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Autophagy in α-Synucleinopathies—An Overstrained System

Lisa Fellner, Elisa Gabassi, Johannes Haybaeck, Frank Edenhofer
2021 Cells  
Alpha-synucleinopathies comprise progressive neurodegenerative diseases, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). They all exhibit the same pathological hallmark, which is the formation of α-synuclein positive deposits in neuronal or glial cells. The aggregation of α-synuclein in the cell body of neurons, giving rise to the so-called Lewy bodies (LBs), is the major characteristic for PD and DLB, whereas the accumulation of
more » ... n in oligodendroglial cells, so-called glial cytoplasmic inclusions (GCIs), is the hallmark for MSA. The mechanisms involved in the intracytoplasmic inclusion formation in neuronal and oligodendroglial cells are not fully understood to date. A possible mechanism could be an impaired autophagic machinery that cannot cope with the high intracellular amount of α-synuclein. In fact, different studies showed that reduced autophagy is involved in α-synuclein aggregation. Furthermore, altered levels of different autophagy markers were reported in PD, DLB, and MSA brains. To date, the trigger point in disease initiation is not entirely clear; that is, whether autophagy dysfunction alone suffices to increase α-synuclein or whether α-synuclein is the pathogenic driver. In the current review, we discuss the involvement of defective autophagy machinery in the formation of α-synuclein aggregates, propagation of α-synuclein, and the resulting neurodegenerative processes in α-synucleinopathies.
doi:10.3390/cells10113143 pmid:34831366 pmcid:PMC8618716 fatcat:uxbdj3yksbfezpiap3pm774yk4

Non-Coding RNAs and Lipid Metabolism

Elisabeth Smolle, Johannes Haybaeck
2014 International Journal of Molecular Sciences  
A high percentage of the mammalian genome consists of non-coding RNAs (ncRNAs). Among ncRNAs two main subgroups have been identified: long ncRNAs (lncRNAs) and micro RNAs (miRNAs). ncRNAs have been demonstrated to play a role in a vast variety of diseases, since they regulate gene transcription and are involved in post-transcriptional regulation. They have the potential to function as molecular signals or as guides for transcription factors and to regulate epigenetic modifiers. In this
more » ... e review we have summarized data on miRNAs and lncRNAs and their involvement in dyslipidaemia, atherosclerosis, insulin resistance and adipogenesis. Outlining certain ncRNAs as disease biomarkers and/or therapeutic targets, and testing them in vivo, will be the next steps in future research.
doi:10.3390/ijms150813494 pmid:25093715 pmcid:PMC4159807 fatcat:lme5s2o2qze73i2elnj6rnqj5e

Steatosis and Steatohepatitis: Complex Disorders

Kira Bettermann, Tabea Hohensee, Johannes Haybaeck
2014 International Journal of Molecular Sciences  
Non-alcoholic fatty liver disease (NAFLD) which includes steatosis and steatohepatitis, in particular non-alcoholic steatohepatitis (NASH), is a rising health problem world-wide and should be separated from alcoholic steatohepatitis (ASH). NAFLD is regarded as hepatic manifestation of the metabolic syndrome (MetSy), being tightly linked to obesity and type 2 diabetes mellitus (T2DM). Development of steatosis, liver fibrosis and cirrhosis often progresses towards hepatocellular carcinogenesis
more » ... frequently results in the indication for liver transplantation, underlining the clinical significance of this disease complex. Work on different murine models and several human patients studies led to the identification of different molecular key players as well as epigenetic factors like miRNAs and SNPs, which have a promoting or protecting function in AFLD/ASH or NAFLD/NASH. To which extent they might be translated into human biology and pathogenesis is still questionable and needs further investigation regarding diagnostic parameters, drug development and a better understanding of the genetic impact. In this review we give an overview about the currently available knowledge and recent findings regarding the development and progression of this disease.
doi:10.3390/ijms15069924 pmid:24897026 pmcid:PMC4100130 fatcat:j6hymksmpvhsfmauh4v4gjewqy

Dural arachnoid granulations and "giant" arachnoid granulations

Johannes Haybaeck, Rene Silye, Dov Soffer
2008 Surgical and Radiologic Anatomy  
Although arachnoid granulations (AGs) were already described by Antonio Pacchioni more than 300 years ago, two issues draw particular attention: first, the radiological features and differential diagnosis of the so-called giant AGs (GAGs) and second, their possible association with various disease processes. In order to evaluate the frequency, size and normal distribution of GAGs, an anatomical study of the dural sinuses was carried out. It involved all the autopsies performed during the period
more » ... August 2002-February 2005 and included 651 cases: 306 females and 345 males, aged 13-99 years (mean 69 years). Grossly visible GAGs were identified in 24 cases: 7 females and 17 males, aged 45-92 years (mean 69 years). This is the largest population-based anatomical study on GAGs. It shows that GAGs, in general a rare finding (3.68%), are rather common in the adult population, especially in the elderly (aged >65 years) and that they can reach remarkable size (up to 2.5 cm and more in diameter). Giant AGs should be considered in the radiological differential diagnosis of intradural lesions, particularly those occurring in the transverse sinus of the elderly.
doi:10.1007/s00276-008-0345-2 pmid:18392764 fatcat:wthzbw2jzra7tn4gpzej7p2aji

Hepatic Response of Magnesium-Restricted Wild Type Mice

Vera H. Fengler, Tanja Macheiner, Walter Goessler, Maria Ratzer, Johannes Haybaeck, Karine Sargsyan
2021 Metabolites  
Magnesium-deficiency is implicated in many metabolic disorders, e.g., type 2 diabetes and metabolic syndrome, representing risk factors for non-alcoholic fatty liver disease (NAFLD). This study aims to investigate the contribution of magnesium-restriction to the development of NAFLD. Magnesium-deficiency was induced in C57BL/6 mice by feeding a magnesium-deficient-diet. Metabolic markers as well as markers of inflammation and liver function were assessed. Furthermore, liver tissue was examined
more » ... istopathologically and compared with specimens from high-fat-diet fed and control mice. Finally, the hepatic inflammatory response was quantified by determining hepatic IL-6, TNFα, and MCP-1. Magnesium-restriction resulted in at least a 2-fold significant reduction of serum magnesium levels compared to the high-fat-diet fed and control mice, whereas the hepatic magnesium content was decreased due to high-fat-diet feeding. No changes in metabolic markers in magnesium-restricted mice were observed, while the cholesterol content was elevated in high-fat-diet fed mice. Magnesium-restricted mice additionally featured inflammation and enlarged hepatocytes in liver histology. Furthermore, magnesium-restricted and high-fat-diet fed mice exhibited elevated hepatic TNFα levels compared to control mice. Accordingly, our data suggest that magnesium is involved in hepatic inflammatory processes and hepatocyte enlargement, key histological features of human NAFLD, and may therefore contribute to development and progression of the disease.
doi:10.3390/metabo11110762 pmid:34822420 pmcid:PMC8625093 fatcat:l4wutbvx3bar5owrbkac77bvxq

Hedgehog Signaling Pathway in Ovarian Cancer

Joanna Szkandera, Tobias Kiesslich, Johannes Haybaeck, Armin Gerger, Martin Pichler
2013 International Journal of Molecular Sciences  
Despite advances in surgical and chemotherapeutic treatment options, less than 50% of patients with advanced-stage ovarian cancer survive five years after initial diagnosis. In this regard, novel treatment approaches are warranted utilizing molecularly targeted therapies directed against particular components of specific signaling pathways which are required for tumor development and progression. One molecular pathway of interest is the hedgehog (Hh) signaling pathway. Activation of the Hh
more » ... ay has been observed in several cancer types, including ovarian cancer. This review highlights the crucial role of Hh signaling in the development and progression of ovarian cancer and might lead to a better understanding of the Hh signaling in ovarian tumorigenesis, thus encouraging the investigation of novel targeted therapies.
doi:10.3390/ijms14011179 pmid:23303278 pmcid:PMC3565315 fatcat:zco5ka2wxjhtlldytpqboachim

Genetic and molecular alterations in olfactory neuroblastoma: implications for pathogenesis, prognosis and treatment

Piotr Czapiewski, Michał Kunc, Johannes Haybaeck
2016 OncoTarget  
Olfactory neuroblastoma (ONB, Esthesioneuroblastoma) is an infrequent neoplasm of the head and neck area derived from olfactory neuroepithelium. Despite relatively good prognosis a subset of patients shows recurrence, progression and/or metastatic disease, which requires additional treatment. However, neither prognostic nor predictive factors are well specified. Thus, we performed a literature search for the currently available data on disturbances in molecular pathways, cytogenetic changes and
more » ... results gained by next generation sequencing (NGS) approaches in ONB in order to gain an overview of genetic alterations which might be useful for treating patients with ONB. We present briefly ONB molecular pathogenesis and propose potential therapeutic targets and prognostic factors. Possible therapeutic targets in ONB include: receptor tyrosine kinases (c-kit, PDGFR-b, TrkB; EGFR); somatostatin receptor; FGF-FGFR1 signaling; Sonic hedgehog pathway; apoptosisrelated pathways (Bcl-2, TRAIL) and neoangiogenesis (VEGF; KDR). Furthermore, we compare high-and low-grade ONB, and describe its frequent mimicker: sinonasal neuroendocrine carcinoma. ONB is often a therapeutic challenge, so our goal should be the implementation of acquired knowledge into clinical practice, especially at pretreated, recurrent and metastatic stages. Moreover, the multicenter molecular studies are needed to increase the amount of available data. 30. Sinkevicius KW, et al. p75 neurotrophin receptor cleavage by α-and γ-secretases is required for neurotrophin-mediated proliferation of brain tumorinitiating cells. J Biol Chem. 2014; 289:8067-8085. 33.
doi:10.18632/oncotarget.9683 pmid:27256979 pmcid:PMC5239575 fatcat:dod2vo7cfrfglhin7gwdtpwztu

The Interplay of Tumor Stroma and Translational Factors in Endometrial Cancer

Monika Sobočan, Maria Anna Smolle, Christoph Schatz, Johannes Haybaeck
2020 Cancers  
Endometrial cancer (EC) is a common gynecologic malignancy which continues to have a poor prognosis in advanced stages due to current therapeutic limitations. A significant mechanism of chemoresistance in EC has been shown to also be the enhancement of epithelial to mesenchymal transition (EMT) and the subsequent obtainment of stem cell-like characteristics of EC. Current evidence on EMT in EC however fails to explain the relationship leading to an EMT signaling enhancement. Our review
more » ... focuses on understanding eukaryotic translation initiation factors (eIFs) as key regulators of the translational process in enhancing EMT and subsequently impacting higher chemoresistance of EC. We identified pathways connected to the development of a microenvironment for EMT, inducers of the process specifically related to estrogen receptors as well as their interplay with eIFs. In the future, investigation elucidating the translational biology of EC in EMT may therefore focus on the signaling between protein kinase RNA-like ER kinase (PERK) and eIF2alpha as well as eIF3B.
doi:10.3390/cancers12082074 pmid:32726992 pmcid:PMC7463731 fatcat:26l2775qhfeuddgzgvo4ysq544

A unilateral dermatomal venous malformation

Elisabeth Smolle, David Benjamin Lumenta, Johannes Haybaeck, Thomas Gary, Marianne Brodmann, Philipp Eller
2015 Journal of Vascular Surgery Cases  
Venous malformations (VMs) are the most common vascular malformations, forming 44% to 64% of all vascular malformations. We report a case of a patient suffering from unilateral dermatomal VM. The VM was strictly confined to the right C6 dermatome. We propose that unilateral dermatomal VM is a prime example of somatic mosaicism in vascular development. Unilateral dermatomal VM seems to have a similar pathogenesis to the Sturge-Weber syndrome and may also be caused by somatic mutations disrupting the development of skin veins.
doi:10.1016/j.jvsc.2015.10.004 pmid:31724654 pmcid:PMC6849999 fatcat:zfithfr6lzgxrol2zl5k7srxlu

Clinical Impact of RANK Signalling in Ovarian Cancer

Verena Wieser, Susanne Sprung, Irina Tsibulak, Johannes Haybaeck, Hubert Hackl, Heidelinde Fiegl, Christian Marth, Alain Gustave Zeimet
2019 Cancers  
Ovarian cancer (OC) is a gynaecological malignancy with poor clinical outcome and limited treatment options. The receptor activator of nuclear factor-κB (RANK) pathway, activated by RANK ligand (RANKL), critically controls bone metabolism, tumourigenesis and tumour immune responses. Denosumab, a monocloncal RANKL antibody, exerts tumour-suppressive effects in mice and humans. Here, we investigated the relevance of RANK signalling in OC. RANK, RANKL and OPG expression in 192 epithelial OC
more » ... was compared to expression in 35 non-malignant control tissues and related to clinico-pathological characteristics. Findings were validated in a cohort of 563 OC patients from The Cancer Genome Atlas (TCGA). The expression of RANK, RANKL and OPG was studied in four OC cell lines and the impact of RANK ligation or blockade on OC cell proliferation was determined. RANK, RANKL and OPG were expressed in epithelial and stromal cells in OC. RANKL expression was elevated in OC tissue, particularly in BRCA1/2 mutated tumours. High RANKL expression independently predicted reduced progression-free (PFS, p = 0.017) and overall survival (OS, p = 0.007), which could be validated in the TCGA cohort (PFS, p = 0.022; OS, p = 0.046, respectively). Expression of RANK and OPG in OC cells was induced by inflammatory cytokines IL-1β and TNFα. Neither recombinant RANK ligation nor denosumab treatment affected OC cell proliferation. Our study independently links RANKL expression with poor clinical outcome in two unrelated OC cohorts. These findings implicate RANK signalling in the immunopathogenesis of OC and warrant clinical trials with denosumab in OC.
doi:10.3390/cancers11060791 pmid:31181781 pmcid:PMC6627676 fatcat:rhzuythsz5dsdf5uvlrgvhjh2e

Nrf2 in the Field of Dentistry with Special Attention to NLRP3

Lisa Schieffer, Claudia Manzl, Christoph Schatz, Johannes Haybaeck, Adriano Crismani
2022 Antioxidants  
The aim of this review article was to summarize the functional implications of the nuclear factor E2-related factor or nuclear factor (erythroid-derived 2)-like 2 (Nrf2), with special attention to the NACHT (nucleotide-binding oligomerization), LRR (leucine-rich repeat), and PYD (pyrin domain) domains-containing protein 3 (NLRP3) inflammasome in the field of dentistry. NLRP3 plays a crucial role in the progression of inflammatory and adaptive immune responses throughout the body. It is already
more » ... nown that this inflammasome is a key regulator of several systemic diseases. The initiation and activation of NLRP3 starts with the oral microbiome and its association with the pathogenesis and progression of several oral diseases, including periodontitis, periapical periodontitis, and oral squamous cell carcinoma (OSCC). The possible role of the inflammasome in oral disease conditions may involve the aberrant regulation of various response mechanisms, not only in the mouth but in the whole body. Understanding the cellular and molecular biology of the NLRP3 inflammasome and its relationship to Nrf2 is necessary for the rationale when suggesting it as a potential therapeutic target for treatment and prevention of oral inflammatory and immunological disorders. In this review, we highlighted the current knowledge about NLRP3, its likely role in the pathogenesis of various inflammatory oral processes, and its crosstalk with Nrf2, which might offer future possibilities for disease prevention and targeted therapy in the field of dentistry and oral health.
doi:10.3390/antiox11010149 pmid:35052653 pmcid:PMC8772975 fatcat:v7vcex6gcfccnjnac4fxq26lqy

Long Non-Coding RNAs in Endometrial Carcinoma

Maria Smolle, Marc Bullock, Hui Ling, Martin Pichler, Johannes Haybaeck
2015 International Journal of Molecular Sciences  
Hui Ling, Martin Pichler and Johannes Haybaeck contributed their expert knowledge about lncRNAs. Conflicts of Interest: The authors declare no conflict of interest.  ... 
doi:10.3390/ijms161125962 pmid:26556343 pmcid:PMC4661821 fatcat:y6yixqrtafatnd7k7tmo2nixty

Therapeutic Potential of PI3K/AKT/mTOR Pathway in Gastrointestinal Stromal Tumors: Rationale and Progress

Yi Duan, Johannes Haybaeck, Zhihui Yang
2020 Cancers  
Gastrointestinal stromal tumor (GIST) originates from interstitial cells of Cajal (ICCs) in the myenteric plexus of the gastrointestinal tract. Most GISTs arise due to mutations of KIT and PDGFRA gene activation, encoding the receptor tyrosine kinase (RTK). The clinical use of the RTK inhibitor imatinib has significantly improved the management of GIST patients; however, imatinib resistance remains a challenge. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of
more » ... apamycin (mTOR) pathway is a critical survival pathway for cell proliferation, apoptosis, autophagy and translation in neoplasms. Constitutive autophosphorylation of RTKs has an impact on the activation of the PI3K/AKT/mTOR pathway. In several preclinical and early-stage clinical trials PI3K/AKT/mTOR signaling inhibition has been considered as a promising targeted therapy strategy for GISTs. Various inhibitory drugs targeting different parts of the PI3K/AKT/mTOR pathway are currently being investigated in phase I and phase II clinical trials. This review highlights the progress for PI3K/AKT/mTOR-dependent mechanisms in GISTs, and explores the relationship between mTOR downstream signals, in particular, eukaryotic initiation factors (eIFs) and the development of GISTs, which may be instrumental for identifying novel therapeutic targets.
doi:10.3390/cancers12102972 pmid:33066449 pmcid:PMC7602170 fatcat:k5cuiaajpngedolygbp4ud3qzq

Impact of Eukaryotic Translation Initiation Factors on Breast Cancer: Still Much to Investigate

Qin Chen, Bo Yang, Norbert Nass, Christoph Schatz, Johannes Haybaeck
2020 Cancers  
Breast carcinoma (BC) remains one of the most serious health problems. It is a heterogeneous entity, and mainly classified according to receptor status for estrogen (ER), progesterone (PR) and egf (HER2/Neu), as well as the proliferation marker ki67. Gene expression in eukaryotes is regulated at the level of both gene transcription and translation, where eukaryotic initiation factors (eIFs) are key regulators of protein biosynthesis. Aberrant translation results in an altered cellular proteome,
more » ... and this clearly effects cell growth supporting tumorigenesis. The relationship between various eIFs and BC entities, as well as the related regulatory mechanisms, has meanwhile become a focus of scientific interest. Here, we give an overview on the current research state of eIF function, focusing on BC.
doi:10.3390/cancers12071984 pmid:32708122 fatcat:4d5u552ypzf7lbznq6wae76ou4

Targeting Signaling Pathways in Epithelial Ovarian Cancer

Elisabeth Smolle, Valentin Taucher, Martin Pichler, Edgar Petru, Sigurd Lax, Johannes Haybaeck
2013 International Journal of Molecular Sciences  
Ovarian carcinoma (OC) is the most lethal gynecological malignancy. Response to platinum-based chemotherapy is poor in some patients and, thus, current research is focusing on new therapy options. The various histological types of OC are characterized by distinctive molecular genetic alterations that are relevant for ovarian tumorigenesis. The understanding of these molecular pathways is essential for the development of novel therapeutic strategies. Purpose: We want to give an overview on the
more » ... lecular genetic changes of the histopathological types of OC and their role as putative therapeutic targets. In Depth Review of Existing Data: In 2012, the vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, was approved for OC treatment. Bevacizumab has shown promising results as single agent and in combination with conventional chemotherapy, but its target is not distinctive when analyzed before treatment. At present, mammalian target of rapamycin (mTOR) inhibitors, poly-ADP-ribose polymerase (PARP) inhibitors and components of the EGFR pathway are in the focus of clinical research. Interestingly, some phytochemical substances show good synergistic effects when used in combination with OPEN ACCESS
doi:10.3390/ijms14059536 pmid:23644885 pmcid:PMC3676798 fatcat:gqfi2xsalzbq5hny6ehchbida4
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