Ewelina Czuba‑Pakuła1 · Jolanta Ochocińska2 · Sebastian Głowiński3 · Alicja Braczko4 · Ryszard T. Smoleński4 · Grażyna Lietzau1 · Przemysław Kowiański1,3
Received: 14 August 2024 / Accepted: 7 May 2025 © The Author(s) 2025
* Ewelina Czuba-Pakuła 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。
* Przemysław Kowiański 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。
Jolanta Ochocińska 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。
Sebastian Głowiński 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。
Alicja Braczko 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。
Ryszard T. Smoleński 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。
Grażyna Lietzau 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。
1 Division of Anatomy and Neurobiology, Faculty of Medicine, Medical University of Gdansk, Dębinki 1, 80-211 Gdańsk, Poland
2 Department of Conservative Dentistry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
3 Institute of Health Sciences, Pomeranian University in Słupsk, Słupsk, Poland
4 Department of Biochemistry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
Abstract
Hypercholesterolemia (Hch) is a risk factor for cerebrovascular and neurodegenerative diseases, manifesting with symptoms that vary depending on damage to specific brain regions. Hch triggers inflammatory responses and cell death. However, the progression of these processes in relation to the duration of Hch and the location of pathology in the central nervous system remains unclear. Therefore, we aimed to investigate (1) the impact of age and duration of Hch on neuroinflammatory responses and programmed cell death in the brain and (2) the intensity of these processes in various brain areas during Hch. In this study, we used 3-, 6-, and 12-month-old male Apo E−/−/LDLR−/− double-knockout mice and age-matched wild-type C57BL/6 mice (control group). Concentrations of cytokines IL-1β, IL-4, and IL-6, as well as apoptotic mediators AIF and Cas-3, were measured using enzyme-linked immunosorbent assay in the whole brain and separately in the prefrontal cortex (PFCx), hippocampus (HIP), and striatum (STR). The results showed that the Hch-induced release of cytokines IL-1β and IL-6, decreased expression of IL-4, and elevated level of apoptotic markers AIF and Cas-3 correlated with Hch duration. The inflammatory response and expression of apoptotic markers were more pronounced in the HIP and STR compared to the PFCx. Our results indicate a correlation between the neurodegenerative effects of Hch and its duration and highlight the varying susceptibility of different brain areas to Hch-induced damage.
Graphical Abstract
Hypercholesterolemia (Hch)-induced inflammatory response and programmed cell death activation in the prefrontal cortex (PFCx), hippocampus (HIP), and striatum (STR) of 3-, 6-, and 12-month-old, Apo E−/−/LDLR−/− double-knockout mice. In three age-groups the Hch-induced response involved release of inflammatory cytokines (IL-1ß and IL-6), a decrease of anti-inflammatory (IL-4) cytokine level, and activation of programmed cell death markers (AIF and Cas-3). The inflam matory response and expression of apoptotic markers were more pronounced in the HIP and STR, compared to the PFCx.
Keywords Apoptosis · Atherosclerosis · Cytokines · Hypercholesterolemia · Neurodegeneration · Neuroinflammation
S.Verouti1,2,3 · G. Aeschlimann1 · Q. Wang4 · D. Ancin Del Olmo1 · A. C. Peyter5 · S. Menétrey5 ·D.V. Winter6 · A. Odermatt6 · D. Pearce7 · E. Hummler1,2 · P. E. Vanderriele1,2
Received: 30 April 2024 / Revised: 22 August 2024 / Accepted: 23 August 2024 / Published online: 10 September 2024 © The Author(s) 2024
* P. E. Vanderriele 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。
1 Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
2 National Center of Competence in Research, Kidney.CH, Lausanne, Switzerland
3 Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
4 Division of Nephrology and Hypertension, Lausanne University Hospital (CHUV), Lausanne, Switzerland
5 Neonatal Research Laboratory, Clinic of Neonatology, Department Woman-Mother-Child, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
6 Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
7 Department of Medicine and Cellular & Molecular Pharmacology, University of California, San Francisco, USA
In humans, glucocorticoid resistance is attributed to mutations in the glucocorticoid receptor (GR). Most of these mutations result in decreased ligand binding, transactivation, and/or translocation, albeit with normal protein abundances. However, there is no clear genotype‒phenotype relationship between the severity or age at disease presentation and the degree of functional loss of the receptor. Previously, we documented that a GR+/− rat line developed clinical features of glucocorticoid resistance, namely, hypercortisolemia, adrenal hyperplasia, and salt-sensitive hypertension. In this study, we analyzed the GR+/em4 rat model heterozygously mutant for the deletion of exon 3, which encompasses the second zinc finger, including the domains of DNA binding, dimerization, and nuclear localization signals. On a standard diet, mutant rats exhibited a trend toward increased corticosterone levels and a normal systolic blood pressure and heart rate but presented with adrenal hyperplasia. They exhibited increased adrenal soluble epoxide hydroxylase (sEH), favoring an increase in less active poly unsaturated fatty acids. Indeed, a significant increase in nonactive omega-3 and omega-6 polyunsaturated fatty acids, such as 5(6)-DiHETrE or 9(10)-DiHOME, was observed with advanced age (10 versus 5 weeks old) and following a switch to a high-salt diet accompanied by salt-sensitive hypertension. In thoracic aortas, a reduced soluble epoxide hydrolase (sEH) protein abundance resulted in altered vascular reactivity upon a standard diet, which was blunted upon a high-salt diet. In conclusion, mutations in the GR affecting the ligand-binding domain as well as the dimerization domain resulted in deregu lated GR signaling, favoring salt-sensitive hypertension in the absence of obvious mineralocorticoid excess.
Keywords Adrenal gland hyperplasia · Hypertension · Glucocorticoid receptor · Soluble epoxide hydrolase · Chrousos syndrome
Abbreviations
ACTH Adrenocorticotropic hormone DiHETrE Dihydroxyeicosatrienoic acid DiHOME Dihydroxy-9Z-octadecenoic acid EET Epoxyeicosatrienoic acid EpETrE Epoxyeicosatrienoic acid GR Glucocorticoid receptor HETE Hydroxyeicosatetraenoic acid KODE Ketooctadecenoic acid sEH Soluble epoxide hydrolase
◂Fig.1 GR+/em4 rats presented adrenal hyperplasia of the cortex and the medulla accompanied by a trend toward an increase in the plasma glucocorticoid concentration under standard diet. A Scheme of the wild-type (GR+, upper panel) and the mutated GRem2 (middle) and GRem4 (lower panel) structure of the GR. B Representation of the zinc finger domain of the GR with the deleted amino acids in red. C Rep resentative macroscopic images (scale bar, 1 mm) and D hematoxy lin/eosin-stained sections of whole adrenal glands (left panels; scale bar, 1 mm) and cortex (right panels; scale bar, 300 µm) from 3- to 4-week-old male GR+/+ and GR+/em4 rats (n=3) fed a standard salt diet; zf, zona fasciculata; zg, zona glomerulosa. E Measurement of the adrenal weight/body weight ratio (GR+/+, n=12; GR+/em4, n=14) and F cortex (left) and medulla (right panel) size (GR+/+ (n=3) and GR+/em4 (n=4)). G Determination of plasma concentrations of the glucocorticoids corticosterone, 11-dehydrocorticosterone and the corticosterone/11-dehydrocorticosterone ratio and H the mineralo corticoid aldosterone and its precursor 11-deoxycorticosterone in the morning (7–8 am) and afternoon (6–7 pm) of GR+/+ and GR.+/em4 (n=4 – 16) rats. The size measurements were evaluated using QuPath (vO.4.4), and the plasma concentrations were evaluated by two-way ANOVA and subsequently compared with an unpaired two tailed t test with Welch’s correction. The values are presented as the mean±SEMs. Differences were assessed at *P<0.05 and **P<0.01
Authors
Tuba Yilmazer
Hilal Tuzer
Cahide Ayik
Dilek Özden
Vita Boyar
Keywords
Juliano Teixeira Moraes
Clara Fonseca Oliveira
伤口世界平台生态圈，以“关爱人间所有伤口患者”为愿景，连接、整合和拓展线上和线下的管理慢性伤口的资源，倡导远程、就近和居家管理慢性伤口，解决伤口专家的碎片化时间的价值创造、诊疗经验的裂变复制、和患者的就近、居家和低成本管理慢性伤口的问题。
2019广东省医疗行业协会伤口管理分会年会
扫一扫了解详情:
任何关于疾病的建议都不能替代执业医师的面对面诊断。所有门诊时间仅供参考，最终以医院当日公布为准。
网友、医生言论仅代表其个人观点，不代表本站同意其说法，请谨慎参阅，本站不承担由此引起的法律责任。
