Search Results (28)

Schizophrenia (SZ) is a chronic disabling mental disorder with high heritability, and several immune-regulating genes have been implicated in its pathophysiology In this study, we investigated the expression of Toll-like receptors (TLRs) 1, 2, and 6 in peripheral blood monocytes from SZ patients and healthy control subjects (HCSs) in the Mexican population, focusing on specific SZ-associated gene variants. Gene expressions were assessed by qPCR, and protein expression was measured using flow cytometry. The secretory profiles of MALP2-stimulated monocytes were evaluated through immunoproteomic arrays. Our results indicate that patients with SZ carrying the rs4833093/TLR1 GG genotype exhibited significantly lower TLR1 gene expression compared to TT carriers. Notably, HCSs with the TT genotype showed markedly higher TLR1 protein expression, while all patients with SZ exhibited significantly reduced protein levels regardless of genotype. Furthermore, monocytes from patients with SZ displayed altered secretion profiles upon TLR stimulation, with significant elevations in IL-18, uPAR, angiopoietin-2, and serpin E1, alongside reductions in MCP-1, IL-17A, IL-24, MIF, and myeloperoxidase compared to HCSs. These findings suggest a dysfunctional TLR-mediated innate immune response in SZ. Full article

Background: The most common cause of death in patients with peripheral artery disease (PAD) are major adverse cardiovascular events (MACEs), including myocardial infarction (MI) and stroke. However, data on biomarkers that could be used to help predict MACEs in patients with PAD to guide clinical decision making is limited. Angiogenesis-related proteins have been demonstrated to play an important role in systemic atherosclerosis and may act as prognostic biomarkers for MACEs in patients with PAD. In this study, we evaluated a large panel of angiogenesis-related proteins and identified specific biomarkers associated with MACEs in patients with PAD. Methods: We conducted a prognostic study using a prospectively recruited cohort of 406 patients (254 with PAD and 152 without PAD). Plasma concentrations of 22 circulating angiogenesis-related proteins were measured at baseline, and the cohort was followed for 2 years. The primary outcome was 2-year MACEs (composite of MI, stroke, or death). Plasma protein concentrations were compared between PAD patients with and without 2-year MACEs using Mann–Whitney U tests. Differentially expressed proteins were further investigated in terms of their prognostic potential. Specifically, Cox proportional hazards analysis was performed to determine the independent association between differentially expressed proteins and 2-year MACEs, controlling for all baseline demographic and clinical characteristics, including existing coronary artery disease and cerebrovascular disease. Kaplan–Meier analysis was conducted to assess 2-year freedom from MACEs in patients with low vs. high levels of the differentially expressed proteins based on median plasma concentrations. Results: The mean age of the cohort was 68.8 (SD 11.1), and 134 (33%) patients were female. Two-year MACEs occurred in 63 (16%) individuals. The following proteins were significantly elevated in PAD patients with 2-year MACEs compared to those without 2-year MACEs: endostatin (69.15 [SD 58.15] vs. 51.34 [SD 29.07] pg/mL, p < 0.001), angiopoietin-like protein 4 (ANGPTL4) (0.20 [SD 0.09] vs. 0.12 [SD 0.04] pg/mL, p < 0.001), and ANGPTL3 (51.57 [SD 21.92] vs. 45.16 [SD 21.90] pg/mL, p = 0.001). Cox proportional hazards analysis demonstrated that these three proteins were independently associated with 2-year MACEs after adjusting for all baseline demographic and clinical characteristics: endostatin (HR 1.39 [95% CI 1.12–1.71] p < 0.001), ANGPTL4 (HR 1.35 [95% CI 1.08–1.68], p < 0.001), and ANGPTL3 (HR 1.35 [95% CI 1.12–1.63], p < 0.001). Over a 2-year follow-up period, patients with higher levels of endostatin, ANGPTL4, and ANGPTL3 had a lower freedom from MACEs. Supplementary analysis demonstrated that these three proteins were not significantly associated with 2-year MACEs in patients without PAD. Conclusions: Among a panel of 22 angiogenesis-related proteins, endostatin, ANGPTL4, and ANGPTL3 were identified to be independently and specifically associated with 2-year MACEs in patients with PAD. Measurement of plasma concentrations of these proteins can support MACE risk stratification in patients with PAD, thereby informing clinical decisions on multidisciplinary referrals to cardiologists, neurologists, and vascular medicine specialists and guiding aggressiveness of medical treatment, thereby improving cardiovascular outcomes in patients with PAD. Full article

Humans are persistently exposed to massive amounts of blue light via sunlight, computers, smartphones, and similar devices. Although the positive and negative effects of blue light on living organisms have been reported, its impact on learning and memory remains unknown. Herein, we examined the effects of widespread blue light exposure on the learning and memory abilities of blue light-exposed mice. Ten-week-old male ICR mice were divided into five groups (five mice/group) and irradiated with blue light from a light-emitting diode daily for 6 months. After 6 months of blue light irradiation, mice exhibited a decline in memory and learning abilities, assessed using the Morris water maze and step-through passive avoidance paradigms. Blue light-irradiated mice exhibited a decreased expression of the clock gene brain and muscle arnt-like 1 (Bmal1). The number of microglia and levels of M1 macrophage CC-chemokine receptor 7 and inducible nitric oxide synthase were increased, accompanied by a decrease in M2 macrophage arginase-1 levels. Levels of angiopoietin-like protein 2 and inflammatory cytokines interleukin-6, tumor necrosis factor-α, and interleukin-1β were elevated. Our findings suggest that long-term blue light exposure could reduce Bmal1 expression, activate the M1 macrophage/Angptl2/inflammatory cytokine pathway, induce neurodegeneration, and lead to a decline in memory. Full article

Betatrophin, also known as angiopoietin-like protein 8 (ANGPTL8), mainly plays a role in lipid metabolism. To date, associations between betatrophin and lipoprotein subfractions are poorly investigated. For this study, 50 obese patients with type 2 diabetes (T2D) and 70 nondiabetic obese (NDO) subjects matched in gender, age, and body mass index (BMI) as well as 49 gender- and age-matched healthy, normal-weight controls were enrolled. Serum betatrophin levels were measured with ELISA, and lipoprotein subfractions were analyzed using Lipoprint gel electrophoresis. Betatrophin concentrations were found to be significantly higher in the T2D and NDO groups compared to the controls in all subjects and in females, but not in males. We found significant positive correlations between triglyceride, very low density lipoprotein (VLDL), large LDL (low density lipoprotein), small LDL, high density lipoprotein (HDL) -6-10 subfractions, and betatrophin, while negative correlations were detected between betatrophin and IDL, mean LDL size, and HDL-1-5. Proportion of small HDL was the best predictor of betatrophin in all subjects. Small LDL and large HDL subfractions were found to be the best predictors in females, while in males, VLDL was found to be the best predictor of betatrophin. Our results underline the significance of serum betatrophin measurement in the cardiovascular risk assessment of obese patients with and without T2D, but gender differences might be taken into consideration. Full article

Hidradenitis suppurativa (HS) is a chronic inflammatory disease whose pathogenesis is not fully understood at present. The role of proinflammatory cytokines, several adipokines, retinol-binding protein 4, angiopoietin-2 and other molecules has been previously reported. Angiopoietin-like 2 protein (ANGPTL2) is a glycoprotein belonging to the angiopoietin-like family that may play a pivotal role in the pathogenesis of several chronic inflammatory diseases. To our knowledge, the role of serum ANGPTL2 levels in HS has not been assessed to date. In the current case–control study, we aimed to investigate serum ANGPTL2 levels in HS patients and controls and to assess whether ANGPTL2 levels could be associated with the severity of HS. Ninety-four patients with HS and sixty controls of similar age and sex were included in the study. Demographic, anthropometric, and clinical data, as well as routine laboratory parameters and serum concentrations of ANGPTL2, were assessed in all participants. HS patients had significantly higher serum ANGPTL2 levels than controls after adjusting for confounders. Moreover, ANGPTL2 concentrations positively correlated with disease duration and severity. Our results indicate for the first time that serum ANGPTL2 concentrations are elevated in HS patients compared to controls and correlate with the duration of the disease. Besides, ANGPTL2 might serve as a biomarker of HS severity. Full article

The purpose of the study was to examine the urinary levels of kidney injury molecule-1 (KIM-1) and angiopoietin-like protein-4 (ANGPTL-4) in individuals with diabetic kidney disease (DKD) and their association with established DKD diagnostic markers such as albuminuria and estimated glomerular filtration rate (eGFR). Levels of ANGPTL-4 and KIM-1 were estimated in urine samples. A total of 135 participants were recruited into three groups: 45 diabetes type 2 patients in the control group and 90 DKD patients in two disease groups. Concentrations of ANGPTL-4 and KIM-1 were conclusively related to the urinary albumin–creatinine ratio (UACR). Also, the levels of both ANGPTL-4 and KIM-1 were negatively associated with the eGFR. Multivariable Poisson regression analysis showed that urinary ANGPTL-4 (PR: 3.40; 95% CI: 2.32 to 4.98; p < 0.001) and KIM-1 (PR: 1.25; 95% CI: 1.14 to 1.38; p < 0.001) were prevalent in DKD patients. Receiver operating characteristic (ROC) analysis of urinary ANGPTL-4 and KIM-1 in the combined form resulted in an area under curve (AUC) of 0.967 (95%CI: 0.932–1.000; p < 0.0001) in the microalbuminuria group and 1 (95%CI: 1.000–1.000; p < 0.0001) in the macroalbuminuria group. The association of urinary levels of ANGPTL-4 and KIM-1 with UACR and eGFR and significant prevalence in the diabetic kidney disease population illustrates the diagnostic potential of these biomarkers. Full article

Measures of cardiovascular health (CVH) assessed by a combination of behavioral and biological factors has shown protective associations with all-cause mortality. The mechanisms underlying these associations have not been fully elucidated. In this study, we characterized the plasma proteomics profile of CVH and tested whether specific proteins mediated the associations between CVH and all-cause mortality in participants of the InCHIANTI study. Of the 1301 proteins tested, 92 proteins were associated with CVH (22 positively, 70 negatively). Proteins most strongly associated with CVH included leptin (LEP), fatty acid binding protein 3 (FABP3), Angiopoietin-2 (ANGPT2), and growth-differential factor 15 (GDF15). Of the 92 CVH-associated proteins, 33 proteins significantly mediated the associations between CVH and all-cause mortality, with percent mediation ranging from 5 to 30%. The most significant mediating proteins were GDF15 and insulin-like growth factor 2 (IGFBP2). Proteins associated with better CVH were enriched for proteins that reflect the suppression of the complement coagulation and GH/IGF pathways. Full article

Osteoarthritis (OA) is one of the most common joint pathologies and a major cause of disability among the population of developed countries. It manifests as a gradual degeneration of the cartilage and subchondral part of the bone, leading to joint damage. Recent studies indicate that not only the cells that make up the articular cartilage but also the synoviocytes, which build the membrane surrounding the joint, contribute to the development of OA. Therefore, the aim of the study was to determine the response to inflammatory factors of osteoarthritic synoviocytes and to identify proteins secreted by them that may influence the progression of OA. This study demonstrated that fibroblast-like synoviocytes of OA patients (FLS-OA) respond more strongly to pro-inflammatory stimulation than cells obtained from control patients (FLS). These changes were observed at the transcriptome level and subsequently confirmed by protein analysis. FLS-OA stimulated by pro-inflammatory factors [such as lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNFα) were shown to secrete significantly more chemokines (CXCL6, CXCL10, and CXCL16) and growth factors [angiopoietin-like protein 1 (ANGPTL1), fibroblast growth factor 5 (FGF5), and insulin-like growth factor 2 (IGF2)] than control cells. Moreover, the translation of proteolytic enzymes [matrix metalloprotease 3 (MMP3), cathepsin K (CTSK), and cathepsin S (CTSS)] by FLS-OA is increased under inflammatory conditions. Our data indicate that the FLS of OA patients are functionally altered, resulting in an enhanced response to the presence of pro-inflammatory factors in the environment, manifested by the increased production of the previously mentioned proteins, which may promote further disease progression. Full article

Betatrophin (angiopoietin-like protein 8 (ANGPTL8)) is a hormone that was recently discovered in the human liver. Multiple homologous sequences have been detected in mammalian liver, white adipose, and brown adipose tissues. Betatrophin is crucial for the development of type 2 diabetes (T2D), insulin resistance, and lipid metabolism. Similar to the intake of insulin, thyroid hormones, irisin, and calories, betatrophin expression in the organism is usually attributed to energy consumption or heat generation. It can mediate the activity of lipoprotein lipase (LPL), which is the key enzyme of lipoprotein lipolysis. Due to its association with metabolic markers and the roles of glucose and lipid, the physiological function of betatrophin in glucose homeostasis and lipid metabolism can be more comprehensively understood. Betatrophin was also shown to facilitate pancreatic β-cell proliferation in a mouse model of insulin resistance. There are also reports that demonstrate that betatrophin regulates triglycerides (TGs) in the liver. Therefore, the process of regulating the physiological function by betatrophin is complicated, and its exact biological significance remains elusive. This study provides a comprehensive review of the current research, and it discusses the possible physiological functions of betatrophin, and specifically the mechanism of betatrophin in regulating blood glucose and blood lipids. Full article

In rats, the time of birth is characterized by a transient rise in beta cell replication, as well as beta cell neogenesis and the functional maturation of the endocrine pancreas. However, the knowledge of the gene expression during this period of beta cell expansion is incomplete. The aim was to characterize the perinatal rat pancreas transcriptome and to identify regulatory pathways differentially regulated at the whole organ level in the offspring of mothers fed a regular control diet (CO) and of mothers fed a low-protein diet (LP). We performed mRNA expression profiling via the microarray analysis of total rat pancreas samples at embryonic day (E) 20 and postnatal days (P) 0 and 2. In the CO group, pancreas metabolic pathways related to sterol and lipid metabolism were highly enriched, whereas the LP diet induced changes in transcripts involved in RNA transcription and gene regulation, as well as cell migration and apoptosis. Moreover, a number of individual transcripts were markedly upregulated at P0 in the CO pancreas: growth arrest specific 6 (Gas6), legumain (Lgmn), Ets variant gene 5 (Etv5), alpha-fetoprotein (Afp), dual-specificity phosphatase 6 (Dusp6), and angiopoietin-like 4 (Angptl4). The LP diet induced the downregulation of a large number of transcripts, including neurogenin 3 (Neurog3), Etv5, Gas6, Dusp6, signaling transducer and activator of transcription 3 (Stat3), growth hormone receptor (Ghr), prolactin receptor (Prlr), and Gas6 receptor (AXL receptor tyrosine kinase; Axl), whereas upregulated transcripts were related to inflammatory responses and cell motility. We identified differentially regulated genes and transcriptional networks in the perinatal pancreas. These data revealed marked adaptations of exocrine and endocrine in the pancreas to the low-protein diet, and the data can contribute to identifying novel regulators of beta cell mass expansion and functional maturation and may provide a valuable tool in the generation of fully functional beta cells from stem cells to be used in replacement therapy. Full article

The reasons for differences in lipid depositions between fatty-type (F-T) and lean-type (L-T) ducks remain unknown. The present study aimed to compare the growth performance, lipid deposition, and gene expression related to lipid droplet formation in F-T and L-T Pekin ducks. One-day-old, 140 each L-T and F-T male ducks were selected and distributed separately into 20 replicate cages. All ducks were fed commercial diets up to 35 d of age. F-T ducks had a higher average daily gain from 21 to 28 d of age. On 35-day-old, F-T ducks had higher serum levels of high- and low-density lipoprotein cholesterol, cholesterol, albumin, and hydroxybutyrate dehydrogenase activity than L-T ducks. F-T ducks had higher abdominal fat and subcutaneous fat percentages than those in L-T ducks. Liver histological examination showed that L-T ducks contained more lipid droplets in the liver, which gradually decreased with increasing age. The average adipocyte area and diameter of abdominal fat and subcutaneous fat in the F-T and L-T ducks increased with age and were higher in F-T ducks than those in L-T ducks. Furthermore, the gene expression of perilipin 1, perilipin 2, angiopoietin-like protein 4, adipose triglyceride lipase, alpha/beta-hydrolase domain-containing protein 5 (ABHD5), and serine/threonine kinase 17a in the liver, abdominal fat, and subcutaneous fat of F-T ducks was higher than that in L-T ducks, and it increased with age. Compared to L-T ducks, F-T ducks had higher expression of ABHD5 in the abdominal fat and subcutaneous fat and lower expression in the liver. Thus, F-T ducks displayed lower hepatic lipid deposition and a higher percentage of abdominal fat and subcutaneous fat, suggesting that F-T ducks had higher lipid storage capacity due to increased gene expression related to lipid droplets. Full article

N-Acetylgalactosaminyltransferase 2 (GALNT2) is associated with serum lipid levels, insulin resistance, and adipogenesis. Additionally, angiopoietin-like (ANGPTL) proteins have emerged as regulators of lipoprotein lipase and lipid metabolism. In this study, we evaluated the association between GALNT2 rs4846914 variant, known for its association with lipid levels in European cohorts, with plasma levels of ANGPTL proteins, apolipoproteins, lipids, and obesity traits in individuals of Arab ethnicity. GALNT2 rs4846914 was genotyped in a cohort of 278 Arab individuals from Kuwait. Plasma levels of ANGPTL3 and ANGPTL8 were measured by ELISA and apolipoproteins by Luminex multiplexing assay. Allele-based association tests were performed with Bonferroni-corrected p-value thresholds. The GALNT2 rs4846914_G allele was associated with increased ANGPTL3 (p-values ≤ 0.05) but not with ANGPTL8 plasma levels. The allele was associated significantly with higher BMI and weight (p-values < 0.003), increased ApoC1 levels (p-values ≤ 0.006), and reduced HDL levels (p-values ≤ 0.05). Individuals carrying the GG genotype showed significantly decreased HDL and increased BMI, WC, ApoC1, and TG. Interactions exist between (AG+GG) genotypes and measures of percentage body fat, ApoA1A, ApoC1, and ApoB48-mediated HDL levels. GALNT2 is confirmed further as a potential link connecting lipid metabolism and obesity and has the potential to be a drug target for treating obesity and dyslipidemia. Full article

Angiopoietin-like protein 8 (ANGPTL8) is an hepatokine altered in several metabolic conditions, such as obesity, type 2 diabetes, dyslipidemia and nonalcoholic fatty liver disease (NAFLD). We sought to explore whether ANGPTL8 is involved in NAFLD amelioration after bariatric surgery in experimental models and patients with severe obesity. Plasma ANGPTL8 was measured in 170 individuals before and 6 months after bariatric surgery. Hepatic ANGPTL8 expression was evaluated in liver biopsies of patients with severe obesity undergoing bariatric surgery with available liver pathology analysis (n = 75), as well as in male Wistar rats with diet-induced obesity subjected to sham operation, sleeve gastrectomy or Roux-en-Y gastric bypass (RYGB) (n = 65). The effect of ANGPTL8 on lipogenesis was assessed in human HepG2 hepatocytes under palmitate-induced lipotoxic conditions. Plasma concentrations and hepatic expression of ANGPTL8 were increased in patients with obesity-associated NAFLD in relation to the degree of hepatic steatosis. Sleeve gastrectomy and RYGB improved hepatosteatosis and reduced the hepatic ANGPTL8 expression in the preclinical model of NAFLD. Interestingly, ANGPTL8 inhibited steatosis and expression of lipogenic factors (PPARG2, SREBF1, MOGAT2 and DGAT1) in palmitate-treated human hepatocytes. Together, ANGPTL8 is involved in the resolution of NAFLD after bariatric surgery partially by the inhibition of lipogenesis in steatotic hepatocytes. Full article

Cellular senescence is a cell fate primarily induced by DNA damage, characterized by irreversible growth arrest in an attempt to stop the damage. Senescence is a cellular response to a stressor and is observed with aging, but also during wound healing and in embryogenic developmental processes. Senescent cells are metabolically active and secrete a multitude of molecules gathered in the senescence-associated secretory phenotype (SASP). The SASP includes inflammatory cytokines, chemokines, growth factors and metalloproteinases, with autocrine and paracrine activities. Among hundreds of molecules, angiopoietin-like 2 (angptl2) is an interesting, although understudied, SASP member identified in various types of senescent cells. Angptl2 is a circulatory protein, and plasma angptl2 levels increase with age and with various chronic inflammatory diseases such as cancer, atherosclerosis, diabetes, heart failure and a multitude of age-related diseases. In this review, we will examine in which context angptl2 was identified as a SASP factor, describe the experimental evidence showing that angptl2 is a marker of senescence in vitro and in vivo, and discuss the impact of angptl2-related senescence in both physiological and pathological conditions. Future work is needed to demonstrate whether the senescence marker angptl2 is a potential clinical biomarker of age-related diseases. Full article

Secreted angiopoietin/angiopoietin-like (ANGPT/ANGPTL) proteins are involved in many biological processes. However, the role of these proteins in human breast cancers (BCs) remains largely unclear. Here, we conducted integrated omics analyses to evaluate the clinical impact of ANGPT/ANGPTL proteins and to elucidate their biological functions. In BCs, we identified rare mutations in ANGPT/ANGPTL genes, frequent gains of ANGPT1, ANGPT4, and ANGPTL1, and frequent losses of ANGPT2, ANGPTL5, and ANGPTL7, but observed that ANGPTL1, 2, and 4 were robustly downregulated in multiple datasets. The expression levels of ANGPTL1, 5, and 8 were positively correlated with overall survival (OS), while the expression levels of ANGPTL4 were negatively correlated with OS. Additionally, the expression levels of ANGPTL1 and 7 were positively correlated with distant metastasis-free survival (DMFS), while the expression levels of ANGPT2 and ANGPTL4 were negatively correlated with DMFS. The prognostic impacts of ANGPT/ANGPTL genes depended on the molecular subtypes and on clinical factors. We discovered that various ANGPT/ANGPTL genes were co-expressed with various genes involved in different pathways. Finally, with the exception of ANGPTL3, the remaining genes showed significant correlations with cancer-associated fibroblasts, endothelial cells, and microenvironment score, whereas only ANGPTL6 was significantly correlated with immune score. Our findings provide strong evidence for the distinct clinical impact and biological function of ANGPT/ANGPTL proteins, but the question of whether some of them could be potential therapeutic targets still needs further investigation in BCs. Full article