TY - JOUR A1 - Meyer, Malin Tordis A1 - Watermann, Christoph A1 - Dreyer, Thomas A1 - Ergün, Süleyman A1 - Karnati, Srikanth T1 - 2021 update on diagnostic markers and translocation in salivary gland tumors JF - International Journal of Molecular Sciences N2 - Salivary gland tumors are a rare tumor entity within malignant tumors of all tissues. The most common are malignant mucoepidermoid carcinoma, adenoid cystic carcinoma, and acinic cell carcinoma. Pleomorphic adenoma is the most recurrent form of benign salivary gland tumor. Due to their low incidence rates and complex histological patterns, they are difficult to diagnose accurately. Malignant tumors of the salivary glands are challenging in terms of differentiation because of their variability in histochemistry and translocations. Therefore, the primary goal of the study was to review the current literature to identify the recent developments in histochemical diagnostics and translocations for differentiating salivary gland tumors. KW - salivary gland tumors KW - epithelial salivary gland KW - adenoid cystic carcinoma (ACC) KW - pleomorphic adenoma KW - mucoepidermoid carcinoma KW - diagnostic markers Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261057 SN - 1422-0067 VL - 22 IS - 13 ER - TY - JOUR A1 - Kleefeldt, Florian A1 - Bömmel, Heike A1 - Broede, Britta A1 - Thomsen, Michael A1 - Pfeiffer, Verena A1 - Wörsdörfer, Philipp A1 - Karnati, Srikanth A1 - Wagner, Nicole A1 - Rueckschloss, Uwe A1 - Ergün, Süleyman T1 - Aging‐related carcinoembryonic antigen‐related cell adhesion molecule 1 signaling promotes vascular dysfunction JF - Aging Cell N2 - Aging is an independent risk factor for cardiovascular diseases and therefore of particular interest for the prevention of cardiovascular events. However, the mechanisms underlying vascular aging are not well understood. Since carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) is crucially involved in vascular homeostasis, we sought to identify the role of CEACAM1 in vascular aging. Using human internal thoracic artery and murine aorta, we show that CEACAM1 is upregulated in the course of vascular aging. Further analyses demonstrated that TNF‐α is CEACAM1‐dependently upregulated in the aging vasculature. Vice versa, TNF‐α induces CEACAM1 expression. This results in a feed‐forward loop in the aging vasculature that maintains a chronic pro‐inflammatory milieu. Furthermore, we demonstrate that age‐associated vascular alterations, that is, increased oxidative stress and vascular fibrosis, due to increased medial collagen deposition crucially depend on the presence of CEACAM1. Additionally, age‐dependent upregulation of vascular CEACAM1 expression contributes to endothelial barrier impairment, putatively via increased VEGF/VEGFR‐2 signaling. Consequently, aging‐related upregulation of vascular CEACAM1 expression results in endothelial dysfunction that may promote atherosclerotic plaque formation in the presence of additional risk factors. Our data suggest that CEACAM1 might represent an attractive target in order to delay physiological aging and therefore the transition to vascular disorders such as atherosclerosis. KW - aging KW - anti‐aging KW - cytokines KW - inflammation KW - mouse KW - reactive oxygen species Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201231 VL - 2019 IS - 18 ER - TY - JOUR A1 - Karnati, Srikanth A1 - Seimetz, Michael A1 - Kleefeldt, Florian A1 - Sonawane, Avinash A1 - Madhusudhan, Thati A1 - Bachhuka, Akash A1 - Kosanovic, Djuro A1 - Weissmann, Norbert A1 - Krüger, Karsten A1 - Ergün, Süleyman T1 - Chronic Obstructive Pulmonary Disease and the Cardiovascular System: Vascular Repair and Regeneration as a Therapeutic Target JF - Frontiers in Cardiovascular Medicine N2 - Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide and encompasses chronic bronchitis and emphysema. It has been shown that vascular wall remodeling and pulmonary hypertension (PH) can occur not only in patients with COPD but also in smokers with normal lung function, suggesting a causal role for vascular alterations in the development of emphysema. Mechanistically, abnormalities in the vasculature, such as inflammation, endothelial dysfunction, imbalances in cellular apoptosis/proliferation, and increased oxidative/nitrosative stress promote development of PH, cor pulmonale, and most probably pulmonary emphysema. Hypoxemia in the pulmonary chamber modulates the activation of key transcription factors and signaling cascades, which propagates inflammation and infiltration of neutrophils, resulting in vascular remodeling. Endothelial progenitor cells have angiogenesis capabilities, resulting in transdifferentiation of the smooth muscle cells via aberrant activation of several cytokines, growth factors, and chemokines. The vascular endothelium influences the balance between vaso-constriction and -dilation in the heart. Targeting key players affecting the vasculature might help in the development of new treatment strategies for both PH and COPD. The present review aims to summarize current knowledge about vascular alterations and production of reactive oxygen species in COPD. The present review emphasizes on the importance of the vasculature for the usually parenchyma-focused view of the pathobiology of COPD. KW - COPD KW - emphysema KW - pulmonary hypertension KW - hypoxia KW - oxidative stress Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235631 SN - 2297-055X VL - 8 ER - TY - JOUR A1 - Gredic, Marija A1 - Karnati, Srikanth A1 - Ruppert, Clemens A1 - Guenther, Andreas A1 - Avdeev, Sergey N. A1 - Kosanovic, Djuro T1 - Combined pulmonary fibrosis and emphysema: when Scylla and Charybdis ally JF - Cells N2 - Combined pulmonary fibrosis and emphysema (CPFE) is a recently recognized syndrome that, as its name indicates, involves the existence of both interstitial lung fibrosis and emphysema in one individual, and is often accompanied by pulmonary hypertension. This debilitating, progressive condition is most often encountered in males with an extensive smoking history, and is presented by dyspnea, preserved lung volumes, and contrastingly impaired gas exchange capacity. The diagnosis of the disease is based on computed tomography imaging, demonstrating the coexistence of emphysema and interstitial fibrosis in the lungs, which might be of various types and extents, in different areas of the lung and several relative positions to each other. CPFE bears high mortality and to date, specific and efficient treatment options do not exist. In this review, we will summarize current knowledge about the clinical attributes and manifestations of CPFE. Moreover, we will focus on pathophysiological and pathohistological lung phenomena and suspected etiological factors of this disease. Finally, since there is a paucity of preclinical research performed for this particular lung pathology, we will review existing animal studies and provide suggestions for the development of additional in vivo models of CPFE syndrome. KW - CPFE KW - lung fibrosis KW - emphysema KW - animal models Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313571 SN - 2073-4409 VL - 12 IS - 9 ER - TY - JOUR A1 - Meyer, Malin Tordis A1 - Watermann, Christoph A1 - Dreyer, Thomas A1 - Wagner, Steffen A1 - Wittekindt, Claus A1 - Klussmann, Jens Peter A1 - Ergün, Süleyman A1 - Baumgart-Vogt, Eveline A1 - Karnati, Srikanth T1 - Differential expression of peroxisomal proteins in distinct types of parotid gland tumors JF - International Journal of Molecular Sciences N2 - Salivary gland cancers are rare but aggressive tumors that have poor prognosis and lack effective cure. Of those, parotid tumors constitute the majority. Functioning as metabolic machinery contributing to cellular redox balance, peroxisomes have emerged as crucial players in tumorigenesis. Studies on murine and human cells have examined the role of peroxisomes in carcinogenesis with conflicting results. These studies either examined the consequences of altered peroxisomal proliferators or compared their expression in healthy and neoplastic tissues. None, however, examined such differences exclusively in human parotid tissue or extended comparison to peroxisomal proteins and their associated gene expressions. Therefore, we examined differences in peroxisomal dynamics in parotid tumors of different morphologies. Using immunofluorescence and quantitative PCR, we compared the expression levels of key peroxisomal enzymes and proliferators in healthy and neoplastic parotid tissue samples. Three parotid tumor subtypes were examined: pleomorphic adenoma, mucoepidermoid carcinoma and acinic cell carcinoma. We observed higher expression of peroxisomal matrix proteins in neoplastic samples with exceptional down regulation of certain enzymes; however, the degree of expression varied between tumor subtypes. Our findings confirm previous experimental results on other organ tissues and suggest peroxisomes as possible therapeutic targets or markers in all or certain subtypes of parotid neoplasms. KW - peroxisomes KW - parotid gland KW - salivary KW - tumors KW - pleomorphic adenoma KW - mucoepidermoid carcinoma KW - acinic cell carcinoma KW - differential expression KW - immunohistochemistry KW - mRNA Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261047 SN - 1422-0067 VL - 22 IS - 15 ER - TY - JOUR A1 - Rajendran, Ranjithkumar A1 - Böttiger, Gregor A1 - Dentzien, Niklas A1 - Rajendran, Vinothkumar A1 - Sharifi, Bischand A1 - Ergün, Süleyman A1 - Stadelmann, Christine A1 - Karnati, Srikanth A1 - Berghoff, Martin T1 - Effects of FGFR tyrosine kinase inhibition in OLN-93 oligodendrocytes JF - Cells N2 - Fibroblast growth factor (FGF) signaling is involved in the pathogenesis of multiple sclerosis (MS). Data from neuropathology studies suggest that FGF signaling contributes to the failure of remyelination in MS. In MOG\(_{35–55}\)-induced EAE, oligodendrocyte-specific deletion of FGFR1 and FGFR2 resulted in a less severe disease course, reduced inflammation, myelin and axon degeneration and changed FGF/FGFR and BDNF/TrkB signaling. Since signaling cascades in oligodendrocytes could not be investigated in the EAE studies, we here aimed to characterize FGFR-dependent oligodendrocyte-specific signaling in vitro. FGFR inhibition was achieved by application of the multi-kinase-inhibitor dovitinib and the FGFR1/2/3-inhibitor AZD4547. Both substances are potent inhibitors of FGF signaling; they are effective in experimental tumor models and patients with malignancies. Effects of FGFR inhibition in oligodendrocytes were studied by immunofluorescence microscopy, protein and gene analyses. Application of the tyrosine kinase inhibitors reduced FGFR1, phosphorylated ERK and Akt expression, and it enhanced BDNF and TrkB expression. Furthermore, the myelin proteins CNPase and PLP were upregulated by FGFR inhibition. In summary, inhibition of FGFR signaling in oligodendrocytes can be achieved by application of tyrosine kinase inhibitors. Decreased phosphorylation of ERK and Akt is associated with an upregulation of BDNF/TrkB signaling, which may be responsible for the increased production of myelin proteins. Furthermore, these data suggest that application of FGFR inhibitors may have the potential to promote remyelination in the CNS. KW - multiple sclerosis KW - oligodendrocytes KW - dovitinib KW - AZD4547 KW - FGFR signaling KW - myelin Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239600 SN - 2073-4409 VL - 10 IS - 6 ER - TY - JOUR A1 - Kustiati, Ulayatul A1 - Ergün, Suleyman A1 - Karnati, Srikanth A1 - Nugrahaningsih, Dwi Aris Agung A1 - Kusindarta, Dwi Liliek A1 - Wihadmadyatami, Hevi T1 - Ethanolic extract of Ocimum sanctum Linn. Inhibits cell migration of human lung adenocarcinoma cells (A549) by downregulation of integrin αvβ3, α5β1, and VEGF JF - Scientia Pharmaceutica N2 - Adenocarcinoma lung cancer is a type of non-small cell lung carcinoma (NSCLC), which accounts for 85% of lung cancer incidence globally. The therapies that are being applied, both conventional therapies and antibody-based treatments, are still found to have side effects. Several previous studies have demonstrated the ability of the ethanolic extract of Ocimum sanctum Linn. (EEOS) as an ethnomedicine with anti-tumor properties. The aim of this study was to determine the effect of Ocimum sanctum Linn. ethanolic extract in inhibiting the proliferation, angiogenesis, and migration of A549 cells (NSCLC). The adhesion as well as the migration assay was performed. Furthermore, enzyme-linked immunosorbent assay (ELISA) was used to measure the expression of αvβ3 integrins, α5β1 integrins, and VEGF. The cells were divided into the following treatment groups: control (non-treated/NT), positive control (AP3/inhibitor β3 80 µg/mL), cisplatin (9 µg/mL), and EEOS at concentrations of 50, 70, 100, and 200 µg/mL. The results showed that EEOS inhibits the adhesion ability and migration of A549 cells, with an optimal concentration of 200 µg/mL. ELISA testing showed that the group of A549 cells given EEOS 200 µg/mL presented a decrease in the optimal expression of integrin α5β1, integrin αvβ3, and VEGF. KW - EEOS KW - A549 cell line KW - integrin α5β1 KW - integrin αvβ3 KW - VEGF Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290540 SN - 2218-0532 VL - 90 IS - 4 ER - TY - JOUR A1 - Rajendran, Ranjithkumar A1 - Böttiger, Gregor A1 - Stadelmann, Christine A1 - Karnati, Srikanth A1 - Berghoff, Martin T1 - FGF/FGFR pathways in multiple sclerosis and in its disease models JF - Cells N2 - Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS) affecting more than two million people worldwide. In MS, oligodendrocytes and myelin sheaths are destroyed by autoimmune-mediated inflammation, while remyelination is impaired. Recent investigations of post-mortem tissue suggest that Fibroblast growth factor (FGF) signaling may regulate inflammation and myelination in MS. FGF2 expression seems to correlate positively with macrophages/microglia and negatively with myelination; FGF1 was suggested to promote remyelination. In myelin oligodendrocyte glycoprotein (MOG)\(_{35–55}\)-induced experimental autoimmune encephalomyelitis (EAE), systemic deletion of FGF2 suggested that FGF2 may promote remyelination. Specific deletion of FGF receptors (FGFRs) in oligodendrocytes in this EAE model resulted in a decrease of lymphocyte and macrophage/microglia infiltration as well as myelin and axon degeneration. These effects were mediated by ERK/Akt phosphorylation, a brain-derived neurotrophic factor, and downregulation of inhibitors of remyelination. In the first part of this review, the most important pharmacotherapeutic principles for MS will be illustrated, and then we will review recent advances made on FGF signaling in MS. Thus, we will suggest application of FGFR inhibitors, which are currently used in Phase II and III cancer trials, as a therapeutic option to reduce inflammation and induce remyelination in EAE and eventually MS. KW - FGF KW - FGFR KW - multiple sclerosis KW - EAE KW - ERK KW - Akt KW - BDNF KW - LINGO-1 KW - SEMA3A Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236594 SN - 2073-4409 VL - 10 IS - 4 ER - TY - JOUR A1 - Rajendran, Ranjithkumar A1 - Rajendran, Vinothkumar A1 - Gupta, Liza A1 - Shirvanchi, Kian A1 - Schunin, Darja A1 - Karnati, Srikanth A1 - Giraldo-Velásquez, Mario A1 - Berghoff, Martin T1 - Interferon beta-1a versus combined interferon beta-1a and oligodendrocyte-specific FGFR1 deletion in experimental autoimmune encephalomyelitis JF - International Journal of Molecular Sciences N2 - Recombinant beta interferons-1 (IFNβ-1) are used as first line therapies in patients with relapsing multiple sclerosis (MS), a chronic inflammatory and neurodegenerative disease of the CNS. IFNβ-1a/b has moderate effects on the prevention of relapses and slowing of disease progression. Fibroblast growth factors (FGFs) and FGF receptors (FGFRs) are known to play a key role in the pathology of MS and its model EAE. To investigate the effects of short-term treatment with s.c. IFNβ-1a versus the combined application of s.c. IFNβ-1a and oligodendrocyte-specific deletion of FGFR1 (Fgfr1\(^{ind−/−}\) mice) in MOG\(_{35-55}\)-induced EAE. IFNβ-1a (30 mg/kg) was applied s.c. from days 0–7 p.i. of EAE in controls and Fgfr1\(^{ind−/−}\) mice. FGFR signaling proteins associated with inflammation/degeneration in MS/EAE were analyzed by western blot in the spinal cord. Further, FGFR1 in Oli-neu oligodendrocytes were inhibited by PD166866 and treated with IFNβ-1a (400 ng/mL). Application of IFNβ-1a over 8 days resulted in less symptoms only at the peak of disease (days 9–11) compared to controls. Application of IFNβ-1a in Fgfr1\(^{ind−/−}\) mice resulted in less symptoms primarily in the chronic phase of EAE. Fgfr1\(^{ind−/−}\) mice treated with IFNβ-1a showed increased expression of pERK and BDNF. In Oli-neu oligodendrocytes, treatment with PD166866 and IFNβ-1a also showed an increased expression of pERK and BDNF/TrkB. These data suggest that the beneficial effects in the chronic phase of EAE and on signaling molecules associated with ERK and BDNF expression are caused by the modulation of FGFR1 and not by interferon beta-1a. FGFR may be a potential target for therapy in MS. KW - FGFR1 KW - interferon beta-1a KW - oligodendrocytes KW - EAE KW - multiple sclerosis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290401 SN - 1422-0067 VL - 23 IS - 20 ER - TY - JOUR A1 - Reschke, Moritz A1 - Salvador, Ellaine A1 - Schlegel, Nicolas A1 - Burek, Malgorzata A1 - Karnati, Srikanth A1 - Wunder, Christian A1 - Förster, Carola Y. T1 - Isosteviol sodium (STVNA) reduces pro-inflammatory cytokine IL-6 and GM-CSF in an in vitro murine stroke model of the blood–brain barrier (BBB) JF - Pharmaceutics N2 - Early treatment with glucocorticoids could help reduce both cytotoxic and vasogenic edema, leading to improved clinical outcome after stroke. In our previous study, isosteviol sodium (STVNA) demonstrated neuroprotective effects in an in vitro stroke model, which utilizes oxygen-glucose deprivation (OGD). Herein, we tested the hypothesis that STVNA can activate glucocorticoid receptor (GR) transcriptional activity in brain microvascular endothelial cells (BMECs) as previously published for T cells. STVNA exhibited no effects on transcriptional activation of the glucocorticoid receptor, contrary to previous reports in Jurkat cells. However, similar to dexamethasone, STVNA inhibited inflammatory marker IL-6 as well as granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion. Based on these results, STVNA proves to be beneficial as a possible prevention and treatment modality for brain ischemia-reperfusion injury-induced blood–brain barrier (BBB) dysfunction. KW - IL-6 KW - ischemia KW - isosteviol sodium (STVNA) KW - dexamethasone KW - glucocorticoid receptor KW - cerebEND Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286275 SN - 1999-4923 VL - 14 IS - 9 ER - TY - JOUR A1 - Behera, Ananyaashree A1 - Jain, Preeti A1 - Ganguli, Geetanjali A1 - Biswas, Mainak A1 - Padhi, Avinash A1 - Pattanaik, Kali Prasad A1 - Nayak, Barsa A1 - Ergün, Süleyman A1 - Hagens, Kristine A1 - Redinger, Natalja A1 - Saqib, Mohd A1 - Mishra, Bibhuti B. A1 - Schaible, Ulrich E. A1 - Karnati, Srikanth A1 - Sonawane, Avinash T1 - Mycobacterium tuberculosis acetyltransferase suppresses oxidative stress by inducing peroxisome formation in macrophages JF - International Journal of Molecular Sciences N2 - Mycobacterium tuberculosis (Mtb) inhibits host oxidative stress responses facilitating its survival in macrophages; however, the underlying molecular mechanisms are poorly understood. Here, we identified a Mtb acetyltransferase (Rv3034c) as a novel counter actor of macrophage oxidative stress responses by inducing peroxisome formation. An inducible Rv3034c deletion mutant of Mtb failed to induce peroxisome biogenesis, expression of the peroxisomal β-oxidation pathway intermediates (ACOX1, ACAA1, MFP2) in macrophages, resulting in reduced intracellular survival compared to the parental strain. This reduced virulence phenotype was rescued by repletion of Rv3034c. Peroxisome induction depended on the interaction between Rv3034c and the macrophage mannose receptor (MR). Interaction between Rv3034c and MR induced expression of the peroxisomal biogenesis proteins PEX5p, PEX13p, PEX14p, PEX11β, PEX19p, the peroxisomal membrane lipid transporter ABCD3, and catalase. Expression of PEX14p and ABCD3 was also enhanced in lungs from Mtb aerosol-infected mice. This is the first report that peroxisome-mediated control of ROS balance is essential for innate immune responses to Mtb but can be counteracted by the mycobacterial acetyltransferase Rv3034c. Thus, peroxisomes represent interesting targets for host-directed therapeutics to tuberculosis. KW - peroxisome KW - Rv3034c KW - acetyltransferase KW - macrophages KW - oxidative stress KW - Mycobacterium tuberculosis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284080 SN - 1422-0067 VL - 23 IS - 5 ER - TY - JOUR A1 - Rajendran, Ranjithkumar A1 - Rajendran, Vinothkumar A1 - Giraldo-Velasquez, Mario A1 - Megalofonou, Fevronia-Foivi A1 - Gurski, Fynn A1 - Stadelmann, Christine A1 - Karnati, Srikanth A1 - Berghoff, Martin T1 - Oligodendrocyte-specific deletion of FGFR1 reduces cerebellar inflammation and neurodegeneration in MOG\(_{35-55}\)-induced EAE JF - International Journal of Molecular Sciences N2 - Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS). MS commonly affects the cerebellum causing acute and chronic symptoms. Cerebellar signs significantly contribute to clinical disability, and symptoms such as tremor, ataxia, and dysarthria are difficult to treat. Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies such as MS. In autopsy tissue from patients with MS, increased expression of FGF1, FGF2, FGF9, and FGFR1 was found in lesion areas. Recent research using mouse models has focused on regions such as the spinal cord, and data on the expression of FGF/FGFR in the cerebellum are not available. In recent EAE studies, we detected that oligodendrocyte-specific deletion of FGFRs results in a milder disease course, less cellular infiltrates, and reduced neurodegeneration in the spinal cord. The objective of this study was to characterize the role of FGFR1 in oligodendrocytes in the cerebellum. Conditional deletion of FGFR1 in oligodendrocytes (Fgfr1\(^{ind−/−}\) was achieved by tamoxifen application, EAE was induced using the MOG\(_{35-55}\) peptide. The cerebellum was analyzed by histology, immunohistochemistry, and western blot. At day 62 p.i., Fgfr1\(^{ind−/−}\) mice showed less myelin and axonal degeneration compared to FGFR1-competent mice. Infiltration of CD3(+) T cells, Mac3(+) cells, B220(+) B cells and IgG(+) plasma cells in cerebellar white matter lesions (WML) was less in Fgfr1\(^{ind−/−}\)mice. There were no effects on the number of OPC or mature oligodendrocytes in white matter lesion (WML). Expression of FGF2 and FGF9 associated with less myelin and axonal degeneration, and of the pro-inflammatory cytokines IL-1β, IL-6, and CD200 was downregulated in Fgfr1\(^{ind−/−}\) mice. The FGF/FGFR signaling protein pAkt, BDNF, and TrkB were increased in Fgfr1\(^{ind−/−}\) mice. These data suggest that cell-specific deletion of FGFR1 in oligodendrocytes has anti-inflammatory and neuroprotective effects in the cerebellum in the EAE disease model of MS. KW - FGFR1 KW - oligodendrocytes KW - demyelination KW - inflammation KW - cerebellum KW - EAE KW - MS Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284296 SN - 1422-0067 VL - 22 IS - 17 ER - TY - JOUR A1 - Kamali, Salar A1 - Rajendran, Ranjithkumar A1 - Stadelmann, Christine A1 - Karnati, Srikanth A1 - Rajendran, Vinothkumar A1 - Giraldo‐Velasquez, Mario A1 - Berghoff, Martin T1 - Oligodendrocyte‐specific deletion of FGFR2 ameliorates MOG\(_{35-55}\)‐induced EAE through ERK and Akt signalling JF - Brain Pathology N2 - Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies including multiple sclerosis (MS). In our recent study, oligodendrocyte‐specific deletion of FGFR1 resulted in a milder disease course, less inflammation, reduced myelin and axon damage in EAE. The objective of this study was to elucidate the role of oligodendroglial FGFR2 in MOG\(_{35-55}\)‐induced EAE. Oligodendrocyte‐specific knockout of FGFR2 (Fgfr2\(^{ind-/-}\)) was achieved by application of tamoxifen; EAE was induced using the MOG\(_{35-55}\) peptide. EAE symptoms were monitored over 62 days. Spinal cord tissue was analysed by histology, immunohistochemistry and western blot. Fgfr2\(^{ind-/-}\) mice revealed a milder disease course, less myelin damage and enhanced axonal density. The number of oligodendrocytes was not affected in demyelinated areas. However, protein expression of FGFR2, FGF2 and FGF9 was downregulated in Fgfr2\(^{ind-/-}\) mice. FGF/FGFR dependent signalling proteins were differentially regulated; pAkt was upregulated and pERK was downregulated in Fgfr2\(^{ind-/-}\) mice. The number of CD3(+) T cells, Mac3(+) cells and B220(+) B cells was less in demyelinated lesions of Fgfr2\(^{ind-/-}\) mice. Furthermore, expression of IL‐1β, TNF‐α and CD200 was less in Fgfr2\(^{ind-/-}\) mice than controls. Fgfr2ind−/− mice showed an upregulation of PLP and downregulation of the remyelination inhibitors SEMA3A and TGF‐β expression. These data suggest that cell‐specific deletion of FGFR2 in oligodendrocytes has anti‐inflammatory and neuroprotective effects accompanied by changes in FGF/FGFR dependent signalling, inflammatory cytokines and expression of remyelination inhibitors. Thus, FGFRs in oligodendrocytes may represent potential targets for the treatment of inflammatory and demyelinating diseases including MS. KW - experimental autoimmune encephalomyelitis KW - FGF/FGFR signalling KW - multiple sclerosis KW - oligodendrocytes Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224354 VL - 31 SP - 297 EP - 311 ER - TY - JOUR A1 - Watermann, Christoph A1 - Meyer, Malin Tordis A1 - Wagner, Steffen A1 - Wittekindt, Claus A1 - Klussmann, Jens Peter A1 - Erguen, Sueleyman A1 - Baumgart-Vogt, Eveline A1 - Karnati, Srikanth T1 - Peroxisomes are highly abundant and heterogeneous in human parotid glands JF - International Journal of Molecular Sciences N2 - The parotid gland is one of the major salivary glands producing a serous secretion, and it plays an essential role in the digestive and immune systems. Knowledge of peroxisomes in the human parotid gland is minimal; furthermore, the peroxisomal compartment and its enzyme composition in the different cell types of the human parotid gland have never been subjected to a detailed investigation. Therefore, we performed a comprehensive analysis of peroxisomes in the human parotid gland’s striated duct and acinar cells. We combined biochemical techniques with various light and electron microscopy techniques to determine the localization of parotid secretory proteins and different peroxisomal marker proteins in parotid gland tissue. Moreover, we analyzed the mRNA of numerous gene encoding proteins localized in peroxisomes using real-time quantitative PCR. The results confirm the presence of peroxisomes in all striated duct and acinar cells of the human parotid gland. Immunofluorescence analyses for various peroxisomal proteins showed a higher abundance and more intense staining in striated duct cells compared to acinar cells. Moreover, human parotid glands comprise high quantities of catalase and other antioxidative enzymes in discrete subcellular regions, suggesting their role in protection against oxidative stress. This study provides the first thorough description of parotid peroxisomes in different parotid cell types of healthy human tissue. KW - peroxisomes KW - parotid gland KW - human KW - catalase KW - differential expression KW - PSP KW - mRNA KW - immunofluorescence Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311079 SN - 1422-0067 VL - 24 IS - 5 ER - TY - JOUR A1 - Karnati, Srikanth A1 - Guntas, Gulcan A1 - Rajendran, Ranjithkumar A1 - Shityakov, Sergey A1 - Höring, Marcus A1 - Liebisch, Gerhard A1 - Kosanovic, Djuro A1 - Ergün, Süleyman A1 - Nagai, Michiaki A1 - Förster, Carola Y. T1 - Quantitative lipidomic analysis of Takotsubo syndrome patients' serum JF - Frontiers in Cardiovascular Medicine N2 - Takotsubo syndrome (TTS), also known as the transient left ventricular apical ballooning syndrome, is in contemporary times known as novel acute cardiac syndrome. It is characterized by transient left ventricular apical akinesis and hyperkinesis of the basal left ventricular portions. Although the precise etiology of TTS is unknown, events like the sudden release of stress hormones, such as the catecholamines and the increased inflammatory status might be plausible causes leading to the cardiovascular pathologies. Recent studies have highlighted that an imbalance in lipid accumulation might promote a deviant immune response as observed in TTS. However, there is no information on comprehensive profiling of serum lipids of TTS patients. Therefore, we investigated a detailed quantitative lipid analysis of TTS patients using ES-MSI. Our results showed significant differences in the majority of lipid species composition in the TTS patients compared to the control group. Furthermore, the computational analyses presented was able to link the altered lipids to the pro-inflammatory cytokines and disseminate possible mechanistic pathways involving TNFα and IL-6. Taken together, our study provides an extensive quantitative lipidome of TTS patients, which may provide a valuable Pre-diagnostic tool. This would facilitate the elucidation of the underlying mechanisms of the disease and to prevent the development of TTS in the future. KW - TTS KW - inflammation KW - lipids KW - TNF-α KW - IL6 KW - PIK3R1 KW - NF-kappa-B KW - phosphatidylinositol Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270832 SN - 2297-055X VL - 9 IS - 797154 ER - TY - JOUR A1 - Wang, Hongjie A1 - Karnati, Srikanth A1 - Madhusudhan, Thati T1 - Regulation of the homeostatic unfolded protein response in diabetic nephropathy JF - Pharmaceuticals N2 - A growing body of scientific evidence indicates that protein homeostasis, also designated as proteostasis, is causatively linked to chronic diabetic nephropathy (DN). Experimental studies have demonstrated that the insulin signaling in podocytes maintain the homeostatic unfolded protein response (UPR). Insulin signaling via the insulin receptor non-canonically activates the spliced X-box binding protein-1 (sXBP1), a highly conserved endoplasmic reticulum (ER) transcription factor, which regulates the expression of genes that control proteostasis. Defective insulin signaling in mouse models of diabetes or the genetic disruption of the insulin signaling pathway in podocytes propagates hyperglycemia induced maladaptive UPR and DN. Insulin resistance in podocytes specifically promotes activating transcription factor 6 (ATF6) dependent pathogenic UPR. Akin to insulin, recent studies have identified that the cytoprotective effect of anticoagulant serine protease-activated protein C (aPC) in DN is mediated by sXBP1. In mouse models of DN, treatment with chemical chaperones that improve protein folding provides an additional benefit on top of currently used ACE inhibitors. Understanding the molecular mechanisms that transmute renal cell specific adaptive responses and that deteriorate renal function in diabetes will enable researchers to develop new therapeutic regimens for DN. Within this review, we focus on the current understanding of homeostatic mechanisms by which UPR is regulated in DN. KW - unfolded protein response KW - ER stress KW - diabetic nephropathy KW - insulin signaling KW - aPC KW - podocytes KW - XBP1 KW - ATF6 Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267143 SN - 1424-8247 VL - 15 IS - 4 ER -