Biomolecules

20 pages, 3105 KiB

Open AccessReview

Binding Molecules in Tick Saliva for Targeting Host Cytokines, Chemokines, and Beyond

by Chamberttan Souza Desidério, Victor Hugo Palhares Flávio-Reis, Yago Marcos Pessoa-Gonçalves, Rafael Destro Rosa Tiveron, Helioswilton Sales-Campos, Andrei Giacchetto Felice, Siomar de Castro Soares, Rhainer Guillermo-Ferreira, Wellington Francisco Rodrigues and Carlo José Freire Oliveira

Biomolecules 2024, 14(12), 1647; https://doi.org/10.3390/biom14121647 (registering DOI) - 21 Dec 2024

Abstract

Ticks have coevolved with their hosts over millions of years, developing the ability to evade hemostatic, inflammatory, and immunological responses. Salivary molecules from these vectors bind to cytokines, chemokines, antibodies, complement system proteins, vasodilators, and molecules involved in coagulation and platelet aggregation, among [...] Read more.

Ticks have coevolved with their hosts over millions of years, developing the ability to evade hemostatic, inflammatory, and immunological responses. Salivary molecules from these vectors bind to cytokines, chemokines, antibodies, complement system proteins, vasodilators, and molecules involved in coagulation and platelet aggregation, among others, inhibiting or blocking their activities. Initially studied to understand the complexities of tick–host interactions, these molecules have been more recently recognized for their potential clinical applications. Their ability to bind to soluble molecules and modulate important physiological systems, such as immunity, hemostasis, and coagulation, positions them as promising candidates for future therapeutic development. This review aims to identify the binding molecules present in tick saliva, determine their primary targets, and explore the tick species involved in these processes. By associating the binding molecules, the molecules to which they bind, and the effect caused, the review provides a basis for understanding how these molecules can contribute to possible future advances in clinical applications. Full article

(This article belongs to the Special Issue Cytokine Signaling in Immunity and Immune Cell-Mediated Diseases)

► Show Figures

Figure 1

23 pages, 2645 KiB

Open AccessReview

Lactate and Lactylation: Dual Regulators of T-Cell-Mediated Tumor Immunity and Immunotherapy

by Zhi-Nan Hao, Xiao-Ping Tan, Qing Zhang, Jie Li, Ruohan Xia and Zhaowu Ma

Biomolecules 2024, 14(12), 1646; https://doi.org/10.3390/biom14121646 (registering DOI) - 21 Dec 2024

Abstract

Lactate and its derivative, lactylation, play pivotal roles in modulating immune responses within the tumor microenvironment (TME), particularly in T-cell-mediated cancer immunotherapy. Elevated lactate levels, a hallmark of the Warburg effect, contribute to immune suppression through CD8⁺ T cell functionality and by [...] Read more.

Lactate and its derivative, lactylation, play pivotal roles in modulating immune responses within the tumor microenvironment (TME), particularly in T-cell-mediated cancer immunotherapy. Elevated lactate levels, a hallmark of the Warburg effect, contribute to immune suppression through CD8⁺ T cell functionality and by promoting regulatory T cell (Treg) activity. Lactylation, a post-translational modification (PTM), alters histone and non-histone proteins, influencing gene expression and further reinforcing immune suppression. In the complex TME, lactate and its derivative, lactylation, are not only associated with immune suppression but can also, under certain conditions, exert immunostimulatory effects that enhance cytotoxic responses. This review describes the dual roles of lactate and lactylation in T-cell-mediated tumor immunity, analyzing how these factors contribute to immune evasion, therapeutic resistance, and immune activation. Furthermore, the article highlights emerging therapeutic strategies aimed at inhibiting lactate production or disrupting lactylation pathways to achieve a balanced regulation of these dual effects. These strategies offer new insights into overcoming tumor-induced immune suppression and hold the potential to improve the efficacy of cancer immunotherapies. Full article

(This article belongs to the Section Molecular Biology)

► Show Figures

Figure 1

28 pages, 8683 KiB

Open AccessArticle

Suppression of MT5-MMP Reveals Early Modulation of Alzheimer’s Pathogenic Events in Primary Neuronal Cultures of 5xFAD Mice

by Dominika Pilat, Jean-Michel Paumier, Laurence Louis, Christine Manrique, Laura García-González, Delphine Stephan, Anne Bernard, Raphaëlle Pardossi-Piquard, Frédéric Checler, Michel Khrestchatisky, Eric Di Pasquale, Kévin Baranger and Santiago Rivera

Biomolecules 2024, 14(12), 1645; https://doi.org/10.3390/biom14121645 (registering DOI) - 21 Dec 2024

Abstract

We previously reported that membrane-type 5-matrix metalloproteinase (MT5-MMP) deficiency not only reduces pathological hallmarks of Alzheimer’s disease (AD) in 5xFAD (Tg) mice in vivo but also impairs interleukin-1 beta (IL-1β)-mediated neuroinflammation and Aβ production in primary Tg immature neural cell cultures after 11 days [...] Read more.

We previously reported that membrane-type 5-matrix metalloproteinase (MT5-MMP) deficiency not only reduces pathological hallmarks of Alzheimer’s disease (AD) in 5xFAD (Tg) mice in vivo but also impairs interleukin-1 beta (IL-1β)-mediated neuroinflammation and Aβ production in primary Tg immature neural cell cultures after 11 days in vitro. We now investigate the effect of MT5-MMP on incipient pathogenic pathways that are activated in cortical primary cultures at 21–24 days in vitro (DIV), during which time neurons are organized into a functional mature network. Using wild-type (WT), MT5-MMP^−/− (MT5^−/−), 5xFAD (Tg), and 5xFADxMT5-MMP^−/− (TgMT5^−/−) mice, we generated primary neuronal cultures that were exposed to IL-1β and/or different proteolytic system inhibitors. We assessed neuroinflammation, APP metabolism, synaptic integrity, and electrophysiological properties using biochemical, imaging and whole-cell patch-clamp approaches. The absence of MT5-MMP impaired the IL-1β-mediated induction of inflammatory genes in TgMT5^−/− cells compared to Tg cells. Furthermore, the reduced density of dendritic spines in Tg neurons was also prevented in TgMT5^−/− neurons. IL-1β caused a strong decrease in the dendritic spine density of WT neurons, which was prevented in MT5^−/− neurons. However, the latter exhibited fewer spines than the WT under untreated conditions. The spontaneous rhythmic firing frequency of the network was increased in MT5^−/− neurons, but not in TgMT5^−/− neurons, and IL-1β increased this parameter only in Tg neurons. In terms of induced somatic excitability, Tg and TgMT5^−/− neurons exhibited lower excitability than WT and MT5^−/−, while IL-1β impaired excitability only in non-AD backgrounds. The synaptic strength of miniature global synaptic currents was equivalent in all genotypes but increased dramatically in WT and MT5^−/− neurons after IL-1β. MT5-MMP deficiency decreased endogenous and overexpressed C83 and C99 levels but did not affect Aβ levels. C99 appears to be cleared by several pathways, including γ-secretase, the autophagolysosomal system, and also α-secretase, via its conversion to C83. In summary, this study confirms that MT5-MMP is a pivotal factor affecting not only neuroinflammation and APP metabolism but also synaptogenesis and synaptic activity at early stages of the pathology, and reinforces the relevance of targeting MT5-MMP to fight AD. Full article

(This article belongs to the Special Issue Role of Matrix Metalloproteinase in Health and Disease)

► Show Figures

Figure 1

12 pages, 4468 KiB

Open AccessArticle

Characterization of the Interaction of Human γS Crystallin with Metal Ions and Its Effect on Protein Aggregation

by Reinier Cardenas, Arline Fernandez-Silva, Vanesa Ramirez-Bello and Carlos Amero

Biomolecules 2024, 14(12), 1644; https://doi.org/10.3390/biom14121644 (registering DOI) - 21 Dec 2024

Abstract

Cataracts are diseases characterized by the opacity of the ocular lens and the subsequent deterioration of vision. Metal ions are one of the factors that have been reported to induce crystallin aggregation. For HγS crystallin, several equivalent ratios of Cu(II) promote protein aggregation. [...] Read more.

Cataracts are diseases characterized by the opacity of the ocular lens and the subsequent deterioration of vision. Metal ions are one of the factors that have been reported to induce crystallin aggregation. For HγS crystallin, several equivalent ratios of Cu(II) promote protein aggregation. However, reports on zinc are contradictory. To characterize the process of metal ion binding and subsequent HγS crystallin aggregation, we performed dynamic light scattering, turbidimetry, isothermal titration calorimetry, fluorescence, and nuclear magnetic resonance experiments. The data show that both metal ions have multiple binding sites and promote aggregation. Zinc interacts mainly with the N-terminal domain, inducing small conformational changes, while copper interacts with both domains and induces unfolding, exposing the tryptophan residues to the solvent. Our work provides insight into the mechanisms of metal-induced aggregation at one of the lowest doses that appreciably promote aggregation over time. Full article

(This article belongs to the Section Biomacromolecules: Proteins)

► Show Figures

Figure 1

32 pages, 2635 KiB

Open AccessReview

The Role of Gut Microbiome in Irritable Bowel Syndrome: Implications for Clinical Therapeutics

by Yucui Zhao, Shixiao Zhu, Yingling Dong, Tian Xie, Zhiqiang Chai, Xiumei Gao, Yongna Dai and Xiaoying Wang

Biomolecules 2024, 14(12), 1643; https://doi.org/10.3390/biom14121643 (registering DOI) - 21 Dec 2024

Abstract

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder (FGID) characterized by chronic or recurrent gastrointestinal symptoms without organic changes, and it is also a common disorder of gut–brain interaction (DGBIs).. The symptoms of IBS not only affect the quality of life for [...] Read more.

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder (FGID) characterized by chronic or recurrent gastrointestinal symptoms without organic changes, and it is also a common disorder of gut–brain interaction (DGBIs).. The symptoms of IBS not only affect the quality of life for individual patients but also place a significant burden on global healthcare systems. The lack of established and universally applicable biomarkers for IBS, along with the substantial variability in symptoms and progression, presents challenges in developing effective clinical treatments. In recent years, preclinical and clinical studies have linked the pathogenesis of IBS to alterations in the composition and function of the intestinal microbiota. Within the complex microbial community of the gut, intricate metabolic and spatial interactions occur among its members and between microbes and their hosts. Amid the multifaceted pathophysiology of IBS, the role of intestinal microenvironment factors in symptom development has become more apparent. This review aims to delve into the changes in the composition and structure of the gut microbiome in individuals with IBS. It explores how diet-mediated alterations in intestinal microbes and their byproducts play a role in regulating the pathogenesis of IBS by influencing the “brain-gut” axis, intestinal barrier function, immune responses, and more. By doing so, this review seeks to lay a theoretical foundation for advancing the development of clinical therapeutics for IBS. Full article

(This article belongs to the Section Molecular Medicine)

► Show Figures

Figure 1

13 pages, 1601 KiB

Open AccessArticle

Gramicidin A in Asymmetric Lipid Membranes

by Oleg V. Kondrashov and Sergey A. Akimov

Biomolecules 2024, 14(12), 1642; https://doi.org/10.3390/biom14121642 (registering DOI) - 20 Dec 2024

Abstract

Gramicidin A is a natural antimicrobial peptide produced by Bacillus brevis. Its transmembrane dimer is a cation-selective ion channel. The channel is characterized by the average lifetime of the conducting state and the monomer–dimer equilibrium constant. Dimer formation is accompanied by deformations [...] Read more.

Gramicidin A is a natural antimicrobial peptide produced by Bacillus brevis. Its transmembrane dimer is a cation-selective ion channel. The channel is characterized by the average lifetime of the conducting state and the monomer–dimer equilibrium constant. Dimer formation is accompanied by deformations of the membrane. We theoretically studied how the asymmetry in lipid membrane monolayers influences the formation of the gramicidin A channel. We calculated how the asymmetry in the spontaneous curvature and/or lateral tension of lipid monolayers changes the channel lifetime and shifts the equilibrium constant of the dimerization/dissociation process. For the asymmetry expected to arise in plasma membranes of mammalian cells upon the addition of gramicidin A or its derivatives to the cell exterior, our model predicts a manifold increase in the average lifetime and equilibrium constant. Full article

(This article belongs to the Section Molecular Biophysics)

14 pages, 2426 KiB

Open AccessArticle

Identifying Hub Genes and miRNAs Associated with Alzheimer’s Disease: A Bioinformatics Pathway to Novel Therapeutic Strategies

by Elisa Gascón, Ana Cristina Calvo, Nora Molina, Pilar Zaragoza and Rosario Osta

Biomolecules 2024, 14(12), 1641; https://doi.org/10.3390/biom14121641 (registering DOI) - 20 Dec 2024

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder that mainly affects the elderly population. It is characterized by cognitive impairment and dementia due to abnormal levels of amyloid beta peptide (Aβ) and axonal Tau protein in the brain. However, the complex underlying mechanisms affecting [...] Read more.

Alzheimer’s disease (AD) is a neurodegenerative disorder that mainly affects the elderly population. It is characterized by cognitive impairment and dementia due to abnormal levels of amyloid beta peptide (Aβ) and axonal Tau protein in the brain. However, the complex underlying mechanisms affecting this disease are not yet known, and there is a lack of standardized biomarkers and therapeutic targets. Therefore, in this study, by means of bioinformatics analysis, AD-affected brain tissue was analyzed using the GSE138260 dataset, identifying 612 differentially expressed genes (DEGs). Functional analysis revealed 388 upregulated DEGs associated with sensory perception and 224 downregulated DEGs linked to the regulation and modulation of synaptic processes. Protein–protein interaction network analysis identified 20 hub genes. Furthermore, miRNA target gene networks revealed 1767 miRNAs linked to hub genes, among which hsa-mir-106a-5p, hsa-mir-17-5p, hsa-mir-26a-5p, hsa-mir-27a-3p and hsa-mir-34a-5p were the most relevant. This study presents novel biomarkers and therapeutic targets for AD by analyzing the information obtained with a comprehensive literature review, providing new potential targets to study their role in AD. Full article

(This article belongs to the Special Issue Pathogenesis and Neuropathology of Alzheimer's Disease)

► Show Figures

Figure 1

17 pages, 6802 KiB

Open AccessArticle

The Effect of Tyre and Road Wear Particles on the Terrestrial Isopod Armadillidium pallasii

by Giorgia Torreggiani, Chiara Manfrin, Anita Giglio, Andrea Dissegna, Cinzia Chiandetti, Paola Giotta, Monia Renzi, Serena Anselmi, Tecla Bentivoglio, Agnieszka Babczyńska, Silvia Battistella, Paolo Edomi and Piero G. Giulianini

Biomolecules 2024, 14(12), 1640; https://doi.org/10.3390/biom14121640 - 20 Dec 2024

Abstract

(1) Car tyre microplastic particles (TMPs) significantly contribute to global microplastic pollution, with an estimated annual production of 6 million tonnes. However, the impact of TMPs, particularly tyre and road wear particles (TRWPs), resulting from tyre abrasion on the road on terrestrial organisms, [...] Read more.

(1) Car tyre microplastic particles (TMPs) significantly contribute to global microplastic pollution, with an estimated annual production of 6 million tonnes. However, the impact of TMPs, particularly tyre and road wear particles (TRWPs), resulting from tyre abrasion on the road on terrestrial organisms, is poorly understood. This study investigated the effects of TMPs and TRWPs on the growth, immune response, behaviour, and cognition of the woodlouse Armadillidium pallasii over 30 days; (2) TMPs and TRWPs were mixed together in the first experiment and provided at different concentrations of 1.25%, 2.5%, 5%, and 10% (w/w), and with soil at 5% and 10% (w/w) concentrations in the second experiment. (3) No differences in survival or immune responses were observed in both experiments. However, isopods exposed to TRWPs showed significant weight gain at lower concentrations but no gain at higher levels. Behavioural tests revealed increased vigilance in TRWP-exposed animals. Micro-FTIR analysis showed that the number of TMPs and TRWPs in the isopods correlated with soil concentrations, and particle size decreased during the experiment. (4) The study highlights the physiological and behavioural effects of TRWPs and the role of detritivorous species in the biofragmentation of TMPs and TRWPs, contributing to the biogeochemical plastic cycle. Full article

(This article belongs to the Special Issue Host Molecules and Molecular Mechanisms in Insects and Crustaceans)

► Show Figures

Figure 1

11 pages, 5048 KiB

Open AccessArticle

High Glucose Sensitizes Male and Female Rat Cardiomyocytes to Wnt/β-Catenin Signaling

by Ruonan Gu, Jerry Wang, Julianne Morin, Aizhu Lu and Wenbin Liang

Biomolecules 2024, 14(12), 1639; https://doi.org/10.3390/biom14121639 - 20 Dec 2024

Abstract

Wnt/β-catenin signaling has been shown to regulate gene expressions in cardiomyocytes. However, it is not known if this effect is dependent on the sex of cells or the glucose level in the culture medium. In the present study, ventricular myocytes were prepared from [...] Read more.

Wnt/β-catenin signaling has been shown to regulate gene expressions in cardiomyocytes. However, it is not known if this effect is dependent on the sex of cells or the glucose level in the culture medium. In the present study, ventricular myocytes were prepared from male and female neonatal rats and maintained in either a glucose-rich (25 mM) medium or a low-glucose (3 mM), lipid-rich medium. A real-time quantitative PCR was used to measure changes in target genes (Axin2, Scn5a, and Tbx3) after treatment with 1, 3, or 10 µM of CHIR-99021, an activator of Wnt/β-catenin signaling. CHIR induced similar changes in Axin2, Tbx3, and Scn5a transcripts in male and female NRVMs in both media, suggesting the absence of sex difference. However, cells in a high-glucose medium showed greater increases in Axin2 and Tbx3 transcripts than cells in a low-glucose medium. In addition, a low concentration of CHIR (1 µM) reduced the Scn5a transcript in cells in a high-glucose medium but not in a low-glucose medium, suggesting an increased sensitivity to Wnt signaling by high glucose. A non-linear relationship was identified between Axin2 transcript upregulation and Scn5a transcript downregulation in CIHR-treated NRVMs. These data suggest that high glucose sensitizes both male and female cardiomyocytes to Wnt/β-catenin signaling. Full article

(This article belongs to the Section Molecular Medicine)

► Show Figures

Figure 1

17 pages, 2717 KiB

Open AccessReview

Enzymatic Regulation of the Gut Microbiota: Mechanisms and Implications for Host Health

by Zipeng Jiang, Liang Mei, Yuqi Li, Yuguang Guo, Bo Yang, Zhiyi Huang and Yangyuan Li

Biomolecules 2024, 14(12), 1638; https://doi.org/10.3390/biom14121638 - 20 Dec 2024

Abstract

The gut microbiota, a complex ecosystem, is vital to host health as it aids digestion, modulates the immune system, influences metabolism, and interacts with the brain-gut axis. Various factors influence the composition of this microbiota. Enzymes, as essential catalysts, actively participate in biochemical [...] Read more.

The gut microbiota, a complex ecosystem, is vital to host health as it aids digestion, modulates the immune system, influences metabolism, and interacts with the brain-gut axis. Various factors influence the composition of this microbiota. Enzymes, as essential catalysts, actively participate in biochemical reactions that have an impact on the gut microbial community, affecting both the microorganisms and the gut environment. Enzymes play an important role in the regulation of the intestinal microbiota, but the interactions between enzymes and microbial communities, as well as the precise mechanisms of enzymes, remain a challenge in scientific research. Enzymes serve both traditional nutritional functions, such as the breakdown of complex substrates into absorbable small molecules, and non-nutritional roles, which encompass antibacterial function, immunomodulation, intestinal health maintenance, and stress reduction, among others. This study categorizes enzymes according to their source and explores the mechanistic principles by which enzymes drive gut microbial activity, including the promotion of microbial proliferation, the direct elimination of harmful microbes, the modulation of bacterial interaction networks, and the reduction in immune stress. A systematic understanding of enzymes in regulating the gut microbiota and the study of their associated molecular mechanisms will facilitate the application of enzymes to precisely regulate the gut microbiota in the future and suggest new therapeutic strategies and dietary recommendations. In conclusion, this review provides a comprehensive overview of the role of enzymes in modulating the gut microbiota. It explores the underlying molecular and cellular mechanisms and discusses the potential applications of enzyme-mediated microbiota regulation for host gut health. Full article

(This article belongs to the Special Issue Novel Antimicrobial Strategies for Animal Health)

► Show Figures

Figure 1

35 pages, 1935 KiB

Open AccessReview

Vaccination as a Promising Approach in Cardiovascular Risk Mitigation: Are We Ready to Embrace a Vaccine Strategy?

by Georgios Tsioulos, Natalia G. Vallianou, Alexandros Skourtis, Maria Dalamaga, Evangelia Kotsi, Sofia Kargioti, Nikolaos Adamidis, Irene Karampela, Iordanis Mourouzis and Dimitris Kounatidis

Biomolecules 2024, 14(12), 1637; https://doi.org/10.3390/biom14121637 - 20 Dec 2024

Abstract

Cardiovascular disease (CVD) remains a leading global health concern, with atherosclerosis being its principal cause. Standard CVD treatments primarily focus on mitigating cardiovascular (CV) risk factors through lifestyle changes and cholesterol-lowering therapies. As atherosclerosis is marked by chronic arterial inflammation, the innate and [...] Read more.

Cardiovascular disease (CVD) remains a leading global health concern, with atherosclerosis being its principal cause. Standard CVD treatments primarily focus on mitigating cardiovascular (CV) risk factors through lifestyle changes and cholesterol-lowering therapies. As atherosclerosis is marked by chronic arterial inflammation, the innate and adaptive immune systems play vital roles in its progression, either exacerbating or alleviating disease development. This intricate interplay positions the immune system as a compelling therapeutic target. Consequently, immunomodulatory strategies have gained increasing attention, though none have yet reached widespread clinical adoption. Safety concerns, particularly the suppression of host immune defenses, remain a significant barrier to the clinical application of anti-inflammatory therapies. Recent decades have revealed the significant role of adaptive immune responses to plaque-associated autoantigens in atherogenesis, opening new perspectives for targeted immunological interventions. Preclinical models indicate that vaccines targeting specific atherosclerosis-related autoantigens can slow disease progression while preserving systemic immune function. In this context, numerous experimental studies have advanced the understanding of vaccine development by exploring diverse targeting pathways. Key strategies include passive immunization using naturally occurring immunoglobulin G (IgG) antibodies and active immunization targeting low-density lipoprotein cholesterol (LDL-C) and apolipoproteins, such as apolipoprotein B100 (ApoB100) and apolipoprotein CIII (ApoCIII). Other approaches involve vaccine formulations aimed at proteins that regulate lipoprotein metabolism, including proprotein convertase subtilisin/kexin type 9 (PCSK9), cholesteryl ester transfer protein (CETP), and angiopoietin-like protein 3 (ANGPTL3). Furthermore, the literature highlights the potential for developing non-lipid-related vaccines, with key targets including heat shock proteins (HSPs), interleukins (ILs), angiotensin III (Ang III), and a disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS-7). However, translating these promising findings into safe and effective clinical therapies presents substantial challenges. This review provides a critical evaluation of current anti-atherosclerotic vaccination strategies, examines their proposed mechanisms of action, and discusses key challenges that need to be overcome to enable clinical translation. Full article

(This article belongs to the Special Issue New Insights into Mechanisms and Therapeutics for Cardiovascular Disorders)

► Show Figures

Figure 1

14 pages, 5656 KiB

Open AccessArticle

Celecoxib Combined with Tocilizumab Has Anti-Inflammatory Effects and Promotes the Recovery of Damaged Cartilage via the Nrf2/HO-1 Pathway In Vitro

by Miyako Shimasaki, Shusuke Ueda, Masaru Sakurai, Norio Kawahara, Yoshimichi Ueda and Toru Ichiseki

Biomolecules 2024, 14(12), 1636; https://doi.org/10.3390/biom14121636 - 20 Dec 2024

Abstract

Inflammation and oxidative stress are crucial for osteoarthritis (OA) pathogenesis. Despite the potential of pharmacological pretreatment of chondrocytes in preventing OA, its efficacy in preventing the progression of cartilage damage and promoting its recovery has not been examined. In this study, an H [...] Read more.

Inflammation and oxidative stress are crucial for osteoarthritis (OA) pathogenesis. Despite the potential of pharmacological pretreatment of chondrocytes in preventing OA, its efficacy in preventing the progression of cartilage damage and promoting its recovery has not been examined. In this study, an H₂O₂-induced human OA-like chondrocyte cell model was created using H1467 primary human chondrocytes to evaluate the efficacy of interleukin (IL)-6 and cyclooxygenase (COX)-2 inhibitors (tocilizumab and celecoxib, respectively) in the prevention and treatment of cartilage damage. H₂O₂ significantly elevated the IL-6, COX-2, and matrix metalloproteinase (MMP)-13 levels. Although monotherapy decreased the levels, nuclear shrinkage and altered cell morphology, similar to those in the H₂O₂ group, were observed. The expression of these factors was significantly lower in the combination therapy group, and the cell morphology was maintained. Moreover, the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was activated, and levels of the antioxidant protein heme oxygenase-1 (HO-1) were increased, especially in the combination group, indicating an anti-inflammatory effect. The treatment groups, particularly the combination group, demonstrated increased cell viability. Overall, the drug combination exhibited superior efficacy in preventing the progression of cartilage damage and promoted its recovery compared with the monotherapy. Given that the drugs herein are already in clinical use, they are suitable candidates for OA treatment. Full article

(This article belongs to the Section Cellular Biochemistry)

► Show Figures

Figure 1

20 pages, 1801 KiB

Open AccessArticle

Bioactive Molecules from the Exoskeleton of Procambarus clarkii: Reducing Capacity, Radical Scavenger, and Antitumor and Anti-Inflammatory Activities

by Francesco Longo, Francesca Di Gaudio, Alessandro Attanzio, Laura Marretta, Claudio Luparello, Serena Indelicato, David Bongiorno, Giampaolo Barone, Luisa Tesoriere, Ilenia Concetta Giardina, Giulia Abruscato, Manuela Perlotti, Lucie Branwen Hornsby, Vincenzo Arizza, Mirella Vazzana, Federico Marrone, Aiti Vizzini, Chiara Martino, Dario Savoca, Vinicius Queiroz, Antonio Fabbrizio and Manuela Mauro Show full author list Hide full author list

Biomolecules 2024, 14(12), 1635; https://doi.org/10.3390/biom14121635 - 20 Dec 2024

Abstract

This study evaluates, for the first time, the reducing capacity, radical scavenger activity, and in vitro antitumor and anti-inflammatory effects of chitosan, astaxanthin, and bio-phenols extracted from the exoskeleton of Sicilian Procambarus clarkii, the most widespread species of invasive crayfish in the [...] Read more.

This study evaluates, for the first time, the reducing capacity, radical scavenger activity, and in vitro antitumor and anti-inflammatory effects of chitosan, astaxanthin, and bio-phenols extracted from the exoskeleton of Sicilian Procambarus clarkii, the most widespread species of invasive crayfish in the Mediterranean region. Among the extracted compounds, astaxanthin exhibited the highest antioxidant activity in all assays. Chitosan and polyphenols demonstrated reducing and radical scavenging activity; chitosan showed significant ferric ion reducing capacity in the FRAP test, while bio-phenolic compounds displayed notable radical scavenging activity in the DPPH and ABTS assays. Both astaxanthin and polyphenols showed dose-dependent cytotoxicity on two different cancer cell lines, with IC50 values of 1.45 µg/mL (phenolic extract) and 4.28 µg/mL (astaxanthin extract) for HepG2 cells and 2.45 µg/mL (phenolic extract) and 4.57 µg/mL (astaxanthin extract) for CaCo-2 cells. The bio-phenolic extract also showed potential anti-inflammatory effects in vitro by inhibiting nitric oxide production in inflamed RAW 264.7 macrophages, reducing the treated/control NO ratio to 77% and 74% at concentrations of 1.25 and 1.5 μg/mL, respectively. These results suggest that P. clarkii exoskeletons could be a valuable source of bioactive molecules for biomedical, pharmaceutical, and nutraceutical application while contributing to the sustainable management of this invasive species. Full article

(This article belongs to the Topic Molecular and Cellular Aspects of the Beneficial Effects of Natural Products on Chronic Diseases)

► Show Figures

Figure 1

18 pages, 1488 KiB

Open AccessReview

Research Progress of Liquid Biopsy Based on DNA Methylation in Tumor Diagnosis and Treatment

by Yunxia Bao, Xianzhao Wang, Bingjie Zeng, Yichun Shi, Yiman Huang, Yiwen Huang, Shuang Shang, Liang Shan and Lifang Ma

Biomolecules 2024, 14(12), 1634; https://doi.org/10.3390/biom14121634 - 19 Dec 2024

Abstract

Liquid biopsy has been gradually applied to the clinical diagnosis and treatment of tumors because of its non-invasive and real-time reflection of the tumor status, as well as the convenience of sample collection, which allows the detection of primary or metastatic malignant tumors [...] Read more.

Liquid biopsy has been gradually applied to the clinical diagnosis and treatment of tumors because of its non-invasive and real-time reflection of the tumor status, as well as the convenience of sample collection, which allows the detection of primary or metastatic malignant tumors and reflects the heterogeneity of the tumors. DNA methylation, which is a type of epigenetic modification, is essential in the progression of tumors. This review introduces the common DNA methylation analysis methods and discusses their advantages and disadvantages, focusing on the new progress of DNA methylation-based liquid biopsy in tumor diagnosis and treatment. Full article

(This article belongs to the Special Issue Emerging Biomarkers Discovery for Molecular Diagnostics)

► Show Figures

Figure 1

10 pages, 899 KiB

Open AccessArticle

The Influence of Bariatric Surgery on Matrix Metalloproteinase Plasma Levels in Patients with Type 2 Diabetes Mellitus

by João Kleber de Almeida Gentile, Renato Migliore, Jaques Waisberg and Marcelo Augusto Fontenelle Ribeiro Junior

Biomolecules 2024, 14(12), 1633; https://doi.org/10.3390/biom14121633 - 19 Dec 2024

Abstract

Background: Bariatric surgery is a safe and effective procedure for treating obesity and metabolic conditions such as type 2 diabetes mellitus (T2DM). Remodeling of the extracellular matrix (ECM) supports adipose tissue expansion and its metabolic activity, where matrix metalloproteinases (MMPs) play a key [...] Read more.

Background: Bariatric surgery is a safe and effective procedure for treating obesity and metabolic conditions such as type 2 diabetes mellitus (T2DM). Remodeling of the extracellular matrix (ECM) supports adipose tissue expansion and its metabolic activity, where matrix metalloproteinases (MMPs) play a key role in ECM regulation. The MMPs, particularly MMP-2 and MMP-9, are elevated in patients with morbid obesity, metabolic syndrome, and T2DM. Objectives: To evaluate the effect of weight loss in bariatric surgery patients using oxidative stress markers and to compare MMP levels in patients undergoing bariatric surgery. Methods: This was a prospective, controlled study including 45 morbidly obese patients with T2DM (BMI > 35 kg/m²) who underwent RYGB (n = 24) or VG (n = 21). Weight loss was assessed through anthropometric measurements (weight, height, BMI). MMP-2 and MMP-9 levels were measured preoperatively and at 3 and 12 months postoperatively. Results: Significant and sustained weight loss was observed after surgery in both groups, with reductions in BMI. MMP-2 and MMP-9 levels decreased significantly after one year of follow-up. Conclusions: Bariatric surgery is an effective long-term intervention for weight loss and associated comorbidities, including T2DM. MMP-2 and MMP-9 proved to be effective markers of extracellular matrix remodeling, with significant reductions following surgery. Full article

(This article belongs to the Special Issue Role of Matrix Metalloproteinase in Health and Disease)

► Show Figures

Figure 1

12 pages, 4744 KiB

Open AccessArticle

Peptide-Mediated Transport Across the Intact Tympanic Membrane Is Intracellular, with the Rate Determined by the Middle Ear Mucosal Epithelium

by Arwa Kurabi, Yuge Xu, Eduardo Chavez, Vivian Khieu and Allen F. Ryan

Biomolecules 2024, 14(12), 1632; https://doi.org/10.3390/biom14121632 - 19 Dec 2024

Abstract

The tympanic membrane forms an impenetrable barrier between the ear canal and the air-filled middle ear, protecting it from fluid, pathogens, and foreign material entry. We previously screened a phage display library and discovered peptides that mediate transport across the intact membrane. The [...] Read more.

The tympanic membrane forms an impenetrable barrier between the ear canal and the air-filled middle ear, protecting it from fluid, pathogens, and foreign material entry. We previously screened a phage display library and discovered peptides that mediate transport across the intact membrane. The route by which transport occurs is not certain, but possibilities include paracellular transport through loosened intercellular junctions and transcellular transport through the cells that comprise the various tympanic membrane layers. We used confocal imaging to resolve the phage’s path through the membrane. Phages were observed in puncta within the cytoplasm of tympanic membrane cells, with no evidence of phages within junctions between epithelial cells. This result indicates that transport across the membrane is transcellular and within vesicles, consistent with the transcytosis process. The trans-tympanic peptide phages display a wide range of transport efficiencies for unknown reasons. This could include variation in tympanic membrane binding, entry into the membrane, crossing the membrane, or exiting into the middle ear. To address this, we titered phages recovered from within the membrane for phages with differing transport rates. We found that differences in the transport rate were inversely related to their presence within the tympanic membrane. This suggests that differences in the transport rate primarily reflect the efficiency of an exocytotic exit from the mucosal epithelium rather than entry into, or passage across, the membrane. Full article

(This article belongs to the Section Cellular Biochemistry)

► Show Figures

Figure 1

21 pages, 1179 KiB

Open AccessSystematic Review

Cytokine Gene Variants as Predisposing Factors for the Development and Progression of Coronary Artery Disease: A Systematic Review

by Fang Li, Yingshuo Zhang, Yichao Wang, Xiaoyan Cai and Xiongwei Fan

Biomolecules 2024, 14(12), 1631; https://doi.org/10.3390/biom14121631 - 19 Dec 2024

Abstract

Coronary artery disease (CAD) is the most prevalent form of cardiovascular disease. A growing body of research shows that interleukins (ILs), such as IL-8, IL-18 and IL-16, elicit pro-inflammatory responses and may play critical roles in the pathologic process of CAD. Single nucleotide [...] Read more.

Coronary artery disease (CAD) is the most prevalent form of cardiovascular disease. A growing body of research shows that interleukins (ILs), such as IL-8, IL-18 and IL-16, elicit pro-inflammatory responses and may play critical roles in the pathologic process of CAD. Single nucleotide polymorphisms (SNPs), capable of generating functional modifications in IL genes, appear to be associated with CAD risk. This study aims to evaluate the associations of ten previously identified SNPs of the three cytokines with susceptibility to or protection of CAD. A systematic review and meta-analysis were conducted using Pubmed, EMBASE, WOS, CENTRAL, CNKI, CBM, Weipu, WANFANG Data and Google Scholar databases for relevant literature published up to September 2024. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for the four genetic models of the investigated SNPs in overall and subgroups analyses. Thirty-eight articles from 16 countries involving 14574 cases and 13001 controls were included. The present meta-analysis revealed no significant association between CAD and IL-8-rs2227306 or five IL-16 SNPs (rs8034928, rs3848180, rs1131445, rs4778889 and rs11556218). However, IL-8-rs4073 was significantly associated with an increased risk of CAD across all genetic models. In contrast, three IL-18 (rs187238, rs1946518 and rs1946519) variants containing minor alleles were associated with decreased risks of CAD under all models. Subgroups analyses by ethnicity indicated that IL-8-rs4073 conferred a significantly higher risk of CAD among Asians, including East, South and West Asians (allelic OR = 1.46, homozygous OR = 1.96, heterozygous OR = 1.47, dominant OR = 1.65), while it showed an inversely significant association with CAD risk in Caucasians (homozygous OR = 0.82, dominant OR = 0.85). Additionally, IL-18-rs187238 and IL-18-rs1946518 were significantly associated with reduced CAD risks in East Asians (for rs187238: allelic OR = 0.72, homozygous OR = 0.33, heterozygous OR = 0.73, dominant OR = 0.71; for rs1946518: allelic OR = 0.62, homozygous OR = 0.38, heterozygous OR = 0.49, dominant OR = 0.45). IL-18-rs187238 also demonstrated protective effects in Middle Eastern populations (allelic OR = 0.76, homozygous OR = 0.63, heterozygous OR = 0.72, dominant OR = 0.71). No significant associations were observed in South Asians or Caucasians for these IL-18 SNPs. Consistent with the overall analysis results, subgroups analyses further highlighted a significant association between IL-8-rs4073 and increased risk of acute coronary syndrome (heterozygous OR = 0.72). IL-18-rs187238 was significantly associated with decreased risks of myocardial infarction (MI) (allelic OR = 0.81, homozygous OR = 0.55, dominant OR = 0.80) and multiple vessel stenosis (allelic OR = 0.54, heterozygous OR = 0.45, dominant OR = 0.45). Similarly, IL-18-rs1946518 was significantly associated with reduced MI risk (allelic OR = 0.75, heterozygous OR = 0.68). These findings support the role of cytokine gene IL-8 and IL-18 variants as predisposing factors for the development and progression of CAD. Full article

(This article belongs to the Special Issue Recent Advances in the Role of Translation Machinery and Translational Control in the Cardiovascular System)

► Show Figures

Figure 1

28 pages, 1200 KiB

Open AccessReview

The Role of Cardiac Troponin and Other Emerging Biomarkers Among Athletes and Beyond: Underlying Mechanisms, Differential Diagnosis, and Guide for Interpretation

by Mihail Celeski, Andrea Segreti, Filippo Crisci, Riccardo Cricco, Mariagrazia Piscione, Giuseppe Di Gioia, Annunziata Nusca, Chiara Fossati, Fabio Pigozzi, Gian Paolo Ussia, Ross John Solaro and Francesco Grigioni

Biomolecules 2024, 14(12), 1630; https://doi.org/10.3390/biom14121630 - 19 Dec 2024

Abstract

Cardiovascular (CV) disease remains the leading cause of morbidity and mortality worldwide, highlighting the necessity of understanding its underlying molecular and pathophysiological pathways. Conversely, physical activity (PA) and exercise are key strategies in reducing CV event risks. Detecting latent CV conditions in apparently [...] Read more.

Cardiovascular (CV) disease remains the leading cause of morbidity and mortality worldwide, highlighting the necessity of understanding its underlying molecular and pathophysiological pathways. Conversely, physical activity (PA) and exercise are key strategies in reducing CV event risks. Detecting latent CV conditions in apparently healthy individuals, such as athletes, presents a unique challenge. The early identification and treatment of CV disorders are vital for long-term health and patient survival. Cardiac troponin is currently the most commonly used biomarker for assessing CV changes in both athletes and the general population. However, there remains considerable debate surrounding the mechanisms underlying exercise-induced troponin elevations and its release in non-ischemic contexts. Thus, there is a pressing need to identify and implement more sensitive and specific biomarkers for CV disorders in clinical practice. Indeed, research continues to explore reliable biomarkers for evaluating the health of athletes and the effectiveness of physical exercise. It is essential to analyze current evidence on troponin release in non-ischemic conditions, post-strenuous exercise, and the complex biological pathways that influence its detection. Furthermore, this study summarizes current research on cytokines and exosomes, including their physiological roles and their relevance in various CV conditions, especially in athletes. In addition, this paper gives special attention to underlying mechanisms, potential biomarkers, and future perspectives. Full article

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

► Show Figures

Figure 1

12 pages, 4071 KiB

Open AccessArticle

IL6 and IL6R as Prognostic Biomarkers in Colorectal Cancer

by Kathryn A. F. Pennel, Ahmad Kurniawan, Sara Samir Foad Al-Badran, Leonor Schubert Santana, Jean Quinn, Colin Nixon, Phimmada Hatthakarnkul, Noori Maka, Campbell Roxburgh, Donald McMillan and Joanne Edwards

Biomolecules 2024, 14(12), 1629; https://doi.org/10.3390/biom14121629 - 19 Dec 2024

Abstract

Colorectal cancer is the third most diagnosed malignancy worldwide and survival outcomes remain poor. Research is focused on the identification of novel prognostic and predictive biomarkers to improve clinical practice. There is robust evidence in the literature that inflammatory cytokine interleukin-6 (IL6) is [...] Read more.

Colorectal cancer is the third most diagnosed malignancy worldwide and survival outcomes remain poor. Research is focused on the identification of novel prognostic and predictive biomarkers to improve clinical practice. There is robust evidence in the literature that inflammatory cytokine interleukin-6 (IL6) is elevated systemically in CRC patients and that this phenomenon is a predictor of poor survival outcome. However, evidence is more limited for the role of IL6 and its cognate receptor, IL6R, within the tumour epithelium and microenvironment. This study aimed to investigate IL6 and IL6R expression in a large cohort of retrospectively collected patient tumour specimens and determine association with clinical outcomes and characteristics. High expression of IL6R in the tumour epithelium was associated with reduced cancer-specific survival in patients with right-sided colon cancer. In these patients, high IL6R expression was also associated with an increased systemic neutrophil-to-lymphocyte ratio. A high number of copies of IL6 mRNA within the tumour-associated stroma, but not epithelium, was associated with reduced cancer-specific survival. The results from this study have validated IL6R as a marker of poor prognosis in a subgroup of CRC patients and identified the spatially resolved prognostic nature of intra-tumoural IL6 expression. This study has also highlighted the need for investigation of IL6/IL6R-targeted therapies as novel treatment strategies for patients with colon cancer. Full article

(This article belongs to the Special Issue Colorectal and Gastric Cancers: Molecular Mechanisms and Potential Biomarkers)

► Show Figures

Figure 1

Journal Description

Biomolecules

Latest Articles

Journal Menu

Journal Browser

Highly Accessed Articles

Latest Books

E-Mail Alert

News

Topics

Conferences

Special Issues

Topical Collections

Further Information

Guidelines

MDPI Initiatives

Follow MDPI