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World Journal of Diabetes Mar 2024The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is rapidly increasing, currently affecting approximately 25% of the global population....
BACKGROUND
The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is rapidly increasing, currently affecting approximately 25% of the global population. Liver fibrosis represents a crucial stage in the development of MAFLD, with advanced liver fibrosis elevating the risks of cirrhosis and hepatocellular carcinoma. Simple serum markers are less effective in diagnosing liver fibrosis compared to more complex markers. However, imaging techniques like transient elastography face limitations in clinical application due to equipment and technical constraints. Consequently, it is imperative to identify a straightforward yet effective method for assessing MAFLD-associated liver fibrosis.
AIM
To investigate the predictive value of angiopoietin-like protein 8 (ANGPTL8) in MAFLD and its progression.
METHODS
We analyzed 160 patients who underwent abdominal ultrasonography in the Endocrinology Department, Xiaogan Central Hospital affiliated to Wuhan University of Science and Technology, during September 2021-July 2022. Using abdominal ultrasonography and MAFLD diagnostic criteria, among the 160 patients, 80 patients (50%) were diagnosed with MAFLD. The MAFLD group was divided into the liver fibrosis group ( = 23) and non-liver fibrosis group ( = 57) by using a cut-off fibrosis-4 index ≥ 1.45. Logistical regression was used to analyze the risk of MAFLD and the risk factors for its progression. Receiver operating characteristic curves were used to evaluate the predictive value of serum ANGPTL8 in MAFLD and its progression.
RESULTS
Compared with non-MAFLD patients, MAFLD patients had higher serum ANGPTL8 and triglyceride-glucose (TyG) index (both < 0.05). Serum ANGPTL8 ( = 0.576, < 0.001) and TyG index ( = 0.473, < 0.001) were positively correlated with MAFLD. Serum ANGPTL8 was a risk factor for MAFLD [odds ratio (OR): 1.123, 95% confidence interval (CI): 1.066-1.184, < 0.001). Serum ANGPTL8 and ANGPTL8 + TyG index predicted MAFLD [area under the curve (AUC): 0.832 and 0.886, respectively; both < 0.05]. Compared with MAFLD patients without fibrosis, those with fibrosis had higher serum ANGPTL8 and TyG index (both < 0.05), and both parameters were positively correlated with MAFLD-associated fibrosis. Elevated serum ANGPTL8 (OR: 1.093, 95%CI: 1.044-1.144, < 0.001) and TyG index (OR: 2.383, 95%CI: 1.199-4.736, < 0.013) were risk factors for MAFLD-associated fibrosis. Serum ANGPTL8 and ANGPTL8 + TyG index predicted MAFLD-associated fibrosis (AUC: 0.812 and 0.835, respectively; both < 0.05).
CONCLUSION
The serum levels of ANGPTL8 are elevated and positively correlated with MAFLD. They can serve as predictors for the risk of MAFLD and liver fibrosis, with the ANGPTL8 + TyG index potentially exhibiting even higher predictive value.
PubMed: 38591072
DOI: 10.4239/wjd.v15.i3.418 -
Ophthalmology Science 2024To investigate preclinical data regarding the efficacy and biocompatibility of a bispecific protein, RO-101, with effects on VEGF-A and angiopoietin-2 (Ang-2) for use in...
OBJECTIVE
To investigate preclinical data regarding the efficacy and biocompatibility of a bispecific protein, RO-101, with effects on VEGF-A and angiopoietin-2 (Ang-2) for use in retinal diseases.
DESIGN
Experimental study.
SUBJECTS
Brown Norway rats and New Zealand White Cross rabbits.
METHODS
Preclinical study data of RO-101 in terms of target-specific enzyme-linked immunosorbent assay binding affinity to VEGF-A and Ang-2, vitreous half-life, inhibition of target-receptor interaction, laser choroidal neovascular membrane animal model, human umbilical vein endothelial cell migration, and biocompatibility was obtained. Where applicable, study data were compared with other anti-VEGF agents.
MAIN OUTCOME MEASURES
Binding affinity, half-life, biocompatibility, and efficacy of RO-101. Neovascularization prevention by RO-101.
RESULTS
RO-101 demonstrated a strong binding affinity for VEGF-A and Ang-2 and in vitro was able to inhibit binding to the receptor with higher affinity than faricimab. The half-life of RO-101 is comparable to or longer than current VEGF inhibitors used in retinal disease. RO-101 was found to be biocompatible with retinal tissue in Brown Norway rats. RO-101 was as effective or more effective than current anti-VEGF therapeutics in causing regression of neovascular growth in vivo.
CONCLUSIONS
RO-101 is a promising candidate for use in retinal diseases. In preclinical models, RO-101 demonstrated similar or higher regression of neovascular growth to current anti-VEGF therapeutics with comparable or longer half-life. It also demonstrates a strong binding affinity for VEGF-A and Ang-2. It also was shown to be biocompatible with retinal tissue in animal studies, indicating potential compatibility for use in humans.
FINANCIAL DISCLOSURES
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
PubMed: 38591047
DOI: 10.1016/j.xops.2024.100467 -
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