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State-of-the-Art Biochemistry in Germany
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State-of-the-Art Biochemistry in Germany

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 12964

Special Issue Editor

Prof. Dr. Burkhard Kleuser

E-Mail Website
Guest Editor
Institute of Pharmacy (Pharmacology and Toxicology), Freie Universität Berlin, Königin-Luise-Straße 2+4, 14195 Berlin, Germany
Interests: sphingolipidomics; sphingosine 1-phosphate; S1P-receptors; insulin resistance; dendritic cells; epigenetics; nanotoxicology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue of the International Journal of Molecular Sciences (IJMS) aims to rapidly publish contributions on all aspects of biochemistry. We encourage the submission of manuscripts that provide novel and mechanistic insights and papers that report significant advances in the fields. Topics include, but are not limited to:

  • the molecular basis of biological processes
  • functional and mechanistic studies of molecular pathways in vivo and in vitro
  • gene and protein structure and expression
  • protein biosynthesis
  • the folding of biomolecules
  • structural biology
  • membrane function and post-translational modification
  • drugs and pharmaceutics
  • advances in biochemical, biophysical, and molecular methodologies, as well as imaging techniques and data analysis.

Prof. Dr. Burkhard Kleuser
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • biochemistry
  • biochemical processes
  • biotechnology
  • genetics
  • genomics
  • proteomics
  • nucleic acid
  • RNA decay
  • DNA structure
  • DNA replication
  • DNA damage and repair
  • RNA structure
  • RNA processing, splicing and polyadenylation
  • transcription
  • non-coding RNAs
  • RNA folding
  • DNA folding
  • translation
  • gene expression and regulation
  • post-translational modifications
  • amino acid
  • proteins
  • enzymes
  • protein synthesis
  • protein folding, processing and degradation
  • membrane proteins
  • biomolecular interactions
  • biomarkers
  • cell–cell interactions
  • stem cells
  • apoptosis
  • cellular and molecular cross-talks
  • cell motility
  • structure biology
  • chromatin structural and function
  • chromosome
  • drugs
  • membrane transport
  • signal transduction
  • signaling networks
  • microscopy
  • data analysis
  • nano-biology

Published Papers (5 papers)

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Research

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12 pages, 880 KiB  
Article
Characterization of a Neutral Sphingomyelinase Activity in Human Serum and Plasma
by Christiane Mühle and Johannes Kornhuber
Int. J. Mol. Sci. 2023, 24(3), 2467; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032467 - 27 Jan 2023
Cited by 1 | Viewed by 1631
Abstract
Alterations of sphingolipids and their metabolizing enzymes play a role in various diseases. However, peripheral biomarkers for such changes are limited. Particularly, in the increasingly reported involvement of neutral sphingomyelinase (NSM) with four described isoforms in tissues or cells, a peripheral marker is [...] Read more.
Alterations of sphingolipids and their metabolizing enzymes play a role in various diseases. However, peripheral biomarkers for such changes are limited. Particularly, in the increasingly reported involvement of neutral sphingomyelinase (NSM) with four described isoforms in tissues or cells, a peripheral marker is lacking. We here describe the detection of an NSM activity in human serum and plasma samples which hydrolyses fluorescently labeled sphingomyelin to ceramide in a time- and volume-dependent manner. Reaction rates were linear up to 10 days, and serum volumes above 2 vol-% were inhibitory. Biochemical properties were different from acid sphingomyelinase (ASM) with respect to detergent specificity (sodium deoxycholate), pH profile (pH 7–9), and cation dependence: Serum NSM activity was inhibited by EDTA ≥ 1 µM and restored in EDTA-anticoagulated plasma with the addition of ≥ 100 µM Co2+. It was independent of Mg2+, the typical cofactor of cellular NSM species, and even inhibited by [Mg2+] ≥ 20 mM. Serum NSM activity was not correlated with ASM activity and was independent of sex and age in 24 healthy adults. Since human peripheral NSM activity is very low and activities in rodents are even lower or undetectable, future research should aim to increase the reaction rate and determine the source of this enzymatic activity. The established activity could serve as a future biomarker or therapeutic target in diseases affected by sphingolipid derangements. Full article
(This article belongs to the Special Issue State-of-the-Art Biochemistry in Germany)
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20 pages, 3156 KiB  
Article
Sedative Properties of Dexmedetomidine Are Mediated Independently from Native Thalamic Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Function at Clinically Relevant Concentrations
by Stefan Schwerin, Catharina Westphal, Claudia Klug, Gerhard Schneider, Matthias Kreuzer, Rainer Haseneder and Stephan Kratzer
Int. J. Mol. Sci. 2023, 24(1), 519; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010519 - 28 Dec 2022
Cited by 3 | Viewed by 1597
Abstract
Dexmedetomidine is a selective α2-adrenoceptor agonist and appears to disinhibit endogenous sleep-promoting pathways, as well as to attenuate noradrenergic excitation. Recent evidence suggests that dexmedetomidine might also directly inhibit hyperpolarization-activated cyclic-nucleotide gated (HCN) channels. We analyzed the effects of dexmedetomidine on [...] Read more.
Dexmedetomidine is a selective α2-adrenoceptor agonist and appears to disinhibit endogenous sleep-promoting pathways, as well as to attenuate noradrenergic excitation. Recent evidence suggests that dexmedetomidine might also directly inhibit hyperpolarization-activated cyclic-nucleotide gated (HCN) channels. We analyzed the effects of dexmedetomidine on native HCN channel function in thalamocortical relay neurons of the ventrobasal complex of the thalamus from mice, performing whole-cell patch-clamp recordings. Over a clinically relevant range of concentrations (1–10 µM), the effects of dexmedetomidine were modest. At a concentration of 10 µM, dexmedetomidine significantly reduced maximal Ih amplitude (relative reduction: 0.86 [0.78–0.91], n = 10, and p = 0.021), yet changes to the half-maximal activation potential V1/2 occurred exclusively in the presence of the very high concentration of 100 µM (−4,7 [−7.5–−4.0] mV, n = 10, and p = 0.009). Coincidentally, only the very high concentration of 100 µM induced a significant deceleration of the fast component of the HCN activation time course (τfast: +135.1 [+64.7–+151.3] ms, n = 10, and p = 0.002). With the exception of significantly increasing the membrane input resistance (starting at 10 µM), dexmedetomidine did not affect biophysical membrane properties and HCN channel-mediated parameters of neuronal excitability. Hence, the sedative qualities of dexmedetomidine and its effect on the thalamocortical network are not decisively shaped by direct inhibition of HCN channel function. Full article
(This article belongs to the Special Issue State-of-the-Art Biochemistry in Germany)
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22 pages, 6050 KiB  
Article
Sequential Targeting of PLK1 and PARP1 Reverses the Resistance to PARP Inhibitors and Enhances Platin-Based Chemotherapy in BRCA-Deficient High-Grade Serous Ovarian Cancer with KRAS Amplification
by Khayal Gasimli, Monika Raab, Morva Tahmasbi Rad, Elisabeth Kurunci-Csacsko, Sven Becker, Klaus Strebhardt and Mourad Sanhaji
Int. J. Mol. Sci. 2022, 23(18), 10892; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810892 - 17 Sep 2022
Cited by 5 | Viewed by 3677
Abstract
Ovarian cancer (OC) accounts for approximately 4% of cancer deaths in women worldwide and is the deadliest gynecologic malignancy. High-grade serous ovarian cancer (HGSOC) is the most predominant ovarian cancer, in which BRCA1/2 gene mutation ranges from 3 to 27%. PARP inhibitors (PARPi) [...] Read more.
Ovarian cancer (OC) accounts for approximately 4% of cancer deaths in women worldwide and is the deadliest gynecologic malignancy. High-grade serous ovarian cancer (HGSOC) is the most predominant ovarian cancer, in which BRCA1/2 gene mutation ranges from 3 to 27%. PARP inhibitors (PARPi) have shown promising results as a synthetically lethal therapeutic approach for BRCA mutant and recurrent OC in clinical use. However, emerging data indicate that BRCA-deficient cancers may be resistant to PARPi, and the mechanisms of this resistance remain elusive. We found that amplification of KRAS likely underlies PARPi resistance in BRCA2-deficient HGSOC. Our data suggest that PLK1 inhibition restores sensitivity to PARPi in HGSOC with KRAS amplification. The sequential combination of PLK1 inhibitor (PLK1i) and PARPi drastically reduces HGSOC cell survival and increases apoptosis. Furthermore, we were able to show that a sequential combination of PLK1i and PARPi enhanced the cellular apoptotic response to carboplatin-based chemotherapy in KRAS-amplified resistant HGSOC cells and 3D spheroids derived from recurrent ovarian cancer patients. Our results shed new light on the critical role of PLK1 in reversing PARPi resistance in KRAS-amplified HGSOC, and offer a new therapeutic strategy for this class of ovarian cancer patients where only limited options currently exist. Full article
(This article belongs to the Special Issue State-of-the-Art Biochemistry in Germany)
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15 pages, 3116 KiB  
Article
Zafirlukast Induces VHL- and HIF-2α-Dependent Oxidative Cell Death in 786-O Clear Cell Renal Carcinoma Cells
by Christopher Wolf, Sonja Smith and Sjoerd J. L. van Wijk
Int. J. Mol. Sci. 2022, 23(7), 3567; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073567 - 25 Mar 2022
Cited by 6 | Viewed by 2345
Abstract
Mutations in the Von Hippel–Lindau (VHL) gene are the driving force in many forms of clear cell renal cell carcinoma (ccRCC) and promote hypoxia-inducible factor (HIF)-dependent tumor proliferation, metastasis and angiogenesis. Despite the progress that has already been made, ccRCC generally remain resistant [...] Read more.
Mutations in the Von Hippel–Lindau (VHL) gene are the driving force in many forms of clear cell renal cell carcinoma (ccRCC) and promote hypoxia-inducible factor (HIF)-dependent tumor proliferation, metastasis and angiogenesis. Despite the progress that has already been made, ccRCC generally remain resistant to conventional therapies and ccRCC patients suffer from metastasis and acquired resistance, highlighting the need for novel therapeutic options. Cysteinyl leukotriene receptor 1 (CysLTR1) antagonists, like zafirlukast, are administered in bronchial asthma to control eicosanoid signaling. Intriguingly, long-term use of zafirlukast decreases cancer risk and leukotriene receptor antagonists inhibit tumor growth, but the mechanisms still remain unexplored. Therefore, we aim to understand the mechanisms of zafirlukast-mediated cell death in ccRCC cells. We show that zafirlukast induces VHL-dependent and TNFα-independent non-apoptotic and non-necroptotic cell death in ccRCC cells. Cell death triggered by zafirlukast could be rescued with antioxidants and the PARP-1 inhibitor Olaparib, and additionally relies on HIF-2α. Finally, MG-132-mediated proteasome inhibition sensitized VHL wild-type cells to zafirlukast-induced cell death and inhibition of HIF-2α rescued zafirlukast- and MG-132-triggered cell death. Together, these results highlight the importance of VHL, HIF and proteasomal degradation in zafirlukast-induced oxidative cell death with potentially novel therapeutic implications for ccRCC. Full article
(This article belongs to the Special Issue State-of-the-Art Biochemistry in Germany)
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Review

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34 pages, 1093 KiB  
Review
Counteracting Immunosuppression in the Tumor Microenvironment by Oncolytic Newcastle Disease Virus and Cellular Immunotherapy
by Volker Schirrmacher, Stefaan van Gool and Wilfried Stuecker
Int. J. Mol. Sci. 2022, 23(21), 13050; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113050 - 27 Oct 2022
Cited by 6 | Viewed by 2947
Abstract
An apparent paradox exists between the evidence for spontaneous systemic T cell- mediated anti-tumor immune responses in cancer patients, observed particularly in their bone marrow, and local tumor growth in the periphery. This phenomenon, known as “concomitant immunity” suggests that the local tumor [...] Read more.
An apparent paradox exists between the evidence for spontaneous systemic T cell- mediated anti-tumor immune responses in cancer patients, observed particularly in their bone marrow, and local tumor growth in the periphery. This phenomenon, known as “concomitant immunity” suggests that the local tumor and its tumor microenvironment (TME) prevent systemic antitumor immunity to become effective. Oncolytic Newcastle disease virus (NDV), an agent with inherent anti-neoplastic and immune stimulatory properties, is capable of breaking therapy resistance and immunosuppression. This review updates latest information about immunosuppression by the TME and discusses mechanisms of how oncolytic viruses, in particular NDV, and cellular immunotherapy can counteract the immunosuppressive effect of the TME. With regard to cellular immunotherapy, the review presents pre-clinical studies of post-operative active-specific immunotherapy and of adoptive T cell-mediated therapy in immunocompetent mice. Memory T cell (MTC) transfer in tumor challenged T cell-deficient nu/nu mice demonstrates longevity and functionality of these cells. Graft-versus-leukemia (GvL) studies in mice demonstrate complete remission of late-stage disease including metastases and cachexia. T cell based immunotherapy studies with human cells in human tumor xenotransplanted NOD/SCID mice demonstrate superiority of bone marrow-derived as compared to blood-derived MTCs. Results from clinical studies presented include vaccination studies using two different types of NDV-modified cancer vaccine and a pilot adoptive T-cell mediated therapy study using re-activated bone marrow-derived cancer-reactive MTCs. As an example for what can be expected from clinical immunotherapy against tumors with an immunosuppressive TME, results from vaccination studies are presented from the aggressive brain tumor glioblastoma multiforme. The last decades of basic research in virology, oncology and immunology can be considered as a success story. Based on discoveries of these research areas, translational research and clinical studies have changed the way of treatment of cancer by introducing and including immunotherapy. Full article
(This article belongs to the Special Issue State-of-the-Art Biochemistry in Germany)
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