Biomolecules

14 pages, 2062 KiB

Open AccessArticle

Effects of Hyaluronic Acid on Three Different Cell Types of the Periodontium in a Novel Multi-Culture Cell Plate: An Exploratory Study

by Alessio Barbieri, Luciano Pitzurra, Bruno Loos and Ineke D. C. Jansen

Biomolecules 2025, 15(1), 152; https://doi.org/10.3390/biom15010152 - 20 Jan 2025

Viewed by 692

Abstract

Hyaluronic acid (HA) has received considerable attention in the reconstruction of lost periodontal tissues. HA has been proposed to play a role in cell proliferation, differentiation, migration, and cell–matrix as well as cell–cell interactions. Although various studies have been conducted, further research is [...] Read more.

Hyaluronic acid (HA) has received considerable attention in the reconstruction of lost periodontal tissues. HA has been proposed to play a role in cell proliferation, differentiation, migration, and cell–matrix as well as cell–cell interactions. Although various studies have been conducted, further research is needed to expand our knowledge based on HA such as its effects on cell proliferation and osteogenic differentiation. The aim of this study is to assess, in single- and multi-culture plate models, the effect of HA on the proliferation, viability, and function of periodontal ligament fibroblasts, osteoblasts, and gingival epithelial cells. A novel multi-culture cell plate was chosen to simulate a cell–cell communication as close as possible to a real clinical condition in an in vitro setting. We found that HA exclusively enhanced epithelial cell proliferation, while intercellular communication stimulated the proliferation and osteogenic potential of the osteoblasts, independently from HA use. The proliferation and function of the periodontal ligament fibroblasts were not changed by HA or the cellular interplay. The use of multi-culture plates could represent a promising method to investigate and compare dental biomaterials in experiments mimicking an in vivo environment. Full article

(This article belongs to the Special Issue Biologics and Biomaterials for Periodontal Treatment: Current and Future Challenges)

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56 pages, 5111 KiB

Open AccessReview

The Role of Quercetin, a Flavonoid in the Management of Pathogenesis Through Regulation of Oxidative Stress, Inflammation, and Biological Activities

by Hajed Obaid A. Alharbi, Mohammad Alshebremi, Ali Yousif Babiker and Arshad Husain Rahmani

Biomolecules 2025, 15(1), 151; https://doi.org/10.3390/biom15010151 - 20 Jan 2025

Viewed by 1426

Abstract

Quercetin, a flavonoid found in vegetables and fruits, has been extensively studied for its health benefits and disease management. Its role in the prevention of various pathogenesis has been well-documented, primarily through its ability to inhibit oxidative stress, inflammation, and enhance the endogenous [...] Read more.

Quercetin, a flavonoid found in vegetables and fruits, has been extensively studied for its health benefits and disease management. Its role in the prevention of various pathogenesis has been well-documented, primarily through its ability to inhibit oxidative stress, inflammation, and enhance the endogenous antioxidant defense mechanisms. Electronic databases such as Google Scholar, Scopus, PubMed, Medline, and Web of Science were searched for information regarding quercetin and its role in various pathogeneses. The included literature comprised experimental studies, randomized controlled trials, and epidemiological studies related to quercetin, while editorials, case analyses, theses, and letters were excluded. It has been reported to have a wide range of health benefits including hepatoprotective, antidiabetic, anti-obesity, neuroprotective, cardioprotective, wound healing, antimicrobial, and immunomodulatory effects, achieved through the modulation of various biological activities. Additionally, numerous in vitro and in vivo studies have shown that quercetin’s efficacies in cancer management involve inhibiting cell signaling pathways, such as inflammation, cell cycle, and angiogenesis, activating cell signaling pathways including tumor suppressor genes, and inducing apoptosis. This review aims to provide a comprehensive understanding of the health benefits of quercetin in various pathogeneses. Additionally, this review outlines the sources of quercetin, nanoformulations, and its applications in health management, along with key findings from important clinical trial studies. Limited clinical data regarding quercetin’s safety and mechanism of action are available. It is important to conduct more clinical trials to gain a deeper understanding of the disease-preventive potential, mechanisms of action, safety, and optimal therapeutic dosages. Furthermore, more research based on nanoformulations should be performed to minimize/overcome the hindrance associated with bioavailability, rapid degradation, and toxicity. Full article

(This article belongs to the Special Issue Feature Papers in the Natural and Bio-Derived Molecules Section)

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22 pages, 13141 KiB

Open AccessArticle

Cell Type Specific Suppression of Hyper-Recombination by Human RAD18 Is Linked to Proliferating Cell Nuclear Antigen K164 Ubiquitination

by Colette B. Rogers, Wendy Leung, Ryan M. Baxley, Rachel E. Kram, Liangjun Wang, Joseph P. Buytendorp, Khoi Le, David A. Largaespada, Eric A. Hendrickson and Anja-Katrin Bielinsky

Biomolecules 2025, 15(1), 150; https://doi.org/10.3390/biom15010150 - 20 Jan 2025

Viewed by 655

Abstract

RAD18 is a conserved eukaryotic E3 ubiquitin ligase that promotes genome stability through multiple pathways. One of these is gap-filling DNA synthesis at active replication forks and in post-replicative DNA. RAD18 also regulates homologous recombination (HR) repair of DNA breaks; however, the current [...] Read more.

RAD18 is a conserved eukaryotic E3 ubiquitin ligase that promotes genome stability through multiple pathways. One of these is gap-filling DNA synthesis at active replication forks and in post-replicative DNA. RAD18 also regulates homologous recombination (HR) repair of DNA breaks; however, the current literature describing the contribution of RAD18 to HR in mammalian systems has not reached a consensus. To investigate this, we examined three independent RAD18-null human cell lines. Our analyses found that loss of RAD18 in HCT116, but neither hTERT RPE-1 nor DLD1 cell lines, resulted in elevated sister chromatid exchange, gene conversion, and gene targeting, i.e., HCT116 mutants were hyper-recombinogenic (hyper-rec). Interestingly, these phenotypes were linked to RAD18’s role in PCNA K164 ubiquitination, as HCT116 PCNA^K164R/+ mutants were also hyper-rec, consistent with previous studies in rad18^−/− and pcna^K164R avian DT40 cells. Importantly, the knockdown of UBC9 to prevent PCNA K164 SUMOylation did not affect hyper-recombination, strengthening the link between increased recombination and RAD18-catalyzed PCNA K164 ubiquitination, but not K164 SUMOylation. We propose that the hierarchy of post-replicative repair and HR, intrinsic to each cell type, dictates whether RAD18 is required for suppression of hyper-recombination and that this function is linked to PCNA K164 ubiquitination. Full article

(This article belongs to the Section Biomacromolecules: Nucleic Acids)

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37 pages, 2651 KiB

Open AccessReview

Targeting the Interplay Between Autophagy and the Nrf2 Pathway in Parkinson’s Disease with Potential Therapeutic Implications

by Mengru Liu, Siqi Liu, Zihan Lin, Xi Chen, Qian Jiao, Xixun Du and Hong Jiang

Biomolecules 2025, 15(1), 149; https://doi.org/10.3390/biom15010149 - 19 Jan 2025

Viewed by 581

Abstract

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder marked by the progressive degeneration of midbrain dopaminergic neurons and resultant locomotor dysfunction. Despite over two centuries of recognition as a chronic disease, the exact pathogenesis of PD remains elusive. The onset and progression of [...] Read more.

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder marked by the progressive degeneration of midbrain dopaminergic neurons and resultant locomotor dysfunction. Despite over two centuries of recognition as a chronic disease, the exact pathogenesis of PD remains elusive. The onset and progression of PD involve multiple complex pathological processes, with dysfunctional autophagy and elevated oxidative stress serving as critical contributors. Notably, emerging research has underscored the interplay between autophagy and oxidative stress in PD pathogenesis. Given the limited efficacy of therapies targeting either autophagy dysfunction or oxidative stress, it is crucial to elucidate the intricate mechanisms governing their interplay in PD to develop more effective therapeutics. This review overviews the role of autophagy and nuclear factor erythroid 2-related factor 2 (Nrf2), a pivotal transcriptional regulator orchestrating cellular defense mechanisms against oxidative stress, and the complex interplay between these processes. By elucidating the intricate interplay between these key pathological processes in PD, this review will deepen our comprehensive understanding of the multifaceted pathological processes underlying PD and may uncover potential strategies for its prevention and treatment. Full article

(This article belongs to the Section Molecular Medicine)

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19 pages, 2476 KiB

Open AccessReview

From Polydeoxyribonucleotides (PDRNs) to Polynucleotides (PNs): Bridging the Gap Between Scientific Definitions, Molecular Insights, and Clinical Applications of Multifunctional Biomolecules

by Cíntia Marques, Alexandre Porcello, Marco Cerrano, Farid Hadjab, Michèle Chemali, Kelly Lourenço, Basste Hadjab, Wassim Raffoul, Lee Ann Applegate and Alexis E. Laurent

Biomolecules 2025, 15(1), 148; https://doi.org/10.3390/biom15010148 - 19 Jan 2025

Viewed by 863

Abstract

Polydeoxyribonucleotides (PDRNs) and polynucleotides (PNs) are similar DNA-derived biopolymers that have garnered significant scientific attention since the 1990s for their potential applications in wound healing and skin rejuvenation. These biopolymers exhibit a broad molecular weight (MW) range, typically spanning from 50 to 1500 [...] Read more.

Polydeoxyribonucleotides (PDRNs) and polynucleotides (PNs) are similar DNA-derived biopolymers that have garnered significant scientific attention since the 1990s for their potential applications in wound healing and skin rejuvenation. These biopolymers exhibit a broad molecular weight (MW) range, typically spanning from 50 to 1500 kDa. However, recent studies have expanded this range to encompass fragments as small as 1 kDa and as large as 10,000 kDa. Clinically, PDRN/PN formulations, commercially available in various galenic forms (gels, creams, serums, masks, and injectables), have demonstrated promising effects in significantly promoting skin regeneration, reducing inflammation, improving skin texture, preventing scar formation, and mitigating wrinkles. Importantly, despite their widespread use in cosmetology and aesthetic dermatology, the interchangeable use of the terms “PDRN” and “PN” in the scientific literature (to describe polymers of varying lengths) has led to considerable confusion within the medical and scientific communities. To specifically address this PDRN/PN ambiguity, this narrative review proposes a standardized structure-based nomenclature for these DNA-derived polymers, the “Marques Polynucleotide Cutoff”, set at 1500 kDa. Thus, we propose that the term “PDRN” should be exclusively reserved for small- and medium-chain polymers (MW < 1500 kDa), while the term “PN” should specifically be used to denote longer-chain polymers (MW ≥ 1500 kDa). In a broader perspective, this classification is based on the distinct physicochemical properties and therapeutic effects of these DNA fragments of various MWs, which are comprehensively discussed in the present review. Full article

(This article belongs to the Special Issue Molecular Advances in Wound Healing and Skin Regeneration)

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20 pages, 4065 KiB

Open AccessArticle

Development of a Combined 2D-MGD TLC/HPTLC Method for the Separation of Terpinen-4-ol and α-Terpineol from Tea Tree, Melaleuca alternifolia, Essential Oil

by Aimé Vázquez and Nurhayat Tabanca

Biomolecules 2025, 15(1), 147; https://doi.org/10.3390/biom15010147 - 18 Jan 2025

Viewed by 518

Abstract

Tea tree oil (TTO), acquired from Melaleuca alternifolia (Maiden & Betche) Cheel, Myrtaceae, is a widely utilized essential oil (EO) due to its bioactive properties. The identification and quantification of TTO ingredients is generally performed by GC-MS, which provides the most accurate results. [...] Read more.

Tea tree oil (TTO), acquired from Melaleuca alternifolia (Maiden & Betche) Cheel, Myrtaceae, is a widely utilized essential oil (EO) due to its bioactive properties. The identification and quantification of TTO ingredients is generally performed by GC-MS, which provides the most accurate results. However, in some instances, the cost and time of analysis may pose a challenge. Thin-layer chromatography (TLC) and high-performance thin-layer chromatography (HPTLC) offer a simpler, faster, cost-effective alternative capable of simultaneously analyzing and quantifying multiple samples. In addition, for more complex oils, two-dimensional (2D) or multigradient development (MGD) TLC provide better separation. Nevertheless, further development is sometimes necessary for the isolation of comigrating components. This study showcases a combined 2D-MGD TLC/HPTLC method for the successful separation of TTO components of interest. While human error, limited separation, and the partial evaporation of volatile components may still present a challenge during the process, considerable recovery of mono- and sesquiterpenes was achieved. This protocol also resulted in the successful isolation of target oxygenated monoterpenes (OMs) producing highly pure terpinen-4-ol (100%) and α-terpineol (≥94%), confirmed by GC-MS. The accurate enantiomeric distribution of these major OMs was verified by GC-FID through the use of a chiral cyclodextrin-based stationary phase. The observed positive enantiomer range (area percent) as well as (+)/(−) ratio for each terpinen-4-ol and α-terpineol were within acceptable ISO criteria. Full article

(This article belongs to the Special Issue Feature Papers in the Natural and Bio-Derived Molecules Section)

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15 pages, 4848 KiB

Open AccessArticle

An Optimized NGS Workflow Defines Genetically Based Prognostic Categories for Patients with Uveal Melanoma

by Michele Massimino, Elena Tirrò, Stefania Stella, Cristina Tomarchio, Sebastiano Di Bella, Silvia Rita Vitale, Chiara Conti, Marialuisa Puglisi, Rosa Maria Di Crescenzo, Silvia Varricchio, Francesco Merolla, Giuseppe Broggi, Federica Martorana, Alice Turdo, Miriam Gaggianesi, Livia Manzella, Andrea Russo, Giorgio Stassi, Rosario Caltabiano, Stefania Staibano and Paolo Vigneri Show full author list Hide full author list

Biomolecules 2025, 15(1), 146; https://doi.org/10.3390/biom15010146 - 18 Jan 2025

Viewed by 608

Abstract

Background: Despite advances in uveal melanoma (UM) diagnosis and treatment, about 50% of patients develop distant metastases, thereby displaying poor overall survival. Molecular profiling has identified several genetic alterations that can stratify patients with UM into different risk categories. However, these genetic alterations [...] Read more.

Background: Despite advances in uveal melanoma (UM) diagnosis and treatment, about 50% of patients develop distant metastases, thereby displaying poor overall survival. Molecular profiling has identified several genetic alterations that can stratify patients with UM into different risk categories. However, these genetic alterations are currently dispersed over multiple studies and several methodologies, emphasizing the need for a defined workflow that will allow standardized and reproducible molecular analyses. Methods: Following the findings published by “The Cancer Genome Atlas–UM” (TCGA-UM) study, we developed an NGS-based gene panel (called the UMpanel) that classifies mutation sets in four categories: initiating alterations (CYSLTR2, GNA11, GNAQ and PLCB4), prognostic alterations (BAP1, EIF1AX, SF3B1 and SRSF2), emergent biomarkers (CDKN2A, CENPE, FOXO1, HIF1A, RPL5 and TP53) and chromosomal abnormalities (imbalances in chromosomes 1, 3 and 8). Results: Employing commercial gene panels, reference mutated DNAs and Sanger sequencing, we performed a comparative analysis and found that our methodological approach successfully predicted survival with great specificity and sensitivity compared to the TCGA-UM cohort that was used as a validation group. Conclusions: Our results demonstrate that a reproducible NGS-based workflow translates into a reliable tool for the clinical stratification of patients with UM. Full article

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

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12 pages, 2097 KiB

Open AccessArticle

Feasibility of Ex Vivo Ligandomics

by Prabuddha Waduge, Remya Ammassam Veettil, Bojun Zhang, Chengchi Huang, Hong Tian and Wei Li

Biomolecules 2025, 15(1), 145; https://doi.org/10.3390/biom15010145 - 18 Jan 2025

Viewed by 393

Abstract

We developed ligandomics for the in vivo profiling of vascular ligands in mice, discovering secretogranin III (Scg3) as a novel angiogenic factor that selectively binds to retinal vessels of diabetic but not healthy mice. This discovery led to the development of anti-Scg3 therapy [...] Read more.

We developed ligandomics for the in vivo profiling of vascular ligands in mice, discovering secretogranin III (Scg3) as a novel angiogenic factor that selectively binds to retinal vessels of diabetic but not healthy mice. This discovery led to the development of anti-Scg3 therapy for ocular vasculopathies. However, in vivo ligandomics requires intracardial perfusion to remove unbound phage clones, limiting its use to vascular endothelial cells (ECs). To extend ligandomics to non-vascular cells, we investigated ex vivo ligandomics. We isolated ECs and retinal ganglion cells (RGCs) from diabetic and healthy mouse retinas by immunopanning. We quantified the binding of clonal phages displaying Scg3 and vascular endothelial growth factor (VEGF), confirming that their binding patterns to isolated diabetic versus healthy ECs matched in vivo patterns. Additionally, Scg3 and VEGF binding to isolated RGCs reflected their in vivo activity. These results support the feasibility of ex vivo ligandomics. We further mapped ligands binding to immunopanned diabetic and healthy ECs and RGCs by ligandomics, confirming that Scg3 was enriched with selective binding to diabetic ECs but not healthy ECs or diabetic/healthy RGCs. These findings demonstrate the feasibility of ex vivo ligandomics, which can be broadly applied to various cell types, tissues, diseases, and species. Full article

(This article belongs to the Section Biomacromolecules: Proteins)

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16 pages, 3195 KiB

Open AccessArticle

Transcriptomic-Based Identification of miR-125a Novel Targets in Human Hepatocarcinoma Cells

by Ilenia De Leo, Nicola Mosca, Mariaceleste Pezzullo, Danila Valletta, Francesco Manfrevola, Vincenza Grazia Mele, Rosanna Chianese, Aniello Russo and Nicoletta Potenza

Biomolecules 2025, 15(1), 144; https://doi.org/10.3390/biom15010144 - 18 Jan 2025

Viewed by 537

Abstract

Hepatocellular carcinoma (HCC) is among the most aggressive and lethal human tumors. Many functional studies have demonstrated the role of non-coding RNAs (ncRNA), particularly microRNAs (miRNA), in the regulation of hepatocarcinogenesis driving pathways. MiR-125a-5p (miR-125a) has been consistently reported as an oncosuppressive miRNA, [...] Read more.

Hepatocellular carcinoma (HCC) is among the most aggressive and lethal human tumors. Many functional studies have demonstrated the role of non-coding RNAs (ncRNA), particularly microRNAs (miRNA), in the regulation of hepatocarcinogenesis driving pathways. MiR-125a-5p (miR-125a) has been consistently reported as an oncosuppressive miRNA, as demonstrated in vivo and in vitro. However, its HCC relevant targets and molecular mechanisms are still largely unknown. Here, a genome-wide perspective of the whole miR-125a targetome has been achieved. In particular, two different HCC cell lines were subjected to a miRNA boosting by mimic transfections, and consequently many genes were de-regulated, as observed by a transcriptomic approach. The merging of down-regulated genes with results from bioinformatic predictive tools yielded a number of candidate direct targets that were further experimentally validated by luciferase-based reporter assays. Different novel targets were found, in particular ARID3A, CCNJ, LIPA, NR6A1, and NUP210, oncogenes in various tumors and here also related to HCC through miR-125a regulation. The RNA interactions investigated in this work could pave the way to piece together the RNA regulatory networks governed by the miRNA impacting on hepatocarcinogenesis, and be exploited in the future for identifying novel biomarkers and therapeutic targets in HCC. Full article

(This article belongs to the Special Issue The Role of Non-Coding RNAs in Health and Disease)

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14 pages, 1310 KiB

Open AccessReview

Sex-Specific Differences in the Pathophysiology of Hypertension

by Hannah Zhang, Pawan K. Singal, Amir Ravandi and Inna Rabinovich-Nikitin

Biomolecules 2025, 15(1), 143; https://doi.org/10.3390/biom15010143 - 18 Jan 2025

Viewed by 999

Abstract

Hypertension is one of the most common comorbidities in cardiometabolic diseases, affecting nearly one third of adults. As a result, its pathophysiological mechanisms have been studied extensively and are focused around pressure natriuresis, the renin–angiotensin system (RAS), the sympathetic nervous system, oxidative stress, [...] Read more.

Hypertension is one of the most common comorbidities in cardiometabolic diseases, affecting nearly one third of adults. As a result, its pathophysiological mechanisms have been studied extensively and are focused around pressure natriuresis, the renin–angiotensin system (RAS), the sympathetic nervous system, oxidative stress, and endothelial dysfunction. Additionally, hypertension secondary to other underlying etiologies also exists. While clinical evidence has clearly shown differences in hypertension development in males and females, relatively little is known about the pathophysiological mechanisms behind these differences. Sex hormones likely play a key role, as they modulate many factors related to hypertension development. In this review, we postulate the potential role for sexually dimorphic fat metabolism in the physiology of hypertension. In brief, estrogen promotes subcutaneous fat deposition over visceral fat and increases in mass via adaptive hyperplasia rather than pathogenic hypertrophy. This adipose tissue subsequently produces anti-inflammatory effects and inhibits metabolic dysfunction-associated fatty liver disease (MAFLD) and RAS activation, ultimately leading to decreased levels of hypertension in pre-menopausal females. On the other hand, androgens and the lack of estrogens promote visceral and ectopic fat deposition, including in the liver, and lead to increased circulating pro-inflammatory cytokines and potentially subsequent RAS activation and hypertension development in males and post-menopausal females. Understanding the sex-specific differences in fat metabolism may provide deeper insights into the patho-mechanisms associated with hypertension and lead to more comprehensive sex-specific care. Full article

(This article belongs to the Special Issue Heart Diseases: Molecular Mechanisms and New Therapies)

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17 pages, 5883 KiB

Open AccessArticle

Astrocytic Acid-Sensing Ion Channel 1a Contributes to the Development of Epileptic Cognitive Impairment

by Wen Li, Huimin Zhou, Xiaona Li, Gengyao Hu and Dong Wei

Biomolecules 2025, 15(1), 142; https://doi.org/10.3390/biom15010142 - 17 Jan 2025

Viewed by 550

Abstract

Reactive astrogliosis and acidosis, common features of epileptogenic lesions, express a high level of astrocytic acid-sensing ion channel-1a (ASIC1a), a proton-gated cation channel and key mediator of responses to neuronal injury. This study investigates the role of astrocytic ASIC1a in cognitive impairment following [...] Read more.

Reactive astrogliosis and acidosis, common features of epileptogenic lesions, express a high level of astrocytic acid-sensing ion channel-1a (ASIC1a), a proton-gated cation channel and key mediator of responses to neuronal injury. This study investigates the role of astrocytic ASIC1a in cognitive impairment following epilepsy. Status epilepticus (SE) in C57/BL6 mice was induced using lithium–pilocarpine; the impact of ASIC1a on astrocytes was assessed using rAAV–ASIC1a–NC and rAAV–ASIC1a–shRNA, injected in the CA3 region of mice. Behavioral assessments were conducted using the Morris water maze (MWM). Western blotting and immunofluorescence were applied to evaluate ASIC1a and Gfap expression while analyzing intracellular calcium and extracellular glutamate (Glu) concentrations in primary cultured astrocytes isolated from the brains of 1 to 3-day-old mice and treated LPS. Results showed enhanced astrocyte proliferation and ASIC1a expression in the dentate gyrus of epileptic mice 7, 21, and 28 days post-SE (all p < 0.05). Escape latency in the MWM further suggested that ASIC1a regulates cognitive function in mice with chronic epilepsy. LPS stimulation in vitro mimicked inflammatory responses, increasing ASIC1a after 24 h, which increased the concentration of intracellular calcium and extracellular expression of Glu; inhibition of ASIC1a expression reversed this process. To sum up, these data confirm that astrocytic ASIC1a may facilitate cognitive dysfunction post-epilepsy, presenting a potential therapeutic target. Full article

(This article belongs to the Special Issue The Role of Astrocytes in Neurodegenerative Diseases)

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23 pages, 845 KiB

Open AccessReview

Structure-Based Approaches for Protein–Protein Interaction Prediction Using Machine Learning and Deep Learning

by Despoina P. Kiouri, Georgios C. Batsis and Christos T. Chasapis

Biomolecules 2025, 15(1), 141; https://doi.org/10.3390/biom15010141 - 17 Jan 2025

Viewed by 923

Abstract

Protein–Protein Interaction (PPI) prediction plays a pivotal role in understanding cellular processes and uncovering molecular mechanisms underlying health and disease. Structure-based PPI prediction has emerged as a robust alternative to sequence-based methods, offering greater biological accuracy by integrating three-dimensional spatial and biochemical features. [...] Read more.

Protein–Protein Interaction (PPI) prediction plays a pivotal role in understanding cellular processes and uncovering molecular mechanisms underlying health and disease. Structure-based PPI prediction has emerged as a robust alternative to sequence-based methods, offering greater biological accuracy by integrating three-dimensional spatial and biochemical features. This work summarizes the recent advances in computational approaches leveraging protein structure information for PPI prediction, focusing on machine learning (ML) and deep learning (DL) techniques. These methods not only improve predictive accuracy but also provide insights into functional sites, such as binding and catalytic residues. However, challenges such as limited high-resolution structural data and the need for effective negative sampling persist. Through the integration of experimental and computational tools, structure-based prediction paves the way for comprehensive proteomic network analysis, holding promise for advancements in drug discovery, biomarker identification, and personalized medicine. Future directions include enhancing scalability and dataset reliability to expand these approaches across diverse proteomes. Full article

(This article belongs to the Special Issue Structural Proteomics–Structural Biology Led by Advancements in Mass Spectrometry Techniques)

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40 pages, 1249 KiB

Open AccessReview

Drug Advances in NAFLD: Individual and Combination Treatment Strategies of Natural Products and Small-Synthetic-Molecule Drugs

by Xing Wan, Jingyuan Ma, He Bai, Xuyang Hu, Yanna Ma, Mingjian Zhao, Jifeng Liu and Zhijun Duan

Biomolecules 2025, 15(1), 140; https://doi.org/10.3390/biom15010140 - 17 Jan 2025

Viewed by 934

Abstract

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease and is closely associated with metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome. However, effective treatment strategies for NAFLD are still lacking. In recent years, [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease and is closely associated with metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome. However, effective treatment strategies for NAFLD are still lacking. In recent years, progress has been made in understanding the pathogenesis of NAFLD, identifying multiple therapeutic targets and providing new directions for drug development. This review summarizes the recent advances in the treatment of NAFLD, focusing on the mechanisms of action of natural products, small-synthetic-molecule drugs, and combination therapy strategies. This review aims to provide new insights and strategies in treating NAFLD. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease: From Molecular Mechanisms to Therapeutic Approaches)

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17 pages, 5830 KiB

Open AccessArticle

Identification and Characterization of a Novel Rat MAVS Variant Modulating NFκB Signaling

by Ihsan Nalkiran and Hatice Sevim Nalkiran

Biomolecules 2025, 15(1), 139; https://doi.org/10.3390/biom15010139 - 16 Jan 2025

Viewed by 648

Abstract

The innate immune response serves as the primary defense against viral infections, with the recognition of viral nucleic acids by pattern recognition receptors (PRRs) initiating antiviral responses. Mitochondrial antiviral-signaling protein (MAVS) acts as a pivotal adaptor protein in the RIG-I pathway. Alternative splicing [...] Read more.

The innate immune response serves as the primary defense against viral infections, with the recognition of viral nucleic acids by pattern recognition receptors (PRRs) initiating antiviral responses. Mitochondrial antiviral-signaling protein (MAVS) acts as a pivotal adaptor protein in the RIG-I pathway. Alternative splicing further diversifies MAVS isoforms. In this study, we identified and characterized a novel rat MAVS variant (MAVS500) with a twenty-one-nucleotide deletion, resulting in a protein seven amino acids shorter than the wild-type (WT) rat MAVS. The MAVS500 was cloned from the rat bladder cancer cell line, NBT-II, using specific primers, and subsequently sequenced. MAVS500 was overexpressed in HEK293T and NBT-II cells and then analyzed using Western Blotting and fluorescence microscopy. MAVS500 overexpression increased downstream signaling proteins, NFκβ and pNFκβ, compared to WT rat MAVS in both human and rat cell lines. Structural analysis revealed a high similarity between MAVS500 and WT rat MAVS. The seven-amino-acid deletion in MAVS500 induces significant conformational rearrangements, reducing helical turns and altering structural dynamics, which may impact its interactions with downstream signaling molecules in the innate immune pathway. The identification of MAVS500 enhances our understanding of MAVS regulation and its role in the innate immune response, providing valuable insights into alternative splicing as a mechanism for diversifying protein function. Full article

(This article belongs to the Section Molecular Biology)

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35 pages, 4036 KiB

Open AccessArticle

Neuroprotective Potential of Origanum majorana L. Essential Oil Against Scopolamine-Induced Memory Deficits and Oxidative Stress in a Zebrafish Model

by Ion Brinza, Razvan Stefan Boiangiu, Iasmina Honceriu, Ahmed M. Abd-Alkhalek, Samir M. Osman, Omayma A. Eldahshan, Elena Todirascu-Ciornea, Gabriela Dumitru and Lucian Hritcu

Biomolecules 2025, 15(1), 138; https://doi.org/10.3390/biom15010138 - 16 Jan 2025

Viewed by 496

Abstract

Origanum majorana L., also known as sweet marjoram, is a plant with multiple uses, both in the culinary field and traditional medicine, because of its major antioxidant, anti-inflammatory, antimicrobial, and digestive properties. In this research, we focused on the effects of O. majorana [...] Read more.

Origanum majorana L., also known as sweet marjoram, is a plant with multiple uses, both in the culinary field and traditional medicine, because of its major antioxidant, anti-inflammatory, antimicrobial, and digestive properties. In this research, we focused on the effects of O. majorana essential oil (OmEO, at concentrations of 25, 150, and 300 μL/L), evaluating chemical structure as well as its impact on cognitive performance and oxidative stress, in both naive zebrafish (Danio rerio), as well as in a scopolamine-induced amnesic model (SCOP, 100 μM). The fish behavior was analyzed in a novel tank-diving test (NTT), a Y-maze test, and a novel object recognition (NOR) test. We also investigated acetylcholinesterase (AChE) activity and the brain’s oxidative stress status. In parallel, we performed in silico predictions (research conducted using computational models) of the pharmacokinetic properties of the main compounds identified in OmEO, using platforms such as SwissADME, pKCSM, ADMETlab 2.0, and ProTox-II. The results revealed that the major compounds were trans-sabinene hydrate (36.11%), terpinen-4-ol (17.97%), linalyl acetate (9.18%), caryophyllene oxide (8.25%), and α-terpineol (6.17%). OmEO can enhance memory through AChE inhibition, reduce SCOP-induced anxiety by increasing the time spent in the top zone in the NTT, and significantly reduce oxidative stress markers. These findings underscore the potential of using O. majorana to improve memory impairment and reduce oxidative stress associated with cognitive disorders, including Alzheimer’s disease (AD). Full article

(This article belongs to the Special Issue Neurological Disorders: From Molecular Mechanisms to Therapy Strategies)

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20 pages, 2444 KiB

Open AccessArticle

Order in Chaos: Lesser-Conserved and Repeat Structures in Dehydrins

by G. Richard Strimbeck

Biomolecules 2025, 15(1), 137; https://doi.org/10.3390/biom15010137 - 16 Jan 2025

Viewed by 371

Abstract

Dehydrins (Dhns) are a group of intrinsically disordered land plant proteins that are closely associated with tolerance of dehydrative stress. Dhns are recognized and classified by the presence and sequence of five different conserved segments, varying in length from 8 to 15 residues, [...] Read more.

Dehydrins (Dhns) are a group of intrinsically disordered land plant proteins that are closely associated with tolerance of dehydrative stress. Dhns are recognized and classified by the presence and sequence of five different conserved segments, varying in length from 8 to 15 residues, separated by highly variable disordered regions. In addition to one or more copies of the diagnostic, fifteen-residue K segment, most Dhns can be classified into one of three major groups based on the mutually exclusive presence of three other conserved segments (H, Y, or F), with all three groups typically incorporating multi-serine S segments. Many Dhns also include repeat structures. From an input library of 8675 non-redundant candidate sequences, a specialized R script identified and classified 2658 complete and 236 partial Dhn sequences in all major green plant (Viridiplantae) lineages, including a few green algal genera. An examination of the connecting segments bridging the conserved segments identified additional conserved patterns, suggesting that multi-Y, S-K, and K-S domains may act as functional units. Dhn Decoder identified 857 Dhns with repeat structures, ranging from 3 short, simple repeats to elaborate variations with up to 45 repeats or repeats of up to 85 residues comprising 1 or more of the conserved segments, suggesting that internal sequence duplication is an important mode of evolution in Dhns. Full article

(This article belongs to the Section Biomacromolecules: Proteins)

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17 pages, 2054 KiB

Open AccessArticle

Restoration of Genetic Code in Macular Mouse Fibroblasts via APOBEC1-Mediated RNA Editing

by Sonali Bhakta, Hiroko Kodama, Masakazu Mimaki and Toshifumi Tsukahara

Biomolecules 2025, 15(1), 136; https://doi.org/10.3390/biom15010136 - 16 Jan 2025

Viewed by 517

Abstract

RNA editing is a significant mechanism underlying genetic variation and protein molecule alteration; C-to-U RNA editing, specifically, is important in the regulation of mammalian genetic diversity. The ability to define and limit accesses of enzymatic machinery to avoid the modification of unintended targets [...] Read more.

RNA editing is a significant mechanism underlying genetic variation and protein molecule alteration; C-to-U RNA editing, specifically, is important in the regulation of mammalian genetic diversity. The ability to define and limit accesses of enzymatic machinery to avoid the modification of unintended targets is key to the success of RNA editing. Identification of the core component of the apoB RNA editing holoenzyme, APOBEC, and investigation into new candidate genes encoding other elements of the complex could reveal further details regarding APOBEC-mediated mRNA editing. Menkes disease is a recessive X-chromosome-linked hereditary syndrome in humans, caused by defective copper metabolism due to mutations in the ATP7A gene, which encodes a copper transport protein. Here, we generated plasmids encoding the MS2 system and the APOBEC1 deaminase domain and used a guide RNA with flanking MS2 sites to restore mutated Atp7a in fibroblasts from a macular mouse model of Menkes disease withs T>C mutation. Around 35% of the mutated C nucleotide (nt) was restored to U, demonstrating that our RNA editing system is reliable and has potential for therapeutic clinical application. RNA base editing via human RNA-guided cytidine deaminases is a potentially attractive approach for in vivo therapeutic application and provides opportunities for new developments in this field. Full article

(This article belongs to the Special Issue Recent Advances in RNA Editing and Modification)

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20 pages, 973 KiB

Open AccessFeature PaperReview

Pseudotyped Viruses: A Useful Platform for Pre-Clinical Studies Conducted in a BSL-2 Laboratory Setting

by Sofiia N. Rizatdinova, Alina E. Ershova and Irina V. Astrakhantseva

Biomolecules 2025, 15(1), 135; https://doi.org/10.3390/biom15010135 - 15 Jan 2025

Viewed by 612

Abstract

The study of pathogenic viruses has always posed significant biosafety challenges. In particular, the study of highly pathogenic viruses requires methods with low biological risk but relatively high sensitivity and convenience in detection. In recent years, pseudoviruses, which consist of a backbone of [...] Read more.

The study of pathogenic viruses has always posed significant biosafety challenges. In particular, the study of highly pathogenic viruses requires methods with low biological risk but relatively high sensitivity and convenience in detection. In recent years, pseudoviruses, which consist of a backbone of one virus and envelope proteins of another virus, have become one of the most widely used tools for exploring the mechanisms of viruses binding to cells, membrane fusion and viral entry, as well as for screening the libraries of antiviral substances, evaluating the potential of neutralizing monoclonal antibodies, developing neutralization tests, and therapeutic platforms. During the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), pseudotyped virus-based assays played a pivotal role in advancing our understanding of virus–cell interactions and the role of its proteins in disease pathogenesis. Such tools facilitated the search for potential therapeutic agents and accelerated epidemiological studies on post-infection and post-vaccination humoral immunity. This review focuses on the use of pseudoviruses as a model for large-scale applications to study enveloped viruses. Full article

(This article belongs to the Section Molecular Medicine)

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16 pages, 1308 KiB

Open AccessReview

Multi-Omics Insights into Regulatory Mechanisms Underlying Differential Deposition of Intramuscular and Abdominal Fat in Chickens

by Yuxin Xing, Chenglin Ma, Hongbo Guan, Jianing Shen, Ying Shen, Guoxi Li, Guirong Sun, Yadong Tian, Xiangtao Kang, Xiaojun Liu, Hong Li and Weihua Tian

Biomolecules 2025, 15(1), 134; https://doi.org/10.3390/biom15010134 - 15 Jan 2025

Viewed by 679

Abstract

Excessive abdominal fat deposition in chickens disadvantages feed conversion, meat production, and reproductive performance. Intramuscular fat contributes to meat texture, tenderness, and flavor, serving as a vital indicator of overall meat quality. Therefore, a comprehensive analysis of the regulatory mechanisms governing differential deposition [...] Read more.

Excessive abdominal fat deposition in chickens disadvantages feed conversion, meat production, and reproductive performance. Intramuscular fat contributes to meat texture, tenderness, and flavor, serving as a vital indicator of overall meat quality. Therefore, a comprehensive analysis of the regulatory mechanisms governing differential deposition of abdominal versus intramuscular fat is essential in breeding higher-quality chickens with ideal fat distribution. This review systematically summarizes the regulatory mechanisms underlying intramuscular and abdominal fat traits at chromatin, genomic, transcriptional, post-transcriptional, translational, and epigenetic-modification scales. Additionally, we summarize the role of non-coding RNAs and protein-coding genes in governing intramuscular and abdominal fat deposition. These insights provide a valuable theoretical foundation for the genetic engineering of high-quality and high-yielding chicken breeds. Full article

(This article belongs to the Section Biomacromolecules: Lipids)

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32 pages, 2248 KiB

Open AccessReview

Developmental and Epileptic Encephalopathy: Pathogenesis of Intellectual Disability Beyond Channelopathies

by Alexandra D. Medyanik, Polina E. Anisimova, Angelina O. Kustova, Victor S. Tarabykin and Elena V. Kondakova

Biomolecules 2025, 15(1), 133; https://doi.org/10.3390/biom15010133 - 15 Jan 2025

Viewed by 1201

Abstract

Developmental and epileptic encephalopathies (DEEs) are a group of neuropediatric diseases associated with epileptic seizures, severe delay or regression of psychomotor development, and cognitive and behavioral deficits. What sets DEEs apart is their complex interplay of epilepsy and developmental delay, often driven by [...] Read more.

Developmental and epileptic encephalopathies (DEEs) are a group of neuropediatric diseases associated with epileptic seizures, severe delay or regression of psychomotor development, and cognitive and behavioral deficits. What sets DEEs apart is their complex interplay of epilepsy and developmental delay, often driven by genetic factors. These two aspects influence one another but can develop independently, creating diagnostic and therapeutic challenges. Intellectual disability is severe and complicates potential treatment. Pathogenic variants are found in 30–50% of patients with DEE. Many genes mutated in DEEs encode ion channels, causing current conduction disruptions known as channelopathies. Although channelopathies indeed make up a significant proportion of DEE cases, many other mechanisms have been identified: impaired neurogenesis, metabolic disorders, disruption of dendrite and axon growth, maintenance and synapse formation abnormalities —synaptopathies. Here, we review recent publications on non-channelopathies in DEE with an emphasis on the mechanisms linking epileptiform activity with intellectual disability. We focus on three major mechanisms of intellectual disability in DEE and describe several recently identified genes involved in the pathogenesis of DEE. Full article

(This article belongs to the Special Issue New Insight into the Molecular Genetics of Neurodevelopmental Disorders)

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22 pages, 9684 KiB

Open AccessArticle

From Waste to Innovation: A Circular Economy Approach for Tissue Engineering by Transforming Human Bone Waste into Novel Collagen Membranes

by Lorena Gallego, Kimberly Harvey, Marta Pevida, Luis García-Consuegra, Olivia García-Suárez, Álvaro Meana, María Alvarez-Viejo and Luis Junquera

Biomolecules 2025, 15(1), 132; https://doi.org/10.3390/biom15010132 - 15 Jan 2025

Viewed by 630

Abstract

The aim of the circular economy is to treat waste as a valuable raw material, reintegrating it into the industrial economy and extending the lifecycle of subsequent products. Efforts to reduce the production of hard-to-recycle waste are becoming increasingly important to manufacturers, not [...] Read more.

The aim of the circular economy is to treat waste as a valuable raw material, reintegrating it into the industrial economy and extending the lifecycle of subsequent products. Efforts to reduce the production of hard-to-recycle waste are becoming increasingly important to manufacturers, not only of consumer goods but also of specialized items that are difficult to manufacture, such as medical supplies, which have now become a priority for the European Union. The purpose of the study is to manufacture a novel human-purified type I collagen membrane from bone remnants typically discarded during the processing of cortico-cancellous bones in tissue banks and to evaluate its mechanical properties and effectiveness in regenerating bone-critical mandibular defects in rabbits. To prepare the novel membrane, cortico-cancellous bone chip samples from a local tissue bank were processed to isolate collagen by demineralization under agitation in HCl, cast into a silicone mold, and air-dried at room temperature and UV irradiation. The average thickness of the four batches analyzed by SEM was 37.3 μm. The average value of Young’s modulus and tensile strength obtained from the specimens was 2.56 GPa and 65.43 Mpa, respectively. The membrane’s efficacy was tested by creating a critical bicortical and bilateral osteoperiosteal defect in rabbit mandibles. The right-side defects were covered with the collagen membrane, while the left-side defects were left untreated as a control. Nine weeks post-surgery, clinical, radiological, and histological analyses demonstrated new bone formation in the treated areas, whereas the control sites showed no bone regeneration. This innovative approach not only contributes to sustainability in healthcare by optimizing biological waste but also exemplifies efficient resource use in line with the circular economy, offering a cost-effective, biocompatible option that could benefit national health systems. Full article

(This article belongs to the Topic Bone-Related Diseases: From Molecular Mechanisms to Therapy Development)

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18 pages, 4200 KiB

Open AccessReview

Alternative Splicing: Emerging Roles in Anti-Aging Strategies

by Lingyue Gao and Rong Jia

Biomolecules 2025, 15(1), 131; https://doi.org/10.3390/biom15010131 - 15 Jan 2025

Viewed by 617

Abstract

Alternative splicing plays a fundamental role in gene expression and protein complexity. Aberrant splicing impairs cell homeostasis and is closely associated with aging and cellular senescence. Significant changes to alternative splicing, including dysregulated splicing events and the abnormal expression of splicing factors, have [...] Read more.

Alternative splicing plays a fundamental role in gene expression and protein complexity. Aberrant splicing impairs cell homeostasis and is closely associated with aging and cellular senescence. Significant changes to alternative splicing, including dysregulated splicing events and the abnormal expression of splicing factors, have been detected during the aging process or in age-related disorders. Here, we highlight the possibility of suppressing aging and cellular senescence by controlling alternative splicing. In this review, we will summarize the latest research progress on alternative splicing in aging and cellular senescence, discuss the roles and regulatory mechanisms of alternative splicing during aging, and then excavate existing and potential approaches to anti-aging by controlling alternative splicing. Novel therapeutic breakthroughs concerning aging and senescence entail a further understanding of regulating alternative splicing mechanically and accurately. Full article

(This article belongs to the Section Molecular Medicine)

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31 pages, 1768 KiB

Open AccessReview

Proteomic Profiling Towards a Better Understanding of Genetic Based Muscular Diseases: The Current Picture and a Look to the Future

by Marc Pauper, Andreas Hentschel, Malte Tiburcy, Sergi Beltran, Tobias Ruck, Ulrike Schara-Schmidt and Andreas Roos

Biomolecules 2025, 15(1), 130; https://doi.org/10.3390/biom15010130 - 15 Jan 2025

Viewed by 537

Abstract

Proteomics accelerates diagnosis and research of muscular diseases by enabling the robust analysis of proteins relevant for the manifestation of neuromuscular diseases in the following aspects: (i) evaluation of the effect of genetic variants on the corresponding protein, (ii) prediction of the underlying [...] Read more.

Proteomics accelerates diagnosis and research of muscular diseases by enabling the robust analysis of proteins relevant for the manifestation of neuromuscular diseases in the following aspects: (i) evaluation of the effect of genetic variants on the corresponding protein, (ii) prediction of the underlying genetic defect based on the proteomic signature of muscle biopsies, (iii) analysis of pathophysiologies underlying different entities of muscular diseases, key for the definition of new intervention concepts, and (iv) patient stratification according to biochemical fingerprints as well as (v) monitoring the success of therapeutic interventions. This review presents—also through exemplary case studies—the various advantages of mass proteomics in the investigation of genetic muscle diseases, discusses technical limitations, and provides an outlook on possible future application concepts. Hence, proteomics is an excellent large-scale analytical tool for the diagnostic workup of (hereditary) muscle diseases and warrants systematic profiling of underlying pathophysiological processes. The steady development may allow to overcome existing limitations including a quenched dynamic range and quantification of different protein isoforms. Future directions may include targeted proteomics in diagnostic settings using not only muscle biopsies but also liquid biopsies to address the need for minimally invasive procedures. Full article

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13 pages, 4518 KiB

Open AccessArticle

Lupeol Attenuates Palmitate-Induced Hypertrophy in 3T3-L1 Adipocytes

by Vaithinathan Selvaraju, Shivani R. Babu, Robert L. Judd and Thangiah Geetha

Biomolecules 2025, 15(1), 129; https://doi.org/10.3390/biom15010129 - 15 Jan 2025

Viewed by 444

Abstract

Obesity is characterized by the enlargement of adipose tissue due to an increased calorie intake exceeding the body’s energy expenditure. Changes in the size of adipose tissue can lead to harmful consequences, with excessive fat accumulation resulting in adipocyte hypertrophy and promoting metabolic [...] Read more.

Obesity is characterized by the enlargement of adipose tissue due to an increased calorie intake exceeding the body’s energy expenditure. Changes in the size of adipose tissue can lead to harmful consequences, with excessive fat accumulation resulting in adipocyte hypertrophy and promoting metabolic dysfunction. These adiposity-associated pathologies can be influenced by dietary components and their potential health benefits. Lupeol, a pharmacologically active pentacyclic triterpenoid found in medicinal plants, vegetables, and fruits, has been shown to exhibit antioxidant and anti-inflammatory properties. This study investigated the role of lupeol on adipocyte hypertrophy by evaluating key adipogenic regulators in vitro. First, 3T3-L1 MBX mouse embryonic cells were differentiated into adipocytes and hypertrophy was induced using 500 µM palmitic acid. The treated adipocytes showed a significantly increased lipid droplet size, confirming adipocyte hypertrophy. Both adipocytes and hypertrophied adipocytes were then treated with or without 60 µM lupeol, following a dose-dependent study. Lipid droplet size was assessed and validated by Oil Red O staining. Western blot analysis was performed to measure the expression of adipogenic and inflammatory markers. Differentiated adipocytes showed increased fatty acid-binding protein 4 (FABP4) expression and Oil Red O staining, indicating an increased lipid content. Western blot analysis revealed that lupeol treatment reduced the expression of FABP4, peroxisome proliferator-activated receptor-γ (PPARγ), and adipokines. In conclusion, the results suggest that lupeol reverts the inflammatory and adipogenic markers that are enhanced in adipocyte hypertrophy. Through its anti-inflammatory effects, lupeol offers protective effects against adipocyte hypertrophy and contributes to reducing hypertrophic adiposity. Full article

(This article belongs to the Special Issue Cutting-Edge Research on the Analysis of Small Biomolecules in Foods, Plants, and Biological Samples, 2nd Edition)

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20 pages, 713 KiB

Open AccessReview

Deciphering the Role of Adrenergic Receptors in Alzheimer’s Disease: Paving the Way for Innovative Therapies

by Androulla N. Miliotou, Andria Kotsoni and Lefteris C. Zacharia

Biomolecules 2025, 15(1), 128; https://doi.org/10.3390/biom15010128 - 15 Jan 2025

Viewed by 2088

Abstract

Neurodegenerative diseases are currently among the most devastating diseases with no effective disease-modifying drugs in the market, with Alzheimer’s disease (AD) being the most prevalent. AD is a complex multifactorial neurodegenerative disorder characterized by progressive and severe cognitive impairment and memory loss. It [...] Read more.

Neurodegenerative diseases are currently among the most devastating diseases with no effective disease-modifying drugs in the market, with Alzheimer’s disease (AD) being the most prevalent. AD is a complex multifactorial neurodegenerative disorder characterized by progressive and severe cognitive impairment and memory loss. It is the most common cause of progressive memory loss (dementia) in the elderly, and to date, there is no effective treatment to cure or slow disease progression substantially. The role of adrenergic receptors in the pathogenesis of Alzheimer’s disease and other tauopathies is poorly understood or investigated. Recently, some studies indicated a potential benefit of drugs acting on the adrenergic receptors for AD and dementias, although due to the heterogeneity of the drug classes used, the results on the whole remain inconclusive. The scope of this review article is to comprehensively review the literature on the possible role of adrenergic receptors in neurodegenerative diseases, stemming from the use of agonists and antagonists including antihypertensive and asthma drugs acting on the adrenergic receptors, but also from animal models and in vitro models where these receptors have been studied. Ultimately, we hope to obtain a better understanding of the role of these receptors, identify the gaps in knowledge, and explore the possibility of repurposing such drugs for AD, given their long history of use and safety. Full article

(This article belongs to the Special Issue Biomolecular Approaches and Drugs for Neurodegeneration)

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13 pages, 3383 KiB

Open AccessArticle

Exploring the Gating Mechanism of the Human Copper Transporter, hCtr1, Using EPR Spectroscopy

by Shahaf Peleg, Shelly Meron, Yulia Shenberger, Lukas Hofmann, Lada Gevorkyan-Airapetov and Sharon Ruthstein

Biomolecules 2025, 15(1), 127; https://doi.org/10.3390/biom15010127 - 14 Jan 2025

Viewed by 578

Abstract

Ctr1 is a membrane-spanning homotrimer that facilitates copper uptake in eukaryotic cells with high affinity. While structural details of the transmembrane domain of human Ctr1 have been elucidated using X-ray crystallography and cryo-EM, the transfer mechanisms of copper and the conformational changes that [...] Read more.

Ctr1 is a membrane-spanning homotrimer that facilitates copper uptake in eukaryotic cells with high affinity. While structural details of the transmembrane domain of human Ctr1 have been elucidated using X-ray crystallography and cryo-EM, the transfer mechanisms of copper and the conformational changes that control the gating mechanism remain poorly understood. The role of the extracellular N-terminal domains is particularly unclear due to the absence of a high-resolution structure of the full-length hCtr1 protein and limited biochemical and biophysical characterization of the transporter in solution and in cell. In this study, we employed distance electron paramagnetic resonance to investigate the conformational changes of the extracellular N-terminal domain of full-length hCtr1, both in vitro and in cells, as a function of Cu(I) binding. Our results demonstrate that at specific Cu(I) concentrations, the extracellular chains move closer to the lumen to facilitate copper transfer. Additionally, while at these concentrations the intracellular part is penetrating the lumen, suggesting a ball-and-chain gating mechanism. Moreover, this phenomenon was observed for both reconstituted protein in micelles and in native cell membranes. However, the measured distance values were slightly different, suggesting that the membrane’s characteristics and therefore its lipid composition also impact and even regulate the gating mechanism of hCtr1. Full article

(This article belongs to the Special Issue Innovative Biomolecular Structure Analysis Techniques)

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18 pages, 3494 KiB

Open AccessArticle

Remodeling of Mitochondria–Endoplasmic Reticulum Contact Sites Accompanies LUHMES Differentiation

by Emad Norouzi Esfahani, Tomas Knedlik, Sang Hun Shin, Ana Paula Magalhães Rebelo, Agnese De Mario, Caterina Vianello, Luca Persano, Elena Rampazzo, Paolo Edomi, Camilla Bean, Dario Brunetti, Luca Scorrano, Samuele Greco, Marco Gerdol and Marta Giacomello

Biomolecules 2025, 15(1), 126; https://doi.org/10.3390/biom15010126 - 14 Jan 2025

Viewed by 620

Abstract

Neural progenitor cells (NPCs) are often used to study the subcellular mechanisms underlying differentiation into neurons in vitro. Works published to date have focused on the pathways that distinguish undifferentiated NPCs from mature neurons, neglecting the earlier and intermediate stages of this process. [...] Read more.

Neural progenitor cells (NPCs) are often used to study the subcellular mechanisms underlying differentiation into neurons in vitro. Works published to date have focused on the pathways that distinguish undifferentiated NPCs from mature neurons, neglecting the earlier and intermediate stages of this process. Current evidence suggests that mitochondria interaction with the ER is fundamental to a wide range of intracellular processes. However, it is not clear whether and how the mitochondria–ER interactions differ between NPCs and their differentiated counterparts. Here we take advantage of the widely used NPC line LUHMES to provide hints on the mitochondrial dynamic trait changes that occur during the first stage of their maturation into dopaminergic-like neurons. We observed that the morphology of mitochondria, their interaction with the ER, and the expression of several mitochondria–ER contact site resident proteins change, which suggests the potential contribution of mitochondria dynamics to NPC differentiation. Further studies will be needed to explore in depth these changes, and their functional outcomes, which may be relevant to the scientific community focusing on embryonic neurogenesis and developmental neurotoxicity. Full article

(This article belongs to the Special Issue Mitochondria and Central Nervous System Disorders: 3rd Edition)

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22 pages, 4408 KiB

Open AccessArticle

iNOS-Produced Nitric Oxide from Cancer Cells as an Intermediate of Stemness Regulation by PARP-1 in Colorectal Cancer

by María del Moral-Martinez, Paula Sánchez-Uceta, Ruben Clemente-Gonzalez, Sara Moreno-SanJuan, Jose D. Puentes-Pardo, Huda Khaldy, David Lopez-Perez, Javier Arnedo, Jorge Casado, Luis Martínez-Heredia, Angel Carazo and Josefa León

Biomolecules 2025, 15(1), 125; https://doi.org/10.3390/biom15010125 - 14 Jan 2025

Viewed by 561

Abstract

PARP-1 has been linked to the progression of several types of cancer. We have recently reported that PARP-1 influences tumor progression in CRC through the regulation of CSCs in a p53-dependent manner. In this study, we propose that nitric oxide (NO) produced by [...] Read more.

PARP-1 has been linked to the progression of several types of cancer. We have recently reported that PARP-1 influences tumor progression in CRC through the regulation of CSCs in a p53-dependent manner. In this study, we propose that nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) could act as a mediator. We evaluated the expression of iNOS in a cohort of patients previously used to analyze the effects of PARP-1 on CRC in relation to p53 status. We also developed an in vitro model in which PARP-1 was stably overexpressed. In CRC patients, iNOS expression correlated with the differentiation grade, and with a high expression of CSC markers, although only in wild-type p53 tumors, as previously found for PARP-1. In vitro, overexpression of PARP-1 induced increased growth and stemness in wild-type p53 cells, while exerting the opposite effect on mutated ones, as expected. Treatment with 1400 W, a selective inhibitor of iNOS, or gene silencing of the gene counteracted the effects of PARP-1 in both p53 wild-type and p53 mutated cells. Given that the development of resistance has been demonstrated after treatment with PARP-1 inhibitors, iNOS could be considered a new therapeutic target in CRC, although only in patients with wild-type p53 tumors. Full article

(This article belongs to the Special Issue PARPs in Cell Death and PARP Inhibitors in Cancers: 2nd Edition)

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16 pages, 5494 KiB

Open AccessArticle

Probing the Dual Role of Ca²⁺ in the Allochromatium tepidum LH1–RC Complex by Constructing and Analyzing Ca²⁺-Bound and Ca²⁺-Free LH1 Complexes

by Mei-Juan Zou, Shuai Sun, Guang-Lei Wang, Yi-Hao Yan, Wei Ji, Zheng-Yu Wang-Otomo, Michael T. Madigan and Long-Jiang Yu

Biomolecules 2025, 15(1), 124; https://doi.org/10.3390/biom15010124 - 14 Jan 2025

Viewed by 604

Abstract

The genome of the mildly thermophilic hot spring purple sulfur bacterium, Allochromatium (Alc.) tepidum, contains a multigene pufBA family that encodes a series of α- and β-polypeptides, collectively forming a heterogeneous light-harvesting 1 (LH1) complex. The Alc. tepidum LH1, therefore, [...] Read more.

The genome of the mildly thermophilic hot spring purple sulfur bacterium, Allochromatium (Alc.) tepidum, contains a multigene pufBA family that encodes a series of α- and β-polypeptides, collectively forming a heterogeneous light-harvesting 1 (LH1) complex. The Alc. tepidum LH1, therefore, offers a unique model for studying an intermediate phenotype between phototrophic thermophilic and mesophilic bacteria, particularly regarding their LH1 Qy transition and moderately enhanced thermal stability. Of the 16 α-polypeptides in the Alc. tepidum LH1, six α1 bind Ca²⁺ to connect with β1- or β3-polypeptides in specific Ca²⁺-binding sites. Here, we use the purple bacterium Rhodospirillum rubrum strain H2 as a host to express Ca²⁺-bound and Ca²⁺-free Alc. tepidum LH1-only complexes composed of α- and β-polypeptides that either contain or lack the calcium-binding motif WxxDxI; purified preparations of each complex were then used to test how Ca²⁺ affects their thermostability and spectral features. The cryo-EM structures of both complexes were closed circular rings consisting of 14 αβ-polypeptides. The Q_y absorption maximum of Ca²⁺-bound LH1 (α1/β1 and α1/β3) was at 894 nm, while that of Ca²⁺-free (α2/β1) was at 888 nm, indicating that Ca²⁺ imparts a Q_y transition of 6 nm. Crucially for the ecological success of Alc. tepidum, Ca²⁺-bound LH1 complexes were more thermostable than Ca²⁺-free complexes, indicating that calcium plays at least two major roles in photosynthesis by Alc. tepidum—improving photocomplex stability and modifying its spectrum. Full article

(This article belongs to the Special Issue New Insights into the Membranes of Anoxygenic Phototrophic Bacteria)

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16 pages, 291 KiB

Open AccessReview

Advances and Challenges in Pediatric Sepsis Diagnosis: Integrating Early Warning Scores and Biomarkers for Improved Prognosis

by Susanna Esposito, Benedetta Mucci, Eleonora Alfieri, Angela Tinella and Nicola Principi

Biomolecules 2025, 15(1), 123; https://doi.org/10.3390/biom15010123 - 14 Jan 2025

Viewed by 1318

Abstract

Identifying and managing pediatric sepsis is a major research focus, yet early detection and risk assessment remain challenging. In its early stages, sepsis symptoms often mimic those of mild infections or chronic conditions, complicating timely diagnosis. Although various early warning scores exist, their [...] Read more.

Identifying and managing pediatric sepsis is a major research focus, yet early detection and risk assessment remain challenging. In its early stages, sepsis symptoms often mimic those of mild infections or chronic conditions, complicating timely diagnosis. Although various early warning scores exist, their effectiveness is limited, particularly in prehospital settings where accurate, rapid assessment is crucial. This review examines the roles of clinical prediction tools and biomarkers in pediatric sepsis. Traditional biomarkers, like procalcitonin (PCT), have improved diagnostic accuracy but are insufficient alone, often resulting in overprescription of antibiotics or delayed treatment. Combining multiple biomarkers has shown promise for early screening, though this approach can be resource-intensive and less feasible outside hospitals. Predicting sepsis outcomes to tailor therapy remains underexplored. While serial measurements of traditional biomarkers offer some prognostic insight, their reliability is limited, with therapeutic decisions often relying on clinical judgment. Novel biomarkers, particularly those identifying early organ dysfunction, hold potential for improved prognostic accuracy, but significant barriers remain. Many are only available in hospitals, require further validation, or need specialized assays not commonly available, limiting broader clinical use. Further research is needed to establish reliable protocols and enhance the clinical applicability of these tools. Meanwhile, a multifaceted approach that combines clinical judgment with existing tools and biomarkers remains essential to optimize pediatric sepsis management, improving outcomes and minimizing risks. Full article

(This article belongs to the Special Issue Immune-Related Biomarkers: 2nd Edition)

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