Biomolecules

19 pages, 1149 KiB

Open AccessReview

Dual Therapy in Inflammatory Bowel Disease

by Gabriele Altieri, Alessandra Zilli, Tommaso Lorenzo Parigi, Mariangela Allocca, Federica Furfaro, Gionata Fiorino, Clelia Cicerone, Laurent Peyrin-Biroulet, Silvio Danese and Ferdinando D’Amico

Biomolecules 2025, 15(2), 222; https://doi.org/10.3390/biom15020222 - 3 Feb 2025

Abstract

Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn’s disease (CD), are chronic and complex autoimmune conditions. Despite the advancements in biologics and small molecules, the therapeutic ceiling persists, posing significant treatment challenges and contributing to the concept of difficult-to-treat IBD. Dual-targeted [...] Read more.

Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn’s disease (CD), are chronic and complex autoimmune conditions. Despite the advancements in biologics and small molecules, the therapeutic ceiling persists, posing significant treatment challenges and contributing to the concept of difficult-to-treat IBD. Dual-targeted therapy (DTT), combining two biologic agents or biologics with small molecules, has emerged as a novel approach to address this unmet need by targeting multiple inflammatory pathways simultaneously. Evidence suggests that DTT holds promise in improving clinical and endoscopic outcomes, especially in patients with refractory disease or extraintestinal manifestations. Safety data, while consistent with monotherapy profiles, highlight the importance of vigilant monitoring for infections and other adverse events. Continued research and high-quality trials are crucial to defining optimal DTT regimens and broadening its clinical applicability. This review explores the efficacy and safety of DTT in IBD, reporting data from clinical trials, systematic reviews, and real-world studies. Full article

(This article belongs to the Special Issue Integrating Genetics, Immune Dysregulation, and the Gut Microbiome: Advances in Elucidating IBD Pathophysiology and Emerging Therapeutic Strategies)

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17 pages, 1516 KiB

Open AccessArticle

Improving Identification of Drug-Target Binding Sites Based on Structures of Targets Using Residual Graph Transformer Network

by Shuang-Qing Lv, Xin Zeng, Guang-Peng Su, Wen-Feng Du, Yi Li and Meng-Liang Wen

Biomolecules 2025, 15(2), 221; https://doi.org/10.3390/biom15020221 - 3 Feb 2025

Abstract

Improving identification of drug-target binding sites can significantly aid in drug screening and design, thereby accelerating the drug development process. However, due to challenges such as insufficient fusion of multimodal information from targets and imbalanced datasets, enhancing the performance of drug-target binding sites [...] Read more.

Improving identification of drug-target binding sites can significantly aid in drug screening and design, thereby accelerating the drug development process. However, due to challenges such as insufficient fusion of multimodal information from targets and imbalanced datasets, enhancing the performance of drug-target binding sites prediction models remains exceptionally difficult. Leveraging structures of targets, we proposed a novel deep learning framework, RGTsite, which employed a Residual Graph Transformer Network to improve the identification of drug-target binding sites. First, a residual 1D convolutional neural network (1D-CNN) and the pre-trained model ProtT5 were employed to extract the local and global sequence features from the target, respectively. These features were then combined with the physicochemical properties of amino acid residues to serve as the vertex features in graph. Next, the edge features were incorporated, and the residual graph transformer network (GTN) was applied to extract the more comprehensive vertex features. Finally, a fully connected network was used to classify whether the vertex was a binding site. Experimental results showed that RGTsite outperformed the existing state-of-the-art methods in key evaluation metrics, such as F1-score (F1) and Matthews Correlation Coefficient (MCC), across multiple benchmark datasets. Additionally, we conducted interpretability analysis for RGTsite through the real-world cases, and the results confirmed that RGTsite can effectively identify drug-target binding sites in practical applications. Full article

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

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19 pages, 10491 KiB

Open AccessArticle

The Inhibitory Effect of Peptide Hydrolysate of Type I Collagen Derived from Pig Skin on Melanogenesis in B16F10 Melanoma Cells

by Jialin Zheng, Dandan Xu and Tianduo Li

Biomolecules 2025, 15(2), 220; https://doi.org/10.3390/biom15020220 - 3 Feb 2025

Abstract

Collagen peptides, as a natural source of peptides, possess multiple advantages such as anti-aging, anti-inflammatory properties, tissue repair, and the ability to inhibit melanin production. In this study, type I collagen extracted from pig skin was hydrolyzed with 1% and 3% hydrochloric acid, [...] Read more.

Collagen peptides, as a natural source of peptides, possess multiple advantages such as anti-aging, anti-inflammatory properties, tissue repair, and the ability to inhibit melanin production. In this study, type I collagen extracted from pig skin was hydrolyzed with 1% and 3% hydrochloric acid, yielding collagen peptides CPH1 and CPH3. The melanin content and tyrosinase activity in B16F10 cells were compared via direct and paracrine action when CPH1 and CPH3 were used to interfere with melanogenesis. It was found that CPH3 significantly inhibited melanogenesis in B16F10 through the paracrine action involving HaCaT keratinocytes. The intracellular melanin content was measured at 65.23 ± 1.30%, and the mRNA levels of tyrosinase and microphthalmia transcription factor in cells were 55.77 ± 6.09% and 50.70 ± 8.18% of the negative control, respectively. Furthermore, pigment deposition assays in zebrafish showed that, at a concentration of 1.0 mg/mL, CPH3 significantly inhibited melanogenesis compared to the negative control. Finally, tyrosinase inhibitory peptides were identified from CPH3 through peptide segment sequence identification and molecular dynamics simulation. The peptides of Nona-AGPPGFPGA, Octa-APGPVGPA, and Octa-GLPGPPGP have a double effect on the inhibition of tyrosinase and melanin content in B16F10 cells. Full article

(This article belongs to the Section Natural and Bio-derived Molecules)

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17 pages, 2583 KiB

Open AccessArticle

A Neuroprotective Peptide Modulates Retinal cAMP Response Element-Binding Protein (CREB), Synapsin I (SYN1), and Growth-Associated Protein 43 (GAP43) in Rats with Silicone Oil-Induced Ocular Hypertension

by Gretchen A. Johnson, Raghu R. Krishnamoorthy, Ram H. Nagaraj and Dorota L. Stankowska

Biomolecules 2025, 15(2), 219; https://doi.org/10.3390/biom15020219 - 3 Feb 2025

Abstract

This study evaluated the neuroprotective potential of peptain-1 conjugated to a cell-penetrating peptide (CPP-P1) in an ocular hypertension model of glaucoma. Brown Norway (BN) rats were subjected to intraocular pressure (IOP) elevation via intracameral injection of silicone oil (SO), with concurrent intravitreal injections [...] Read more.

This study evaluated the neuroprotective potential of peptain-1 conjugated to a cell-penetrating peptide (CPP-P1) in an ocular hypertension model of glaucoma. Brown Norway (BN) rats were subjected to intraocular pressure (IOP) elevation via intracameral injection of silicone oil (SO), with concurrent intravitreal injections of either CPP-P1 or a vehicle. Retinal cross-sections were analyzed for markers of neuroprotection, including cAMP response element-binding protein (CREB), phosphorylated CREB (p-CREB), growth-associated protein-43 (GAP43), synapsin-1 (SYN1), and superoxide dismutase 2 (SOD2). Hematoxylin and eosin staining was used to assess retinal-layer thickness. SO-treated rats exhibited significant reductions in the thickness of the inner nuclear layer (INL, 41%, p = 0.016), inner plexiform layer (IPL, 52%, p = 0.0002), and ganglion cell layer (GCL, 57%, p = 0.001). CPP-P1 treatment mitigated these reductions, preserving INL thickness by 32% (p = 0.059), IPL by 19% (p = 0.119), and GCL by 31% (p = 0.057). Increased levels of CREB (p = 0.17) and p-CREB (p = 0.04) were observed in IOP-elevated, CPP-P1-treated retinas compared to IOP-elevated, vehicle-treated retinas. Although overall GAP43 levels were low, there was a modest increase in expression within the IPL and GCL in SO- and CPP-P1-treated retinas (p = 0.15 and p = 0.09, respectively) compared to SO- and vehicle-treated retinas. SO injection reduced SYN1 expression in both IPL and GCL (p = 0.01), whereas CPP-P1 treatment significantly increased SYN1 levels in the IPL (p = 0.03) and GCL (p = 0.002). While SOD2 expression in the GCL was minimal across all groups, a trend toward increased expression was observed in CPP-P1-treated animals (p = 0.16). The SO model was replicated with SO removal after 7 days and monitored for 21 days followed by retinal flat-mount preparation to assess retinal ganglion cell (RGC) survival. A 42% loss in RGCs (p = 0.009) was observed in SO-injected eyes, which were reduced by approximately 37% (p = 0.03) with CPP-P1 treatment. These findings suggest that CPP-P1 is a promising neuroprotective agent that promotes retinal ganglion cell survival and the preservation of other retinal neurons, potentially through enhanced CREB signaling in a rat model of SO-induced ocular hypertension. Full article

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

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17 pages, 1794 KiB

Open AccessReview

Heavy Chalcogen Properties of Sulfur and Selenium Enhance Nucleic Acid-Based Therapeutics

by Stephen J. Dansereau and Jia Sheng

Biomolecules 2025, 15(2), 218; https://doi.org/10.3390/biom15020218 - 2 Feb 2025

Abstract

The Group 16 elements of the periodic table have a characteristic valence shell configuration instrumental to their chemical properties and reactivities. The electrostatic potentials of these so-called chalcogens have been exploited in the design of materials that require the efficient passage of electrons [...] Read more.

The Group 16 elements of the periodic table have a characteristic valence shell configuration instrumental to their chemical properties and reactivities. The electrostatic potentials of these so-called chalcogens have been exploited in the design of materials that require the efficient passage of electrons including supermagnets, photocatalytic dyes, and solar panels. Likewise, the incorporation of the heavy chalcogen selenium into organic frameworks has been shown to increase the reactivities of double bonds and heterocyclic rings, while its interactions with aromatic side chains in the hydrophobic core of proteins such as selenomethionine impart a stabilizing effect. Typically present in the active site, the hypervalence of selenocysteine enables it to further stabilize the folded protein and mediate electron transfer. Selenium’s native occurrence in bacterial tRNA maintains base pair fidelity, most notably during oxidative stress, through its electronic and steric effects. Such native modifications at the position 2 and 5 of uridine render these sites relevant in the design of RNA-based therapeutics. Innocuous selenium substitution for oxygen in the former and the standard methods of selenium-derivatized oligonucleotide synthesis and detection have led to the establishment of a novel class of therapeutics. In this review, we summarize some progress in this area. Full article

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

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20 pages, 5250 KiB

Open AccessArticle

Computational Elucidation of a Monobody Targeting the Phosphatase Domain of SHP2

by Yang Wang, Xin Qiao, Ruidi Zhu, Linxuan Zhou, Quan Zhang, Shaoyong Lu and Zongtao Chai

Biomolecules 2025, 15(2), 217; https://doi.org/10.3390/biom15020217 - 2 Feb 2025

Abstract

Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) is a key regulator in cellular signaling pathways because its dysregulation has been implicated in various pathological conditions, including cancers and developmental disorders. Despite its importance, the molecular basis of SHP2’s regulatory mechanism remains poorly [...] Read more.

Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) is a key regulator in cellular signaling pathways because its dysregulation has been implicated in various pathological conditions, including cancers and developmental disorders. Despite its importance, the molecular basis of SHP2’s regulatory mechanism remains poorly understood, hindering the development of effective targeted therapies. In this study, we utilized the high-specificity monobody Mb11 to investigate its interaction with the SHP2 phosphatase domain (PTP) using multiple replica molecular dynamics simulations. Our analyses elucidate the precise mechanisms through which Mb11 achieves selective recognition and stabilization of the SHP2-PTP domain, identifying key residues and interaction networks essential for its high binding specificity and regulatory dynamics. Furthermore, the study highlights the pivotal role of residue C459 in preserving the structural integrity and functional coherence of the complex, acting as a central node within the interaction network and underpinning its stability and efficiency. These findings have significantly advanced the understanding of the mechanisms underlying SHP2’s involvement in disease-related signaling and pathology while simultaneously paving the way for the rational design of targeted inhibitors, offering significant implications for therapeutic strategies in SHP2-associated diseases and contributing to the broader scope of precision medicine. Full article

(This article belongs to the Special Issue Computational Analysis and Conformational Modeling for Protein Structure and Interaction)

22 pages, 5340 KiB

Open AccessReview

Carnitine O-Acetyltransferase as a Central Player in Lipid and Branched-Chain Amino Acid Metabolism, Epigenetics, Cell Plasticity, and Organelle Function

by Mariateresa Volpicella, Maria Noemi Sgobba, Luna Laera, Anna Lucia Francavilla, Danila Imperia De Luca, Lorenzo Guerra, Ciro Leonardo Pierri and Anna De Grassi

Biomolecules 2025, 15(2), 216; https://doi.org/10.3390/biom15020216 - 2 Feb 2025

Abstract

Carnitine O-acetyltransferase (CRAT) is a key mitochondrial enzyme involved in maintaining metabolic homeostasis by mediating the reversible transfer of acetyl groups between acetyl-CoA and carnitine. This enzymatic activity ensures the optimal functioning of mitochondrial carbon flux by preventing acetyl-CoA accumulation, buffering metabolic flexibility, [...] Read more.

Carnitine O-acetyltransferase (CRAT) is a key mitochondrial enzyme involved in maintaining metabolic homeostasis by mediating the reversible transfer of acetyl groups between acetyl-CoA and carnitine. This enzymatic activity ensures the optimal functioning of mitochondrial carbon flux by preventing acetyl-CoA accumulation, buffering metabolic flexibility, and regulating the balance between fatty acid and glucose oxidation. CRAT’s interplay with the mitochondrial carnitine shuttle, involving carnitine palmitoyltransferases (CPT1 and CPT2) and the carnitine carrier (SLC25A20), underscores its critical role in energy metabolism. Emerging evidence highlights the structural and functional diversity of CRAT and structurally related acetyltransferases across cellular compartments, illustrating their coordinated role in lipid metabolism, amino acid catabolism, and mitochondrial bioenergetics. Moreover, the structural insights into CRAT have paved the way for understanding its regulation and identifying potential modulators with therapeutic applications for diseases such as diabetes, mitochondrial disorders, and cancer. This review examines CRAT’s structural and functional aspects, its relationships with carnitine shuttle members and other carnitine acyltransferases, and its broader role in metabolic health and disease. The potential for targeting CRAT and its associated pathways offers promising avenues for therapeutic interventions aimed at restoring metabolic equilibrium and addressing metabolic dysfunction in disease states. Full article

(This article belongs to the Special Issue Research on Fatty Acid Oxidation and Fatty Acid Oxidation Disorders)

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23 pages, 2343 KiB

Open AccessReview

Autophagy and Cancer: Insights into Molecular Mechanisms and Therapeutic Approaches for Chronic Myeloid Leukemia

by Mohd Adnan Kausar, Sadaf Anwar, Yusuf Saleem Khan, Ayman A. Saleh, Mai Ali Abdelfattah Ahmed, Simran Kaur, Naveed Iqbal, Waseem Ahmad Siddiqui and Mohammad Zeeshan Najm

Biomolecules 2025, 15(2), 215; https://doi.org/10.3390/biom15020215 - 2 Feb 2025

Abstract

Autophagy is a critical cellular process that maintains homeostasis by recycling damaged or aberrant components. This process is orchestrated by a network of proteins that form autophagosomes, which engulf and degrade intracellular material. In cancer, autophagy plays a dual role: it suppresses tumor [...] Read more.

Autophagy is a critical cellular process that maintains homeostasis by recycling damaged or aberrant components. This process is orchestrated by a network of proteins that form autophagosomes, which engulf and degrade intracellular material. In cancer, autophagy plays a dual role: it suppresses tumor initiation in the early stages but supports tumor growth and survival in advanced stages. Chronic myeloid leukemia (CML), a hematological malignancy, is characterized by the Philadelphia chromosome, a chromosomal abnormality resulting from a translocation between chromosomes 9 and 22. Autophagy has emerged as a key factor in CML pathogenesis, promoting cancer cell survival and contributing to resistance against tyrosine kinase inhibitors (TKIs), the primary treatment for CML. Targeting autophagic pathways is being actively explored as a therapeutic approach to overcome drug resistance and enhance cancer cell death. Recent research highlights the intricate interplay between autophagy and CML progression, underscoring its role in disease biology and treatment outcomes. This review aims to provide a comprehensive analysis of the molecular and cellular mechanisms underlying CML, with a focus on the therapeutic potential of targeting autophagy. Full article

(This article belongs to the Special Issue Cellular Signaling in Cancer)

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24 pages, 3300 KiB

Open AccessArticle

α-Synuclein Iron-Responsive-Element RNA and Iron Regulatory Protein Affinity Is Specifically Reduced by Iron in Parkinson’s Disease

by Mateen A. Khan

Biomolecules 2025, 15(2), 214; https://doi.org/10.3390/biom15020214 - 2 Feb 2025

Abstract

α-Synuclein (α-Syn) is implicated in the pathophysiology of Parkinson’s disease (PD) and plays a significant role in neuronal degeneration. Iron response proteins (IRPs) bind to iron response elements (IREs) found in the 5′-untranslated regions (5′-UTRs) of the messenger RNA that encode the α-Syn [...] Read more.

α-Synuclein (α-Syn) is implicated in the pathophysiology of Parkinson’s disease (PD) and plays a significant role in neuronal degeneration. Iron response proteins (IRPs) bind to iron response elements (IREs) found in the 5′-untranslated regions (5′-UTRs) of the messenger RNA that encode the α-Syn gene. This study used multi-spectroscopic approach techniques to investigate the impact of iron on α-Syn IRE RNA binding to IRP1. The formation of a stable complex between α-Syn RNA and IRP1 was suggested by fluorescence quenching results. Fluorescence measurements showed that α-Syn RNA and IRP1 had a strong interaction, with a binding constant (K_a) of 21.0 × 10⁶ M⁻¹ and 1:1 binding stoichiometry. About one binding site per IRP1 molecule was suggested by the α-Syn RNA binding. The K_a for α-Syn RNA•IRP1 with added Fe²⁺ (50 μM) was 6.4 μM⁻¹. When Fe²⁺ was added, the K_a of α-Syn RNA•IRP1 was reduced by 3.3 times. These acquired K_a values were used to further understand the thermodynamic characteristics of α-Syn RNA•IRP1 interactions. The thermodynamic properties clearly suggested that α-Syn RNA binding to IRP1 was an entropy-favored and enthalpy-driven event, with significant negative ΔH and small positive ΔS. For α-Syn RNA•IRP1, the Gibbs free energy (ΔG) was −43.7 ± 2.7 kJ/mol, but in the presence of Fe²⁺, it was −36.3 ± 2.1 kJ/mol. These thermodynamic calculations indicated that hydrogen bonding as well as van der Waals interactions might help to stabilize the complex formation. Additionally, far-UV CD spectra verified α-Syn RNA•IRP1 complex formation, and α-Syn RNA and Fe²⁺ induce secondary structural alteration of IRP1. According to our findings, iron alters the hydrogen bonding in α-Syn RNA•IRP1 complexes and induces a structural change in IRP1. This suggests that iron selectively affects the thermodynamics of these RNA–protein interactions. Full article

(This article belongs to the Special Issue Protein Misfolding Diseases: Molecular Mechanisms and Therapeutic Strategies)

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24 pages, 1648 KiB

Open AccessPerspective

From Cardiovascular-Kidney-Metabolic Syndrome to Cardiovascular-Renal-Hepatic-Metabolic Syndrome: Proposing an Expanded Framework

by Nikolaos Theodorakis and Maria Nikolaou

Biomolecules 2025, 15(2), 213; https://doi.org/10.3390/biom15020213 - 2 Feb 2025

Abstract

Cardiometabolic diseases represent an escalating global health crisis, slowing or even reversing earlier declines in cardiovascular disease (CVD) mortality. Traditionally, conditions such as obesity, type 2 diabetes mellitus (T2DM), atherosclerotic CVD, heart failure (HF), chronic kidney disease (CKD), and metabolic dysfunction-associated steatotic liver [...] Read more.

Cardiometabolic diseases represent an escalating global health crisis, slowing or even reversing earlier declines in cardiovascular disease (CVD) mortality. Traditionally, conditions such as obesity, type 2 diabetes mellitus (T2DM), atherosclerotic CVD, heart failure (HF), chronic kidney disease (CKD), and metabolic dysfunction-associated steatotic liver disease (MASLD) were managed in isolation. However, emerging evidence reveals that these disorders share overlapping pathophysiological mechanisms and treatment strategies. In 2023, the American Heart Association proposed the Cardiovascular-Kidney-Metabolic (CKM) syndrome, recognizing the interconnected roles of the heart, kidneys, and metabolic system. Yet, this model omits the liver—a critical organ impacted by metabolic dysfunction. MASLD, which can progress to metabolic dysfunction-associated steatohepatitis (MASH), is closely tied to insulin resistance and obesity, contributing directly to cardiovascular and renal impairment. Notably, MASLD is bidirectionally associated with the development and progression of CKM syndrome. As a result, we introduce an expanded framework—the Cardiovascular-Renal-Hepatic-Metabolic (CRHM) syndrome—to more comprehensively capture the broader inter-organ dynamics. We provide guidance for an integrated diagnostic approach aimed at halting progression to advanced stages and preventing further organ damage. In addition, we highlight advances in medical management that target shared pathophysiological pathways, offering benefits across multiple organ systems. Viewing these conditions as an integrated whole, rather than as discrete entities, and incorporating the liver into this framework fosters a more holistic management strategy and offers a promising path to addressing the cardiometabolic pandemic. Full article

(This article belongs to the Special Issue Cardiometabolic Disease: Molecular Basis and Therapeutic Approaches)

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15 pages, 4793 KiB

Open AccessArticle

Regulatory Role of a Hydrophobic Core in the FliG C-Terminal Domain in the Rotary Direction of a Flagellar Motor

by Tatsuro Nishikino, Akihiro Hatano, Seiji Kojima and Michio Homma

Biomolecules 2025, 15(2), 212; https://doi.org/10.3390/biom15020212 - 1 Feb 2025

Abstract

A flagellar motor can rotate either counterclockwise (CCW) or clockwise (CW), and rotational switching is triggered by conformational changes in FliG, although the molecular mechanism is still unknown. Here, we found that cheY deletion, which locks motor rotation in the CCW direction, restored [...] Read more.

A flagellar motor can rotate either counterclockwise (CCW) or clockwise (CW), and rotational switching is triggered by conformational changes in FliG, although the molecular mechanism is still unknown. Here, we found that cheY deletion, which locks motor rotation in the CCW direction, restored the motility abolished by the fliG L259Q mutation. We found that the CCW-biased fliG G214S mutation also restored the swimming of the L259Q mutant, but the CW-biased fliG G215A mutation did not. Since the L259 residue participates in forming the FliG hydrophobic core at its C-terminal domain, mutations were introduced into residues structurally closer to L259, and their motility was examined. Two mutants, D251R and L329Q, exhibited CW-biased rotation. Our results suggest that mutations in the hydrophobic core of FliG_C collapse its conformational switching and/or stator interaction; however, the CCW state of the rotor enables rotation even with this disruption. Full article

(This article belongs to the Special Issue Recent Advances in Supramolecular Motility Machinery of Microorganisms)

28 pages, 18002 KiB

Open AccessArticle

Single-Cell Landscape of the Cochlea Revealed Cell-Type-Specific Diversification in Hipposideros armiger Based on PacBio Long-Read Sequencing

by Mingyue Bao, Xue Wang, Xintong Li, Ruyi Sun, Zhiqiang Wang, Tinglei Jiang, Hui Wang and Jiang Feng

Biomolecules 2025, 15(2), 211; https://doi.org/10.3390/biom15020211 - 1 Feb 2025

Abstract

Echolocation represents one of the most rapid adaptive sensorimotor modulation behaviors observed in mammals, establishing bats as one of the most evolutionarily successful mammals. Bats rely on high-frequency hearing for survival, but our understanding of its cellular molecular basis is scattered and segmented. [...] Read more.

Echolocation represents one of the most rapid adaptive sensorimotor modulation behaviors observed in mammals, establishing bats as one of the most evolutionarily successful mammals. Bats rely on high-frequency hearing for survival, but our understanding of its cellular molecular basis is scattered and segmented. Herein, we constructed the first single-cell transcriptomic landscape of the cochlea in Hipposideros armiger, a CF-FM bat, using a PacBio-optimized genome and compared it with the results obtained from unoptimized original genomes. Sixteen distinct cell types were distributed across five spatial regions of the cochlea. Notably, through hematoxylin and eosin staining and fluorescence in situ hybridization, we identified new types of spiral ganglion neuron (SGN) cells in the cochlea of H. armiger. These SGN cells are likely critical for auditory perception and may have driven the adaptive evolution of high-frequency hearing in this species. Furthermore, we uncovered the differentiation relationships of among specific cell types, such as the transition from supporting cells to hair cells. Using the cochlear cell atlas as a reference, cell types susceptible to deafness-associated genes (in the human) were also identified. In summary, this study provides novel insights into the cellular and molecular mechanisms underlying the adaptive high-frequency hearing in bats and highlights potential candidate cell types and genes for therapeutic interventions in hearing loss. Full article

(This article belongs to the Section Molecular Genetics)

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38 pages, 1651 KiB

Open AccessReview

Quinazolinones as Potential Anticancer Agents: Synthesis and Action Mechanisms

by Zhijiang Deng, Jieming Li, Pengbo Zhu, Jie Wang, Yuanfang Kong, Yulong Hu, Juntao Cai and Chunhong Dong

Biomolecules 2025, 15(2), 210; https://doi.org/10.3390/biom15020210 - 1 Feb 2025

Abstract

Quinazolinones, essential quinazoline derivatives, exhibit diverse biological activities with applications in pharmaceuticals and insecticides. Some derivatives have already been developed as commercial drugs. Given the rising cancer incidence, there is a critical need for new anticancer agents, and quinazolinones show promising potential in [...] Read more.

Quinazolinones, essential quinazoline derivatives, exhibit diverse biological activities with applications in pharmaceuticals and insecticides. Some derivatives have already been developed as commercial drugs. Given the rising cancer incidence, there is a critical need for new anticancer agents, and quinazolinones show promising potential in this domain. The present review focuses on novel advances in the synthesis of these important scaffolds and other medicinal aspects involving drug design, the structure–activity relationship, and action mechanisms of quinazoline and quinazolinone derivatives, to help in the development of new quinazoline and quinazolinone derivatives. Full article

(This article belongs to the Section Natural and Bio-derived Molecules)

12 pages, 843 KiB

Open AccessReview

Pro-Opiomelanocortin and Melanocortin Receptor 3 and 4 Mutations in Genetic Obesity

by Tulin Yanik and Seyda Tugce Durhan

Biomolecules 2025, 15(2), 209; https://doi.org/10.3390/biom15020209 - 1 Feb 2025

Abstract

Genetic obesity results from loss-of-function mutations, including those affecting the leptin–melanocortin system, which regulates body weight. Pro-opiomelanocortin (POMC)-derived neurohormones act as ligands for melanocortin receptors (MCRs), regulating the leptin–melanocortin pathway through protein–protein interactions. Loss-of-function mutations in the genes encoding POMC, MC3R, and MC4R [...] Read more.

Genetic obesity results from loss-of-function mutations, including those affecting the leptin–melanocortin system, which regulates body weight. Pro-opiomelanocortin (POMC)-derived neurohormones act as ligands for melanocortin receptors (MCRs), regulating the leptin–melanocortin pathway through protein–protein interactions. Loss-of-function mutations in the genes encoding POMC, MC3R, and MC4R can lead to the dysregulation of energy expenditure and feeding balance, early-onset obesity, and developmental dysregulation. Recent studies have identified new genetic regulatory mechanisms and potential biomarker regions for the POMC gene and MC4R secondary messenger pathway associated with obesity. Recent advances in crystal structure studies have enhanced our understanding of the protein interactions in this pathway. This narrative review focuses on recent developments in two key areas related to POMC regulation and the leptin–melanocortin pathway: (1) genetic variations in and functions of POMC, and (2) MC3R and MC4R variants that lead to genetic obesity in humans. Understanding these novel mutations in POMC and MC4R/MC3R, as well as their structural and intracellular mechanisms, may help identify strategies for the treatment and diagnosis of obesity, particularly childhood obesity. Full article

(This article belongs to the Collection Molecular Mechanisms of Obesity, Diabetes, Inflammation and Aging)

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18 pages, 3519 KiB

Open AccessArticle

PAR2 Participates in the Development of Cough Hypersensitivity in Guinea Pigs by Regulating TRPA1 Through PKC

by Yiqing Zhu, Tongyangzi Zhang, Haodong Bai, Wanzhen Li, Shengyuan Wang, Xianghuai Xu and Li Yu

Biomolecules 2025, 15(2), 208; https://doi.org/10.3390/biom15020208 - 1 Feb 2025

Abstract

Objective: This study was conducted to validate the involvement of the PAR2-PKC-TRPA1 pathway in cough hypersensitivity (CHS) development. Methods: Guinea pigs were divided into a blank control, a citric acid-induced enhanced cough model, and drug intervention groups. The effects of the drugs on [...] Read more.

Objective: This study was conducted to validate the involvement of the PAR2-PKC-TRPA1 pathway in cough hypersensitivity (CHS) development. Methods: Guinea pigs were divided into a blank control, a citric acid-induced enhanced cough model, and drug intervention groups. The effects of the drugs on capsaicin-induced cough responsiveness in a cough model were observed. The effects of individual and combined treatments (including PAR2 agonists, TRPA1 agonists, PAR2 antagonists, TRPA1 antagonists, PKC agonists, and PKC antagonists) on PAR2, phospho-PKC (pPKC), and TRPA1 expression in bronchial tissues and the vagus ganglion (jugular and nodose) in the cough model and control groups were assessed. Additionally, whole-cell patch-clamp recordings were conducted to evaluate the effects of the drugs on vagus ganglion neuron electrophysiological activity. Results: ① Both PAR2 antagonists and TRPA1 antagonists significantly reduced cough frequency in guinea pigs with a cough, and the PAR2 antagonist inhibited coughing induced by the TRPA1 agonist. ② Western blotting and multiplex immunohistochemistry (mIHC) indicated that PAR2, pPKCα, PKCα, and TRPA1 expression in bronchial and vagus ganglion tissues was elevated in the cough model compared with the control, with TRPA1 expression being regulated by PAR2 and PKC being involved in this regulatory process. ③ Whole-cell patch-clamp recordings demonstrated that TRPA1 agonists induced an inward current in nodose ganglion neurons, which was further amplified by PAR2 agonists; this amplification effect was blocked by PKC antagonist. Additionally, PAR2 antagonists inhibited the inward current induced by TRPA1 agonists. ④ At various concentrations, including the optimal antitussive concentration, PAR2 antagonists did not significantly affect pulse amplitude, arterial oxygen saturation, heart rate, body temperature, or respiratory rate in guinea pigs. Conclusion: PAR2 regulates TRPA1 through PKC in cough syndrome (CHS) pathogenesis, making targeting PAR2 a safe and effective therapeutic strategy for CHS. Full article

(This article belongs to the Special Issue TRP Channels in Cardiovascular and Inflammatory Disease)

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15 pages, 639 KiB

Open AccessArticle

Altered Monocyte Populations and Activation Marker Expression in Children with Autism and Co-Occurring Gastrointestinal Symptoms

by Rachel J. Moreno, Yasmin W. Azzam, Serena Eng, Destanie Rose and Paul Ashwood

Biomolecules 2025, 15(2), 207; https://doi.org/10.3390/biom15020207 - 1 Feb 2025

Abstract

Autism spectrum disorder (ASD) is an early-onset neurodevelopmental condition that now impacts 1 in 36 children in the United States and is characterized by deficits in social communication, repetitive behaviors, and restricted interests. Children with ASD also frequently experience co-morbidities including anxiety and [...] Read more.

Autism spectrum disorder (ASD) is an early-onset neurodevelopmental condition that now impacts 1 in 36 children in the United States and is characterized by deficits in social communication, repetitive behaviors, and restricted interests. Children with ASD also frequently experience co-morbidities including anxiety and ADHD, and up to 80% experience gastrointestinal (GI) symptoms such as constipation, diarrhea, and/or abdominal pain. Systemic immune activation and dysregulation, including increased pro-inflammatory cytokines, are frequently observed in ASD. Evidence has shown that the innate immune system may be impacted in ASD, as altered monocyte gene expression profiles and cytokine responses to pattern recognition ligands have been observed compared to typically developing (TD) children. In humans, circulating monocytes are often categorized into three subpopulations—classical, transitional (or “intermediate”), and nonclassical monocytes, which can vary in functions, including archetypal inflammatory and/or reparative functions, as well as their effector locations. The potential for monocytes to contribute to immune dysregulation in ASD and its comorbidities has so far not been extensively studied. This study aims to determine whether these monocyte subsets differ in frequency in children with ASD and if the presence of GI symptoms alters subset distribution, as has been seen for T cell subsets. Whole blood from ASD children with (ASD⁺GI⁺) and without gastrointestinal symptoms (ASD⁺GI⁻) and their TD counterparts was collected from children enrolled in the Childhood Autism Risk from Genetics and Environment (CHARGE) study. Peripheral blood mononuclear cells were isolated and stained for commonly used subset identifiers CD14 and CD16 as well as activation state markers CCR2, HLA-DR, PD-1, and PD-L1 for flow cytometry analysis. We identified changes in monocyte subpopulations and their expression of surface markers in children with ASD compared to TD children. These differences in ASD appear to be dependent on the presence or absence of GI symptoms. We found that the ASD⁺GI⁺ group have a different monocyte composition, evident in their classical, transitional, and nonclassical populations, compared to the ASD⁺GI⁻ and TD groups. Both the ASD⁺GI⁺ and ASD⁺GI⁻ groups exhibited greater frequencies of classical monocytes compared to the TD group. However, the ASD⁺GI⁺ group demonstrated lower frequencies of transitional and nonclassical monocytes than their ASD⁺GI⁻ and TD counterparts. CCR2⁺ classical monocyte frequencies were highest in the ASD⁺GI⁻ group. HLA-DR⁺ classical, transitional, and nonclassical monocytes were statistically comparable between groups, however, HLA-DR⁻ nonclassical monocyte frequencies were lower in both ASD groups compared to TD. The frequency of classical monocytes displaying exhaustion markers PD-1 and PD-L1 were increased in the ASD⁺GI⁺ group compared to ASD⁺GI⁻ and TD, suggesting potentially impaired ability for clearance of foreign pathogens or debris, typically associated with worsened inflammation. Taken together, the findings of differential proportions of the monocyte subpopulations and altered surface markers may explain some of the characteristics of immune dysregulation, such as in the gastrointestinal tract, observed in ASD. Full article

(This article belongs to the Special Issue Neuroimmune Interactions in Neuropsychiatric Diseases)

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9 pages, 1776 KiB

Open AccessPerspective

Unraveling the Engagement of Kinases to CRBN Through a Shared Structural Motif to Optimize PROTACs Efficacy

by Serena Rosignoli, Sara Giordani, Maddalena Pacelli, Giulia Guarguaglini and Alessandro Paiardini

Biomolecules 2025, 15(2), 206; https://doi.org/10.3390/biom15020206 - 1 Feb 2025

Abstract

PROteolysis TArgeting Chimeras (PROTACs) offer a therapeutic modality for protein target engagement, exploiting the ubiquitin–proteasome system to achieve precise degradation of a protein of interest. Recent advancements in understanding the structural biology of the CRL4A E3 ligase complex, particularly its recruitment of neo-substrates [...] Read more.

PROteolysis TArgeting Chimeras (PROTACs) offer a therapeutic modality for protein target engagement, exploiting the ubiquitin–proteasome system to achieve precise degradation of a protein of interest. Recent advancements in understanding the structural biology of the CRL4A E3 ligase complex, particularly its recruitment of neo-substrates through the G-loop motif, have provided valuable insights into the optimization of PROTAC efficacy. This perspective delves into the molecular determinants governing PROTAC selectivity and degradation efficiency, with a specific focus on kinases showing distinct G-loop conformations. By employing computational approaches to predict ternary complexes, along with the identification of binding patterns, it is possible to address limitations posed by structural data scarcity, thereby enhancing rational design strategies. Full article

(This article belongs to the Special Issue Protein Structure Prediction in Drug Discovery: 2nd Edition)

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12 pages, 1499 KiB

Open AccessPerspective

APOL1 Dynamics in Diabetic Kidney Disease and Hypertension

by Pravin C. Singhal and Karl Skorecki

Biomolecules 2025, 15(2), 205; https://doi.org/10.3390/biom15020205 - 1 Feb 2025

Abstract

APOL1 Renal Risk Variants (APOL1RRVs, G1, and G2) are known to be toxic to glomerular podocytes and causally associated with an enhanced prevalence and progression of many different etiologies of chronic kidney disease (CKD), leading to the delineation of a new disease designation [...] Read more.

APOL1 Renal Risk Variants (APOL1RRVs, G1, and G2) are known to be toxic to glomerular podocytes and causally associated with an enhanced prevalence and progression of many different etiologies of chronic kidney disease (CKD), leading to the delineation of a new disease designation of APOL1-Mediated Kidney Disease (AMKD). Notably, APOL1RRVs have not consistently been shown to increase the prevalence or severity of diabetic kidney disease (DKD) progression, which is the most common cause of End-Stage Kidney Disease (ESKD). While this apparent discrepancy seems perplexing, its clarification should provide important mechanistic and therapeutic insights. Activation of the Renin–Angiotensin System (RAS) plays a critical role in the development and progression of DKD. Recent in vitro and in vivo studies also demonstrated that RAS activation contributes to kidney cell injury in AMKD experimental models. Both high glucose, as well as APOL1RRVs escalate the podocyte expression of miR193a, a known mediator of glomerulosclerosis, including idiopathic Focal Segmental Glomerular Sclerosis (FSGS) and DKD. We propose that either the RAS and/or miR193a levels in the diabetic milieu are already maximally conducive to kidney target cell injury and, therefore, are agnostic to further injury in response to APOL1RRVs. Similarly, the contributory role of hypertension (which is frequently reported as the second most common cause of ESKD) in the progression of AMKD remains a controversial issue. Since several clinical reports have shown that controlling hypertension does not consistently slow the progression of AMKD, this has led to a formulation wherein APOL1-RRVs primarily lead to kidney injury with accompanying hypertension. Notably, half a decade later, the notion that hypertension is not a cause but rather a consequence of kidney injury was contested by investigators analyzing the Mount Sinai BioMe repository, a comprehensive clinical and genetic database including participants with APOL1RRVs. These investigators observed that hypertension predated the observed decline in GFR in individuals with APOL1RRVs by ten years. In the present study, we discuss the mechanistic forces that may underpin the gaps in these clinical manifestations, which did not allow the temporal association of hypertension with AMKD to be translated into causation and may also dissociate DKD and AMKD. We have hypothesized models that need to be validated in future experimental studies. Full article

(This article belongs to the Section Molecular Medicine)

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17 pages, 7954 KiB

Open AccessArticle

A Modular Customizable Ligand-Conjugate (LC) System Targeting Ghrelin O-Acyltransferase

by Amber L. Ford, Caine W. Taft, Andrea M. Sprague-Getsy, Gracie C. Carlson, Nilamber A. Mate, Michelle A. Sieburg, John D. Chisholm and James L. Hougland

Biomolecules 2025, 15(2), 204; https://doi.org/10.3390/biom15020204 - 1 Feb 2025

Abstract

Ghrelin is a 28 amino acid peptide hormone that impacts a wide range of biological processes, including appetite regulation, glucose metabolism, growth hormone regulation, and cognitive function. To bind and activate its cognate receptor, ghrelin must be acylated on a serine residue in [...] Read more.

Ghrelin is a 28 amino acid peptide hormone that impacts a wide range of biological processes, including appetite regulation, glucose metabolism, growth hormone regulation, and cognitive function. To bind and activate its cognate receptor, ghrelin must be acylated on a serine residue in a post-translational modification performed by ghrelin O-acyltransferase (GOAT). GOAT is a membrane-bound O-acyltransferase (MBOAT) responsible for the catalysis of the addition of an octanoyl fatty acid to the third serine of desacyl ghrelin. Beyond its canonical role for ghrelin maturation in endocrine cells within the stomach, GOAT was recently reported to be overexpressed in prostate cancer (PCa) cells and detected at increased levels in the serum and urine of PCa patients. This suggests GOAT can serve as a potential route for the detection and therapeutic targeting of PCa and other diseases that exhibit GOAT overexpression. Building upon a ghrelin mimetic peptide with nanomolar affinity for GOAT, we developed an antibody-conjugate-inspired system for customizable ligand-conjugate (LC) synthesis allowing for the attachment of a wide range of cargoes. The developed synthetic scheme allows for the easy synthesis of the desired LCs and demonstrates that our ligand system tolerates an extensive palette of cargoes while maintaining nanomolar affinity against GOAT. Full article

(This article belongs to the Special Issue Feature Papers in Cellular Biochemistry)

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