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  • 1
    Online Resource
    Online Resource
    Frontiers Media SA ; 2021
    In:  Frontiers in Physiology Vol. 12 ( 2021-8-12)
    In: Frontiers in Physiology, Frontiers Media SA, Vol. 12 ( 2021-8-12)
    Abstract: Oral treatment of apolipoprotein E-knockout (ApoE-KO) mice with the putative sirtuin 1 (SIRT1) activator resveratrol led to a reduction of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in the heart. In contrast, the SIRT1 inhibitor EX527 enhanced the superoxide production in isolated human polymorphonuclear granulocytes. In human monocytic THP-1 cells, phorbol ester-stimulated superoxide production was enhanced by inhibitors of histone deacetylases (HDACs; including quisinostat, trichostatin A (TSA), PCI34051, and tubastatin A) and decreased by inhibitors of histone acetyltransferases [such as garcinol, curcumin, and histone acetyltransferase (HAT) Inhibitor II]. These results indicate that protein acetylation and deacetylation may represent crucial mechanisms regulating NADPH oxidase-mediated superoxide production. In cell-free systems, incubation of recombinant Rac1 with SIRT1 resulted in decreased Rac1 acetylation. Mass spectrometry analyses identified lysine 166 (K166) in Rac1 as a residue targeted by SIRT1. Deacetylation of Rac1 by SIRT1 markedly reduced the interaction of Rac1 with p67phox in in vitro assays. Computational modeling analyses revealed that K166 deacetylation of Rac1 led to a 5-fold reduction in its binding affinity to guanosine-5'-triphosphate, and a 21-fold decrease in its binding potential to p67phox. The latter is crucial for Rac1-mediated recruitment of p67phox to the membrane and for p67phox activation. In conclusion, both SIRT1 and non-sirtuin deacetylases play a role in regulating NADPH oxidase activity. Rac1 can be directly deacetylated by SIRT1 in a cell-free system, leading to an inhibition of Rac1-p67phox interaction. The downstream targets of non-sirtuin deacetylases are still unknown. The in vivo significance of these findings needs to be investigated in future studies.
    Type of Medium: Online Resource
    ISSN: 1664-042X
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2564217-0
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  • 2
    Online Resource
    Online Resource
    Frontiers Media SA ; 2021
    In:  Frontiers in Immunology Vol. 12 ( 2021-6-30)
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 12 ( 2021-6-30)
    Abstract: AA amyloidosis belongs to the group of amyloid diseases which can follow chronic inflammatory conditions of various origin. The disease is characterized by the deposition of insoluble amyloid fibrils formed by serum amyloid A1 (SAA1) leading eventually to organ failure. Macrophages are intimately involved in the fibrillogenesis as well as in the clearance of amyloid fibrils. In vivo , macrophages may occur as classically (M1) or alternatively activated (M2) macrophages. We investigate here how SAA1 might affect the macrophage phenotype and function. Gene microarray analysis revealed upregulation of 64 M1-associated genes by SAA1. M1-like polarization was further confirmed by the expression of the M1-marker MARCO, activation of the NF-κB transcription factor, and secretion of the M1-cytokines TNF-α, IL-6, and MCP-1. Additionally, we demonstrate here that M1-polarized macrophages exhibit enhanced fibrillogenic activity towards SAA1. Based on our data, we propose reconsideration of the currently used cellular amyloidosis models towards an in vitro model employing M1-polarized macrophages. Furthermore, the data suggest macrophage repolarization as potential intervention strategy in AA amyloidosis.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2606827-8
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  • 3
    Online Resource
    Online Resource
    Frontiers Media SA ; 2021
    In:  Frontiers in Chemistry Vol. 9 ( 2021-11-22)
    In: Frontiers in Chemistry, Frontiers Media SA, Vol. 9 ( 2021-11-22)
    Abstract: A series of aryl-substituted 3-amino-1-aryl-8-methoxy-1 H -benzo[ f ]chromene-2-carbonitriles (4a–4q) were designed and synthesized via reaction of 6-methoxy-2-naphthol with a mixture of appropriate aromatic aldehydes and malononitrile under microwave conditions. The structures of the novel compounds 4b, 4c, 4f, 4g, 4i, 4l, 4m, and 4o–4q were established according to IR, 1 H-NMR, 13 C-NMR/ 13 C-NMR-DEPT, and MS. The benzochromene derivative 4c with a single chlorine at the meta position of the phenyl ring and, to a lesser extent, other benzochromenes with monohalogenated phenyl ring (4a, 4c–4f) exhibited the highest cytotoxicity against six human cancer cell lines MDA-MB-231, A549, HeLa, MIA PaCa-2, 5,637, and Hep G2. The mechanisms of the cytotoxic activities of benzochromenes with monohalogenated phenyl ring (4a, 4c–4f) were further analyzed using triple-negative breast cancer cell line MDA-MB-231. Cell cycle analysis showed accumulation of the treated cells in S phase for 4a, 4d–4f, and S-G 2 /M phases for 4c. In vivo , 4a and 4c–4f inhibited growth, proliferation, and triggered apoptosis in preestablished breast cancer xenografts grown on the chick chorioallantoic membranes while exhibiting low systemic toxicity. Compounds 4a and 4c–4f increased levels of mitochondrial superoxide and decreased mitochondrial membrane potential resulting in initiation of apoptosis as demonstrated by caspase 3/7 activation. In addition, 4c induced general oxidative stress in cancer cells. The SAR study confirmed that halogens of moderate size at meta or para positions of the pendant phenyl ring enhance the cytotoxic activity of 3-amino-1-aryl-8-methoxy-1 H -benzo[ f ]chromene-2-carbonitriles, and these compounds could serve as leads for the development of novel anticancer therapies.
    Type of Medium: Online Resource
    ISSN: 2296-2646
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2711776-5
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  • 4
    Online Resource
    Online Resource
    Frontiers Media SA ; 2019
    In:  Frontiers in Immunology Vol. 10 ( 2019-7-18)
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 10 ( 2019-7-18)
    Type of Medium: Online Resource
    ISSN: 1664-3224
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2019
    detail.hit.zdb_id: 2606827-8
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  • 5
    Online Resource
    Online Resource
    Frontiers Media SA ; 2021
    In:  Frontiers in Pharmacology Vol. 12 ( 2021-9-17)
    In: Frontiers in Pharmacology, Frontiers Media SA, Vol. 12 ( 2021-9-17)
    Abstract: Oleanolic acid is a widely distributed natural product, which possesses promising antitumor, antiviral, antihyperlipidemic, and anti-inflammatory activities. A heterodimeric complex formed by integrin α M (CD11b) and integrin β 2 (CD18) is highly expressed on monocytes and macrophages. In the current study, we demonstrate that the I domain of α M (α M -I domain) might present a potential cellular target for oleanolic acid. In vitro data show that oleanolic acid induces clustering of α M on macrophages and reduces their non-directional migration. In accordance with experimental data, molecular docking revealed that oleanolic acid binds to the α M -I domain in its extended-open form, the dominant conformation found in α M clusters. Molecular dynamics simulation revealed that oleanolic acid can increase the flexibility of the α7 helix and promote its movement away from the N-terminus, indicating that oleanolic acid may facilitate the conversion of the α M -I domain from the extended-closed to the extended-open conformation. As demonstrated by metadynamics simulation, oleanolic acid can destabilize the local minimum of the α M -I domain in the open conformation partially through disturbance of the interactions between α1 and α7 helices. In summary, we demonstrate that oleanolic acid might function as an allosteric agonist inducing clustering of α M on macrophages by shifting the balance from the closed to the extended-open conformation. The molecular target identified in this study might hold potential for a purposeful use of oleanolic acid to modulate chronic inflammatory responses.
    Type of Medium: Online Resource
    ISSN: 1663-9812
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2587355-6
    SSG: 15,3
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  • 6
    Online Resource
    Online Resource
    Frontiers Media SA ; 2024
    In:  Frontiers in Medicine Vol. 11 ( 2024-5-9)
    In: Frontiers in Medicine, Frontiers Media SA, Vol. 11 ( 2024-5-9)
    Abstract: The use of Complementary and Integrative Medicine (CIM) is very popular among the general population in Germany. However, international studies show that nurses, physicians, and other health care professionals (HCPs) at hospitals often do not feel sufficiently informed about different CIM approaches. Moreover, they do not feel trained enough to counsel their patients appropriately. In the German-speaking context, particularly within university hospitals, research on this subject is scarce. Therefore, the aim of this explorative study was to evaluate attitudes, subjective knowledge, and needs regarding CIM among HCPs with direct patient interaction across all four university hospitals in the federal state of Baden-Württemberg, Germany (Tübingen, Ulm, Freiburg, Heidelberg). Methods The multicenter, cross-sectional, anonymous full survey was conducted online using a self-developed, semi-structured, web-based questionnaire. Recruitment took place via all-inclusive e-mail distribution lists of all four university hospitals. Results A total of n = 2,026 participants (response rate varied by location from about 5 to 14%) fully answered the questionnaire. Nurses constituted the largest professional group ( n = 1,196; 59%), followed by physicians ( n = 567; 28%), physiotherapists ( n = 54), psychologists ( n = 48), midwives ( n = 37), and other professions ( n = 124). More than two-thirds (71%, n = 1,437) of the participants were female and 14% ( n = 286) reported additional training in CIM. The overall attitude toward CIM (10-point Likert scale, 10 = “very favorable”) was clearly positive ( M ± SD : 7.43 ± 2.33), with notable differences between professional groups: midwives (9.05 ± 1.18), physiotherapists (8.44 ± 1.74), and nurses (8.08 ± 1.95) expressed the highest support, whereas physicians (5.80 ± 2.39) the lowest. 42% of the participants incorporated CIM in patient care (from 33% of physicians to 86% of midwives). Overall, relaxation therapy ( n = 1,951; 96%), external applications ( n = 1,911; 94%), massage ( n = 1,836; 91%), and meditation/mindfulness ( n = 1,812; 89%) were rated as useful or rather useful for patients. The average self-assessed knowledge level about CIM was moderate (M ± SD: 5.83 ± 2.03). Most of the participants found CIM training at university hospitals important and saw research about CIM as one of the tasks of university hospitals. The participants expressed the highest interest in education for acupuncture/acupressure, relaxation therapies, and manual medicine. Discussion This comprehensive survey of health care professionals (HCPs) at university hospitals in Germany reveals a clearly positive disposition toward CIM, aligning with findings from other hospital-based surveys and highlighting differences among professional groups. While most therapies deemed beneficial for patient care are supported by positive evidence, further research is required for others. Given the average self-reported knowledge of CIM, targeted education is essential to meet the needs of both HCPs and patients and to ensure the provision of evidence-based information on the risks and benefits of CIM.
    Type of Medium: Online Resource
    ISSN: 2296-858X
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2024
    detail.hit.zdb_id: 2775999-4
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