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  - 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  - 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  - 
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  - 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  - 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  - 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  -