Biomolecules

17 pages, 4788 KiB

Open AccessArticle

Identification of Marine Compounds Inhibiting NF-κBInducing Kinase Through Molecular Docking and Molecular Dynamics Simulations

by Muhammad Yasir, Jinyoung Park, Eun-Taek Han, Jin-Hee Han, Won Sun Park, Jongseon Choe and Wanjoo Chun

Biomolecules 2024, 14(12), 1490; https://doi.org/10.3390/biom14121490 - 22 Nov 2024

Abstract

NF-κB-inducing kinase (NIK) plays a pivotal role in regulating both the canonical and non-canonical NF-κB signaling pathways, driving the expression of proteins involved in inflammation, immune responses, and cell survival. Overactivation of NIK is linked to various pathological conditions, including chronic inflammation, autoimmune [...] Read more.

NF-κB-inducing kinase (NIK) plays a pivotal role in regulating both the canonical and non-canonical NF-κB signaling pathways, driving the expression of proteins involved in inflammation, immune responses, and cell survival. Overactivation of NIK is linked to various pathological conditions, including chronic inflammation, autoimmune diseases, metabolic disorders, and cancer progression. As such, NIK represents a compelling target for therapeutic intervention in these diseases. In this study, we explored the inhibitory potential of marine-derived compounds against NIK using integrated computational techniques, including molecular docking, molecular dynamics (MD) simulations, and free energy calculations. By screening a library of bioactive marine compounds, we identified several promising candidates with strong binding affinity to the NIK active site. By continuously narrowing down the library at each step, we found that the compounds santacruzamate A, xanthosine, and actinonine stand out at each step by demonstrating compact binding, highly stable interactions, and the most favorable free energy profiles, indicating their potential as effective NIK inhibitors. These findings not only advance our understanding of marine compounds as valuable resources for drug discovery but also highlight their potential for the development of natural anti-inflammatory therapies targeting NIK. This study opens new avenues for future research and therapeutic development aimed at combating inflammation and cancer through NIK inhibition. Full article

(This article belongs to the Collection Biomolecules In Silico: Contemporary Advances in Computational Approaches to Investigating the Molecular Dynamics of Biological Systems)

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19 pages, 1959 KiB

Open AccessReview

Interleukin-27 and Autoimmune Disorders: A Compressive Review of Immunological Functions

by Esmaeil Yazdanpanah, Alireza Pazoki, Sepehr Dadfar, Mohammad Hosein Nemati, Seyed Mohammad Sajad Siadati, Mahdieh Tarahomi, Niloufar Orooji, Dariush Haghmorad and Valentyn Oksenych

Biomolecules 2024, 14(12), 1489; https://doi.org/10.3390/biom14121489 - 22 Nov 2024

Abstract

Autoimmune disorders (ADs) pose significant health and economic burdens globally, characterized by the body’s immune system mistakenly attacking its own tissues. While the precise mechanisms driving their development remain elusive, a combination of genetic predisposition(s) and environmental triggers is implicated. Interleukin-27 (IL-27), among [...] Read more.

Autoimmune disorders (ADs) pose significant health and economic burdens globally, characterized by the body’s immune system mistakenly attacking its own tissues. While the precise mechanisms driving their development remain elusive, a combination of genetic predisposition(s) and environmental triggers is implicated. Interleukin-27 (IL-27), among numerous cytokines involved, has emerged as a key regulator, exhibiting dual roles in immune modulation. This review delves into the molecular structure and signaling mechanisms of IL-27, highlighting its diverse effects on various immune cells. Additionally, it explores the involvement of IL-27 in autoimmune diseases, such as multiple sclerosis (MS) and rheumatoid arthritis (RA), offering insights into its potential therapeutic implications. Moreover, its involvement in autoimmune diseases like type 1 diabetes (T1D), inflammatory bowel disease (IBD), myasthenia gravis (MG), Sjögren’s syndrome (SS), and Guillain-Barré syndrome (GBS) is multifaceted, with potential diagnostic and therapeutic implications across these conditions. Further research is essential to fully understand IL-27’s mechanisms of action and therapeutic potential in autoimmune diseases. Full article

(This article belongs to the Section Molecular Structure and Dynamics)

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20 pages, 3445 KiB

Open AccessReview

Structure and Dynamics of the Bacterial Flagellar Motor Complex

by Shuichi Nakamura and Tohru Minamino

Biomolecules 2024, 14(12), 1488; https://doi.org/10.3390/biom14121488 - 22 Nov 2024

Abstract

Many bacteria swim in liquids and move over solid surfaces by rotating flagella. The bacterial flagellum is a supramolecular protein complex that is composed of about 30 different flagellar proteins ranging from a few to tens of thousands. Despite structural and functional diversities [...] Read more.

Many bacteria swim in liquids and move over solid surfaces by rotating flagella. The bacterial flagellum is a supramolecular protein complex that is composed of about 30 different flagellar proteins ranging from a few to tens of thousands. Despite structural and functional diversities of the flagella among motile bacteria, the flagellum commonly consists of a membrane-embedded rotary motor fueled by an ion motive force across the cytoplasmic membrane, a universal joint, and a helical propeller that extends several micrometers beyond the cell surface. The flagellar motor consists of a rotor and several stator units, each of which acts as a transmembrane ion channel complex that converts the ion flux through the channel into the mechanical work required for force generation. The rotor ring complex is equipped with a reversible gear that is regulated by chemotactic signal transduction pathways. As a result, bacteria can move to more desirable locations in response to environmental changes. Recent high-resolution structural analyses of flagella using cryo-electron microscopy have provided deep insights into the assembly, rotation, and directional switching mechanisms of the flagellar motor complex. In this review article, we describe the current understanding of the structure and dynamics of the bacterial flagellum. Full article

(This article belongs to the Section Molecular Biophysics)

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15 pages, 4682 KiB

Open AccessArticle

Involvement of Metalloproteases in the Fertilization of the Ascidian Halocynthia roretzi

by Hitoshi Sawada, Ikuya Hattori, Noritaka Hashii and Takako Saito

Biomolecules 2024, 14(12), 1487; https://doi.org/10.3390/biom14121487 - 22 Nov 2024

Abstract

We previously reported that five astacin-like metalloproteases with thrombospondin type-1 repeats (Tasts) located on the sperm surface are a promising candidate as the protease involved in sperm penetration of the vitelline coat (VC) during fertilization of the ascidian Ciona intestinalis type A (Phlebobranchia). [...] Read more.

We previously reported that five astacin-like metalloproteases with thrombospondin type-1 repeats (Tasts) located on the sperm surface are a promising candidate as the protease involved in sperm penetration of the vitelline coat (VC) during fertilization of the ascidian Ciona intestinalis type A (Phlebobranchia). However, whether such a protease is involved in the fertilization of other ascidians is unknown. Here, we investigated the effects of four metalloprotease inhibitors on the fertilization of the ascidian Halocynthia roretzi (Stolidobranchia). Three metalloprotease inhibitors, GM6001, TAPI-0, and TAPI-1, strongly inhibited fertilization at 33 and 11 μM, whereas TAPI-2 weakly inhibited fertilization at 33 μM. In contrast, GM6001NC (negative control) had no effect on fertilization at 100 μM. Furthermore, GM6001 had no inhibitory effect on the fertilization of VC-deprived eggs. The metalloprotease appears to function at the middle or late stage of fertilization. Ten Tast genes were identified in the H. roretzi genome database, among which four genes (HrTast1, HrTast2b, HrTast2c, and HrTast3c) possessed a single transmembrane domain in the N-terminal region. These four genes are transcribed in the testis and ovary, as revealed by RT-PCR. Anti-HrTast2c IgG raised against a peptide corresponding to the Zn-binding consensus sequence weakly inhibited fertilization at 0.5 mg/mL. These results led us to propose that sperm astacin-like metalloproteases may be involved in sperm penetration of the VC during H. roretzi fertilization. Full article

(This article belongs to the Special Issue Gametogenesis and Gamete Interaction, 2nd Edition)

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15 pages, 2488 KiB

Open AccessSystematic Review

Prevalence and Predictors of Diabetic Retinopathy in Saudi Arabia: Insights from a Systematic Review and Meta-Analysis

by Ali Mohammed Alshahrani, Alaa Mohammed Alshahrani, Beshayer Abdullah H. Al-Boqami, Alwaleed Abdulhadi Alqahtani, Bassam Alzahrani, Yousef Bassi, Mohammed Yousef Almohaimeed, Abeer Mohammed Alalmaai, Ariana Saraiva, Bandar Naffaa Alhumaidi, Najla A. Albaridi, Maria João Lima, Conrado Carrascosa and António Raposo

Biomolecules 2024, 14(12), 1486; https://doi.org/10.3390/biom14121486 - 22 Nov 2024

Abstract

Background: Diabetic retinopathy (DR) is one of the leading causes of blindness among diabetic patients, particularly in areas with an increase in diabetes epidemics, such as Saudi Arabia. Notwithstanding the significant public health implications, data on the prevalence and risk factors of DR [...] Read more.

Background: Diabetic retinopathy (DR) is one of the leading causes of blindness among diabetic patients, particularly in areas with an increase in diabetes epidemics, such as Saudi Arabia. Notwithstanding the significant public health implications, data on the prevalence and risk factors of DR in Saudi Arabia are few and scattered, limited to certain geographic areas. Our study objective is to conduct a systematic review of the literature and a meta-analysis of the prevalence and predictors for DR in Saudi Arabia, within both type 1 and type 2 diabetes. Methods: A systematic review and meta-analysis were constructed according to PRISMA guidelines. We searched PubMed, Embase, Web of Science, and Google Scholar electronic databases for studies published from 2000–2023. Any study related to the prevalence of diabetic retinopathy in T1DM or T2DM among adult patients aged ≥18 years that was conducted in Saudi Arabia was included. Pooling prevalence estimates were calculated using a random-effects model, and heterogeneity across the studies was tested by the I² statistic and Cochran’s Q test. Results: A total of 11 studies published between 2006 and 2019 met the inclusion criteria, with sample sizes ranging from 99 to over 50,000 participants. The overall pooled prevalence of DR was estimated to be 31% (95% CI: 24–39%), with substantial heterogeneity observed across studies (I² = 99%). Prevalence estimates ranged from 16.7% to 69.8% and were influenced by variables such as study design, duration of diabetes, and glycemic control. Among individuals with type 2 diabetes, the pooled prevalence was 24% (95% CI: 20–28%). Poor glycemic control and longer diabetes duration were consistently identified as significant predictors of DR, while other factors, such as obesity and hypertension, were also associated with an increased risk of DR. Conclusions: The high prevalence of DR in Saudi Arabia highlights the critical need for focused public health initiatives, especially among those with type 2 diabetes. To minimize the effects of DR, early intervention, routine DR screening programs, and optimal diabetes control are essential. The increasing prevalence of DR in Saudi Arabia requires careful consideration of healthcare policy and resource allocation, which is made possible by our results. Full article

(This article belongs to the Special Issue Diabetic Retinopathy: From Pathophysiology to Therapeutic Perspectives)

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29 pages, 2260 KiB

Open AccessReview

Hedgehog Signaling Pathway in Fibrosis and Targeted Therapies

by Yuchen Hu, Linrui Peng, Xinyu Zhuo, Chan Yang and Yuwei Zhang

Biomolecules 2024, 14(12), 1485; https://doi.org/10.3390/biom14121485 - 22 Nov 2024

Abstract

Hedgehog (Hh) signaling is a well-established developmental pathway; it is crucial for early embryogenesis, cell differentiation, and damage-driven regeneration. It is being increasingly recognized that dysregulated Hh signaling is also involved in fibrotic diseases, which are characterized by excessive extracellular matrix deposition that [...] Read more.

Hedgehog (Hh) signaling is a well-established developmental pathway; it is crucial for early embryogenesis, cell differentiation, and damage-driven regeneration. It is being increasingly recognized that dysregulated Hh signaling is also involved in fibrotic diseases, which are characterized by excessive extracellular matrix deposition that compromises tissue architecture and function. As in-depth insights into the mechanisms of Hh signaling are obtained, its complex involvement in fibrosis is gradually being illuminated. Notably, some Hh-targeted inhibitors are currently under exploration in preclinical and clinical trials as a means to prevent fibrosis progression. In this review, we provide a concise overview of the biological mechanisms involved in Hh signaling. We summarize the latest advances in our understanding of the roles of Hh signaling in fibrogenesis across the liver, kidneys, airways, and lungs, as well as other tissues and organs, with an emphasis on both the shared features and, more critically, the distinct functional variations observed across these tissues and organs. We thus highlight the context dependence of Hh signaling, as well as discuss the current status and the challenges of Hh-targeted therapies for fibrosis. Full article

(This article belongs to the Section Molecular Medicine)

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14 pages, 4332 KiB

Open AccessArticle

Differential Effects of Biomimetic Thymine Dimers and Corresponding Photo-Adducts in Primary Human Keratinocytes and Fibroblasts

by Rosanna Monetta, Denise Campagna, Valeria Bartolocci, Alessio Capone, Massimo Teson, Silvia Filippi, Sofia Gabellone, Davide Piccinino, Raffaele Saladino and Elena Dellambra

Biomolecules 2024, 14(12), 1484; https://doi.org/10.3390/biom14121484 - 21 Nov 2024

Abstract

UVB radiation induces DNA damage generating several thymine photo-adducts (TDPs), which can lead to mutations and cellular transformation. The DNA repair pathways preserve genomic stability by recognizing and removing photodamage. These DNA repair side products may affect cellular processes. We previously synthesized novel [...] Read more.

UVB radiation induces DNA damage generating several thymine photo-adducts (TDPs), which can lead to mutations and cellular transformation. The DNA repair pathways preserve genomic stability by recognizing and removing photodamage. These DNA repair side products may affect cellular processes. We previously synthesized novel thymine biomimetic thymine dimers (BTDs) bearing different alkane spacers between nucleobases. Thus, the present study investigates whether novel BTDs and their TDPs can modulate DNA damage safeguard pathways of primary keratinocytes and fibroblasts using 2D and 3D models. We found that the p53/p21^waf1 pathway is activated by BTDs and TDPs in primary cells similar to UVB exposure. Compound 1b can also induce the p53/p21^waf1 pathway in a 3D skin model. However, BTDs and TDPs exhibit distinct effects on cell survival. They have a protective action in keratinocytes, which maintain their clonogenic ability following treatments. Conversely, compounds induce pro-apoptotic pathways in fibroblasts that exhibit reduced clonogenicity. Moreover, compounds induce inflammatory cytokines mainly in keratinocytes rather than fibroblasts. Matrix metalloproteinase 1 is up-regulated in both cell types after treatments. Therefore, BTDs and TDPs can act in the short term as safeguard mechanisms helping DNA damage response. Furthermore, they have distinct biological effects depending on photodamage form and cell type. Full article

(This article belongs to the Special Issue DNA Damage, Mutagenesis, and Repair Mechanisms)

17 pages, 3721 KiB

Open AccessArticle

Structural Insights into Mechanisms Underlying Mitochondrial and Bacterial Cytochrome c Synthases

by Pema L. Childs, Ethan P. Lowder, Deanna L. Mendez, Shalon E. Babbitt, Amidala Martinie, Jonathan Q. Huynh and Robert G. Kranz

Biomolecules 2024, 14(12), 1483; https://doi.org/10.3390/biom14121483 - 21 Nov 2024

Abstract

Mitochondrial holocytochrome c synthase (HCCS) is an essential protein in assembling cytochrome c (cyt c) of the electron transport system. HCCS binds heme and covalently attaches the two vinyls of heme to two cysteine thiols of the cyt c CXXCH motif. Human HCCS [...] Read more.

Mitochondrial holocytochrome c synthase (HCCS) is an essential protein in assembling cytochrome c (cyt c) of the electron transport system. HCCS binds heme and covalently attaches the two vinyls of heme to two cysteine thiols of the cyt c CXXCH motif. Human HCCS recognizes both cyt c and cytochrome c₁ of complex III (cytochrome bc₁). HCCS is mutated in some human diseases and it has been investigated recombinantly by mutational, biochemical, and reconstitution studies in the past decade. Here, we employ structural prediction programs (e.g., AlphaFold 3) on HCCS and its two substrates, heme and cytochrome c. The results, when combined with spectroscopic and functional analyses of HCCS and variants, provide insights into the structural basis for heme binding, apocyt c binding, covalent attachment, and release of the holocyt c product. Results from in vitro reconstitution of purified human HCCS using cyt c and cyt c₁ peptides as acceptors are consistent with the structural modeling of substrate binding. Reconstitution of HCCS and cyt c₁ provides an approach to studying cyt c₁ assembly, which has been refractile to recombinant in vivo reconstitution (unlike HCCS and cyt c). We propose a structural basis for release of the holocyt c product from HCCS based on in vitro studies and on cryoEM structures of the bacterial cyt c synthase (CcsBA) active site. We analyze the kinetoplastid mitochondrial synthase (KCCS), and hypothesize a molecular evolutionary path from mitochondrial endosymbiosis to the current HCCS. Full article

(This article belongs to the Special Issue Unraveling Mysteries of Heme Metabolism)

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Graphical abstract

19 pages, 2472 KiB

Open AccessArticle

Thyroid Carcinoma Glycoproteins Express Altered N-Glycans with 3-O-Sulfated Galactose Residues

by Jordan M. Broekhuis, Dongli Lu, Rajindra P. Aryal, Yasuyuki Matsumoto, Lauren E. Pepi, Natalia Chaves, Jorge L. Gomez-Mayorga, Benjamin C. James and Richard D. Cummings

Biomolecules 2024, 14(12), 1482; https://doi.org/10.3390/biom14121482 - 21 Nov 2024

Abstract

Aberrant protein glycosylation is a hallmark alteration of cancer and is highly associated with cancer progression. Papillary thyroid cancer (PTC) is the most common type of thyroid cancer, but the N-glycosylation of its glycoproteins has not been well characterized. In this work, [...] Read more.

Aberrant protein glycosylation is a hallmark alteration of cancer and is highly associated with cancer progression. Papillary thyroid cancer (PTC) is the most common type of thyroid cancer, but the N-glycosylation of its glycoproteins has not been well characterized. In this work, we analyzed multiple freshly prepared PTC specimens along with paired normal tissue obtained from thyroidectomies. Glycomic analyses focused on Asn-linked (N)-glycans and employed mass spectrometry (MS), along with Western blot approaches of total solubilized materials that were examined for binding by specific lectins and a monoclonal antibody (mAb) O6, specific for 3-O-sulfated galactose residues. We observed major differences in PTC versus paired normal specimens, as PTC specimens exhibited higher levels of N-glycan branching and bisection with N-acetylglucosamine residues, consistent with RNAseq data. We also found that 3-O-sulfated galactose was present in N-glycans of multiple glycoproteins from both PTC and control specimens, as recognized by the O6 mAb and as confirmed by MS analyses. These results provide new insights into the N-glycans present in glycoproteins of thyroid cancer and context for further studies of these altered glycans as biomarkers and targets for therapeutics. Full article

(This article belongs to the Section Biomacromolecules: Carbohydrates)

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22 pages, 3215 KiB

Open AccessArticle

Tailored Combinations of Human Milk Oligosaccharides Modulate the Immune Response in an In Vitro Model of Intestinal Inflammation

by Clodagh Walsh, Jonathan A. Lane, Douwe van Sinderen and Rita M. Hickey

Biomolecules 2024, 14(12), 1481; https://doi.org/10.3390/biom14121481 - 21 Nov 2024

Abstract

Infants rely on their developing immune system and the protective components of breast milk to defend against bacterial and viral pathogens, as well as immune disorders such as food allergies, prior to the introduction of solid foods. When breastfeeding is not feasible, fortified [...] Read more.

Infants rely on their developing immune system and the protective components of breast milk to defend against bacterial and viral pathogens, as well as immune disorders such as food allergies, prior to the introduction of solid foods. When breastfeeding is not feasible, fortified infant formula will most frequently be offered, usually based on a cow’s milk-based substitute. The current study aimed to explore the immunomodulatory effects of combinations of commercially available human milk oligosaccharides (HMOs). An in vitro co-culture model of Caco-2 intestinal epithelial cells and THP-1 macrophages was established to replicate the hallmarks of intestinal inflammation and to evaluate the direct effects of different synthetic HMO combinations. Notably, a blend of the most prevalent fucosylated and sialylated HMOs, 2′-fucosyllactose (2′-FL) and 6′-siallylactose (6′-SL), respectively, resulted in decreased pro-inflammatory cytokine levels. These effects were dependent on the HMO concentration and on the HMO ratio resembling those in breastmilk. Interestingly, adding additional HMO structures did not enhance the anti-inflammatory effects. This research highlights the importance of carefully selecting HMO combinations in nutritional products, particularly for infant milk formulations, to effectively mimic the benefits associated with breastmilk. Full article

(This article belongs to the Section Biomacromolecules: Carbohydrates)

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21 pages, 1423 KiB

Open AccessArticle

Analysis of Bacterial Metabolites in Breath Gas of Critically Ill Patients for Diagnosis of Ventilator-Associated Pneumonia—A Proof of Concept Study

by Wojciech Filipiak, Robert Włodarski, Karolina Żuchowska, Alicja Tracewska, Magdalena Winiarek, Dawid Daszkiewicz, Marta Marszałek, Dagmara Depka and Tomasz Bogiel

Biomolecules 2024, 14(12), 1480; https://doi.org/10.3390/biom14121480 - 21 Nov 2024

Abstract

Bacterial infection of the lower respiratory tract frequently occurs in mechanically ventilated patients and may develop into life-threatening conditions. Yet, existing diagnostic methods have moderate sensitivity and specificity, which results in the overuse of broad-spectrum antibiotics administered prophylactically. This study aims to evaluate [...] Read more.

Bacterial infection of the lower respiratory tract frequently occurs in mechanically ventilated patients and may develop into life-threatening conditions. Yet, existing diagnostic methods have moderate sensitivity and specificity, which results in the overuse of broad-spectrum antibiotics administered prophylactically. This study aims to evaluate the suitability of volatile bacterial metabolites for the breath-based test, which is used for diagnosing Ventilation-Associated Pneumonia (VAP). The in vitro experiments with pathogenic bacteria most prevalent in VAP etiology (i.e., Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa) were performed to identify bacteria-derived metabolites using a specially designed cultivation system enabling headspace sampling for GC-MS analysis. Thirty-nine compounds were found to be significantly metabolized by tested species and, therefore, selected for monitoring in the exhaled breath of critically ill, mechanically ventilated (MV) patients. The emission of volatiles from medical respiratory devices was investigated to estimate the risk of spoiling breath results with exogenous pollutants. Bacterial metabolites were then evaluated to differentiate VAP patients from non-infected MV controls using Receiver Operating Characteristic (ROC) analysis, with AUC, sensitivity, and specificity calculated. Nine bacterial metabolites that passed verification through a non-parametric ANOVA test for significance and LASSO penalization were identified as key discriminators between VAP and non-VAP patients. The diagnostic model achieved an AUC of 0.893, with sensitivity and specificity values of 87% and 82.4%, respectively, being competitive with traditional methods. Further validation could solidify its clinical utility in critical care settings. Full article

(This article belongs to the Section Molecular Biomarkers)

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50 pages, 3272 KiB

Open AccessReview

Anti-Diabetic Therapies and Cancer: From Bench to Bedside

by Dimitris Kounatidis, Natalia G. Vallianou, Irene Karampela, Eleni Rebelos, Marina Kouveletsou, Vasileios Dalopoulos, Petros Koufopoulos, Evanthia Diakoumopoulou, Nikolaos Tentolouris and Maria Dalamaga

Biomolecules 2024, 14(11), 1479; https://doi.org/10.3390/biom14111479 - 20 Nov 2024

Abstract

Diabetes mellitus (DM) is a significant risk factor for various cancers, with the impact of anti-diabetic therapies on cancer progression differing across malignancies. Among these therapies, metformin has gained attention for its potential anti-cancer effects, primarily through modulation of the AMP-activated protein kinase/mammalian [...] Read more.

Diabetes mellitus (DM) is a significant risk factor for various cancers, with the impact of anti-diabetic therapies on cancer progression differing across malignancies. Among these therapies, metformin has gained attention for its potential anti-cancer effects, primarily through modulation of the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) pathway and the induction of autophagy. Beyond metformin, other conventional anti-diabetic treatments, such as insulin, sulfonylureas (SUs), pioglitazone, and dipeptidyl peptidase-4 (DPP-4) inhibitors, have also been examined for their roles in cancer biology, though findings are often inconclusive. More recently, novel medications, like glucagon-like peptide-1 (GLP-1) receptor agonists, dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists, and sodium-glucose co-transporter-2 (SGLT-2) inhibitors, have revolutionized DM management by not only improving glycemic control but also delivering substantial cardiovascular and renal benefits. Given their diverse metabolic effects, including anti-obesogenic properties, these novel agents are now under meticulous investigation for their potential influence on tumorigenesis and cancer advancement. This review aims to offer a comprehensive exploration of the evolving landscape of glucose-lowering treatments and their implications in cancer biology. It critically evaluates experimental evidence surrounding the molecular mechanisms by which these medications may modulate oncogenic signaling pathways and reshape the tumor microenvironment (TME). Furthermore, it assesses translational research and clinical trials to gauge the practical relevance of these findings in real-world settings. Finally, it explores the potential of anti-diabetic medications as adjuncts in cancer treatment, particularly in enhancing the efficacy of chemotherapy, minimizing toxicity, and addressing resistance within the framework of immunotherapy. Full article

(This article belongs to the Special Issue Nutrition, Metabolism, and Obesity: Novel Strategies and Molecular Mechanisms—Future Perspectives)

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25 pages, 3893 KiB

Open AccessReview

Research Progress of Fibroblasts in Human Diseases

by Xiaodong Li, Nana Li, Yujie Wang, Qixiang Han and Boshi Sun

Biomolecules 2024, 14(11), 1478; https://doi.org/10.3390/biom14111478 - 20 Nov 2024

Abstract

Fibroblasts, which originate from embryonic mesenchymal cells, are the predominant cell type seen in loose connective tissue. As the main components of the internal environment that cells depend on for survival, fibroblasts play an essential role in tissue development, wound healing, and the [...] Read more.

Fibroblasts, which originate from embryonic mesenchymal cells, are the predominant cell type seen in loose connective tissue. As the main components of the internal environment that cells depend on for survival, fibroblasts play an essential role in tissue development, wound healing, and the maintenance of tissue homeostasis. Furthermore, fibroblasts are also involved in several pathological processes, such as fibrosis, cancers, and some inflammatory diseases. In this review, we analyze the latest research progress on fibroblasts, summarize the biological characteristics and physiological functions of fibroblasts, and delve into the role of fibroblasts in disease pathogenesis and explore treatment approaches for fibroblast-related diseases. Full article

(This article belongs to the Section Molecular Medicine)

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20 pages, 2485 KiB

Open AccessArticle

Supplementation of Oocytes by Microinjection with Extra Copies of mtDNA Alters Metabolite Profiles and Interactions with Expressed Genes in a Tissue-Specific Manner

by Eryk Andreas, Alexander Penn, Takashi Okada and Justin C. St. John

Biomolecules 2024, 14(11), 1477; https://doi.org/10.3390/biom14111477 - 20 Nov 2024

Abstract

Mitochondrial DNA (mtDNA) supplementation can rescue poor oocyte quality and overcome embryonic arrest. Here, we investigated a series of sexually mature pigs generated through autologous and heterologous mtDNA supplementation. Brain, liver and heart tissues underwent metabolite profiling using gas chromatography–mass spectrometry and gene [...] Read more.

Mitochondrial DNA (mtDNA) supplementation can rescue poor oocyte quality and overcome embryonic arrest. Here, we investigated a series of sexually mature pigs generated through autologous and heterologous mtDNA supplementation. Brain, liver and heart tissues underwent metabolite profiling using gas chromatography–mass spectrometry and gene expression analysis through RNA-seq. They were then assessed for mRNA–metabolite interactions. The comparison between overall mtDNA supplemented and control pigs revealed that mtDNA supplementation reduced the lipids stearic acid and elaidic acid in heart tissue. However, heterologous mtDNA supplemented-derived pigs exhibited lower levels of abundance of metabolites when compared with autologous-derived pigs. In the brain, these included mannose, mannose 6-phosphate and fructose 6-phosphate. In the liver, maltose and cellobiose, and in the heart, glycine and glutamate were affected. mRNA–metabolite pathway analysis revealed a correlation between malate and CS, ACLY, IDH2 and PKLR in the liver and glutamate and PSAT1, PHGDH, CDO1 and ANPEP in the heart. Our outcomes demonstrate that mtDNA supplementation, especially heterologous supplementation, alters the metabolite and transcriptome profiles of brain, liver, and heart tissues. This is likely due to the extensive resetting of the balance between the nuclear and mitochondrial genomes in the preimplantation embryo, which induces a series of downstream effects. Full article

(This article belongs to the Section Molecular Genetics)

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15 pages, 4970 KiB

Open AccessArticle

Metabolites and Metabolic Functional Changes—Potential Markers for Endothelial Cell Senescence

by Jingyuan Ya, Alison Whitby and Ulvi Bayraktutan

Biomolecules 2024, 14(11), 1476; https://doi.org/10.3390/biom14111476 - 20 Nov 2024

Abstract

Accumulation of senescent endothelial cells (ECs) in vasculature represents a key step in the development of vascular aging and ensuing age-related diseases. Given that removal of senescent ECs may prevent disease and improve health and wellbeing, the discovery of novel biomarkers that effectively [...] Read more.

Accumulation of senescent endothelial cells (ECs) in vasculature represents a key step in the development of vascular aging and ensuing age-related diseases. Given that removal of senescent ECs may prevent disease and improve health and wellbeing, the discovery of novel biomarkers that effectively identify senescent cells is of particular importance. As crucial elements for biological pathways and reliable bioindicators of cellular processes, metabolites demand attention in this context. Using senescent human brain microvascular endothelial cells (HBMECs) displaying a secretory phenotype and significant morphological, nuclear, and enzymatic changes compared to their young counterparts, this study has shown that senescent HBMECs lose their endothelial characteristics as evidenced by the disappearance of CD31/PECAM-1 from interendothelial cell junctions. The metabolic profiling of young versus senescent HBMECs also indicates significant differences in glucose, glutamine, and fatty acid metabolism. The analysis of intracellular and secreted metabolites proposes L-proline, L-glutamate, NAD⁺, and taurine/hypotaurine pathway components as potential biomarkers. However, further studies are required to assess the value of these agents as potential biomarkers and therapeutic targets. Full article

(This article belongs to the Special Issue Biomarkers of Cardiovascular and Cerebrovascular Diseases)

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16 pages, 946 KiB

Open AccessReview

Insulin-like Growth Factor-Binding Protein-1 (IGFBP-1) as a Biomarker of Cardiovascular Disease

by Moira S. Lewitt and Gary W. Boyd

Biomolecules 2024, 14(11), 1475; https://doi.org/10.3390/biom14111475 - 20 Nov 2024

Abstract

Insulin-like growth factor-binding protein-1 (IGFBP-1) contributes to the regulation of IGFs for metabolism and growth and has IGF-independent actions. IGFBP-1 in the circulation is derived from the liver, where it is inhibited by insulin and stimulated by multiple factors, including proinflammatory cytokines. IGFBP-1 [...] Read more.

Insulin-like growth factor-binding protein-1 (IGFBP-1) contributes to the regulation of IGFs for metabolism and growth and has IGF-independent actions. IGFBP-1 in the circulation is derived from the liver, where it is inhibited by insulin and stimulated by multiple factors, including proinflammatory cytokines. IGFBP-1 levels are influenced by sex and age, which also determine cardiometabolic risk and patterns of disease presentation. While lower circulating IGFBP-1 concentrations are associated with an unfavorable cardiometabolic risk profile, higher IGFBP-1 predicts worse cardiovascular disease outcomes. This review explores these associations and the possible roles of IGFBP-1 in the pathophysiology of atherosclerosis. We recommend the evaluation of dynamic approaches, such as simultaneous measurements of fasting IGFBP-1 and proinsulin level in response to an oral glucose challenge, as well as multi-marker approaches incorporating markers of inflammation. Full article

(This article belongs to the Special Issue Biomarkers of Cardiovascular and Cerebrovascular Diseases)

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9 pages, 442 KiB

Open AccessArticle

Serum Leucine-Rich Alpha-2 Glycoprotein 1 Levels in Patients with Lipodystrophy Syndromes

by Michelle Krienke, Susan Kralisch, Leonie Wagner, Anke Tönjes and Konstanze Miehle

Biomolecules 2024, 14(11), 1474; https://doi.org/10.3390/biom14111474 - 19 Nov 2024

Abstract

Serum concentrations of leucine-rich alpha-2 glycoprotein 1 (LRG1) are elevated in several cardio-metabolic and inflammatory diseases. LRG1 also plays an important role in the development of hepatic steatosis and insulin resistance. In lipodystrophies (LDs), severe cardio-metabolic complications can be observed. The dysregulation of [...] Read more.

Serum concentrations of leucine-rich alpha-2 glycoprotein 1 (LRG1) are elevated in several cardio-metabolic and inflammatory diseases. LRG1 also plays an important role in the development of hepatic steatosis and insulin resistance. In lipodystrophies (LDs), severe cardio-metabolic complications can be observed. The dysregulation of several adipokines plays a significant role in the clinical manifestation of this syndrome. To date, there have been no studies of LRG1 levels in non-HIV-LD patients. We performed a cross-sectional analysis of LRG1 serum levels in 60 patients with non-HIV-associated LD and in 60 age-, sex-, and BMI-matched healthy controls. Furthermore, we investigated the gene expression of Lrg1 in a mouse model of generalised LD. No significant difference was found in the median concentration of LRG1 serum levels between LD patients (18.2 ng/L; interquartile range 8.3 ng/L) and healthy controls (17.8 ng/L; interquartile range 11.0 ng/L). LRG1 serum concentrations correlated positively with CRP serum levels (p < 0.001). Lrg1 mRNA expression was downregulated in the adipose tissue, whereas in the liver, no difference in Lrg1 expression between LD and wild-type mice was detected. In summary, circulating levels of LRG1 are associated with low-grade inflammation but cannot distinguish between patients with LD and controls. Full article

(This article belongs to the Special Issue Diabetes, Overweight and Obesity: From Molecular Mechanisms to Therapies Strategies)

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18 pages, 4941 KiB

Open AccessArticle

Computational Study of Network and Type-I Functional Divergence in Alcohol Dehydrogenase Enzymes Across Species Using Molecular Dynamics Simulation

by Suhyun Park, Petrina Jebamani, Yeon Gyo Seo and Sangwook Wu

Biomolecules 2024, 14(11), 1473; https://doi.org/10.3390/biom14111473 - 19 Nov 2024

Abstract

Alcohol dehydrogenases (ADHs) are critical enzymes involved in the oxidation of alcohols, contributing to various metabolic pathways across organisms. This study investigates type I functional divergence within three ADH1 families: Saccharomyces cerevisiae (PDB ID: 4W6Z), Gadus morhua (PDB ID: 1CDO), and Homo sapiens [...] Read more.

Alcohol dehydrogenases (ADHs) are critical enzymes involved in the oxidation of alcohols, contributing to various metabolic pathways across organisms. This study investigates type I functional divergence within three ADH1 families: Saccharomyces cerevisiae (PDB ID: 4W6Z), Gadus morhua (PDB ID: 1CDO), and Homo sapiens (PDB ID: 1HDX). Understanding the molecular evolution and mechanisms underlying functional divergence of ADHs is essential for comprehending their adaptive significance. For this purpose, we performed a computational analysis that included structural characterization of ADHs through three-dimensional modeling, site-specific analysis to evaluate selective pressures and evolutionary constraints, and network analysis to elucidate relationships between structural features and functional divergence. Our findings indicate substantial variations in evolutionary and structural adaptations among the ADH families. Full article

(This article belongs to the Section Bioinformatics and Systems Biology)

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17 pages, 3880 KiB

Open AccessArticle

The Antifungal Potential of Ozonated Extra-Virgin Olive Oil Against Candida albicans: Mechanisms and Efficacy

by Simone Augello, Valentina Cameli, Arianna Montanari, Stefano Tacconi, Daniela Uccelletti, Luciana Dini and Emily Schifano

Biomolecules 2024, 14(11), 1472; https://doi.org/10.3390/biom14111472 - 19 Nov 2024

Abstract

The growing emergence of resistance mechanisms and side effects associated with antifungal agents highlight the need for alternative therapies. This study aims to investigate the antifungal potential of ozonated extra-virgin olive oil (EOO) against Candida albicans, with the goal of developing eco-friendly [...] Read more.

The growing emergence of resistance mechanisms and side effects associated with antifungal agents highlight the need for alternative therapies. This study aims to investigate the antifungal potential of ozonated extra-virgin olive oil (EOO) against Candida albicans, with the goal of developing eco-friendly and highly effective treatments based on natural products. Antifungal activity was evaluated via cell viability and biofilm formation assays using Crystal Violet and Sytox green staining. The results showed that EOO reduced C. albicans viability in a dose-dependent manner, achieving over 90% cell death at a 3% (v/v) concentration. Transmission Electron Microscopy (TEM) revealed cell wall structural damage, and ROS levels increased by approximately 60% compared to untreated controls within 10 min of treatment. Additionally, the expression of autophagy-related genes atg-7 and atg-13was upregulated by 2- and 3.5-fold, respectively, after 15 min, suggesting a stress-induced cell death response. EOO also significantly inhibited hyphal formation and biofilm development, thus reducing C. albicans pathogenicity while preserving cell biocompatibility. EOO antifungal activity was also observed in the case of Candida glabrata. In conclusion, ozonated olive oil demonstrates potent antifungal activity against C. albicans by reducing cell viability, inhibiting hyphal and biofilm formation, and triggering oxidative stress and autophagy pathways. These findings position EOO as a promising alternative therapy for fungal infections. Full article

(This article belongs to the Special Issue Molecular Profiling and Identification of Molecular Signatures Associated with Natural Products)

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