-
Heliyon Apr 2024Familial combined hypolipidemia, previously known as Familial hypobetalipoproteinemia 2 (FHBL2) is considered as an extremely rare recessive disease. Here, we present...
Familial combined hypolipidemia, previously known as Familial hypobetalipoproteinemia 2 (FHBL2) is considered as an extremely rare recessive disease. Here, we present the case of familial combined hypolipidemia with homozygous loss-of function (LOF) variants in angiopoietin-like protein 3 () ((NM_014495.4) c.439_442del (p.Thr146_Asn147insTer)) using panel sequencing (46 yr male whose LDL cholesterol = 34 mg/dL). The serum level of ANGPTL3 was quite low (undetectable). Despite of extreme decreasing LDL cholesterol, this case did not have any complications as hypobetalipidemia (HBL), such as steatorrhea vomiting, hematological, neuromuscular, or ophthalmological symptoms. In addition, we did not find any systemic atherosclerosis in his carotid arteries and in coronary arteries. Based on the findings suggest that inhibition of ANGPTL3 effectively reduce LDL cholesterol without any apparent side effects, although it is still unclear if he will suffer any disadvantages because of this situation in the future.
PubMed: 38699738
DOI: 10.1016/j.heliyon.2024.e29924 -
Computational and Structural... Dec 2024Patients with RA are at a higher risk of developing CV diseases than the general population. The precise mechanisms are still unknown. We evaluated the associations...
Angiopoietin-2, vascular endothelial growth factor family, and heparin binding endothelial growth factor are associated with subclinical atherosclerosis in rheumatoid arthritis.
INTRODUCTION
Patients with RA are at a higher risk of developing CV diseases than the general population. The precise mechanisms are still unknown. We evaluated the associations between 8 plasma growth factors (GFs) (angiopoietin-2, EGF, HB-EGF, PLGF, TGF-α, VEGFa, VEGFc, and VEGFd) and subclinical arteriosclerosis in RA patients.
MATERIALS AND METHODS
A total of 199 patients with RA treated at the Hospital Universitari Sant Joan de Reus (Spain) between 2011 and 2015 were included in this cross-sectional study. Carotid intima media thickness (cIMT), carotid plaque presence (cPP) and pulse wave velocity (PWV) were measured. GFs were measured with Bio-Plex Pro Human Cancer Biomarker Panel 2 (Bio-Rad). Multivariate models and partial least square discriminant analysis (PLS-DA) were used for analysis (RStudio, version 4.0.1).
RESULTS
Multivariate models showed that angiopoietin-2 was associated with cPP and PWV in the overall cohort (OR = 1.53 and β = 0.20, respectively). VEGFc (β = 0.29), VEGFa (β = 0.26) and HB-EGF (β = 0.22) were also associated with PWV. VEGFa (OR = 2.36), VEGFd (OR = 2.29), EGF (OR = 2.62), PLGF (OR = 2.54), and HB-EGF (OR = 2.24) were associated with cPP in men. According to PLS-DA, GFs were able to distinguish between patients with and without cPP in the overall cohort, male cohort, and female cohort. In women, angiopoietin-2 was associated with PWV (β = 0.18).
CONCLUSIONS
The selected GFs were closely related to atherosclerosis in patients with RA and are potential predictors of CV disease in patients with RA.
PubMed: 38689721
DOI: 10.1016/j.csbj.2024.04.042 -
Frontiers in Bioscience (Landmark... Mar 2024The endogenous metabolism of polyunsaturated fatty acids is regulated by the fatty acid desaturase (FADS) gene cluster and is strongly associated with diseases such as...
BACKGROUND
The endogenous metabolism of polyunsaturated fatty acids is regulated by the fatty acid desaturase (FADS) gene cluster and is strongly associated with diseases such as atherosclerosis, dyslipidemia, and type 2 diabetes. However, the association between FADS and atherosclerosis remains a subject of debate.
METHODS
In this study, we specifically investigated the physiological role of Δ-5 fatty acid desaturase (FADS1) in aortic and peripheral vessel (namely, the femoral artery) atherosclerosis by targeting the selective knockdown of hepatic in apolipoprotein E-null (ApoE-/-) mice with antisense oligonucleotides (ASOs).
RESULTS
Knockdown of hepatic in ApoE-/- mice exacerbated aortic atherosclerosis and non-alcoholic fatty liver disease (NAFLD), resulting in weight loss. Upregulation of FADS1 mRNA expression in more severe atherosclerosis vascular tissues potentially caused the upregulation of angiopoietin-like 4 expression.
CONCLUSIONS
Our study demonstrated that knockdown of hepatic in ApoE-/- mice aggravates spontaneous atherosclerosis and NAFLD but does not affect peripheral atherosclerosis (femoral artery) induced by vascular cuff combined with tandem stenosis.
Topics: Animals; Fatty Acid Desaturases; Delta-5 Fatty Acid Desaturase; Atherosclerosis; Liver; Apolipoproteins E; Mice; Gene Knockdown Techniques; Male; Non-alcoholic Fatty Liver Disease; Mice, Inbred C57BL; Mice, Knockout; Oligonucleotides, Antisense
PubMed: 38682200
DOI: 10.31083/j.fbl2904131 -
Nutrients Apr 2024The burden of cardiovascular disease and the percentage of frail patients in the aging population will increase. This study aims to assess the circulating levels of...
The burden of cardiovascular disease and the percentage of frail patients in the aging population will increase. This study aims to assess the circulating levels of several cytokines in frail patients. This is an ancillary analysis of the FRAPICA trial. The ratio of men/women changed from robust through frail groups from 3:1 to 1:2. The groups are comparable in terms of age and body measurements analysis (weight, height, and BMI), yet the frail patients have significantly reduced fat-free mass, and more often have been diagnosed with diabetes. Frail patients have higher fibroblast growth factor basic (FGF basic) and follistatin levels (borderline significance). In multiple linear regression modeling of fat-free mass, we identified FGF basic, osteopontin, stem cell factor, soluble suppression of tumorigenicity 2, soluble epidermal growth factor receptor, soluble human epidermal growth factor receptor 2, follistatin, prolactin, soluble interleukin 6 receptor alfa, platelet endothelial cell adhesion molecule 1, soluble vascular endothelial cell growth factor receptor 1, leptin, soluble angiopoietin/tyrosine kinase 2, and granulocyte colony-stimulating factor. We have identified a few cytokines that correlate with fat-free mass, a hallmark of frailty. They comprise the kinins implicated in bone and muscle metabolism, fibrosis, vascular wall function, inflammation, endocrine function, or regulation of bone marrow integrity.
Topics: Humans; Male; Female; Aged; Cardiovascular Diseases; Cytokines; Body Composition; Frail Elderly; Aged, 80 and over; Frailty; Middle Aged
PubMed: 38674917
DOI: 10.3390/nu16081227 -
Journal of Clinical Medicine Apr 2024: The effective treatment of chronic myeloid leukemia leads to the restoration of proper immune system function. We aimed to investigate fluctuations in circulating...
: The effective treatment of chronic myeloid leukemia leads to the restoration of proper immune system function. We aimed to investigate fluctuations in circulating cytokines, angiogenic factors and complement components in patients with CML during the first year of treatment with TKI and correlate them with the degree of achieved molecular response. : We recruited 31 patients with newly diagnosed CML. Peripheral blood and bone marrow samples were obtained, and concentrations of serum proteins were measured using an immunology multiplex assay. : The study cohort was divided into two groups of optimal or non-optimal in accordance with the European Leukemia Net (ELN) guidelines. We found significantly higher concentrations of C1q, C4 and C5a in serum after 3 months of TKI treatment in patients who achieved optimal responses in the 6 months after diagnosis. The most alterations were observed during 12 months of therapy. Patients in the optimal response group were characterized by higher serum concentrations of TGF-β, EGF, VEGF, Angiopoietin 1, IFN-γ and IL-8. : The later plasma concentrations of complement components were significantly increased in patients with optimal responses. The changes after 12 months of treatment were particularly significant. Similar changes in bone marrow samples were observed.
PubMed: 38673624
DOI: 10.3390/jcm13082353 -
Biomedicines Apr 2024Tumor angiogenesis, the formation of new blood vessels within the tumor microenvironment, is considered a hallmark of cancer progression and represents a crucial target... (Review)
Review
Tumor angiogenesis, the formation of new blood vessels within the tumor microenvironment, is considered a hallmark of cancer progression and represents a crucial target for therapeutic intervention. The tumor microenvironment is characterized by a complex interplay between proangiogenic and antiangiogenic factors, regulating the vascularization necessary for tumor growth and metastasis. The study of angiogenesis involves a spectrum of techniques, spanning from biomarker assessment to advanced imaging modalities. This comprehensive review aims to provide insights into the molecular intricacies, regulatory dynamics, and clinical implications of tumor angiogenesis. By delving into these aspects, we gain a deeper understanding of the processes driving vascularization in tumors, paving the way for the development of novel and effective antiangiogenic therapies in the fight against cancer.
PubMed: 38672182
DOI: 10.3390/biomedicines12040827 -
Children (Basel, Switzerland) Apr 2024Childhood glaucoma, a significant cause of global blindness, represents a heterogeneous group of disorders categorized into primary or secondary forms. Primary childhood... (Review)
Review
Childhood glaucoma, a significant cause of global blindness, represents a heterogeneous group of disorders categorized into primary or secondary forms. Primary childhood glaucoma stands as the most prevalent subtype, comprising primary congenital glaucoma (PCG) and juvenile open-angle glaucoma (JOAG). Presently, multiple genes are implicated in inherited forms of primary childhood glaucoma. This comprehensive review delves into genetic investigations into primary childhood glaucoma, with a focus on identifying causative genes, understanding their inheritance patterns, exploring essential biological pathways in disease pathogenesis, and utilizing animal models to study these mechanisms. Specifically, attention is directed towards genes such as (cytochrome P450 family 1 subfamily B member 1), (latent transforming growth factor beta binding protein 2), (TEK receptor tyrosine kinase), (angiopoietin 1), and (forkhead box C1), all associated with PCG; and (myocilin), associated with JOAG. Through exploring these genetic factors, this review aims to deepen our understanding of the intricate pathogenesis of primary childhood glaucoma, thereby facilitating the development of enhanced diagnostic and therapeutic strategies.
PubMed: 38671671
DOI: 10.3390/children11040454 -
Journal of Cardiovascular Development... Apr 2024Patients with atherosclerotic disease remain at increased risk of future events despite receiving optimal medical treatment. This residual risk is widely heterogeneous,... (Review)
Review
Patients with atherosclerotic disease remain at increased risk of future events despite receiving optimal medical treatment. This residual risk is widely heterogeneous, but lipoprotein particles and their content play a major role in determining future cardiovascular events. Beyond low-density lipoprotein cholesterol (LDL-c), other lipoprotein particles have not demonstrated similar contribution to the progression of atherosclerosis. Statins, ezetimibe, and more recently, proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors and bempedoic acid have confirmed the causal role of LDL-c in the development of atherosclerosis. Data on high-density lipoprotein cholesterol (HDL-c) suggested a possible causal role for atherosclerosis; nonetheless, HDL-c-raising treatments, including cholesteryl-ester transfer protein (CETP) inhibitors and niacin, failed to confirm this relationship. On the other hand, mendelian randomisation revealed that triglycerides are more implicated in the development of atherosclerosis. Although the use of highly purified eicosapentaenoic acid (EPA) was associated with a reduction in the risk of adverse cardiovascular events, this beneficial effect did not correlate with the reduction in triglycerides level and has not been consistent across large phase 3 trials. Moreover, other triglyceride-lowering treatments, such as fibrates, were not associated with a reduction in future cardiovascular risk. Studies assessing agents targeting angiopoietin-like 3 (lipoprotein lipase inhibitor) and apolipoprotein C3 antisense will add further insights into the role of triglycerides in atherosclerosis. Emerging lipid markers such as lipoprotein (a) and cholesterol efflux capacity may have a direct role in the progression of atherosclerosis. Targeting these biomarkers may provide incremental benefits in reducing cardiovascular risk when added to optimal medical treatment. This Review aims to assess available therapies for current lipid biomarkers and provide mechanistic insight into their potential role in reducing future cardiovascular risk.
PubMed: 38667744
DOI: 10.3390/jcdd11040126 -
Journal of Cardiovascular Development... Mar 2024Any difference in biomarkers between genotype-positive individuals with overt hypertrophic cardiomyopathy (HCM), and genotype-positive but phenotype-negative...
Any difference in biomarkers between genotype-positive individuals with overt hypertrophic cardiomyopathy (HCM), and genotype-positive but phenotype-negative individuals (G+P-) in HCM-associated pathways might shed light on pathophysiological mechanisms. We studied this in young HCM patients. 29 HCM patients, 17 G+P--individuals, and age- and sex-matched controls were prospectively included. We analyzed 184 cardiovascular disease-associated proteins by two proximity extension assays, categorized into biological pathways, and analyzed with multivariate logistic regression analysis. Significant proteins were dichotomized into groups above/below median concentration in control group. Dichotomized values of significant proteins showed high odds ratio (OR) in overt HCMphenotype for Fibroblast growth factor-21 (FGF-21) 10 ( = 0.001), P-selectin glycoprotein ligand-1 (PSGL-1) OR 8.6 ( = 0.005), and Galectin-9 (Gal-9) OR 5.91 ( = 0.004). For G+P-, however, angiopoietin-1 receptor (TIE2) was notably raised, OR 65.5 ( = 0.004), whereas metalloproteinase inhibitor 4 (TIMP4) involved in proteolysis, in contrast, had reduced OR 0.06 ( = 0.013). This study is one of the first in young HCM patients and G+P- individuals. We found significantly increased OR for HCM in FGF-21 involved in RAS-MAPK pathway, associated with cardiomyocyte hypertrophy. Upregulation of FGF-21 indicates involvement of the RAS-MAPK pathway in HCM regardless of genetic background, which is a novel finding.
PubMed: 38667723
DOI: 10.3390/jcdd11040105 -
Stem Cell Research & Therapy Apr 2024Adipose stromal cells (ASC) are a form of mesenchymal stromal cells that elicit effects primarily via secreted factors, which may have advantages for the treatment of...
BACKGROUND
Adipose stromal cells (ASC) are a form of mesenchymal stromal cells that elicit effects primarily via secreted factors, which may have advantages for the treatment of injury or disease. Several previous studies have demonstrated a protective role for MSC/ASC on mitigating acute kidney injury but whether ASC derived factors could hasten recovery from established injury has not been evaluated.
METHODS
We generated a concentrated secretome (CS) of human ASC under well-defined conditions and evaluated its ability to improve the recovery of renal function in a preclinical model of acute kidney injury (AKI) in rats. 24 h following bilateral ischemia/reperfusion (I/R), rats were randomized following determination of plasma creatinine into groups receiving vehicle -control or ASC-CS treatment by subcutaneous injection (2 mg protein/kg) and monitored for evaluation of renal function, structure and inflammation.
RESULTS
Renal function, assessed by plasma creatinine levels, recovered faster in ASC-CS treated rats vs vehicle. The most prominent difference between the ASC-CS treated vs vehicle was observed in rats with the most severe degree of initial injury (P > 3.0 mg/dl 24 h post I/R), whereas rats with less severe injury (P < 2.9 mg/dl) recovered quickly regardless of treatment. The quicker recovery of ASC-treated rats with severe injury was associated with less tissue damage, inflammation, and lower plasma angiopoietin 2. In vitro, ASC-CS attenuated the activation of the Th17 phenotype in lymphocytes isolated from injured kidneys.
CONCLUSIONS
Taken together, these data suggest that ASC-CS represents a potent therapeutic option to improve established AKI.
Topics: Acute Kidney Injury; Animals; Rats; Humans; Inflammation; Male; Secretome; Adipose Tissue; Rats, Sprague-Dawley; Injections, Subcutaneous; Kidney; Mesenchymal Stem Cells; Reperfusion Injury; Stromal Cells
PubMed: 38659070
DOI: 10.1186/s13287-024-03736-x