Hypercholesterolemia Duration and Brain Area Determine Inflammatory Response Intensity and Apoptotic Mediator Activation in Apo E−/−/LDLR−/− Double‑Knockout Mice

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

Salt‑sensitive hypertension in GR mutant rats is associated with altered plasma polyunsaturated fatty acid levels and aortic vascular reactivity

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

Abstract

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

Nutritional Interventions for Pressure Ulcer Prevention in Hip Fracture Patients: A Systematic Review and Meta-Analysis of Controlled Trials

Jose M. Moran 1,* , Laura Trigo-Navarro 2 , Esther Diestre-Morcillo 3 , Elena Pastor-Ramon 4 and Luis M. Puerto-Parejo 5

1 Nursing and Occupational Therapy College, University of Extremadura, 10001 Caceres, Spain

2 Área de Salud de Badajoz, Supervisora del Bloque Quirúrgico, Hospital Materno Infantil de Badajoz, Calle Violeta 3, 06010 Badajoz, Spain; 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。

3 Área de Salud de Badajoz, Banco de Sangre, Hospital Universitario de Badajoz, Av. de Elvas, s/n, 06080 Badajoz, Spain

4 Biblioteca Virtual de ciencias de la Salud de las Illes Balears (Bibliosalut), Ctra. De Valldemossa, 79,  mòdul L+1, 07120 Palma, Spain; 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。

5 Gerencia del Área de Salud de Badajoz, Supervisor del Área de Investigación, Proyectos y Gestión, Av. de Huelva, 8, 06005 Badajoz, Spain; 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。

* Correspondence: 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。

Academic Editor: Yi-Chia Huang

Received: 22 January 2025

Revised: 6 February 2025

Accepted: 8 February 2025

Published: 11 February 2025

Citation: Moran, J.M.; Trigo-Navarro, L.; Diestre-Morcillo, E.; Pastor-Ramon, E.; Puerto-Parejo, L.M. Nutritional Interventions for Pressure Ulcer Prevention in Hip Fracture Patients: A Systematic Review and Meta-Analysis of Controlled Trials. Nutrients 2025, 17, 644. https://doi.org/10.3390/ nu17040644

Copyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/ licenses/by/4.0/

Abstract: Background/Objective: Pressure ulcers represent a significant complication in patients with reduced mobility, such as those recovering from hip fractures. In the present study, we aimed to comprehensively assess the impact of oral nutritional interventions on the development of pressure ulcers in hip fracture patients via a systematic review and meta analysis of controlled studies evaluating the effectiveness of oral nutritional supplements compared with standard care. Methods: In accordance with PRISMA standards, this systematic review and meta-analysis of controlled studies evaluated the effectiveness of any type of oral nutritional supplements compared with standard care in hip fracture patients. The risk of bias was evaluated using the Cochrane ROB2 tool for randomized controlled trials and the ROBINS-1 tool for nonrandomized trials. Results: Fourteen studies (10 randomized controlled trials and 4 controlled trials) published since 1990 (n = 1648) were included. Oral nutritional supplementation was associated with a statistically significant decrease in the odds ratio of developing pressure ulcers in hip fracture patients (OR 0.54, 95% CI: 0.40–0.73, p < 0.001). Conclusions: The incidence and evolution of pressure ulcers can be improved by oral dietary supplementation in patients who have undergone hip fracture surgery. Accordingly, we propose that oral nutritional supplementation should be considered an essential component of comprehensive post-hip-fracture care.

Keywords: hip fracture; pressure ulcers; oral nutritional supplement; pressure sores; meta-analysis; wound healing; nutritional intervention

CB-MNCs@ CS/HEC/GP promote wound healing in aged murine pressure ulcer model

Zhi‑cheng Yang1,3, He Lin1 , Guo‑jun Liu2 , Hui Pan1 , Jun‑lu Zhu3 , Xiao‑hong Zhang3 , Feng Gao2 , Zhong Wang2 and Zhi‑hao Wang1* *Correspondence: Zhi‑hao Wang 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 Geriatric Medicine & Laboratory of Gerontology and Anti‑Aging Research, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China 2 Shandong Qilu Stem Cell Engineering Co., Ltd, Jinan 250012, Shandong, China 3 School of Nursing and Rehabilitation, Shandong University, Jinan 250012, Shandong, China

© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-​nc-​nd/4.0/.

Abstract

Background Non-healing pressure ulcers impose heavy burdens on patients and clinicians. Cord blood mononu‑ clear cells (CB-MNCs) are a novel type of tissue repair seed cells. However, their clinical application is restricted by low retention and survival rates post-transplantation. This study aims to investigate the role of thermo-sensitive chitosan/ hydroxyethyl cellulose/glycerophosphate (CS/HEC/GP) hydrogel encapsulated CB-MNCs in pressure ulcer wound

Methods Pressure ulcers were induced on the backs of aged mice. After construction and validation of the charac‑ terization of thermo-sensitive CS/HEC/GP hydrogel, CB-MNCs are encapsulated in the hydrogel, called CB-MNCs@ CS/HEC/GP which was locally applied to the mouse wounds. Mouse skin tissues were harvested for histological and molecular biology analyses.

Results CB-MNCs@CS/HEC/GP therapy accelerated pressure ulcer wound healing, attenuated inflammatory responses, promoted cell proliferation, angiogenesis, and collagen synthesis. Further investigation revealed that CB MNCs@CS/HEC/GP exerted therapeutic effects by promoting changes in cell types, including fibroblasts, endothelial cells, keratinocytes, and smooth muscle cells.

Conclusion CB-MNCs@CS/HEC/GP enhanced the delivery efficiency of CB-MNCs, preserved the cell viability, and contributed to pressure ulcer wound healing. Thus, CB-MNCs@CS/HEC/GP represents a novel therapeutic approach for skin regeneration of chronic wounds.

Keywords Wound healing, Aged, Pressure ulcers, Cord blood mononuclear cells, Thermo-sensitive hydrogel

The association between obesity indicators and mortality among individuals with hyperlipidemia: evidence from the NHANES 2003–2018

Yiheng Zhang1 and Yajun Yao2,3* *Correspondence: Yajun Yao 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。 Full list of author information is available at the end of the article

The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creati vecommons.org/licenses/by-nc-nd/4.0/

Abstract

Background Obesity is linked to a variety of metabolic issues, with hyperlipidemia being a crucial adjustable risk element for cardiovascular diseases (CVD). However, the connection between indicators of obesity with overall and CVD mortality in American adults with hyperlipidemia remains unknown.

Methods This research employed an extensive cohort drawn from the National Health and Nutrition Examination Survey (NHANES) (2003–2018). Hyperlipidemia was identified through either elevated lipid profiles or self-reported utilization of lipid-reducing medications. Obesity indicators (weight-adjusted waist index (WWI), waist-to-height ratio (WHtR), body mass index (BMI)) were evaluated by physical measurement data. Weighted Cox regression models and restricted cubic splines (RCS) were employed to assess the potential links between obesity indicators and mortality outcomes. Results were further validated through subgroup analyses to ensure robustness and reliability. The receiver operating characteristic (ROC) curve was utilized to evaluate the prognostic capability of obesity indicators for

Results This cohort study included data from 12,785 participants with hyperlipidemia. Over an average follow-up period of 8.4 years, a total of 1,454 deaths were documented, 380 of which were related to heart diseases. Cox analysis manifested that, after adjusting covariates, increased WWI was linked to a higher likelihood of overall and CVD mortality (both P<0.05). RCS analysis illustrated that BMI and WHtR had U-shaped relationships with the overall and CVD mortality. Conversely, a linear positive association was uncovered between WWI and mortality (both P>0.05 for nonlinearity). Age, alcohol consumption and chronic kidney disease had modifying effects on the relationship between WWI and total mortality among those with hyperlipidemia. The area under ROC indicated that WWI was more effective than for BMI and WHtR in predicting overall and CVD deaths.

Conclusions In US adults with hyperlipidemia, the connection between BMI, WHtR, with overall and CVD mortality followed a U-shaped pattern, whereas a positive linear correlation was identified between WWI and mortality. WWI has superior predictive capability for the prognosis of individuals with hyperlipidemia compared to BMI and WHtR. These findings provide new insights and targets for the health management of individuals affected by hyperlipidemia.

Keywords Obesity, Hyperlipidemia, Weight-adjusted waist index, Mortality, NHANES

Impact of fospropofol disodium on lipid metabolism and inflammatory response in patients with hyperlipidemia: a randomized trial

Chuan Yang1*†, Tian-Bo Chai1†, Xing-Zhu Yao1 , Li Zhang1 , Wen-Ming Qin2 , Hong Liang3 , Qiong-Zhen He4 and Ze-Yu Zhao5*Chuan Yang and Tian-Bo Chai contributed equally to this work.

*Correspondence:Chuan Yang 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。 Ze-Yu Zhao 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。 Full list of author information is available at the end of the article

© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creati  vecommons.org/licenses/by-nc-nd/4.0/.

Abstract

Objective This study aims to assess the impact of intravenous infusion of fospropofol disodium on lipid metabolism and the inflammatory response in individuals with hyperlipidemia.

Methods A total of 360 preoperative individuals with hyperlipidemia were selected and randomly assigned to either the treatment group or the control group, with 180 participants in each group. The treatment group received an induction dose of fospropofol disodium at 10 mg/kg intravenously, followed by maintenance at a rate of 10 mg/ (kg·h). The control group was administered propofol intravenously at 2 mg/kg for induction and maintained at 4 mg/(kg·h). All other medications were consistent between the two groups. Blood samples (3 ml of venous blood) were collected from patients at four-time points: 1 day before surgery (T0), 3 h after anesthesia induction (T1), 4 h post-surgery (T2), and 24 h post-surgery (T3), to measure levels of triglycerides (TG), cholesterol (CHOL), high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB). C-reactive protein (CRP) and interleukin-6 (IL-6) levels were assessed at T0 and T3. Sedation onset time and adverse reactions were recorded for both groups.

Results At T0, the control group exhibited increased TG, CHOL, LDL-C, ApoB, and the ApoB/ApoA1 ratio, while the ApoA1 level had decreased. The LDL-C level and the ApoB/ApoA1 ratio showed significant increases (P<0.01). Both groups showed elevated CRP and IL-6 levels at T3 (P<0.01). Compared to the control group, the treatment group demonstrated reduced levels of TG, CHOL, LDL-C, ApoB, and the ApoB/ApoA1 ratio at T1-T3, while ApoA1 levels were higher at T1-T2 (P<0.01 or P<0.05). The sedation onset time was notably longer in the treatment group, and the incidence of injection-related pain, respiratory depression, hypotension, and other adverse reactions was significantly lower (P<0.01).

Conclusion Compared with propofol, intravenous infusion of fospropofol disodium for more than 3 h during anesthesia has lesser impact on lipid metabolism in patients with hyperlipidemia and does not increase inflammatory factors levels.

Keywords Fospropofol disodium, Hyperlipidemia, Inflammation, Lipid metabolism disorders, Propofol