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Journal of Diabetes Research 2024Diabetes mellitus is often accompanied by dyslipidemia. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, as a novel therapeutic agent for the treatment of type 2...
BACKGROUND
Diabetes mellitus is often accompanied by dyslipidemia. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, as a novel therapeutic agent for the treatment of type 2 diabetes mellitus (T2DM), have been reported to exert effects on lipid, while the results remain controversial. This study is aimed at exploring the effect of SGLT2 inhibitor canagliflozin on lipid profile.
METHODS
This study was a single-center, open-label, nonrandomized, prospective study. Metformin (500 mg three times per day) or canagliflozin (100 mg, once daily) was administered for 12 weeks. Fasting blood samples were collected before and 12 weeks after treatment. Serum lipid profile levels and angiopoietin-like protein 3 (ANGPTL3) were determined. In animal experiment, C57BL/6 J mice were divided into three groups including control, STZ + HFD, and STZ + HFD + canagliflozin. Lipid profile and plasma ANGPTL3 level were measured after 12 week's treatment. Moreover, the expression of ANGPTL3 was detected in the liver tissues.
RESULTS
There was a decreased trend in low-density lipoprotein cholesterol (LDL-c) and triglycerides (TG) after canagliflozin treatment, while canagliflozin significantly increased high-density lipoprotein cholesterol (HDL-c) level and decreased plasma ANGPTL3 level. In addition, the expression of ANGPTL3 in liver tissues decreased obviously in diabetic mice with canagliflozin treatment.
CONCLUSIONS
Canagliflozin increases HDL-c level and suppresses ANGPTL3 expression in patients with T2DM and diabetic mice. The reduction of ANGPTL3 may contribute to the increase of HDL-c. However, the specific mechanism needs further research. This trial is registered with ChiCTR1900021231.
Topics: Humans; Mice; Animals; Canagliflozin; Diabetes Mellitus, Type 2; Angiopoietin-Like Protein 3; Cholesterol, HDL; Diabetes Mellitus, Experimental; Prospective Studies; Mice, Inbred C57BL; Triglycerides; Angiopoietin-like Proteins
PubMed: 38577301
DOI: 10.1155/2024/2431441 -
World Journal of Gastroenterology Mar 2024Approximately 20%-30% of patients with acute necrotizing pancreatitis develop infected pancreatic necrosis (IPN), a highly morbid and potentially lethal complication....
Approximately 20%-30% of patients with acute necrotizing pancreatitis develop infected pancreatic necrosis (IPN), a highly morbid and potentially lethal complication. Early identification of patients at high risk of IPN may facilitate appropriate preventive measures to improve clinical outcomes. In the past two decades, several markers and predictive tools have been proposed and evaluated for this purpose. Conventional biomarkers like C-reactive protein, procalcitonin, lymphocyte count, interleukin-6, and interleukin-8, and newly developed biomarkers like angiopoietin-2 all showed significant association with IPN. On the other hand, scoring systems like the Acute Physiology and Chronic Health Evaluation II and Pancreatitis Activity Scoring System have also been tested, and the results showed that they may provide better accuracy. For early prevention of IPN, several new therapies were tested, including early enteral nutrition, antibiotics, probiotics, immune enhancement, , but the results varied. Taken together, several evidence-supported predictive markers and scoring systems are readily available for predicting IPN. However, effective treatments to reduce the incidence of IPN are still lacking apart from early enteral nutrition. In this editorial, we summarize evidence concerning early prediction and prevention of IPN, providing insights into future practice and study design. A more homogeneous patient population with reliable risk-stratification tools may help find effective treatments to reduce the risk of IPN, thereby achieving individualized treatment.
Topics: Humans; Pancreatitis, Acute Necrotizing; Biomarkers; C-Reactive Protein; Treatment Outcome; Acute Disease; Necrosis
PubMed: 38577189
DOI: 10.3748/wjg.v30.i9.1005 -
Annals of Medicine Dec 2024Angiopoietin-like protein 4 (ANGPTL4) is recognized as a crucial regulator in lipid metabolism. Acetyl-CoA carboxylases (ACACAs) play a role in the β-oxidation of fatty...
BACKGROUND
Angiopoietin-like protein 4 (ANGPTL4) is recognized as a crucial regulator in lipid metabolism. Acetyl-CoA carboxylases (ACACAs) play a role in the β-oxidation of fatty acids. Yet, the functions of ANGPTL4 and ACACA in dyslipidemia of obstructive sleep apnea (OSA) remain unclear.
METHODS
This study included 125 male OSA subjects from the Shanghai Sleep Health Study (SSHS) who were matched for age, body mass index (BMI), and lipid profile. Serum ANGPTL4 levels were measured ELISA. The ANGPTL4 T266M variants of 4455 subjects along with their anthropometric, fasting biochemical, and standard polysomnographic parameters were collected. Linear regression was used to analyze the associations between quantitative traits and ANGPTL4 T266M. Molecular docking and molecular dynamic simulation were employed to compare the effects of the wild-type ANGPTL4 and its T266M mutation on ACACA.
RESULTS
Serum ANGPTL4 levels significantly decreased with increasing OSA severity (non-OSA: 59.6 ± 17.4 ng/mL, mild OSA: 50.0 ± 17.5 ng/mL, moderate OSA: 46.3 ± 15.5 ng/mL, severe OSA: 19.9 ± 14.3 ng/mL, respectively, = 6.02 × 10). No associations were found between T266M and clinical characteristics. Molecular docking indicated that mutant ANGTPL4 T266M had stronger binding affinity for the ACACA protein, compared with wild-type ANGPTL4. In terms of protein secondary structure, mutant ANGTPL4 T266M demonstrated greater stability than wild-type ANGPTL4.
CONCLUSIONS
Serum ANGTPL4 levels were significantly decreased in OSA patients, particularly among individuals with severe OSA. Although functional ANGTPL4 T266M variants were not associated with lipid levels in OSA, ANGTPL4 T266M could enhance binding affinity for the ACACA protein, potentially regulating lipid metabolism.
Topics: Humans; Male; Acetyl-CoA Carboxylase; Angiopoietin-Like Protein 4; Lipid Metabolism; Molecular Docking Simulation; China; Sleep Apnea, Obstructive; Lipids
PubMed: 38574398
DOI: 10.1080/07853890.2024.2337740 -
The Journal of Clinical Investigation Apr 2024BACKGROUNDThe molecular signature of pediatric acute respiratory distress syndrome (ARDS) is poorly described, and the degree to which hyperinflammation or specific... (Clinical Trial)
Clinical Trial
BACKGROUNDThe molecular signature of pediatric acute respiratory distress syndrome (ARDS) is poorly described, and the degree to which hyperinflammation or specific tissue injury contributes to outcomes is unknown. Therefore, we profiled inflammation and tissue injury dynamics over the first 7 days of ARDS, and associated specific biomarkers with mortality, persistent ARDS, and persistent multiple organ dysfunction syndrome (MODS).METHODSIn a single-center prospective cohort of intubated pediatric patients with ARDS, we collected plasma on days 0, 3, and 7. Nineteen biomarkers reflecting inflammation, tissue injury, and damage-associated molecular patterns (DAMPs) were measured. We assessed the relationship between biomarkers and trajectories with mortality, persistent ARDS, or persistent MODS using multivariable mixed effect models.RESULTSIn 279 patients (64 [23%] nonsurvivors), hyperinflammatory cytokines, tissue injury markers, and DAMPs were higher in nonsurvivors. Survivors and nonsurvivors showed different biomarker trajectories. IL-1α, soluble tumor necrosis factor receptor 1, angiopoietin 2 (ANG2), and surfactant protein D increased in nonsurvivors, while DAMPs remained persistently elevated. ANG2 and procollagen type III N-terminal peptide were associated with persistent ARDS, whereas multiple cytokines, tissue injury markers, and DAMPs were associated with persistent MODS. Corticosteroid use did not impact the association of biomarker levels or trajectory with mortality.CONCLUSIONSPediatric ARDS survivors and nonsurvivors had distinct biomarker trajectories, with cytokines, endothelial and alveolar epithelial injury, and DAMPs elevated in nonsurvivors. Mortality markers overlapped with markers associated with persistent MODS, rather than persistent ARDS.FUNDINGNIH (K23HL-136688, R01-HL148054).
Topics: Humans; Biomarkers; Male; Female; Child; Child, Preschool; Respiratory Distress Syndrome; Infant; Inflammation; Prospective Studies; Adolescent; Multiple Organ Failure; Cytokines
PubMed: 38573766
DOI: 10.1172/JCI177896 -
Heliyon Apr 2024Non-alcoholic fatty liver disease (NAFLD) is the most frequent cause of chronic liver disease, with a range of conditions including non-alcoholic fatty liver,... (Review)
Review
Non-alcoholic fatty liver disease (NAFLD) is the most frequent cause of chronic liver disease, with a range of conditions including non-alcoholic fatty liver, non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Currently recognized as the liver component of the metabolic syndrome, NAFLD is intimately linked to metabolic diseases. Angiopoietin-like proteins (ANGPTLs) comprise a class of proteins that resemble angiopoietins structurally. It is closely related to obesity, insulin resistance and lipid metabolism, and may be the critical factor of metabolic syndrome. In recent years, many studies have found that there is a certain correlation between ANGPTLs and the occurrence and progression of NAFLD disease spectrum. This article reviews the possible mechanisms and roles of ANGPTL protein in the pathogenesis and progression of NAFLD.
PubMed: 38560164
DOI: 10.1016/j.heliyon.2024.e27739 -
Resuscitation Plus Jun 2024Acute blood loss not only leads to systemic compensatory response, but also the induced changes in vascular endothelial function.These pathological changes may have...
BACKGROUND
Acute blood loss not only leads to systemic compensatory response, but also the induced changes in vascular endothelial function.These pathological changes may have potential compensatory significance for maintaining organ perfusion and fluid resuscitation.
OBJECTIVE
To understand trauma-induced endotheliopathy and their compensatory roles in acute hemorrhage, a porcine model of hemorrhagic shock (HS) was used to evaluate changes in vascular endothelial factors and catecholamine levels at different time points from shock to fluid resuscitation. Methods: HS was induced in female pigs by rapid bleeding via the arterial sheath. Hemodynamic monitoring was performed using a pulse index continuous cardiac output (PiCCO) system in HS and fluid resuscitation. Femoral vein blood samples were collected at baseline and 40% mean arterial pressure (MAP, shock), MAP recovery, and 30 min, 1 h, and 2 h after recovery. Serum levels of catecholamine and Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), Tie-2, Eselectin, intracellular adhesion molecule-1 (ICAM-1), soluble thrombomodulin (sTM), and Syndecan-1 (SDC-1) were evaluated using enzyme-linked immunosorbent assay (ELISA).
RESULTS
Serum catecholamine levels were significantly higher in the shock than in the baseline state. Ang-1 and Ang-2 are endothelial growth factors secreted with distinct roles. Ang-1 stabilizes the endothelium and inhibits vascular leakage, and Ang-2 has the opposite effect. The ratio of Ang-2/Ang-1 was significantly higher in the shock state than in the baseline state; however, the Ang-1/Tie-2 ratio was comparable between the two states. This suggests that changes in vascular permeability may mainly depend on the upregulation of Ang-2 function. Serum levels of E-selectin, ICAM-1, sTM, and SDC-1 were significantly higher in the shock state than in the baseline state. After the MAP was restored to the baseline state, the levels of E-selectin, and SDC-1 remained higher compared with the baseline state until 1 h after MAP recovery. Conclusions: serum levels of catecholamines and vascular endothelial markers increased transiently under HS, promoting a compensatory response of the circulatory system to acute bleeding. This may be one of the potential theoretical basis for restrictive fluid resuscitation.
PubMed: 38549695
DOI: 10.1016/j.resplu.2024.100618 -
International Journal of Molecular... Mar 2024Angiopoietin-like protein 3 (ANGPTL3) is a plasmatic protein that plays a crucial role in lipoprotein metabolism by inhibiting the lipoprotein lipase (LPL) and the...
Angiopoietin-like protein 3 (ANGPTL3) is a plasmatic protein that plays a crucial role in lipoprotein metabolism by inhibiting the lipoprotein lipase (LPL) and the endothelial lipase (EL) responsible for the hydrolysis of phospholipids on high-density lipoprotein (HDL). Interest in developing new pharmacological therapies aimed at inhibiting ANGPTL3 has been growing due to the hypolipidemic and antiatherogenic profile observed in its absence. The goal of this study was the in silico characterization of the interaction between ANGPTL3 and EL. Because of the lack of any structural information on both the trimeric coiled-coil N-terminal domain of ANGPTL3 and the EL homodimer as well as data regarding their interactions, the first step was to obtain the three-dimensional model of these two proteins. The models were then refined via molecular dynamics (MD) simulations and used to investigate the interaction mechanism. The analysis of interactions in different docking poses and their refinement via MD allowed the identification of three specific glutamates of ANGPTL3 that recognize a positively charged patch on the surface of EL. These ANGPTL3 key residues, i.e., Glu154, Glu157, and Glu160, could form a putative molecular recognition site for EL. This study paves the way for future investigations aimed at confirming the recognition site and at designing novel inhibitors of ANGPTL3.
Topics: Angiopoietin-Like Protein 3; Angiopoietin-like Proteins; Lipase; Lipoprotein Lipase; Lipoproteins, HDL; Phospholipids; Triglycerides; Angiopoietins
PubMed: 38542527
DOI: 10.3390/ijms25063555 -
International Journal of Molecular... Mar 2024Hypoxia-inducible factor-1α (HIF-1α) is a major transcriptional factor, which plays an important role in cellular reprogramming processes under hypoxic conditions,... (Review)
Review
Hypoxia-inducible factor-1α (HIF-1α) is a major transcriptional factor, which plays an important role in cellular reprogramming processes under hypoxic conditions, which facilitate solid tumors' progression. HIF-1α is directly involved in the regulation of the angiogenesis, metabolic reprogramming, and extracellular matrix remodeling of the tumor microenvironment. Therefore, an in-depth study on the role of HIF-1α in solid tumor malignancies is required to develop novel anti-cancer therapeutics. HIF-1α also plays a critical role in regulating growth factors, such as the vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor, in a network manner. Additionally, it plays a significant role in tumor progression and chemotherapy resistance by regulating a variety of angiogenic factors, including angiopoietin 1 and angiopoietin 2, matrix metalloproteinase, and erythropoietin, along with energy pathways. Therefore, this review attempts to provide comprehensive insight into the role of HIF-1α in the energy and angiogenesis pathways of solid tumors.
Topics: Humans; Vascular Endothelial Growth Factor A; Signal Transduction; Cell Line, Tumor; Transcription Factors; Vascular Endothelial Growth Factors; Hypoxia-Inducible Factor 1, alpha Subunit; Neovascularization, Pathologic
PubMed: 38542288
DOI: 10.3390/ijms25063313 -
Acta Neuropathologica Communications Mar 2024Sturge-Weber syndrome (SWS), a neurocutaneous disorder, is characterized by capillary malformations (CM) in the skin, brain, and eyes. Patients may suffer from seizures,...
Sturge-Weber syndrome (SWS), a neurocutaneous disorder, is characterized by capillary malformations (CM) in the skin, brain, and eyes. Patients may suffer from seizures, strokes, and glaucoma, and only symptomatic treatment is available. CM are comprised of enlarged vessels with endothelial cells (ECs) and disorganized mural cells. Our recent finding indicated that the R183Q mutation in ECs leads to heightened signaling through phospholipase Cβ3 and protein kinase C, leading to increased angiopoietin-2 (ANGPT2). Furthermore, knockdown of ANGPT2, a crucial mediator of pro-angiogenic signaling, inflammation, and vascular remodeling, in EC-R183Q rescued the enlarged vessel phenotype in vivo. This prompted us to look closer at the microenvironment in CM-affected vascular beds. We analyzed multiple brain histological sections from patients with GNAQ-R183Q CM and found enlarged vessels devoid of mural cells along with increased macrophage-like cells co-expressing MRC1 (CD206, a mannose receptor), CD163 (a scavenger receptor and marker of the monocyte/macrophage lineage), CD68 (a pan macrophage marker), and LYVE1 (a lymphatic marker expressed by some macrophages). These macrophages were not found in non-SWS control brain sections. To investigate the mechanism of increased macrophages in the perivascular environment, we examined THP1 (monocytic/macrophage cell line) cell adhesion to EC-R183Q versus EC-WT under static and laminar flow conditions. First, we observed increased THP1 cell adhesion to EC-R183Q compared to EC-WT under static conditions. Next, using live cell imaging, we found THP1 cell adhesion to EC-R183Q was dramatically increased under laminar flow conditions and could be inhibited by anti-ICAM1. ICAM1, an endothelial cell adhesion molecule required for leukocyte adhesion, was strongly expressed in the endothelium in SWS brain histological sections, suggesting a mechanism for recruitment of macrophages. In conclusion, our findings demonstrate that macrophages are an important component of the perivascular environment in CM suggesting they may contribute to the CM formation and SWS disease progression.
Topics: Humans; Sturge-Weber Syndrome; Endothelial Cells; Capillaries; Macrophages; Tumor Microenvironment; Vesicular Transport Proteins; GTP-Binding Protein alpha Subunits, Gq-G11; Vascular Malformations
PubMed: 38532508
DOI: 10.1186/s40478-024-01757-4 -
American Journal of Veterinary Research Jun 2024To evaluate the relationships between the severity of myxomatous mitral valve disease (MMVD) and pulmonary hypertension (PH) and serum angiopoietin (Ang)-1 and Ang-2...
OBJECTIVE
To evaluate the relationships between the severity of myxomatous mitral valve disease (MMVD) and pulmonary hypertension (PH) and serum angiopoietin (Ang)-1 and Ang-2 concentrations in dogs with MMVD.
ANIMALS
74 dogs (control, n = 12; MMVD, n = 62) were included.
METHODS
Serum Ang-1 and Ang-2 concentrations were estimated using the canine-specific ELISA kit. The concentrations were compared between dogs with MMVD and healthy dogs, and they were analyzed according to the severity of MMVD and PH.
RESULTS
The median serum Ang-1 concentration did not differ among the study groups. The median serum Ang-2 concentration was higher in dogs with stage B2 MMVD (P = .041) and acute congestive heart failure (P = .002) than in control dogs. In addition, the median serum Ang-2 concentration was higher in MMVD dogs with PH than in those without PH (P = .031). Serum Ang-2 concentration was correlated with vertebral heart score (rs = 0.36, P = .004) and vertebral left atrial score (r = 0.50, P < .001) in dogs with MMVD, and correlated with vertebral heart score (r = 0.63, P = .01), maximum E wave amplitude of the diastolic transmitral flow (rs = 0.61, P = .018), ejection fraction (rs = -0.77, P < .001) and fractional shortening (rs = -0.56, P = .032) in dogs with acute congestive heart failure.
CLINICAL RELEVANCE
Circulating Ang-2 levels increase in dogs with the severity of MMVD and the presence of PH.
Topics: Animals; Dogs; Dog Diseases; Hypertension, Pulmonary; Angiopoietin-2; Male; Female; Mitral Valve Insufficiency; Angiopoietin-1; Case-Control Studies; Heart Valve Diseases
PubMed: 38531156
DOI: 10.2460/ajvr.23.12.0289