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International Journal of Molecular... Jun 2024GV1001, an anticancer vaccine, exhibits other biological functions, including anti-inflammatory and antioxidant activity. It also suppresses the development of...
GV1001, an anticancer vaccine, exhibits other biological functions, including anti-inflammatory and antioxidant activity. It also suppresses the development of ligature-induced periodontitis in mice. (), a major human oral bacterium implicated in the development of periodontitis, is associated with various systemic disorders, such as atherosclerosis and Alzheimer's disease (AD). This study aimed to explore the protective effects of GV1001 against -induced periodontal disease, atherosclerosis, and AD-like conditions in ()-deficient mice. GV1001 effectively mitigated the development of -induced periodontal disease, atherosclerosis, and AD-like conditions by counteracting -induced local and systemic inflammation, partly by inhibiting the accumulation of DNA aggregates, lipopolysaccharides (LPS), and gingipains in the gingival tissue, arterial wall, and brain. GV1001 attenuated the development of atherosclerosis by inhibiting vascular inflammation, lipid deposition in the arterial wall, endothelial to mesenchymal cell transition (EndMT), the expression of Cluster of Differentiation 47 (CD47) from arterial smooth muscle cells, and the formation of foam cells in mice with -induced periodontal disease. GV1001 also suppressed the accumulation of AD biomarkers in the brains of mice with periodontal disease. Overall, these findings suggest that GV1001 holds promise as a preventive agent in the development of atherosclerosis and AD-like conditions associated with periodontal disease.
Topics: Animals; Porphyromonas gingivalis; Mice; Apolipoproteins E; Periodontal Diseases; Atherosclerosis; Telomerase; Peptide Fragments; Alzheimer Disease; Periodontitis; Bacteroidaceae Infections; Disease Models, Animal; Mice, Inbred C57BL; Male; Humans
PubMed: 38892314
DOI: 10.3390/ijms25116126 -
International Journal of Molecular... May 2024Human abdominal aortic aneurysms (AAAs) are characterized by increased activity of matrix metalloproteinases (MMP), including MMP-12, alongside macrophage accumulation...
Human abdominal aortic aneurysms (AAAs) are characterized by increased activity of matrix metalloproteinases (MMP), including MMP-12, alongside macrophage accumulation and elastin degradation, in conjunction with superimposed atherosclerosis. Previous genetic ablation studies have proposed contradictory roles for MMP-12 in AAA development. In this study, we aimed to elucidate if pharmacological inhibition of MMP-12 activity with a phosphinic peptide inhibitor protects from AAA formation and progression in angiotensin (Ang) II-infused Apoe mice. Complimentary studies were conducted in a human ex vivo model of early aneurysm development. Administration of an MMP-12 inhibitor (RXP470.1) protected hypercholesterolemia Apoe mice from Ang II-induced AAA formation and rupture-related death, associated with diminished medial thinning and elastin fragmentation alongside increased collagen deposition. Proteomic analyses confirmed a beneficial effect of MMP-12 inhibition on extracellular matrix remodeling proteins combined with inflammatory pathways. Furthermore, RXP470.1 treatment of mice with pre-existing AAAs exerted beneficial effects as observed through suppressed aortic dilation and rupture, medial thinning, and elastin destruction. Our findings indicate that pharmacological inhibition of MMP-12 activity retards AAA progression and improves survival in mice providing proof-of-concept evidence to motivate translational work for MMP-12 inhibitor therapy in humans.
Topics: Animals; Aortic Aneurysm, Abdominal; Angiotensin II; Matrix Metalloproteinase 12; Mice; Apolipoproteins E; Humans; Matrix Metalloproteinase Inhibitors; Male; Disease Models, Animal; Mice, Knockout; Mice, Inbred C57BL; Elastin; Proteomics
PubMed: 38891996
DOI: 10.3390/ijms25115809 -
International Journal of Molecular... May 2024Alzheimer's disease (AD) is a devastating disorder with a global prevalence estimated at 55 million people. In clinical studies administering certain anti-beta-amyloid...
Alzheimer's disease (AD) is a devastating disorder with a global prevalence estimated at 55 million people. In clinical studies administering certain anti-beta-amyloid (Aβ) antibodies, amyloid-related imaging abnormalities (ARIAs) have emerged as major adverse events. The frequency of these events is higher among apolipoprotein ε4 allele carriers () compared to non-carriers. To reflect patients most at risk for vascular complications of anti-Aβ immunotherapy, we selected an APPswe/PS1dE9 transgenic mouse model bearing the human gene (APPPS1:E4) and compared it with the same APP/PS1 mouse model bearing the human gene ( ε3 allele; APPPS1:E3). Using histological and biochemical analyses, we characterized mice at three ages: 8, 12, and 16 months. Female and male mice were assayed for general cerebral fibrillar and pyroglutamate (pGlu-3) Aβ deposition, cerebral amyloid angiopathy (CAA), microhemorrhages, apoE and cholesterol composition, astrocytes, microglia, inflammation, lysosomal dysfunction, and neuritic dystrophy. Amyloidosis, lipid deposition, and astrogliosis increased with age in APPPS1:E4 mice, while inflammation did not reveal significant changes with age. In general, carriers showed elevated Aβ, apoE, reactive astrocytes, pro-inflammatory cytokines, microglial response, and neuritic dystrophy compared to carriers at different ages. These results highlight the potential of the APPPS1:E4 mouse model as a valuable tool in investigating the vascular side effects associated with anti-amyloid immunotherapy.
Topics: Animals; Alzheimer Disease; Disease Models, Animal; Mice, Transgenic; Mice; Humans; Female; Male; Amyloid beta-Peptides; Apolipoprotein E4; Presenilin-1; Amyloid beta-Protein Precursor; Cerebral Amyloid Angiopathy; Brain
PubMed: 38891941
DOI: 10.3390/ijms25115754 -
Matrix Remodeling Enzymes as Potential Fluid Biomarkers of Neurodegeneration in Alzheimer's Disease.International Journal of Molecular... May 2024This study investigated the diagnostic accuracy of plasma biomarkers-specifically, matrix metalloproteinase (MMP-9), tissue inhibitor of metalloproteinase (TIMP-1),...
This study investigated the diagnostic accuracy of plasma biomarkers-specifically, matrix metalloproteinase (MMP-9), tissue inhibitor of metalloproteinase (TIMP-1), CD147, and the MMP-/TIMP-1 ratio in patients with Alzheimer's disease (AD) dementia. The research cohort comprised patients diagnosed with probable AD dementia and a control group of cognitively unimpaired (CU) individuals. Neuroradiological assessments included brain magnetic resonance imaging (MRI) following dementia protocols, with subsequent volumetric analysis. Additionally, cerebrospinal fluid (CSF) AD biomarkers were classified using the A/T/N system, and apolipoprotein E () ε4 carrier status was determined. Findings revealed elevated plasma levels of MMP-9 and TIMP-1 in AD dementia patients compared to CU individuals. Receiver operating characteristic (ROC) curve analysis demonstrated significant differences in the areas under the curve (AUC) for MMP-9 ( < 0.001) and TIMP-1 ( < 0.001). Notably, plasma TIMP-1 levels were significantly lower in ε4+ patients than in ε4- patients ( = 0.041). Furthermore, ε4+ patients exhibited reduced hippocampal volume, particularly in total, right, and left hippocampal measurements. TIMP-1 levels exhibited a positive correlation, while the MMP-9/TIMP-1 ratio showed a negative correlation with hippocampal volume parameters. This study sheds light on the potential use of TIMP-1 as a diagnostic marker and its association with hippocampal changes in AD.
Topics: Humans; Alzheimer Disease; Male; Biomarkers; Female; Tissue Inhibitor of Metalloproteinase-1; Aged; Matrix Metalloproteinase 9; Magnetic Resonance Imaging; Middle Aged; Apolipoprotein E4; Hippocampus; Aged, 80 and over; ROC Curve
PubMed: 38891891
DOI: 10.3390/ijms25115703 -
Cells May 2024Apolipoprotein E (ApoE) is a lipid carrier in both the peripheral and the central nervous systems (CNSs). Lipid-loaded ApoE lipoprotein particles bind to several cell...
Apolipoprotein E (ApoE) is a lipid carrier in both the peripheral and the central nervous systems (CNSs). Lipid-loaded ApoE lipoprotein particles bind to several cell surface receptors to support membrane homeostasis and brain injury repair. In the brain, ApoE is produced predominantly by astrocytes, but it is also abundantly expressed in most neurons of the CNS. In this study, we addressed the role of ApoE in the hippocampus in mice, focusing on its role in response to radiation injury. To this aim, 8-week-old, wild-type, and ApoE-deficient (ApoE) female mice were acutely whole-body irradiated with 3 Gy of X-rays (0.89 Gy/min), then sacrificed 150 days post-irradiation. In addition, age-matching ApoE females were chronically whole-body irradiated (20 mGy/d, cumulative dose of 3 Gy) for 150 days at the low dose-rate facility at the Institute of Environmental Sciences (IES), Rokkasho, Japan. To seek for ApoE-dependent modification during lineage progression from neural stem cells to neurons, we have evaluated the cellular composition of the dentate gyrus in unexposed and irradiated mice using stage-specific markers of adult neurogenesis. Our findings indicate that ApoE genetic inactivation markedly perturbs adult hippocampal neurogenesis in unexposed and irradiated mice. The effect of ApoE inactivation on the expression of a panel of miRNAs with an established role in hippocampal neurogenesis, as well as its transcriptional consequences in their target genes regulating neurogenic program, have also been analyzed. Our data show that the absence of ApoE also influences synaptic functionality and integration by interfering with the regulation of mir-34a, mir-29b, and mir-128b, leading to the downregulation of synaptic markers PSD95 and synaptophysin mRNA. Finally, compared to acute irradiation, chronic exposure of ApoE null mice yields fewer consequences except for the increased microglia-mediated neuroinflammation. Exploring the function of ApoE in the hippocampus could have implications for developing therapeutic approaches to alleviate radiation-induced brain injury.
Topics: Animals; Apolipoproteins E; Hippocampus; Mice; Radiation, Ionizing; Female; MicroRNAs; Mice, Inbred C57BL; Neurons; Neurogenesis; Whole-Body Irradiation; Radiation Exposure; Dentate Gyrus
PubMed: 38891031
DOI: 10.3390/cells13110899 -
Biomarker Insights 2024Polycystic ovary syndrome (PCOS) is a common endocrinological condition affecting women of reproductive age, associated with insulin resistance and obesity. PCOS...
BACKGROUND
Polycystic ovary syndrome (PCOS) is a common endocrinological condition affecting women of reproductive age, associated with insulin resistance and obesity. PCOS pathogenesis is complex and multifactorial, involving genetic and environmental factors.
OBJECTIVES
This study aimed to determine and compare genotype and allele frequencies of single nucleotide polymorphisms (SNPs) in the apolipoprotein A5 (; rs662799) and perilipin 1 (; rs894160, rs1052700 and rs6496589) genes in Western Saudi women to investigate their association with PCOS and its clinical characteristics.
DESIGN AND METHODS
This was a case-control study conducted on women with ( = 104) and without ( = 87) PCOS. The SNPs were genotyped using TaqMan genotyping assays.
RESULTS
Significant and direct associations were detected between PCOS susceptibility and SNP rs662799 and SNP rs894160 ( < .001). For SNP rs662799, women with the A allele were more likely to have PCOS (relative risk [RR] = 1.348, odds ratio [OR] = 2.313, < .001) and hypertriglyceridaemia (OR = 17.0, = .5) than women with the G allele. For SNP rs894160, women with the T allele were more likely to have PCOS than women with the C allele (RR = 8.043, OR = 7.427, < .001). For SNP rs1052700, women with the TT genotype were more likely to have hyperandrogenism (OR = 29.75, = .02) and an irregular period (OR = 0.07, = .040) than women with the AT genotype.
CONCLUSION
We identified novel alleles and genotypes contributing to the genetic risk of PCOS in the Western Saudi population.
PubMed: 38887365
DOI: 10.1177/11772719241258585 -
Journal of Ethnopharmacology Jun 2024Zhishi Xiebai Guizhi Decoction (ZSXBGZD) is a traditional herbal manuscript used to treat cardiovascular disease, including atherosclerosis and coronary heart disease....
ETHNOPHARMACOLOGICAL RELEVANCE
Zhishi Xiebai Guizhi Decoction (ZSXBGZD) is a traditional herbal manuscript used to treat cardiovascular disease, including atherosclerosis and coronary heart disease. The decoction has demonstrated its capability to protect arteries and resist atherosclerosis. Its mechanisms for anti-atherosclerosis effect, nevertheless, remain unknown.
AIMS OF THE STUDY
The goal of the present study is to explore the effectiveness of ZSXBGZD acting on atherosclerosis and its key components based on experimental verification and network pharmacology analysis.
MATERIALS AND METHODS
The ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) and databases were used to identify chemical components in ZSXBGZD. Network pharmacological analysis and molecular docking were implemented in order to reveal the possible therapeutic targets of ZSXBGZD. To form the model of atherosclerosis, we gave Apolipoprotein E knocked out mice a high-fat diet. H&E staining was performed to observe the effects of ZSXBGZD on atherosclerosis. Immunofluorescence and Western blot were used to investigate whether ZSXBGZD could affect autophagy, apoptosis, AGE-RAGE signaling pathway and other related mechanisms.
RESULTS
In total, 30 core compounds were screened through intersecting UPLC-Q-TOF-MS and the databases. The anti-atherosclerotic effect of ZSXBGZD might relate to the AGE-RAGE signaling pathway via network pharmacology analysis. ZSXBGZD could inhibit apoptosis, activate autophagy and ease inflammation by modifying AGE-RAGE signaling pathway to reduce the area of atherosclerotic plaque.
CONCLUSION
ZSXBGZD could treat atherosclerosis by regulating autophagy and apoptosis via adjusting the AGE-RAGE signaling pathway.
PubMed: 38885915
DOI: 10.1016/j.jep.2024.118466 -
Frontiers in Endocrinology 2024The global prevalence of cardiovascular diseases (CVD) continues to rise steadily, making it a leading cause of mortality worldwide. Atherosclerosis (AS) serves as a... (Review)
Review
The global prevalence of cardiovascular diseases (CVD) continues to rise steadily, making it a leading cause of mortality worldwide. Atherosclerosis (AS) serves as a primary driver of these conditions, commencing silently at an early age and culminating in adverse cardiovascular events that severely impact patients' quality of life or lead to fatality. Dyslipidemia, particularly elevated levels of low-density lipoprotein cholesterol (LDL-C), plays a pivotal role in AS pathogenesis as an independent risk factor. Research indicates that abnormal LDL-C accumulation within arterial walls acts as a crucial trigger for atherosclerotic plaque formation. As the disease progresses, plaque accumulation may rupture or dislodge, resulting in thrombus formation and complete blood supply obstruction, ultimately causing myocardial infarction, cerebral infarction, and other common adverse cardiovascular events. Despite adequate pharmacologic therapy targeting LDL-C reduction, patients with cardiometabolic abnormalities remain at high risk for disease recurrence, highlighting the importance of addressing lipid risk factors beyond LDL-C. Recent attention has focused on the causal relationship between triglycerides, triglyceride-rich lipoproteins (TRLs), and their remnants in AS risk. Genetic, epidemiologic, and clinical studies suggest a causal relationship between TRLs and their remnants and the increased risk of AS, and this dyslipidemia may be an independent risk factor for adverse cardiovascular events. Particularly in patients with obesity, metabolic syndrome, diabetes, and chronic kidney disease, disordered TRLs and its remnants levels significantly increase the risk of atherosclerosis and cardiovascular disease development. Accumulation of over-synthesized TRLs in plasma, impaired function of enzymes involved in TRLs lipolysis, and impaired hepatic clearance of cholesterol-rich TRLs remnants can lead to arterial deposition of TRLs and its remnants, promoting foam cell formation and arterial wall inflammation. Therefore, understanding the pathogenesis of TRLs-induced AS and targeting it therapeutically could slow or impede AS progression, thereby reducing cardiovascular disease morbidity and mortality, particularly coronary atherosclerotic heart disease.
Topics: Humans; Cardiovascular Diseases; Lipoproteins; Triglycerides; Atherosclerosis; Animals; Dyslipidemias; Risk Factors
PubMed: 38883601
DOI: 10.3389/fendo.2024.1409653 -
Frontiers in Neurology 2024The role of lipopolysaccharide binding protein (LBP), an inflammation marker of bacterial translocation from the gastrointestinal tract, in Alzheimer's disease (AD) is...
INTRODUCTION
The role of lipopolysaccharide binding protein (LBP), an inflammation marker of bacterial translocation from the gastrointestinal tract, in Alzheimer's disease (AD) is not clearly understood.
METHODS
In this study the concentrations of LBP were measured in = 79 individuals: 20 apolipoprotein E (APOE)3/E3 carriers with and 20 without AD dementia, and 19 carriers with and 20 without AD dementia. LBP was found to be enriched in the 1.21-1.25 g/mL density fraction of plasma, which has previously been shown to be enriched in intestinally derived high-density lipoproteins (HDL). LBP concentrations were measured by ELISA.
RESULTS
LBP was significantly increased within the 1.21-1.25 g/mL density fraction of plasma in AD patients compared to controls, but not patients. LBP was positively correlated with Clinical Dementia Rating (CDR) and exhibited an inverse relationship with Verbal Memory Score (VMS).
DISCUSSION
These results underscore the potential contribution of gut permeability to bacterial toxins, measured as LBP, as an inflammatory mediator in the development of AD, particularly in individuals with the genotype, who are genetically at 4-12-fold lower risk of AD than individuals who express .
PubMed: 38882697
DOI: 10.3389/fneur.2024.1408220 -
Heliyon Jun 2024Hypercholesterolemia is a metabolic disease characterized by elevated cholesterol level in the blood, which is a risk factor for many diseases. Probiotic intervention...
Limosilactobacillus fermentum TY-S11 ameliorates hypercholesterolemia via promoting cholesterol excretion and regulating gut microbiota in high-cholesterol diet-fed apolipoprotein E-deficient mice.
Hypercholesterolemia is a metabolic disease characterized by elevated cholesterol level in the blood, which is a risk factor for many diseases. Probiotic intervention may be one of the ways to improve hypercholesterolemia. In this study, three strains with better cholesterol removal ability were selected from 60 strains of lactic acid bacteria, and were orally administered to apolipoprotein E-deficient mice on a high-cholesterol diet. Among the three strains, only TY-S11, which was isolated from the intestine of a longevity person, significantly improved serum and liver lipid levels in hypercholesterolemic mice. Further study found that TY-S11 promoted the excretion of cholesterol in the feces and inhibited the absorption of cholesterol in the small intestine. As for gut microbiota, the results showed that TY-S11 not only prevented the reduction of diversity caused by high-cholesterol diet, but also increased the contents of short-chain fatty acids in feces. These results confirmed the ameliorative effect of TY-S11 on hypercholesterolemia.
PubMed: 38882320
DOI: 10.1016/j.heliyon.2024.e32059