmacological modulation of Survivin`s functions to attenuate the harmful effects of acute or chronic inhalative NP exposure.
    Language English
    Publishing date 2023-09-12
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2662255-5
    ISSN 2079-4991
    ISSN 2079-4991
    DOI 10.3390/nano13182546
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Cochlear implantation impairs intracochlear microcirculation and counteracts iNOS induction in guinea pigs.

    Ernst, Benjamin Philipp / Heinrich, Ulf-Rüdiger / Fries, Mathias / Meuser, Regina / Rader, Tobias / Eckrich, Jonas / Stauber, Roland H / Strieth, Sebastian

    Frontiers in cellular neuroscience

    2023  Volume 17, Page(s) 1189980

    Abstract: Introduction: Preservation of residual hearing remains a great challenge during cochlear implantation. Cochlear implant (CI) electrode array insertion induces changes in the microvasculature as well as nitric oxide (NO)-dependent vessel dysfunction ... ...

    Abstract Introduction: Preservation of residual hearing remains a great challenge during cochlear implantation. Cochlear implant (CI) electrode array insertion induces changes in the microvasculature as well as nitric oxide (NO)-dependent vessel dysfunction which have been identified as possible mediators of residual hearing loss after cochlear implantation.
    Methods: A total of 24 guinea pigs were randomized to receive either a CI (
    Results: The sham control group showed no change in mean CBF after 1 h (104.2 ± 0.7%) and 2 h (100.8 ± 3.6%) compared to baseline. In contrast, cochlear implantation resulted in a significant continuous decrease in CBF after 1 h (78.8 ± 8.1%,
    Conclusion: Mechanical and NO-dependent microvascular dysfunction seem to play a pivotal role in residual hearing loss after CI electrode array insertion. This may be facilitated by the implantation associated decrease in iNOS expression. Therefore, stabilization of cochlear microcirculation could be a therapeutic strategy to preserve residual hearing.
    Language English
    Publishing date 2023-06-28
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2452963-1
    ISSN 1662-5102
    ISSN 1662-5102
    DOI 10.3389/fncel.2023.1189980
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Tuning Nanobodies' Bioactivity: Coupling to Ultrasmall Gold Nanoparticles Allows the Intracellular Interference with Survivin.

    Stahl, Paul / Kollenda, Sebastian / Sager, Jonas / Schmidt, Laura / Schroer, Martin A / Stauber, Roland H / Epple, Matthias / Knauer, Shirley K

    Small (Weinheim an der Bergstrasse, Germany)

    2023  Volume 19, Issue 33, Page(s) e2300871

    Abstract: Nanobodies are highly affine binders, often used to track disease-relevant proteins inside cells. However, they often fail to interfere with pathobiological functions, required for their clinical exploitation. Here, a nanobody targeting the disease- ... ...

    Abstract Nanobodies are highly affine binders, often used to track disease-relevant proteins inside cells. However, they often fail to interfere with pathobiological functions, required for their clinical exploitation. Here, a nanobody targeting the disease-relevant apoptosis inhibitor and mitosis regulator Survivin (SuN) is utilized. Survivin's multifaceted functions are regulated by an interplay of dynamic cellular localization, dimerization, and protein-protein interactions. However, as Survivin harbors no classical "druggable" binding pocket, one must aim at blocking extended protein surface areas. Comprehensive experimental evidence demonstrates that intracellular expression of SuN allows to track Survivin at low nanomolar concentrations but failed to inhibit its biological functions. Small angle X-ray scattering of the Survivin-SuN complex locates the proposed interaction interface between the C-terminus and the globular domain, as such not blocking any pivotal interaction. By clicking multiple SuN to ultrasmall (2 nm) gold nanoparticles (SuN-N), not only intracellular uptake is enabled, but additionally, Survivin crosslinking and interference with mitotic progression in living cells are also enabled. In sum, it is demonstrated that coupling of nanobodies to nanosized scaffolds can be universally applicable to improve their function and therapeutic applicability.
    MeSH term(s) Survivin ; Gold ; Single-Domain Antibodies ; Microtubule-Associated Proteins/metabolism ; Inhibitor of Apoptosis Proteins/metabolism ; Neoplasm Proteins/metabolism ; Metal Nanoparticles ; Apoptosis
    Chemical Substances Survivin ; Gold (7440-57-5) ; Single-Domain Antibodies ; Microtubule-Associated Proteins ; Inhibitor of Apoptosis Proteins ; Neoplasm Proteins
    Language English
    Publishing date 2023-04-10
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2168935-0
    ISSN 1613-6829 ; 1613-6810
    ISSN (online) 1613-6829
    ISSN 1613-6810
    DOI 10.1002/smll.202300871
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Biosynthesized tumor acidity and MMP dual-responsive plant toxin gelonin for robust cancer therapy.

    Ding, Guo-Bin / Cao, Huiyan / Zhu, Chenchen / Chen, Fangyuan / Ye, Jiaqi / Li, Bin-Chun / Yang, Peng / Stauber, Roland H / Qiao, Mingqiang / Li, Zhuoyu

    Biomaterials science

    2024  Volume 12, Issue 2, Page(s) 346–360

    Abstract: Among all kinds of anticancer agents, small molecule drugs produce an unsatisfactory therapeutic effect due to the lack of selectivity, notorious drug resistance and side effects. Therefore, researchers have begun to pay extensive attention to ... ...

    Abstract Among all kinds of anticancer agents, small molecule drugs produce an unsatisfactory therapeutic effect due to the lack of selectivity, notorious drug resistance and side effects. Therefore, researchers have begun to pay extensive attention to macromolecular drugs with high efficacy and specificity. As a plant toxin, gelonin exerts potent antitumor activity
    MeSH term(s) Humans ; Mice ; Animals ; Matrix Metalloproteinase 2 ; Ribosome Inactivating Proteins, Type 1/chemistry ; Ribosome Inactivating Proteins, Type 1/genetics ; Ribosome Inactivating Proteins, Type 1/pharmacology ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; MCF-7 Cells ; Neoplasms/drug therapy
    Chemical Substances GEL protein, Gelonium multiflorum (75037-46-6) ; Matrix Metalloproteinase 2 (EC 3.4.24.24) ; Ribosome Inactivating Proteins, Type 1 ; Antineoplastic Agents
    Language English
    Publishing date 2024-01-16
    Publishing country England
    Document type Journal Article
    ZDB-ID 2693928-9
    ISSN 2047-4849 ; 2047-4830
    ISSN (online) 2047-4849
    ISSN 2047-4830
    DOI 10.1039/d3bm01779f
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Colonization with Altered Schaedler Flora Impacts Leukocyte Adhesion in Mesenteric Ischemia-Reperfusion Injury

    Bayer, Franziska / Ascher, Stefanie / Kiouptsi, Klytaimnistra / Kittner, Jens M. / Stauber, Roland H. / Reinhardt, Christoph

    Microorganisms. 2021 July 27, v. 9, no. 8

    2021  

    Abstract: The microbiota impacts mesenteric ischemia-reperfusion injury, aggravating the interaction of leukocytes with endothelial cells in mesenteric venules. The role of defined gut microbiomes in this life-threatening pathology is unknown. To investigate how a ...

    Abstract The microbiota impacts mesenteric ischemia-reperfusion injury, aggravating the interaction of leukocytes with endothelial cells in mesenteric venules. The role of defined gut microbiomes in this life-threatening pathology is unknown. To investigate how a defined model microbiome affects the adhesion of leukocytes in mesenteric ischemia-reperfusion, we took advantage of gnotobiotic isolator technology and transferred altered Schaedler flora (ASF) from C3H/HeNTac to germ-free C57BL/6J mice. We were able to detect all eight bacterial taxa of ASF in fecal samples of colonized C57BL/6J mice by PCR. Applying qRT-PCR for quantification of species-specific 16S rDNA sequences of ASF bacteria, we found a major shift in the abundance of ASF 500, which was greater in C57BL/6J mice relative to the C3H/HeNTac founder breeding pair. Using high-speed epifluorescence intravital microscopy to visualize the venules of the small bowel mesentery, we found that gnotobiotic ASF-colonized mice showed reduced leukocyte adherence, both pre- and post-ischemia. Relative to germ-free mice, the counts of adhering leukocytes were increased pre-ischemia but did not significantly increase in ASF-colonized mice in the post-ischemic state. Collectively, our results suggest a protective role of the minimal microbial consortium ASF in mesenteric ischemia-reperfusion injury.
    Keywords adhesion ; flora ; germ-free animals ; leukocytes ; mesentery ; microbiome ; microscopy ; protective effect
    Language English
    Dates of publication 2021-0727
    Publishing place Multidisciplinary Digital Publishing Institute
    Document type Article
    ZDB-ID 2720891-6
    ISSN 2076-2607
    ISSN 2076-2607
    DOI 10.3390/microorganisms9081601
    Database NAL-Catalogue (AGRICOLA)

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  10. Article: Colonization with Altered Schaedler Flora Impacts Leukocyte Adhesion in Mesenteric Ischemia-Reperfusion Injury.

    Bayer, Franziska / Ascher, Stefanie / Kiouptsi, Klytaimnistra / Kittner, Jens M / Stauber, Roland H / Reinhardt, Christoph

    Microorganisms

    2021  Volume 9, Issue 8

    Abstract: The microbiota impacts mesenteric ischemia-reperfusion injury, aggravating the interaction of leukocytes with endothelial cells in mesenteric venules. The role of defined gut microbiomes in this life-threatening pathology is unknown. To investigate how a ...

    Abstract The microbiota impacts mesenteric ischemia-reperfusion injury, aggravating the interaction of leukocytes with endothelial cells in mesenteric venules. The role of defined gut microbiomes in this life-threatening pathology is unknown. To investigate how a defined model microbiome affects the adhesion of leukocytes in mesenteric ischemia-reperfusion, we took advantage of gnotobiotic isolator technology and transferred altered Schaedler flora (ASF) from C3H/HeNTac to germ-free C57BL/6J mice. We were able to detect all eight bacterial taxa of ASF in fecal samples of colonized C57BL/6J mice by PCR. Applying qRT-PCR for quantification of species-specific 16S rDNA sequences of ASF bacteria, we found a major shift in the abundance of ASF 500, which was greater in C57BL/6J mice relative to the C3H/HeNTac founder breeding pair. Using high-speed epifluorescence intravital microscopy to visualize the venules of the small bowel mesentery, we found that gnotobiotic ASF-colonized mice showed reduced leukocyte adherence, both pre- and post-ischemia. Relative to germ-free mice, the counts of adhering leukocytes were increased pre-ischemia but did not significantly increase in ASF-colonized mice in the post-ischemic state. Collectively, our results suggest a protective role of the minimal microbial consortium ASF in mesenteric ischemia-reperfusion injury.
    Language English
    Publishing date 2021-07-27
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2720891-6
    ISSN 2076-2607
    ISSN 2076-2607
    DOI 10.3390/microorganisms9081601
    Database MEDical Literature Analysis and Retrieval System OnLINE

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