Biomolecules

Research

15 pages, 2558 KiB

Open AccessArticle

Plasma Levels of Propionylcarnitine Improved Prediction of Heart Failure and All-Cause Mortality in Patients with Stable Coronary Artery Disease

by Jairo Lumpuy-Castillo, Francisco J. Rupérez, Brenda Lee Simas Porto, Carmen Cristóbal, Nieves Tarín, Ana Isabel Huelmos, Joaquín Alonso, Jesús Egido, Ignacio Mahíllo-Fernández, Lorenzo López-Bescós, José Tuñón and Óscar Lorenzo

Biomolecules 2025, 15(1), 27; https://doi.org/10.3390/biom15010027 - 29 Dec 2024

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Abstract

Background: Plasma metabolites could be suitable as predictive biomarkers for cardiovascular pathologies or death, thereby improving the prediction of protein biomarkers. The release of acylcarnitines may be altered after coronary artery disease (CAD) in subjects with recurrent clinical outcomes, and this could be [...] Read more.

Background: Plasma metabolites could be suitable as predictive biomarkers for cardiovascular pathologies or death, thereby improving the prediction of protein biomarkers. The release of acylcarnitines may be altered after coronary artery disease (CAD) in subjects with recurrent clinical outcomes, and this could be used as a prognosis tool. Methods: Patients with stable coronary artery disease (SCAD) who had suffered an acute coronary syndrome 6–9 months before were followed for up to 4.3 years for adverse events. Soluble pro-inflammatory/fibrotic proteins, and a panel of 13 amino acids and 13 acylcarnitines, were evaluated by ELISA and metabolomics analyses as potential predictors of a primary outcome [heart failure (HF) or death]. Results: Among 139 patients (67.0 years old, BMI = 28.6 kg/m², and 71.2% male), 25 developed the primary outcome after a mean follow-up of 2.2 years. These patients showed increased plasma levels of NT-proBNP (1300 vs. 250 pg/mL; p < 0.001), pro-inflammatory/fibrotic MCP-1 (1.7 vs. 1.4 × 10² pg/mL; p = 0.043), Gal-3 (12.7 vs. 7.9 ng/mL; p < 0.001), and NGAL (2.7 vs. 1.6 × 10² ng/mL; p < 0.001), and lower acetyl- and propionylcarnitines (0.59 vs. 0.99 µM, p = 0.007, and 3.22 vs. 6.49 × 10⁻² µM, p < 0.001, respectively). Instead, plasma amino acids were not significantly changed. Through a multivariable logistic regression analysis, a combined model of age, Gal-3, and the NGAL/propionylcarnitine ratio showed the highest prediction for HF or death (AUC = 0.88, sensitivity = 0.8, and specificity = 0.81; p < 0.001). Conclusions: Patients with SCAD led to recurrent HF or all-cause death. Interestingly, increased levels of plasma NGAL and Gal-3, and a reduction in propionylcarnitine, could predict the occurrence of these events. Full article

(This article belongs to the Special Issue New Insights into Cardiometabolic Diseases)

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19 pages, 1313 KiB

Open AccessArticle

Cardiovascular Risk Biomarkers in Women with and Without Polycystic Ovary Syndrome

by Manjula Nandakumar, Priya Das, Thozhukat Sathyapalan, Alexandra E. Butler and Stephen L. Atkin

Biomolecules 2025, 15(1), 4; https://doi.org/10.3390/biom15010004 - 24 Dec 2024

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Abstract

Objective: Polycystic ovary syndrome (PCOS) is a prevalent metabolic disorder with an increased risk for cardiovascular disease (CVD) that is enhanced by obesity. This study sought to determine whether a panel of cardiovascular risk proteins (CVRPs) would be dysregulated in overweight/obese PCOS patients, [...] Read more.

Objective: Polycystic ovary syndrome (PCOS) is a prevalent metabolic disorder with an increased risk for cardiovascular disease (CVD) that is enhanced by obesity. This study sought to determine whether a panel of cardiovascular risk proteins (CVRPs) would be dysregulated in overweight/obese PCOS patients, highlighting potential biomarkers for CVD in PCOS. Methods: In this exploratory cross-sectional study, plasma levels of 54 CVRPs were analyzed in women with PCOS (n = 147) and controls (n = 97). CVRPs were measured using the SOMAscan proteomic platform (version 3.1), with significant proteins identified through linear models, regression analysis, and receiver operating characteristic (ROC) analysis. Analysis on BMI-matched subsets of the cohort were undertaken. Functional enrichment and protein–protein interaction analyses elucidated the pathways involved. Results: Eleven CVRPs were dysregulated in PCOS (whole set, without matching for body mass index (BMI) or insulin resistance (IR)): leptin, Interleukin-1 receptor antagonist protein (IL-1Ra), polymeric immunoglobulin receptor (PIGR), interleukin-18 receptor (IL-18Ra), C-C motif chemokine 3 (MIP-1a), and angiopoietin-1 (ANGPT1) were upregulated whilst advanced glycosylation end product-specific receptor, soluble (sRAGE), bone morphogenetic protein 6 (BMP6); growth/differentiation factor 2 (GDF2), superoxide dismutase [Mn] mitochondrial (MnSOD), and SLAM family member 5 (SLAF5) were downregulated versus the controls. In BMI-matched (overweight/obese, BMI ≥ 26 kg/m²) subset analysis, six CVRPs were common to the whole set: ANGPT1 and IL-1Ra were upregulated; and sRAGE, BMP6, GDF2, and Mn-SOD were downregulated. In addition, lymphotactin (XCL1) was upregulated and placenta growth factor (PIGF), alpha-L-iduronidase (IDUA), angiopoietin-1 receptor, and soluble (sTie-2) and macrophage metalloelastase (MMP12) were downregulated. A subset analysis of BMI-matched plus insulin resistance (IR)-matched women revealed only upregulation of tissue factor (TF) and renin in PCOS, potentially serving as biomarkers for cardiovascular risk in overweight/obese women with PCOS. Conclusions: A combination of upregulated obesity-related CVRPs (ANGPT1/IL/1Ra/XCL1) and downregulated cardioprotective proteins (sRAGE/BMP6/Mn-SOD/GDF2) in overweight/obese PCOS women may contribute to the increased risk for CVD. TF and renin upregulation observed in the BMI- and IR-matched limited sample PCOS subgroup indicates their potential risk of CVD. Full article

(This article belongs to the Special Issue New Insights into Cardiometabolic Diseases)

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13 pages, 795 KiB

Open AccessArticle

Irisin Predicts Poor Clinical Outcomes in Patients with Heart Failure with Preserved Ejection Fraction and Low Levels of N-Terminal Pro-B-Type Natriuretic Peptide

by Tetiana A. Berezina, Oleksandr O. Berezin, Evgen V. Novikov, Michael Lichtenauer and Alexander E. Berezin

Biomolecules 2024, 14(12), 1615; https://doi.org/10.3390/biom14121615 - 17 Dec 2024

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Abstract

Background: Despite existing evidence of the high predictive value of natriuretic peptides (NPs) in patients with heart failure (HF), patients treated with guideline-directed therapy who have low or near-normal NP levels are unlikely to be correctly stratified for risk of clinical outcomes. The [...] Read more.

Background: Despite existing evidence of the high predictive value of natriuretic peptides (NPs) in patients with heart failure (HF), patients treated with guideline-directed therapy who have low or near-normal NP levels are unlikely to be correctly stratified for risk of clinical outcomes. The aim of this study is to detect plausible predictors for poor one-year clinical outcomes in patients with HFpEF and low NT-proBNP treated with in accordance with conventional guidelines. Methods: A total of 337 patients with HF with preserved ejection fraction (HFpEF) who had low levels of N-terminal natriuretic pro-peptide (NT-proBNP) at discharge due to optimal guideline-based therapy were enrolled in the study. The course of the observation was 3 years. Echocardiography and the assessment of conventional hematological and biochemical parameters, including NT-proBNP, tumor necrosis factor-alpha, high-sensitivity C-reactive protein (hs-CRP), adropin, irisin, visfatin, and fetuin-A, were performed at baseline and at the end of the study. Results: Three-year cumulative clinical endpoints (cardiovascular death, myocardial infarction or unstable angina or acute coronary syndrome, worsening HF, sudden cardiac death, or cardiac-related surgery or all-cause death) were detected in 104 patients, whereas 233 did not meet the endpoint. After adjusting for an age ≥ 64 years and a presence of atrial fibrillation, diabetes mellitus, chronic kidney disease (CKD) stages 1–3 and dilated cardiomyopathy, the multivariable Cox regression analysis showed that an irisin level of ≤7.2 ng/mL was an independent predictor of cumulative clinical endpoint. Moreover, patients with levels of irisin > 7.2 ng/mL had a better Kaplan–Meier survival rate than those with a lower serum irisin level (≤7.2 ng/mL). Conclusions: Multivariable analysis showed that an age ≥ 64 years; the presence of atrial fibrillation, diabetes mellitus, CKD stages 1–3 and dilated cardiomyopathy; an LAVI ≥ 39 mL/m²; and serum levels of hs-CRP ≥ 6.10 mg/L, irisin ≤ 7.2 ng/mL, and visfatin ≤ 1.1 ng/mL were predictors of poor clinical outcomes in HFpEF with low levels of NT-proBNP. A serum level of irisin ≤ 7.2 ng/mL could emerge as valuable biomarker for predicting long-term prognosis among HFpEF patients with low or near-normal levels of NT-proBNP. Full article

(This article belongs to the Special Issue New Insights into Cardiometabolic Diseases)

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14 pages, 2003 KiB

Open AccessArticle

Exploring Causal Associations Between Serum Inflammatory Markers and Female Reproductive Disorders: A Mendelian Randomisation Study

by Simon Alesi, Helena Teede, Lisa Moran, Joanne Enticott, Kushan De Silva and Aya Mousa

Biomolecules 2024, 14(12), 1544; https://doi.org/10.3390/biom14121544 - 2 Dec 2024

Viewed by 950

Abstract

Although inflammation may disrupt immunoendocrine crosstalk essential for female reproductive function, causal links to disorders like polycystic ovary syndrome (PCOS) and endometriosis remain unestablished. This study aimed to utilise Mendelian randomisation (MR) methods to explore causal associations between serum inflammatory markers and common [...] Read more.

Although inflammation may disrupt immunoendocrine crosstalk essential for female reproductive function, causal links to disorders like polycystic ovary syndrome (PCOS) and endometriosis remain unestablished. This study aimed to utilise Mendelian randomisation (MR) methods to explore causal associations between serum inflammatory markers and common reproductive disorders, aiming to identify novel mechanisms and potential avenues for treatment. Total causal effects of serum inflammatory markers (interleukins, monocyte chemoattractant protein-1, etc.) on female reproductive disorders in large sample cohorts of Finnish ancestry were assessed using univariable two-sample MR methods, including the inverse variance weighted (IVW) method as the primary analysis, with relevant quality assessments (e.g., leave-one out, heterogeneity, and horizontal pleiotropy testing). The main outcome measures were PCOS (642 cases and 118,228 controls) and endometriosis (8288 cases and 68,969 controls) from the FINNGEN cohort. Monocyte chemoattractant protein-1/C-C motif chemokine ligand demonstrated a positive causal association with polycystic ovary syndrome (odds ratio [95% CI]: 1.48 [1.10, 2.00], p = 0.0097), while higher interleukin-9 levels were positively associated with endometriosis (1.15 [1.02, 1.30], p = 0.0277), both via the IVW method. These markers should be investigated as key candidates for future research into the mechanistic pathways underpinning these conditions. Full article

(This article belongs to the Special Issue New Insights into Cardiometabolic Diseases)

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16 pages, 1557 KiB

Open AccessArticle

Urate Levels as a Predictor of the Prevalence and Level of Cardiovascular Risk Factors: An Identificación de La PoBlación Española de Riesgo Cardiovascular y Renal Study

by Paula Antelo-Pais, Miguel Ángel Prieto-Díaz, Rafael M. Micó-Pérez, Vicente Pallarés-Carratalá, Sonsoles Velilla-Zancada, José Polo-García, Alfonso Barquilla-García, Leovigildo Ginel-Mendoza, Antonio Segura-Fragoso, Facundo Vitelli-Storelli, Vicente Martín-Sánchez, Álvaro Hermida-Ameijerias, Sergio Cinza-Sanjurjo and on behalf of the Investigators of the IBERICAN Study and of the Spanish Society of Primary Care Physicians (SEMERGEN) Foundation

Biomolecules 2024, 14(12), 1530; https://doi.org/10.3390/biom14121530 - 29 Nov 2024

Viewed by 807

Abstract

(1) Background: Urate levels lower than the classical cut-off point for defining hyperuricemia can increase cardiovascular risks. The aim of this study is to determine if there is a relationship between different urate levels and classic cardiovascular risk factors (CVRFs). (2) Methods: A [...] Read more.

(1) Background: Urate levels lower than the classical cut-off point for defining hyperuricemia can increase cardiovascular risks. The aim of this study is to determine if there is a relationship between different urate levels and classic cardiovascular risk factors (CVRFs). (2) Methods: A cross-sectional study of the inclusion visits of the patients recruited to the IBERICAN study was conducted. The patients were classified into quartiles according to their distribution of urate levels and separated by sex; the three lower points corresponded to normal levels of urate, and the highest quartile was determined according to the classical definition of HU. Multivariate analysis models, adjusted for epidemiological variables, were used to analyze the association of urate levels with CVRFs. (3) Results: The presence of CVRFs was higher across the quartiles of urate, with a continuous increase along the quartiles in both sexes in accordance with body mass index (p < 0.01), waist circumference (p < 0.01), blood pressure (p < 0.01), and LDL cholesterol (p < 0.01). The CV risk estimated by SCORE was associated with an increase along the quartiles in women (p = 0.02). (4) Conclusions: A progressive increase in the frequency of CVRFs, as well as in their levels, was observed across the quartiles of uricemia, which reflects an increase in the CVRs associated with uricemia. Full article

(This article belongs to the Special Issue New Insights into Cardiometabolic Diseases)

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21 pages, 6756 KiB

Open AccessEditor’s ChoiceArticle

Plasma and Myocardial miRNomes Similarities and Differences during Cardiac Remodelling and Reverse Remodelling in a Murine Model of Heart Failure with Preserved Ejection Fraction

by Sara-Ève Thibodeau, Emylie-Ann Labbé, Élisabeth Walsh-Wilkinson, Audrey Morin-Grandmont, Marie Arsenault and Jacques Couet

Biomolecules 2024, 14(8), 892; https://doi.org/10.3390/biom14080892 - 24 Jul 2024

Viewed by 1254

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome characterised by multiple risk factors touching various organs outside the heart. Using a murine HFpEF model, we studied cardiac reverse remodelling (RR) after stopping the causing metabolic-hypertensive stress (MHS; Angiotensin II [AngII] [...] Read more.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome characterised by multiple risk factors touching various organs outside the heart. Using a murine HFpEF model, we studied cardiac reverse remodelling (RR) after stopping the causing metabolic-hypertensive stress (MHS; Angiotensin II [AngII] and a high-fat diet [HFD]) after 28 days and introducing voluntary exercise (VE) for four more weeks. We measured the effects of MHS and RR on the plasma and myocardial microRNA (miR) profile (miRNome) to characterise better cardiac and non-cardiac responses to HFpEF-inducing risk factors and their reversibility. AngII alone, the HFD or the MHS caused cardiac hypertrophy (CH), left ventricular (LV) concentric remodelling and left atrial enlargement in females. Only AngII and the MHS, but not HFD, did in males. After RR, CH, LV concentric remodelling and atrial enlargement were normalised. Among the 25 most abundant circulating miRs, 10 were modulated by MHS. Plasma miRNomes from AngII, HFD or MHS mice shared 31 common significantly modulated miRs (24 upregulated and 7 downregulated), suggesting that the response of organs producing the bulk of those circulating miRs was similar even for seemingly different stress. In the LV, 19 out of 25 most expressed miRs were modulated. RR restored normality for the plasma miRNome but not for the LV miRNome, which remained mostly unchanged. Our results suggest that abnormalities persist in the myocardium of the HFpEF mice and that the normalisation of circulatory markers may be falsely reassuring after recovery. Full article

(This article belongs to the Special Issue New Insights into Cardiometabolic Diseases)

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Review

Jump to: Research, Other

28 pages, 12695 KiB

Open AccessReview

Advances in the Development of Mitochondrial Pyruvate Carrier Inhibitors for Therapeutic Applications

by Henry Politte, Lingaiah Maram and Bahaa Elgendy

Biomolecules 2025, 15(2), 223; https://doi.org/10.3390/biom15020223 - 3 Feb 2025

Abstract

The mitochondrial pyruvate carrier (MPC) is a transmembrane protein complex critical for cellular energy metabolism, enabling the transport of pyruvate from the cytosol into the mitochondria, where it fuels the citric acid cycle. By regulating this essential entry point of carbon into mitochondrial [...] Read more.

The mitochondrial pyruvate carrier (MPC) is a transmembrane protein complex critical for cellular energy metabolism, enabling the transport of pyruvate from the cytosol into the mitochondria, where it fuels the citric acid cycle. By regulating this essential entry point of carbon into mitochondrial metabolism, MPC is pivotal for maintaining cellular energy balance and metabolic flexibility. Dysregulation of MPC activity has been implicated in several metabolic disorders, including type 2 diabetes, obesity, and cancer, underscoring its potential as a therapeutic target. This review provides an overview of the MPC complex, examining its structural components, regulatory mechanisms, and biological functions. We explore the current understanding of transcriptional, translational, and post-translational modifications that modulate MPC function and highlight the clinical relevance of MPC dysfunction in metabolic and neurodegenerative diseases. Progress in the development of MPC-targeting therapeutics is discussed, with a focus on challenges in designing selective and potent inhibitors. Emphasis is placed on modern approaches for identifying novel inhibitors, particularly virtual screening and computational strategies. This review establishes a foundation for further research into the medicinal chemistry of MPC inhibitors, promoting advances in structure-based drug design to develop therapeutics for metabolic and neurodegenerative diseases. Full article

(This article belongs to the Special Issue New Insights into Cardiometabolic Diseases)

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22 pages, 2458 KiB

Open AccessReview

Metabolic Dysfunction-Associated Steatotic Liver Disease: Pathogenetic Links to Cardiovascular Risk

by Vlad Alexandru Ionescu, Gina Gheorghe, Nicolae Bacalbasa and Camelia Cristina Diaconu

Biomolecules 2025, 15(2), 163; https://doi.org/10.3390/biom15020163 - 22 Jan 2025

Viewed by 477

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is correlated with an increased cardiovascular risk, independent of other traditional risk factors. The mechanisms underlying this pathogenic link are complex yet remain incompletely elucidated. Among these, the most significant are visceral adiposity, low-grade inflammation and oxidative [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is correlated with an increased cardiovascular risk, independent of other traditional risk factors. The mechanisms underlying this pathogenic link are complex yet remain incompletely elucidated. Among these, the most significant are visceral adiposity, low-grade inflammation and oxidative stress, endothelial dysfunction, prothrombotic status, insulin resistance, dyslipidemia and postprandial hyperlipemia, gut dysbiosis, and genetic mutations. Cardiovascular diseases are the leading cause of death in patients with MASLD. These patients have an increased incidence of coronary artery disease, carotid artery disease, structural and functional cardiac abnormalities, and valvulopathies, as well as arrhythmias and cardiac conduction disorders. In this review, we present the latest data on the association between MASLD and cardiovascular risk, focusing on the pathogenic mechanisms that explain the correlation between these two pathologies. Given the high rates of cardiovascular morbidity and mortality among patients with MASLD, we consider it imperative to raise awareness of the risks associated with this condition within the general population. Further research is essential to clarify the mechanisms underlying the increased cardiovascular risk linked to MASLD. This understanding may facilitate the identification of new diagnostic and prognostic biomarkers for these patients, as well as novel therapeutic targets. Full article

(This article belongs to the Special Issue New Insights into Cardiometabolic Diseases)

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20 pages, 1734 KiB

Open AccessReview

Interaction Between Lipoprotein(a) and Other Lipid Molecules: A Review of the Current Literature

by Hesham Sheashaa, Hana Mousa, Mohammed Tiseer Abbas, Juan M. Farina, Kamal Awad, Milagros Pereyra, Isabel G. Scalia, Nima Baba Ali, Niloofar Javadi, Nadera N. Bismee, Sogol Attaripour Esfahani, Omar Ibrahim, Fatmaelzahraa Abdelfattah, Ramzi Ibrahim, Mahmoud Abdelnabi, Chadi Ayoub and Reza Arsanjani

Biomolecules 2025, 15(2), 162; https://doi.org/10.3390/biom15020162 - 22 Jan 2025

Viewed by 856

Abstract

Lipoprotein(a) [Lp(a)] is a well-established causal risk factor for cardiovascular diseases (CVDs), as reported by multiple Mendelian randomization studies and large epidemiological studies. When elevated Lp(a) is combined with other risk factors, most notably elevated low-density lipoprotein cholesterol (LDL-C), a synergistic atherogenic effect [...] Read more.

Lipoprotein(a) [Lp(a)] is a well-established causal risk factor for cardiovascular diseases (CVDs), as reported by multiple Mendelian randomization studies and large epidemiological studies. When elevated Lp(a) is combined with other risk factors, most notably elevated low-density lipoprotein cholesterol (LDL-C), a synergistic atherogenic effect has been reported. However, the current literature is conflicting regarding how Lp(a) interacts in the context of controlled LDL-C levels (e.g., <70 mg/dL) and whether reducing LDL-C can modify the atherogenic effect of Lp(a). In some studies, elevated Lp(a) was still significantly associated with a higher risk of cardiovascular events, despite controlled levels of LDL-C. In contrast, multiple studies have reported attenuation of the cardiovascular risk mediated by elevated Lp(a) with lower LDL-C levels. Moreover, the relationship between Lp(a) and triglycerides, high-density lipoprotein, and very low-density lipoprotein remains unclear. In this literature review, we summarize and discuss the current evidence regarding the interactions between Lp(a) and other lipid molecules, how they contribute to the pathogenesis of CVD, and future perspectives, particularly in the current era where promising targeted Lp(a)-lowering therapies are under development. Full article

(This article belongs to the Special Issue New Insights into Cardiometabolic Diseases)

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23 pages, 1790 KiB

Open AccessReview

The Role of the Liver in the Pathophysiology of PCOS: A Literature Review

by Abrar Alhermi, Heather Perks, Varsha Nigi, Noor Altahoo, Stephen L. Atkin and Alexandra E. Butler

Biomolecules 2025, 15(1), 51; https://doi.org/10.3390/biom15010051 - 2 Jan 2025

Viewed by 856

Abstract

Polycystic ovary syndrome (PCOS) is the most common endocrine metabolic disorder found in women of reproductive age and is characterized by both metabolic and reproductive dysfunction. Women with PCOS commonly have insulin resistance, increased susceptibility to type 2 diabetes mellitus, dyslipidemia, hyperinsulinemia, increased [...] Read more.

Polycystic ovary syndrome (PCOS) is the most common endocrine metabolic disorder found in women of reproductive age and is characterized by both metabolic and reproductive dysfunction. Women with PCOS commonly have insulin resistance, increased susceptibility to type 2 diabetes mellitus, dyslipidemia, hyperinsulinemia, increased cardiovascular risk, hepatic steatosis, infertility, and an overall reduction in physical and psychological well-being. Several previous studies have shown a causal association between PCOS and hepatic disorders, such as chronic liver disease (CLD) and nonalcoholic fatty liver disease (NAFLD), where PCOS was identified as contributing to the hepatic features. Whilst it is recognized that PCOS may contribute to hepatic dysfunction, there is also evidence that the liver may contribute to the features of PCOS. The purpose of this review is to discuss the current understanding regarding hepatic involvement in PCOS pathophysiology, the inflammatory markers and hepatokines involved in the development of PCOS, and the role of genetics in the occurrence of PCOS. This review illustrates that PCOS and NAFLD are both common disorders and that there is both genetic and metabolic linkage between the disorders. As such, whilst PCOS may contribute to NAFLD development, the converse may also be the case, with a potential bidirectional relationship between PCOS and liver disease. Full article

(This article belongs to the Special Issue New Insights into Cardiometabolic Diseases)

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21 pages, 3792 KiB

Open AccessReview

MetAP2 as a Therapeutic Target for Obesity and Type 2 Diabetes: Structural Insights, Mechanistic Roles, and Inhibitor Development

by Dong Oh Moon

Biomolecules 2024, 14(12), 1572; https://doi.org/10.3390/biom14121572 - 10 Dec 2024

Viewed by 893

Abstract

Type 2 Diabetes Mellitus (T2DM) and obesity are globally prevalent metabolic disorders characterized by insulin resistance, impaired glucose metabolism, and excessive adiposity. Methionine aminopeptidase 2 (MetAP2), an intracellular metalloprotease, has emerged as a promising therapeutic target due to its critical role in regulating [...] Read more.

Type 2 Diabetes Mellitus (T2DM) and obesity are globally prevalent metabolic disorders characterized by insulin resistance, impaired glucose metabolism, and excessive adiposity. Methionine aminopeptidase 2 (MetAP2), an intracellular metalloprotease, has emerged as a promising therapeutic target due to its critical role in regulating lipid metabolism, energy balance, and protein synthesis. This review provides a comprehensive analysis of MetAP2, including its structural characteristics, catalytic mechanism, and functional roles in the pathophysiology of T2DM and obesity. The unique architecture of MetAP2’s active site and its interactions with substrates are examined to elucidate its enzymatic function. The review also explores the development of MetAP2 inhibitors, focusing on their mechanisms of action, preclinical and clinical findings, and therapeutic potential. Special emphasis is placed on docking studies to analyze the binding interactions of six key inhibitors (fumagillin, TNP-470, beloranib, ZGN-1061, indazole, and pyrazolo[4,3-b]indole) with MetAP2, revealing their structural determinants for efficacy and specificity. These findings underscore the potential of MetAP2 as a therapeutic target and provide valuable insights for the rational design of next-generation inhibitors to address obesity and T2DM. Full article

(This article belongs to the Special Issue New Insights into Cardiometabolic Diseases)

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22 pages, 2116 KiB

Open AccessReview

Glycosphingolipids in Cardiovascular Disease: Insights from Molecular Mechanisms and Heart Failure Models

by Sarah Huang, Karima Abutaleb and Sumita Mishra

Biomolecules 2024, 14(10), 1265; https://doi.org/10.3390/biom14101265 - 8 Oct 2024

Viewed by 1767

Abstract

This review explores the crucial role of glycosphingolipids (GSLs) in the context of cardiovascular diseases (CVDs), focusing on their biosynthesis, metabolic pathways, and implications for clinical outcomes. GSLs are pivotal in regulating a myriad of cellular functions that are essential for heart health [...] Read more.

This review explores the crucial role of glycosphingolipids (GSLs) in the context of cardiovascular diseases (CVDs), focusing on their biosynthesis, metabolic pathways, and implications for clinical outcomes. GSLs are pivotal in regulating a myriad of cellular functions that are essential for heart health and disease progression. Highlighting findings from both human cohorts and animal models, this review emphasizes the potential of GSLs as biomarkers and therapeutic targets. We advocate for more detailed mechanistic studies to deepen our understanding of GSL functions in cardiovascular health, which could lead to innovative strategies for diagnosis, treatment, and personalized medicine in cardiovascular care. Full article

(This article belongs to the Special Issue New Insights into Cardiometabolic Diseases)

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19 pages, 1547 KiB

Open AccessReview

The Significance of Endothelial Dysfunction in Long COVID-19 for the Possible Future Pandemic of Chronic Kidney Disease and Cardiovascular Disease

by Hidekatsu Yanai, Hiroki Adachi, Mariko Hakoshima, Hisayuki Katsuyama and Akahito Sako

Biomolecules 2024, 14(8), 965; https://doi.org/10.3390/biom14080965 - 8 Aug 2024

Cited by 1 | Viewed by 2211

Abstract

Various symptoms have been reported to persist beyond the acute phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which is referred to as long coronavirus disease 19 (long COVID-19). Over 65 million individuals suffer from long COVID-19. However, the causes of long [...] Read more.

Various symptoms have been reported to persist beyond the acute phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which is referred to as long coronavirus disease 19 (long COVID-19). Over 65 million individuals suffer from long COVID-19. However, the causes of long COVID-19 are largely unknown. Since long COVID-19 symptoms are observed throughout the body, vascular endothelial dysfunction is a strong candidate explaining the induction of long COVID-19. The angiotensin-converting enzyme 2 (ACE2), the entry receptor for SARS-CoV-2, is ubiquitously expressed in endothelial cells. We previously found that the risk factors for atherosclerotic cardiovascular disease (ASCVD) and a history of ASCVD raise the risk of severe COVID-19, suggesting a contribution of pre-existing endothelial dysfunction to severe COVID-19. Here, we show a significant association of endothelial dysfunction with the development of long COVID-19 and show that biomarkers for endothelial dysfunction in patients with long COVID-19 are also crucial players in the development of ASCVD. We consider the influence of long COVID-19 on the development of chronic kidney disease (CKD) and ASCVD. Future assessments of the outcomes of long COVID-19 in patients resulting from therapeutic interventions that improve endothelial function may imply the significance of endothelial dysfunction in the development of long COVID-19. Full article

(This article belongs to the Special Issue New Insights into Cardiometabolic Diseases)

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20 pages, 3448 KiB

Open AccessReview

Inflammation: Is It a Healer, Confounder, or a Promoter of Cardiometabolic Risks?

by Amit R. Tate and Gundu H. R. Rao

Biomolecules 2024, 14(8), 948; https://doi.org/10.3390/biom14080948 - 6 Aug 2024

Cited by 2 | Viewed by 3143

Abstract

Inflammation is the body’s non-specific response to injury or infection. It is a natural defense mechanism that helps to maintain homeostasis and promotes tissue repair. However, excessive inflammation can lead to cellular, tissue, or organ dysfunction, as well as contribute to the development [...] Read more.

Inflammation is the body’s non-specific response to injury or infection. It is a natural defense mechanism that helps to maintain homeostasis and promotes tissue repair. However, excessive inflammation can lead to cellular, tissue, or organ dysfunction, as well as contribute to the development of acute vascular events and diseases like Crohn’s disease, psoriasis, obesity, diabetes, and cancer. The initial response to injury involves the activation of platelets and coagulation mechanisms to stop bleeding. This is followed by the recruitment of immune cells and the release of cytokines to promote tissue repair. Over time, the injured tissue undergoes remodeling and returns to its pre-injury state. Inflammation is characterized by the activation of inflammatory signaling pathways involving cytokines, chemokines, and growth factors. Mast cells play a role in initiating inflammatory responses. Pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and nucleotide-binding domain (NOD)-like receptors (NLRs) are involved in the activation of these inflammatory pathways. Inflammasomes, which are cytoplasmic complexes, also contribute to inflammation by activating cytokines. Inflammation can also be triggered by factors like dietary components and the composition of the gut microbiota. Dysregulation of the gut microbiome can lead to excessive inflammation and contribute to diseases like atherosclerosis and irritable bowel syndrome (IBS). The immune system and gut-associated lymphoid tissue (GALT) play crucial roles in the inflammatory response and the development of conditions like colorectal cancer. Anti-inflammatory therapy can play a significant role in reducing or inducing the remission of inflammatory diseases such as Crohn’s disease and ulcerative colitis. The fetal origin of adult diseases theory suggests that conditions during fetal development, such as low birth weight and maternal obesity, can influence the risk of cardiometabolic diseases later in life. All of the known risk factors associated with cardiometabolic diseases such as hypertension, excess weight, obesity, type-2 diabetes, and vascular diseases are accompanied by chronic low-grade inflammation. Inflammation seems to have a role in precipitating even acute vascular events such as heart attacks and stroke. Common markers of inflammation associated with cardiometabolic disease include interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF-α), C-reactive protein (CRP), and soluble TNF receptors such as sTNFR1 and sTNFR2. These markers serve as indicators of systemic inflammation. However, these markers are not disease-specific but provide an insight into the overall chronic inflammatory status. In fact, inflammation has been identified as a potential target for future treatments to reduce or reverse the risk of atherosclerosis-related complications. The regulation of inflammation is complex, and further research is needed to better understand its mechanisms and develop strategies for managing inflammatory disorders. In summary, inflammation is a natural response to injury or infection, but excessive or prolonged inflammation can lead to the progression of various diseases. Understanding the underlying mechanisms of inflammation is important for developing treatments and preventive measures for inflammatory disorders. Full article

(This article belongs to the Special Issue New Insights into Cardiometabolic Diseases)

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17 pages, 5086 KiB

Open AccessReview

The Role of Hyperuricemia in Cardiac Diseases: Evidence, Controversies, and Therapeutic Strategies

by Yue Zheng, Zhirui Chen, Jinya Yang, Jing Zheng, Xiaorong Shui, Yiguang Yan, Shian Huang, Zheng Liang, Wei Lei and Yuan He

Biomolecules 2024, 14(7), 753; https://doi.org/10.3390/biom14070753 - 25 Jun 2024

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Abstract

Hyperuricemia (HUA) may lead to myocardial cell damage, thereby promoting the occurrence and adverse outcomes of heart diseases. In this review, we discuss the latest clinical research progress, and explore the impact of HUA on myocardial damage-related diseases such as myocardial infarction, arrhythmias, [...] Read more.

Hyperuricemia (HUA) may lead to myocardial cell damage, thereby promoting the occurrence and adverse outcomes of heart diseases. In this review, we discuss the latest clinical research progress, and explore the impact of HUA on myocardial damage-related diseases such as myocardial infarction, arrhythmias, and heart failure. We also combined recent findings from basic research to analyze potential mechanisms linking HUA with myocardial injury. In different pathological models (such as direct action of high uric acid on myocardial cells or combined with myocardial ischemia-reperfusion model), HUA may cause damage by activating the NOD-like receptor protein 3 inflammasome-induced inflammatory response, interfering with cardiac cell energy metabolism, affecting antioxidant defense systems, and stimulating reactive oxygen species production to enhance the oxidative stress response, ultimately resulting in decreased cardiac function. Additionally, we discuss the impact of lowering uric acid intervention therapy and potential safety issues that may arise. However, as the mechanism underlying HUA-induced myocardial injury is poorly defined, further research is warranted to aid in the development novel therapeutic strategies for HUA-related cardiovascular diseases. Full article

(This article belongs to the Special Issue New Insights into Cardiometabolic Diseases)

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Open AccessSystematic Review

Comparative Efficacy and Safety of Cardio-Renoprotective Pharmacological Interventions in Chronic Kidney Disease: An Umbrella Review of Network Meta-Analyses and a Multicriteria Decision Analysis

by Ioannis Bellos, Smaragdi Marinaki, Pagona Lagiou and Vassiliki Benetou

Biomolecules 2025, 15(1), 39; https://doi.org/10.3390/biom15010039 - 31 Dec 2024

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Abstract

Sodium-glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP1a), and non-steroidal mineralocorticoid receptor antagonists (ns-MRA) are promising treatments for chronic kidney disease. This umbrella review of network meta-analyses evaluated their effects on cardiovascular outcomes, kidney disease progression, and adverse events, using the [...] Read more.

Sodium-glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP1a), and non-steroidal mineralocorticoid receptor antagonists (ns-MRA) are promising treatments for chronic kidney disease. This umbrella review of network meta-analyses evaluated their effects on cardiovascular outcomes, kidney disease progression, and adverse events, using the TOPSIS method to identify the optimal intervention based on P-scores. A total of 19 network meta-analyses and 44 randomized controlled trials involving 86,150 chronic kidney disease patients were included. Compared to placebo, SGLT2i were associated with reduced risks of cardiovascular events [Hazard ratio (HR): 0.776, 95% confidence intervals (CI): 0.727–0.998], kidney disease progression (HR: 0.679, 95% CI: 0.629–0.733), acute kidney injury (HR: 0.873, 95% CI: 0.773–0.907), and serious adverse events (HR: 0.881, 95% CI: 0.847–0.916). GLP1a and ns-MRA were also associated with significant reductions in cardiovascular and kidney-specific composite outcomes. Indirect evidence showed that SGLT2i demonstrated a lower risk of kidney disease progression compared to GLP1a (HR: 0.826, 95% CI: 0.716–0.952) and ns-MRA (HR: 0.818, 95% CI: 0.673–0.995), representing the best intervention across all endpoints. In conclusion, while SGLT2i, GLP1a, and ns-MRA all reduce cardiovascular and kidney disease risks in chronic kidney disease, SGLT2i appears to provide the most favorable balance of efficacy and safety. Full article

(This article belongs to the Special Issue New Insights into Cardiometabolic Diseases)

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