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  - 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  - 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  - 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  - 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  - 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  - 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  - 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  - 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  - 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  -