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Aging and male sex are major risk factors for abdominal aortic aneurysm (AAA), a disease characterized by vascular cell phenotypic switching and aortic wall remodeling. Mitochondrial oxidative stress has been implicated in these changes. We previously demonstrated that NOX4 (NADPH oxidase 4) expression and activity increase with age in cardiovascular cells, promoting mitochondrial oxidative stress and vascular dysfunction. This study investigates whether NOX4-driven mitochondrial oxidative stress and DNA damage promote AAA development through vascular cell reprogramming. We used mitochondria-targeted NOX4-dependent mitochondrial DNA damage and activation of DNA-sensing pathways promote SMC phenotypic switching, inflammation, and aortic wall remodeling in AAA. Targeting NOX4 and enhancing mitochondrial function may offer therapeutic strategies for AAA prevention. Show less

Chemokines C-X-C Motif Chemokine Ligand 9 (CXCL9) and C-C Motif Chemokine Ligand 2 (CCL2) were previously linked to incident cognitive impairment and dementia in the Northern Manhattan Study (NOMAS). We investigated whether circulating CXCL9 and CCL2 are independently associated with the cerebral white matter disease (WMD) burden and whether WMD mediates their association with prospective cognitive outcomes. In the stroke-free, prospective, community-dwelling NOMAS cohort (age≥50) we examined white matter hyperintensity volume (WMHV) on brain MRI and serum chemokine levels. WMHV was normalized, log-transformed, and standardized. Cognitive status was assessed at MRI and again 12.2±1.3 years later to adjudicate incident cognitive decline and dementia. Multivariable linear regression models with either CXCL9 or CCL2 (in quartiles) as exposures and WMHV as the outcome were adjusted for socio-demographics and key contributors to WMD, including vascular risk factors (Model 1), kidney function (2), and APOE ε4 status (3). Mediation of the CXCL9-cognitive outcome association by WMHV was tested using Monte Carlo integration. Among 1,179 participants (mean age 70±9 years; 60% female), elevated CXCL9 (Q4 vs. Q1) was associated with greater WMHV (Model 1: β=0.20, 95%CI 0.06-0.34). This association persisted even after adjusting for kidney function (Model 2: β=0.17, 95%CI 0.03-0.34) and APOE ε4 status (Model 3: β=0.19, 95%CI 0.04-0.33). CXCL9 (Q4 vs. Q1) effect magnitude in Model 3 approximated ~4 years of aging (β=0.05/year, 95%CI 0.04-0.06), exceeding that of hypertension (β=0.16, 95%CI 0.05-0.27), with a stepwise trend present across quartiles (β/quartile increase=0.07, 95%CI 0.02-0.12, p=0.003). Among 1,166 participants (dementia-free at MRI), the indirect, WMHV-mediated pathway was statistically significant for the association of CXCL9 with incident cognitive decline (ACME 0.009, 95%CI 0.002-0.018, p=0.016) and with dementia (ACME 0.008, 95%CI 0.003-0.016, p=0.004). CCL2 showed no association with WMHV. Greater CXCL9 levels were associated with greater white matter lesion load, independent of vascular, renal, and genetic factors, suggesting a role in WMD pathogenesis. WMHV mediated CXCL9's association with cognitive decline and dementia risk. This IFN-γ-induced monokine (MIG) warrants further evaluation as a biomarker of white matter and cognitive health as well as a potentially modifiable therapeutic target. Show less

Imaging studies showed early atrophy of the cholinergic basal forebrain (BF) already at prodromal stages of sporadic Alzheimer's disease (AD). Women and carriers of the ApoE epsilon 4 (ApoE ε4) allele are more likely to develop the disease; however, the underlying mechanisms are still unclear. Here we aimed at exploring the impact of sex and ApoE ε4 genotype in the AD spectrum on longitudinal measures of the basal forebrain and hippocampus, as a comparison region. We leveraged the German multi-centered study DELCODE and analyzed 712 individuals (median age: 71.25 years, interquartile range [IQR] = 9.22) with follow-up MRI scans (median time: 2.8 years, [IQR] = 1.75). Diagnostic groups comprised cognitively normal ( The hippocampus, but not the basal forebrain, showed significant atrophy over time (Hipp: Our findings did not show the anticipated longitudinal effects of sex and ApoE ε4 on longitudinal basal forebrain volume. Only hippocampal atrophy progressed significantly faster in ApoE ε4 homozygote carriers. This dissociation may reflect stage-dependent neurodegenerative processes, with early basal forebrain vulnerability followed by more rapid hippocampal decline, as well as methodological and sample-related constraints. If replicated, these findings suggest that hippocampal measures may be more sensitive longitudinal biomarkers in ApoE ε4 homozygotes, while sex- and ApoE ε4-related effects on the cholinergic system may be more prominent at earlier disease stages. Show less

Abdominal aortic aneurysm (AAA) is a fatal cardiovascular disease with no effective drug treatment currently available. The aberrant expression levels of microRNAs (miRNAs or miRs) contribute to AAA pathogenesis. In the present study, miRNA microarray analysis was performed to screen for differentially expressed miRNAs in the aortas of AAA mice compared with those in control mice, and to clarify the role and mechanism of miRNA‑378a‑5p (miR‑378a‑5p) in the AAA development. A comprehensive miRNA microarray analysis was conducted to screen for differentially expressed miRNAs in the aortas of AAA mice and control mice. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) was used to detect the expression levels of miR‑378a‑5p in the serum and aortas of patients with AAA and mice. To clarify the role of miR‑378a‑5p in the AAA development Show less

The transient, heterogeneous nano-bio interface defined by the protein corona in biological environments dictates the biodistribution, immune recognition, metabolism, and clearance of nanomaterials. Far from being a drawback, this corona can be harnessed for targeted nanodrug delivery when its composition is predictably tuned or deliberately modulated. We hypothesized that preloading apolipoprotein E (ApoE), previously identified as a constituent of the corona of β-sheet-breaker peptide-functionalized gold nanoparticles (AuNPs), would enhance transport across the blood-brain barrier (BBB) and increase brain uptake. To test this, we synthesized AuNPs (approximately 12 nm) functionalized (AuNP-f) with CLPFFD or THRPPMWSPVWPCLPFFD peptides, both containing the β-sheet-breaker motif LPFFD, which recognizes β-amyloid aggregates implicated in Alzheimer's disease. After incubation with human plasma, hard-corona proteins were profiled by 2D IEF/SDS-PAGE and LC-MS/MS. Proteins were ranked based on their roles in nanoparticle trafficking and BBB transcytosis, and ApoE was selected for deliberate enrichment due to its recurrent presence. ApoE-decorated AuNP-f were evaluated in an in vitro BBB model and in vivo biodistribution assays using Sprague-Dawley rats. Brain accumulation was assessed ex vivo. Preloading ApoE onto AuNP-f significantly enhanced nanoparticle transport across the BBB in vitro and increased brain accumulation in rats. These results demonstrate that rational corona enrichment with ApoE improves BBB transit and brain accumulation without altering nanoparticle surface chemistry. Corona engineering thus offers a pragmatic route to brain-targeted nanodrug delivery and may be extended to other protein-receptor axes for organ-specific targeting. Show less

Apolipoprotein E (ApoE) is a key regulator of lipid metabolism that binds to lipid nanoparticle (LNP) surfaces to mediate cellular interactions. However, the ApoE-LNP behavior is highly dependent on the LNP composition, and the underlying mechanisms remain unclear. Here, we show that subtle alterations in LNP surface lipids profoundly reshape the ApoE-LNP structure and intracellular trafficking. Using cryogenic electron microscopy and live-cell imaging, we demonstrate that replacing 10 mol % 1,2-distearoyl- Show less

We sought to examine the cross-sectional associations of social support and depressive symptoms with cognitive function in dementia-free rural older adults. This population-based cross-sectional study included 4719 participants (age ≥ 60 years) living in rural China. Social support and depressive symptoms were measured using the Social Support Rating Scale and the 15-item Geriatric Depression Scale, respectively. Global cognition, memory, verbal fluency, attention, and executive function were assessed using a neuropsychological test battery. Mild cognitive impairment (MCI) was defined following Petersen's criteria. Data were analyzed using general linear and logistic regression models. Greater social support was associated with lower likelihood of MCI and greater z-scores of global cognition, memory, verbal fluency, and executive function (all P < 0.05). Having depressive symptoms was associated with increased likelihood of MCI and lower z-scores of global cognition, memory, verbal fluency, attention, and executive function (all P < 0.05). Greater social support was associated with higher global cognitive z-score in men, higher memory z-score in APOE ε4 non-carriers, and higher executive function z-score in participants with school education (all P < 0.01). The association of depressive symptoms with lower z-scores of global cognition and attention was stronger among people with formal schooling than those without (P < 0.01). Furthermore, depressive symptoms could significantly mediate 46.97 % of the cross-sectional association between social support and global cognition. Late-life social support and having no depressive symptoms are associated with a reduced likelihood of MCI and better cognitive function in a rural Chinese older population, with the associations varying by sex, education, and APOE genotype. Show less

Periodontitis is linked to dyslipidaemia, but the mechanism still requires further investigation. This study aimed to investigate the periodontitis-dyslipidaemia interplay, comparing the impact of periodontitis-associated versus healthy salivary microbiota on systemic lipid metabolism in mice via the oral-gut axis. NHANES analysis established epidemiological link. ApoE-/- mice received salivary microbiota from periodontally healthy (A-PH) or severe periodontitis (A-SP) donors. Serum lipids and gut microbiota were assessed; correlations between microbial shifts and lipid changes were evaluated. NHANES confirmed significant association between self-reported physician-diagnosed bone loss around teeth and hypercholesterolemia (OR=1.266). A-SP mice exhibited higher TC, LDL and non-HDL compared with A-PH group. Gut dysbiosis featured increased proinflammatory genera ( Collectively, building upon the NHANES link, our findings demonstrate that the salivary microbiome from periodontitis patients, compared to that from healthy individuals, disrupts systemic lipid metabolism and induces gut dysbiosis in mice. The correlation between specific gut microbial shifts and atherogenic lipid profiles provides experimental support for the mediating role of the oral‒gut axis in linking periodontitis to hyperlipidaemia. Show less

The Timed Up and Go (TUG) is a 20-foot gait assessment, with TUG-dual task (DT) serial subtractions to determine dual-task cost. Alzheimer's disease (AD) risk is established using plasma biomarkers and APOE genotyping. We investigated: 1) TUG/TUG-DT differences between AD low-risk cognitively unimpaired (CU) older adults (N = 74), AD high-risk CU older adults (N = 87), and mild cognitively impaired (MCI) older adults (N = 33) and 2) the relationship between TUG/TUG-DT performance and plasma biomarkers. One hundred and ninety-four older adults ages 55-80 completed TUG/TUG-DT, a fasting blood draw, and APOE genotyping. Scores on the Clinical Dementia Rating Scale (CU = 0; CI = ≥0.5) and Montreal Cognitive Assessment (CU ≥ 24; CI = ≤23) determined whether participants were placed into the CU low-risk, CU high-risk, or MCI groups. Risk level for CU participants were assessed by APOE genotyping. Those participants who carried at least one copy of the APOE ε4 allele were designated to the high-risk group (n = 87). Participants with no APOE ε4 allele were assigned to the low-risk group (n = 75). MCI participants took longer to perform the TUG than CU participants ( Step count may be more sensitive, compared to speed alone, in identifying those in preclinical AD stages. Gait metrics (speed and efficiency) played a key role as a clinical manifestation of early AD pathophysiology determined by blood-based biomarker concentration. Combining these assessments offers a multidimensional, cost-effective approach for preclinical-AD screening and potential early intervention. Show less

The apolipoprotein E ( APOE ) genotype has traditionally been associated with Alzheimer's disease (AD) and, more specifically, with the severity of cerebral β-amyloidosis in the form of Aβ plaques and cerebral amyloid angiopathy (CAA). However, a growing body of research has examined its potential impact on Tau pathology. Here we critically review the evidence supporting a differential effect of APOE alleles on Tau in the context of AD and non-AD tauopathies, from genetic, neuropathological, and biomarker studies to preclinical studies in mouse models and human inducible pluripotent stem-cells (hiPSCs)-derived brain cells. Genetic, neuropathological, and preclinical studies in transgenic mice have yielded somewhat conflicting results, whereas most multitracer PET imaging studies on individuals along the normal aging to AD dementia continuum support an Aβ-independent effect of the APOE ε4 allele on the tauopathy of AD. More clinical and preclinical research is needed to elucidate the link between APOE and Tau. Show less

Alzheimer's disease (AD) has a strong genetic component, with APOE ε4 being the most established risk factor through its effects on beta-amyloid (Aβ) metabolism and microglial function. Recent genetic studies have also implicated microglial genes, such as the ABI3 We used FinnGen R12 data (> 500,000 individuals), including 8,490 ABI3 ABI3 ABI3 Show less

The poor efficacy of chemotherapy for glioma is mainly due to the difficulty of drug penetration through the blood-brain barrier (BBB), as well as the difficulty of drug concentration in the tumor tissue to reach the effective therapeutic level. The emerging tumor-targeted delivery technology can facilitate the precise enrichment of drugs in the tumor site. Apolipoprotein E (ApoE(159-167) Show less

Atherosclerosis is attributable to a series of diabetes-related complications. CAV1 (caveolin 1)-mediated low-density lipoprotein (LDL) particle transcytosis across endothelial cells (ECs) is the initial step of atherosclerosis. MAP1LC3/LC3-interacting regions in the intramembrane domain (IMD) of CAV1 were buried in the caveolae and were not accessible for LC3B interaction, protecting CAV1 from autophagic degradation. However, the CSD domain of CAV1, exposed in the cytosol, directly interacted with a CBM domain of LC3B and inhibited autophagy. Therefore, the peptide IMD-CBM was constructed to induce the selective autophagic degradation of CAV1 and suppress LDL transcytosis in diabetic atherosclerosis. EC-specific expression of IMD-CBM was achieved using adenovirus. IMD-CBM directly interacted with CAV1 and LC3B in ECs, leading to the selective autophagic degradation of CAV1, activation of autophagy, and subsequent inhibition of LDL transcytosis. IMD-CBM promoted the autophagic degradation of CAV1 and consequently reduced the area of atherosclerotic plaques in Show less

Alzheimer's disease (AD) disproportionately affects women and carriers of the apolipoprotein E ε4 allele (APOE4), yet little is known about how sex and APOE interact to influence white matter (WM) integrity during disease progression. We integrated diffusion MRI and matched blood transcriptomic data to investigate these interactions and their underlying biological mechanisms. WM microstructure was quantified using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), and regional vulnerability was assessed with a composite vulnerability score (CVS) derived from associations between diffusion features and AD severity across clinical traits in each of the four sex-APOE groups (female or male, with or without APOE4). Brain parcellation with the Eve atlas revealed regions consistently affected across sex-APOE groups (e.g., parahippocampal and superior temporal gyri) and regions specific to individual groups (e.g., the cingulum in females with APOE4 and the middle frontal gyrus in males without APOE4). Gene co-expression network analysis of the matched blood expression data identified gene subnetworks linked to group-specific regional vulnerability, including a muscle tissue morphogenesis module regulated by NEURL1B and HIST1H2BN associated with middle frontal gyrus vulnerability. These findings demonstrate that sex and APOE genotype jointly shape region-specific WM vulnerability and its molecular signatures in AD. Understanding these interactions provides novel mechanistic insights and may inform precision approaches to drug development, biomarker discovery, and clinical trial design for AD. Show less

Age-related macular degeneration (AMD) and Alzheimer's disease (AD) are neurodegenerative conditions that afflict millions of elderly people around the world. AMD is a progressive retinal disorder that leads to central vision loss whereas AD primarily causes cognitive decline and behavioral changes. While each disease has distinct clinical manifestations, the accumulation of extracellular amyloid-β is a common histopathologic finding. Similarly, cerebral amyloid angiopathy (CAA), a vascular condition that can exist independent or with AD, is characterized by the accumulation of amyloid-β in cerebral blood vessels. While significant investigation of the pathophysiologic links between AMD and AD has been conducted, the underlying similarities and differences in the pathobiology of AMD and CAA has not been considered. In this review, we discuss the common pathological features of these two conditions. We then discuss the similar pathobiology that involves cholesterol metabolism, apolipoprotein E, amyloid-β, and complement mediated inflammation. At the same time, we discuss key differences in their pathobiology. This discussion sheds new perspective and insights of their pathobiology. Show less

Apolipoprotein E (APOE) genotype influences the presence, course and severity of sporadic cerebral amyloid angiopathy (sCAA). We investigated the effect of the APOE ε4-allele on clinical and neuroradiological outcomes in mutation-carriers with Dutch-type hereditary (D-)CAA. Participants with D-CAA from a prospective cohort study, with data collected on history of symptomatic intracerebral hemorrhages (sICH) and vascular risk factors, underwent 3 Tesla magnetic resonance imaging (MRI) scans to assess macrobleeds, cerebral microbleeds (CMBs), cortical superficial siderosis (cSS), enlarged perivascular spaces (EPVS), white matter hyperintensity (WMH) volume and WMH multispot lesions. Global cognition was measured using Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) scores. Associations between ≥1 APOE ε4-allele and age of first sICH, time to recurrence, cognition and radiological data were analyzed with adjustments for confounders. Eighty-one participants (mean age 47 years, 54% women, 38% with sICH history) were included. The APOE ε4-allele was not associated with earlier sICH onset (median age 56 versus 57 years; p = 0.6) or time to recurrence (5.0 versus 3.9 years; p = 0.4), nor was it associated with macrobleeds (β 2.0; 95%CI 2.4- -2.7; p = 0.4), CMBs (β 2.9; 95%CI 1.0-8.9; p = 0.06), cSS (aOR 0.5; 95%CI 0.1-2.0; p = 0.3), EPVS (aOR 0.4; 95%CI 0.1-1.5; p = 0.6), WMH volume (β 6.8; 95%CI -1.9-15.4; p = ), a multispot pattern (OR 0.7; 95%CI 0.2-2.7, p = 0.6), or cognition (β -0.3; 95%CI -0.4- -0.5; p = 0.5). APOE ε4 does not affect key clinical parameters or D-CAA neuroradiological markers and therefore does not explain the large variation in disease course in D-CAA. Show less

COG133, a peptide fragment derived from apolipoprotein E (ApoE) corresponding to residues 133-149, has demonstrated significant anti-inflammatory and neuroprotective activity. However, its precise anti-inflammatory mechanisms and its potential to ameliorate depression-like behaviors remain incompletely understood. This study investigated the effects of COG133 in mouse models of depression induced by lipopolysaccharide (LPS), chronic social defeat stress (CSDS), and corticosterone (CORT), as well as in LPS-stimulated BV-2 microglial cells. We found that COG133 treatment significantly alleviated depression-like phenotypes and suppressed hippocampal neuroinflammation by inhibiting microglial overactivation. Using RNA sequencing (RNA-seq) and biochemical validation, we identified the MKK3/6-p38-ATF2 signaling axis as a central mechanism underlying the anti-inflammatory effects of COG133. Pharmacological modulation of p38 MAPK further confirmed that this pathway is essential for COG133-mediated behavioral and cellular recovery. Together, these findings identify COG133 as a promising peptide candidate for the treatment of depression through modulation of the p38 MAPK-mediated neuroinflammation axis. Show less

Atherosclerosis (AS) is closely associated with gut microbiota that plays an important role in regulating intestinal mucosal barrier function, chronic inflammation, and immune homeostasis. Thus, targeting the modulation of gut microbitoa repesents a promising strategy for the control of AS. Clostridium butyricum (C. butyricum) serving as a kind of probiotics has shown a variety of biological benefits, but it's impact on atherosclerosis remains poorly understood. Sixty male ApoE C. butyricum ameliorated dyslipidemia and attenuated atherosclerotic plaque formation in ApoE C. butyricum intervention may exert anti-AS effects by reshaping gut homeostasis via the regulation of immune cells, providing a potential strategy for clinical treatment. Show less

Cancer cachexia involves severe skeletal muscle and adipose tissue loss. The role of Apolipoprotein E (ApoE) in adipose remodeling remains unclear. This study investigated ApoE's function in cancer cachexia. We found cachectic patients had decreased plasma ApoE but elevated expression in subcutaneous adipose. In vitro, ApoE knockdown in adipocytes downregulated both lipogenesis and lipolysis genes. In vivo, ApoE Show less

Apolipoprotein E receptor 2 (apoER2), a primary receptor for apoE, has recently been linked to Alzheimer's disease. Compared with the most common form of apoE, apoE3, the apoE4 isoform increases the risk for developing Alzheimer's disease. ApoE4 impairs brain insulin signaling, a feature of Alzheimer's disease that correlates with cognitive decline. Insulin availability in the brain largely depends on blood-brain barrier (BBB) transport and contributes to brain insulin signaling. We have previously shown that the apoE4 isoform leads to regional reductions in insulin BBB transport in mice on a Western diet compared to apoE3 isoform. However, how insulin transport across the BBB is regulated by apoE isoforms is not well understood. Here we investigated a role of endothelial apoER2 in the effects of apoE isoforms on insulin BBB transport, using mice genetically expressing human apoE3 or apoE4 and expressing or lacking endothelial apoER2. We found that a loss of endothelial apoER2 did not overtly affect insulin BBB transport in either apoE3- or apoE4-expressing mice, except in the frontal cortex and pons/medulla, where decreased transport was observed in apoE3 mice lacking endothelial apoER2. These findings indicate that the effect of apoE4 on insulin BBB transport is largely independent of endothelial apoER2. In contrast, endothelial apoER2 may regulate insulin BBB transport in limited regions of the brain through its binding to apoE3. Show less

Inter-individual responses to omega-3 and omega-6 polyunsaturated fatty acid (PUFA) interventions vary substantially, complicating standardized dietary recommendations and suggesting a role for genetic differences that influence fatty acid biosynthesis, metabolism, and downstream health effects. A PRISMA 2020-guided systematic search of PubMed, Embase, and Web of Science identified adult studies assessing nutrigenetic interactions in the context of PUFA interventions and outcomes, yielding 132 eligible studies (79 Tier 1; 53 Tier 2) that collectively indicate pathway-specific genetic control of PUFA handling. Across 38 studies (combined Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized primarily by deterioration in memory, cognition, and learning ability. Its etiology is complex and influenced by multiple factors, including genetics and environment. With advancing research into mitochondrial function and mechanisms, impaired mitophagy has been proposed as a significant mechanism contributing to AD. The ApoE ε4 allele, a high-risk genetic factor for AD, may play a key role in disease pathogenesis by inducing mitophagy dysfunction and apoptosis. From the perspective of APOE gene polymorphisms, this study investigates abnormal changes in mitochondrial function and autophagy in humanized APOE4 mice primary astrocytes under oxidative stress, as well as the regulatory effect of curcumin (Cur) on mitophagy and oxidative stress-induced apoptosis, thereby exploring its potential to ameliorate AD through targeting mitophagy. Mitochondrial function analysis revealed that APOE4 expression reduced the antioxidant capacity and respiratory function of primary astrocytes, leading to mitochondrial membrane damage, intracellular reactive oxygen species (ROS) accumulation, and decreased ATP production. Curcumin effectively protected mitochondrial integrity, reduced the number of damaged mitochondria, improved overall mitochondrial function, and helped maintain mitochondrial homeostasis involving in PINK1/Parkin pathway. Regarding autophagy and apoptosis, curcumin was shown to restore autophagic flux, mitigate autophagy disruption caused by oxidative stress, and reverse early-stage apoptosis. Show less

Chronic low-grade inflammation underlies many microvascular complications of diabetes, including diabetic kidney disease (DKD). Lipoxins (LXs), an endogenously produced family of lipid mediators, resolve inflammation and protect against renal scarring as occurs in DKD. This study examined the mechanism by which LXs protect against DKD, focusing on the regulation of VCAM-1 and the recruitment of macrophages to the diabetic glomerulus. LXA4 and two fourth-generation mimetics were assessed in diabetic ApoE knockout mice, followed by in vitro studies in the main renal cell populations, including podocytes, proximal tubular, mesangial, and glomerular endothelial cells. LXs attenuated albuminuria, mesangial expansion, and collagen and fibronectin deposition as both a preventive and delayed intervention in experimental DKD. LXs also consistently attenuated the TNF-α-induced expression of VCAM-1 in all the human and mouse renal cell populations examined. Further analysis identified that the renoprotection was in part mediated by an epigenetic modification of the VCAM-1 gene through H3K4 monomethylation, which did not appear to be dependent on NF-κB activation in human glomerular endothelial cells. LXs protect against DKD by modulating glomerular endothelial cell inflammation and via a novel LX-mediated epigenetic mechanism regulating the VCAM-1 promoter in these cells. Lipoxins (LXs) protect against diabetic kidney disease (DKD) by resolving chronic low-grade inflammation, but the exact mechanism by which this occurs is not known. We investigated the effect of LXs on inflammatory markers and the recruitment of macrophages to the diabetic glomerulus by using LXs as both a preventive and delayed interventional treatment in streptozotocin-induced diabetic ApoE knockout mice. Protection against DKD was associated with reduced glomerular macrophage accumulation. LXs also attenuated the expression of VCAM1 in glomerular endothelial cells. LXs protect against DKD in part by a mechanism that reduces VCAM1 gene expression via H3K4 monomethylation on the VCAM1 gene. Show less

Women show higher levels of Alzheimer's disease (AD) pathology than men, but the implications for cognitive decline remain unclear. Determining the extent to which tau burden differentially accelerates cognitive decline in men and women will provide critical insights into sex-specific pathways of disease progression. We leveraged tau positron emission tomography (PET), amyloid beta (Aβ) PET, apolipoprotein E (APOE) ε4 genotyping, and longitudinal cognitive data over approximately 8.6 (standard deviation [SD] = 3.8) years from 1007 cognitively unimpaired adults across three cohorts. Cognitive trajectories were modeled with linear mixed-effects regression including sex × tau × time interactions, and results were synthesized using random-effects meta-analysis. Higher tau burden in medial and lateral temporal regions was associated with faster cognitive decline in women than in men. High tau burden carries a disproportionately greater cognitive cost for women, underscoring the need for sex-specific approaches to early detection and therapeutic intervention in AD. A meta-analysis across three independent cohorts shows that female cognitive advantage at low tau shifts to vulnerability at higher tau. Sex differences in tau-related cognitive decline were consistent after accounting for amyloid burden. Sex-specific rates of cognitive decline should be considered in clinical trial design. Show less

Improving the patency rate of small-diameter vascular grafts in a pathological environment is the key to achieving their clinical translation and application. The current approach to in vivo implantation evaluations of small-diameter vascular grafts is predominantly based on healthy animal models. However, the majority of patients who undergo vascular transplantation are afflicted with vascular diseases, such as hyperlipidaemia or atherosclerosis. In this study, we constructed an ApoE gene knockout atherosclerotic mouse model and investigated the patency and regenerative performance of small-diameter vascular grafts in a diseased environment. We prepared heparinized Poly (ε-caprolactone) (PCL) vascular grafts (PCL-Hep) using electrospinning technology. By taking advantage of the physical adsorption of heparin, rapamycin (RM) was loaded onto the surface of grafts to obtain PCL-Hep-RM vascular grafts, which exhibited exceptional mechanical properties and drug sustained-release characteristics. Subsequently, the PCL-Hep-RM vascular grafts were implanted into the carotid arteries of atherosclerotic mice. The results demonstrated that PCL-Hep-RM significantly enhanced the patency rate and suppressed intimal hyperplasia in comparison with the PCL control group. This study offers novel concepts and methodologies for addressing challenges such as the low long-term patency rate and luminal stenosis of vascular grafts in a diseased environment, thereby promoting the translational medicine research of small-diameter vascular grafts. Show less

C1q/TNF-related proteins (CTRPs) belong to the adipokine family. Here, we aimed to assess the relation of CTRP4 levels in serum and perivascular adipose tissue (PVAT) with coronary artery disease (CAD), and investigate the effect of CTRP4 on atherosclerosis and the underlying mechanisms. CTRP4 levels were examined in serum and epicardial adipose tissue (a major PVAT) from patients with CAD. Atherosclerotic lesions were analysed in CTRP4 CTRP4 levels were lower in serum and epicardial adipose tissue of patients with CAD compared to non-CAD controls. CTRP4 knockout promoted atherosclerosis in ApoE Decreased CTRP4 levels in serum and epicardial adipose tissue are associated with CAD in patients. CTRP4 deficiency promotes the development of atherosclerosis in ApoE Show less

Atherosclerosis presents a persistent health challenge, with limited therapies addressing residual cardiovascular risk. Gualou Xiebai Banxia Decoction (GXBD), a classical Chinese herbal formula traditionally used for chest obstruction syndromes, was evaluated as a dietary-style intervention in ApoE Show less

Alzheimer's disease (AD) is a progressive neurodegenerative condition in which genetic predisposition plays a key role, yet the sex-specific mechanisms linking genetic risk to early cognitive changes remain unclear. This study examined the impact of polygenic risk scores (PRS) on early cognitive changes in 318 cognitively unimpaired participants from the ALFA+ cohort, a nested longitudinal cohort from the ALFA study (see details in Study Participants Section, Methods). Participants were followed for three years, with assessments across five cognitive domains and a preclinical composite (PACC). Global AD PRS, including and excluding the apolipoprotein E (APOE) gene, alongside five biologically informed pathway-specific PRS (amyloid, immune, external stimuli signaling, cholesterol efflux, lipoprotein metabolism) were computed. Generalized linear models including interaction by sex and stratified by sex and amyloid status (CSF Aβ42/40 < 0.071) assessed associations between PRS and cognitive change. In women, APOE-independent AD genetic risk predicted worse executive function, particularly via cholesterol efflux and external stimuli signaling pathways. Among Aβ + women, PRS also predicted lower memory performance, partially modulated by reproductive span. In Aβ - women, worse executive functioning performance was linked to amyloid, immune, and signaling pathways. In contrast, men showed associations between AD PRS and worse visual (Aβ-) and attentional (Aβ+) performance, independent of pathway-specific mechanisms. These findings reveal distinct, domain-specific cognitive vulnerabilities to AD genetic risk by sex and amyloid status, highlighting APOE-independent and mechanistic contributions to early and subtle cognitive changes. Results support the need for sex-aware, biologically informed genetic models in preclinical AD for risk stratification and early intervention. Show less

Alzheimer' s disease (AD) is a progressive neurodegenerative disorder characterized by a spectrum of cognitive impairments, ranging from mild memory loss to severe cognitive decline and, ultimately, death. The global incidence of AD is projected to increase significantly, with late-onset AD being predominantly sporadic in nature. Over the past three decades, the Apolipoprotein E (APOE) gene has been recognized as the most important single genetic determinant of sporadic AD risk. The APOE4 allele is a major risk factor for AD and is known to exacerbate the pathological process for AD. Identifying protective variants that may reduce the risk or delay the onset of AD is of great significance for the development of effective treatments. This review comprehensively examines the protective effects of APOE and its related protective mutations. It also explores the impact of these unique protective variants at the cellular level during the pathological progression of AD. Furthermore, the review compiles new insights for AD treatment offered by these protective mutations, exploring the potential applications of APOE and its related protective variants in advanced therapeutic strategies, including gene editing, RNA editing, and stem cell therapy. Show less