Biomolecules

20 pages, 1221 KiB

Open AccessArticle

Circulating Lipid Profiles Indicate Incomplete Metabolic Recovery After Weight Loss, Suggesting the Need for Additional Interventions in Severe Obesity

by Alina-Iuliana Onoiu, Vicente Cambra-Cortés, Andrea Jiménez-Franco, Anna Hernández-Aguilera, David Parada, Francesc Riu, Antonio Zorzano, Jordi Camps and Jorge Joven

Biomolecules 2025, 15(8), 1112; https://doi.org/10.3390/biom15081112 (registering DOI) - 1 Aug 2025

Abstract

The effects of long-term adjustments in body weight on the lipid balance in patients with severe obesity are not well understood. This study aimed to evaluate a non-invasive lipidomic approach to identifying biomarkers that could help predict which patients may require additional therapies [...] Read more.

The effects of long-term adjustments in body weight on the lipid balance in patients with severe obesity are not well understood. This study aimed to evaluate a non-invasive lipidomic approach to identifying biomarkers that could help predict which patients may require additional therapies before and after weight loss. Using mass spectrometry, 275 lipid species were analysed in non-obese controls, patients with severe obesity, and patients one year after bariatric surgery. The results showed that severe obesity disrupts lipid pathways, contributing to lipotoxicity, inflammation, mitochondrial stress, and abnormal lipid metabolism. Although weight loss improved these disturbances, surgery did not fully normalise the lipid profiles of all patients. Outcomes varied depending on their baseline liver health and genetic differences. Persistent alterations in cholesterol handling, membrane composition, and mitochondrial function were observed in partial responders. Elevated levels of sterol lipids, glycerophospholipids, and sphingolipids emerged as markers of complete metabolic recovery, identifying candidates for targeted post-surgical interventions. These findings support the use of lipidomics to personalise obesity treatment and follow-up. Full article

(This article belongs to the Section Molecular Biomarkers)

19 pages, 1259 KiB

Open AccessArticle

Influence of Monosodium Glutamate on Astroglia of Rat Habenula

by Aleksandra Krawczyk, Karol Rycerz, Jadwiga Jaworska-Adamu and Marcin B. Arciszewski

Biomolecules 2025, 15(8), 1111; https://doi.org/10.3390/biom15081111 (registering DOI) - 1 Aug 2025

Abstract

The habenula (Hb) of the epithalamus is formed of the medial (MHb) and lateral (LHb) parts. The improper functioning of the Hb may lead to depression and anxiety. The glutamate excitotoxicity is accompanied by astroglia reactivity and leads to the damage of nervous [...] Read more.

The habenula (Hb) of the epithalamus is formed of the medial (MHb) and lateral (LHb) parts. The improper functioning of the Hb may lead to depression and anxiety. The glutamate excitotoxicity is accompanied by astroglia reactivity and leads to the damage of nervous system structures. The aim of the study was to assess the influence of monosodium glutamate (MSG) administrated subcutaneously to rats in doses of 2 g/kg b.w. (I) and 4 g/kg b.w. (II), on astroglia in the MHb and LHb. Based on immunohistochemical reactions, the morphology, number of astrocytes immunoreactive for glial fibrillary acidic protein (GFAP-IR) and S100β protein (S100β-IR), and their surface area, perimeter, number and length of processes, and cytoplasmic-nuclear immunostaining intensity for the studied proteins were assessed. In the MHb of animals receiving MSG, especially at a high dose, hypertrophy and an increase in the number of GFAP-IR and S100β-IR cells were demonstrated. In the LHb, only hypertrophy of processes in S100β-positive glia was observed. The immunostaining intensity increased in GFAP-IR glia and decreased in S100β-IR cells only in animals from group I. The results revealed that astroglia respond to MSG depending on its dose and the Hb part. This different behavior of glia may indicate their different sensitivity and resistance to damaging factors. Full article

(This article belongs to the Special Issue Glutamate and Glutamate Receptors in Health and Diseases, Second Edition)

17 pages, 17758 KiB

Open AccessArticle

Piezo1 Channel Activators Yoda1 and Yoda2 in the Context of Red Blood Cells

by Min Qiao, Reetta Penttinen, Ariel Coli, Nicoletta Murciano, Felix M. Maurer, Christian Wagner, Maria Giustina Rotordam and Lars Kaestner

Biomolecules 2025, 15(8), 1110; https://doi.org/10.3390/biom15081110 (registering DOI) - 1 Aug 2025

Abstract

Piezo1 is a mechanosensitive non-selective cation channel. Genetic alterations of the channel result in a hematologic phenotype named Hereditary Xerocytosis. With Yoda1 and, more recently, Yoda2, compounds to increase the activity of Piezo1 have become available. However, their concrete effect depends on the [...] Read more.

Piezo1 is a mechanosensitive non-selective cation channel. Genetic alterations of the channel result in a hematologic phenotype named Hereditary Xerocytosis. With Yoda1 and, more recently, Yoda2, compounds to increase the activity of Piezo1 have become available. However, their concrete effect depends on the nano environment of the channel and hence on the cell type. Here we compare the potency of Yoda1 and Yoda2 in red blood cells (RBCs). We investigate the effect of the compounds on direct channel activity using automated patch clamp, as well as the secondary effects of channel activation on signalling molecules and cellular response. In terms of signalling, we investigate the temporal response of the second messenger Ca²⁺, and in terms of cellular response, the activity of the Gárdos channel. The opening of the Gárdos channel leads to a hyperpolarisation of the RBCs, which is measured by the Macey–Bennekou–Egée (MBE) method. Although the interpretation of the data is not straightforward, we discuss the results in a physiological context and provide recommendations for the use of Yoda1 and Yoda2 to investigate RBCs. Full article

(This article belongs to the Special Issue Mechanosensitivity and Ion Channels)

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20 pages, 1383 KiB

Open AccessReview

The Multifaceted Role of miR-211 in Health and Disease

by Juan Rayo Parra, Zachary Grand, Gabriel Gonzalez, Ranjan Perera, Dipendra Pandeya, Tracey Weiler and Prem Chapagain

Biomolecules 2025, 15(8), 1109; https://doi.org/10.3390/biom15081109 (registering DOI) - 1 Aug 2025

Abstract

MicroRNA-211 (miR-211) is a versatile regulatory molecule that plays critical roles in cellular homeostasis and disease progression through the post-transcriptional regulation of gene expression. This review comprehensively examines miR-211’s multifaceted functions across various biological systems, highlighting its context-dependent activity as both a tumor [...] Read more.

MicroRNA-211 (miR-211) is a versatile regulatory molecule that plays critical roles in cellular homeostasis and disease progression through the post-transcriptional regulation of gene expression. This review comprehensively examines miR-211’s multifaceted functions across various biological systems, highlighting its context-dependent activity as both a tumor suppressor and oncogene. In physiological contexts, miR-211 regulates cell cycle progression, metabolism, and differentiation through the modulation of key signaling pathways, including TGF-β/SMAD and PI3K/AKT. miR-211 participates in retinal development, bone physiology, and protection against renal ischemia–reperfusion injury. In pathological conditions, miR-211 expression is altered in various diseases, particularly cancer, where it may be a useful diagnostic and prognostic biomarker. Its stability in serum and differential expression in various cancer types make it a promising candidate for non-invasive diagnostics. The review also explores miR-211’s therapeutic potential, discussing both challenges and opportunities in developing miRNA-based treatments. Understanding miR-211’s complex regulatory interactions and context-dependent functions is crucial for advancing its clinical applications for diagnosis, prognosis, and targeted therapy in multiple diseases. Full article

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

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16 pages, 2742 KiB

Open AccessArticle

miRNA408 from Camellia japonica L. Mediates Cross-Kingdom Regulation in Human Skin Recovery

by Soll Jin, Jae-Goo Kim, Hye Jin Kim, Ji Young Kim, Sang Hoon Kim, Hee Cheol Kang and Mi Jung Kim

Biomolecules 2025, 15(8), 1108; https://doi.org/10.3390/biom15081108 - 1 Aug 2025

Abstract

Wound healing is a complex and dynamic process involving several stages of tissue repair. This study has shown that extracellular vesicles (EVs) derived from the callus of Camellia japonica L. and their associated microRNAs (miRNAs) possess significant wound healing activities. In human fibroblasts, [...] Read more.

Wound healing is a complex and dynamic process involving several stages of tissue repair. This study has shown that extracellular vesicles (EVs) derived from the callus of Camellia japonica L. and their associated microRNAs (miRNAs) possess significant wound healing activities. In human fibroblasts, EVs from C. japonica L. stimulated wound healing and upregulated collagen gene expression. The EVs also decreased inflammation levels in human keratinocytes, supporting wound healing. Among the miRNAs identified, miR408, one of the abundant miRNAs in the EVs, also showed similar wound healing efficacy. These findings suggest that both EVs and miR408 from the callus of C. japonica L. play a pivotal role in promoting wound healing. Additionally, this study shows that the regulation of miRNAs between different kingdoms can be achieved and suggests a new direction for the utilization of plant-derived components. Full article

(This article belongs to the Section Molecular Biophysics: Structure, Dynamics, and Function)

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18 pages, 7271 KiB

Open AccessArticle

ENO1 from Mycoplasma bovis Disrupts Host Glycolysis and Inflammation by Binding ACTB

by Rui-Rui Li, Xiao-Jiao Yu, Jia-Yin Liang, Jin-Liang Sheng, Hui Zhang, Chuang-Fu Chen, Zhong-Chen Ma and Yong Wang

Biomolecules 2025, 15(8), 1107; https://doi.org/10.3390/biom15081107 - 1 Aug 2025

Abstract

Mycoplasma bovis is an important pathogen that is associated with respiratory diseases, mastitis, and arthritis in cattle, leading to significant economic losses in the global cattle industry. Most notably in this study, we pioneer the discovery that its secreted effector ENO1 (α-enolase) directly [...] Read more.

Mycoplasma bovis is an important pathogen that is associated with respiratory diseases, mastitis, and arthritis in cattle, leading to significant economic losses in the global cattle industry. Most notably in this study, we pioneer the discovery that its secreted effector ENO1 (α-enolase) directly targets host cytoskeletal proteins for metabolic–immune regulation. Using an innovative GST pull-down/mass spectrometry approach, we made the seminal discovery of β-actin (ACTB) as the primary host target of ENO1—the first reported bacterial effector–cytoskeleton interaction mediating metabolic reprogramming. ENO1–ACTB binding depends on a hydrogen bond network involving ACTB’s 117Glu and 372Arg residues. This interaction triggers (1) glycolytic activation via Glut1 upregulation, establishing Warburg effect characteristics (lactic acid accumulation/ATP inhibition), and (2) ROS-mediated activation of dual inflammatory axes (HIF-1α/IL-1β and IL-6/TNF-α). This work establishes three groundbreaking concepts: (1) the first evidence of a pathogen effector hijacking host ACTB for metabolic manipulation, (2) a novel ‘glycolysis–ACTB–ROS-inflammation’ axis, and (3) the first demonstration of bacterial proteins coordinating a Warburg effect with cytokine storms. These findings provide new targets for anti-infection therapies against Mycoplasma bovis. Full article

(This article belongs to the Section Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates)

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23 pages, 40218 KiB

Open AccessArticle

ACSL4 Drives C5a/C5aR1–Calcium-Induced Fibroblast-to-Myofibroblast Transition in a Bleomycin-Induced Mouse Model of Pulmonary Fibrosis

by Tingting Ren, Jia Shi, Lili Zhuang, Ruiting Su, Yimei Lai and Niansheng Yang

Biomolecules 2025, 15(8), 1106; https://doi.org/10.3390/biom15081106 - 31 Jul 2025

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by excessive extracellular matrix (ECM) deposition driven by aberrant fibroblast-to-myofibroblast transition (FMT). However, the upstream regulators and downstream effectors of this process remain incompletely understood. Here, we identify acyl-CoA synthetase long-chain family member 4 (ACSL4), a lipid [...] Read more.

Idiopathic pulmonary fibrosis (IPF) is characterized by excessive extracellular matrix (ECM) deposition driven by aberrant fibroblast-to-myofibroblast transition (FMT). However, the upstream regulators and downstream effectors of this process remain incompletely understood. Here, we identify acyl-CoA synthetase long-chain family member 4 (ACSL4), a lipid metabolic enzyme, as a critical mediator linking complement component 5a (C5a)/C5a receptor 1 (C5aR1) signaling to FMT via calcium signaling. In bleomycin (BLM)-induced pulmonary fibrosis of C57BL/6JGpt mice, and in C5a-stimulated primary lung fibroblasts, the expression of ACSL4 was markedly upregulated. Pharmacological inhibition of ACSL4 (PRGL493) or C5aR1 (PMX53) attenuated the deposition of ECM and suppressed the expression of fibrotic markers in vivo and in vitro. Mechanistically, the activation of C5a/C5aR1 signaling increased intracellular calcium levels and promoted the expression of ACSL4, while inhibition of calcium signaling (FK506) reversed the upregulation of ACSL4 and FMT-related changes, including the expression of α-smooth muscle actin (αSMA) and the migration of fibroblasts. Notably, inhibition of ACSL4 did not affect the proliferation of fibroblasts, suggesting its specific role in phenotypic transition. These findings demonstrate that ACSL4 functions downstream of C5a/C5aR1-induced calcium signaling to promote FMT and the progression of pulmonary fibrosis. Targeting ACSL4 may therefore offer a novel therapeutic strategy for IPF. Full article

(This article belongs to the Section Cellular Biochemistry)

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19 pages, 4441 KiB

Open AccessArticle

In Silico and In Vivo Pharmacological Evaluation of Iridoid Compounds: Geniposide and Asperuloside Profile Study Through Molecular Docking Assay and in the Caenorhabditis elegans Model

by Mariana Uczay, Péterson Alves Santos, Pricila Pflüger, Gilsane von Poser, José Brea, Maria Isabel Loza, Patrícia Pereira and José Angel Fontenla

Biomolecules 2025, 15(8), 1105; https://doi.org/10.3390/biom15081105 - 31 Jul 2025

Abstract

Iridoids are compounds recognized for their neuroprotective properties and their potential application in the treatment of neurodegenerative diseases. Geniposide (GP) and asperuloside (ASP) are iridoids that have demonstrated some biological activities. In this study, the potential neuroprotective effects of these iridoids were evaluated [...] Read more.

Iridoids are compounds recognized for their neuroprotective properties and their potential application in the treatment of neurodegenerative diseases. Geniposide (GP) and asperuloside (ASP) are iridoids that have demonstrated some biological activities. In this study, the potential neuroprotective effects of these iridoids were evaluated through in silico and in vivo assays, using Caenorhabditis elegans (C. elegans) strains CF1553 (sod-3::GFP), GA800 (cat::GFP), and CL2166 (gst-4::GFP). The results suggested that neither compound appears to have good passive permeability through the blood–brain barrier (BBB). However, an active transport mechanism involving the glucose transporter GLUT-1 may be present, as both compounds contain glucose in their molecular structure. In addition, they can inhibit the activity of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). GP at 1 and 2 mM reversed the H₂O₂-induced increase in sod-3 expression, while ASP at 1 and 2 mM reversed the increase in gst-4 expression. Worm survival was more adversely affected by higher concentrations of GP than ASP, although both similarly reduced acetylcholinesterase activity. These findings suggest that GP and ASP exhibit very low toxicity both in silico and in vivo in C. elegans, and positively modulate key enzymes involved in antioxidant pathways, highlighting their potential for neuroprotective applications. Full article

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

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13 pages, 823 KiB

Open AccessReview

m6A Methylation Modification: Perspectives on the Early Reproduction of Females

by Yan Yang and Zhanhong Zheng

Biomolecules 2025, 15(8), 1102; https://doi.org/10.3390/biom15081102 - 31 Jul 2025

Abstract

This review examines the regulatory role of m6A methylation modification in embryo implantation, focusing specifically on its impact on uterine receptivity and decidualization. It offers a comprehensive examination of the essential theoretical research on m6A methylation, clarifying its molecular mechanisms and roles in [...] Read more.

This review examines the regulatory role of m6A methylation modification in embryo implantation, focusing specifically on its impact on uterine receptivity and decidualization. It offers a comprehensive examination of the essential theoretical research on m6A methylation, clarifying its molecular mechanisms and roles in uterine receptivity and decidualization. Furthermore, this review examined the effects of m6A methylation on endometrial-related diseases and early embryonic development. It synthesizes early findings and recent advancements in m6A methylation studies. Through a comprehensive analysis of relevant studies, this review offers novel insights into the molecular mechanisms underlying embryo implantation and suggests potential strategies for assisted reproductive technologies and the treatment of related disorders, thereby serving as a comprehensive reference for future research in this domain. Full article

(This article belongs to the Section Molecular Reproduction)

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16 pages, 7401 KiB

Open AccessArticle

Sitagliptin Mitigates Diabetic Cardiomyopathy Through Oxidative Stress Reduction and Suppression of VEGF and FLT-1 Expression in Rats

by Qamraa H. Alqahtani, Tahani A. ALMatrafi, Amira M. Badr, Sumayya A. Alturaif, Raeesa Mohammed, Abdulaziz Siyal and Iman H. Hasan

Biomolecules 2025, 15(8), 1104; https://doi.org/10.3390/biom15081104 - 30 Jul 2025

Abstract

Diabetes mellitus (DM) is a global health challenge marked by chronic hyperglycemia, which can result in complications such as diabetic cardiomyopathy. Sitagliptin, an oral anti-hyperglycemic drug, has demonstrated efficacy in alleviating cardiovascular complications associated with DM. This study explored the impact of Sitagliptin’s [...] Read more.

Diabetes mellitus (DM) is a global health challenge marked by chronic hyperglycemia, which can result in complications such as diabetic cardiomyopathy. Sitagliptin, an oral anti-hyperglycemic drug, has demonstrated efficacy in alleviating cardiovascular complications associated with DM. This study explored the impact of Sitagliptin’s potential as a therapeutic agent, functioning not only to control blood sugar levels but also to enhance vascular health and strengthen cardiac resilience in diabetes. The investigation focused on alterations in the vascular endothelial growth factor (VEGF) and its receptor-1 (FLT-1) signaling pathways, as well as its potential to suppress inflammation and oxidative stress. A number of rats received a single dose of streptozotocin (STZ) 55 mg/kg (i.p.) to induce DM. Sitagliptin was administered orally (100 mg/kg/90 days) to normal and diabetic rats, after which samples were collected for investigation. Sitagliptin significantly mitigated weight loss in diabetic rats. Its administration significantly reduced blood glucose levels and improved serum troponin I and CK-MB levels. Heart sections from diabetic rats showed a marked increase in mTOR, VEGF, and FLT-1 immune reaction, while sitagliptin-treated diabetic rats’ heart sections showed moderate immune reactions. Sitagliptin’s protective effect was also associated with reduced inflammation, and apoptotic markers. In conclusion, Sitagliptin is suggested to offer beneficial effects on the vascular health of cardiac blood vessels, thereby potentially reducing myocardial stress in diabetic patients. Full article

(This article belongs to the Special Issue Pharmacology of Cardiovascular Diseases)

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27 pages, 1485 KiB

Open AccessReview

Involvement of Pathogenesis-Related Proteins and Their Roles in Abiotic Stress Responses in Plants

by Yilin Zhu and Fei Gao

Biomolecules 2025, 15(8), 1103; https://doi.org/10.3390/biom15081103 - 30 Jul 2025

Abstract

Plant pathogenesis-related (PR) proteins are a large and diverse family of proteins with antimicrobial activity, often induced by pathogen attack. Traditionally, PR proteins were thought to mainly participate in plant defense mechanisms against biotic stress. However, in recent years, increasing evidence has shown [...] Read more.

Plant pathogenesis-related (PR) proteins are a large and diverse family of proteins with antimicrobial activity, often induced by pathogen attack. Traditionally, PR proteins were thought to mainly participate in plant defense mechanisms against biotic stress. However, in recent years, increasing evidence has shown that these proteins also play important roles in the response to abiotic stress in plants. In the present review, we provide a summary of the latest findings on PR proteins and focus on their response to various abiotic stresses, the mechanism by which PR proteins are activated by external and internal signals, and their biological functions in plant responses to abiotic stresses. In addition, the existing challenges and future applications are also summarized, aiming to provide a reference for further research on PR proteins in the context of plant physiology. Full article

(This article belongs to the Special Issue Key Molecules Regulating Plant Response to Abiotic Stress: Transcription Factors and Stress-Induced Proteins)

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24 pages, 2944 KiB

Open AccessArticle

Oral Pharmacokinetic Evaluation of a Microemulsion-Based Delivery System for Novel A190 Prodrugs

by Sagun Poudel, Chaolong Qin, Rudra Pangeni, Ziwei Hu, Grant Berkbigler, Madeline Gunawardena, Adam S. Duerfeldt and Qingguo Xu

Biomolecules 2025, 15(8), 1101; https://doi.org/10.3390/biom15081101 - 30 Jul 2025

Abstract

Peroxisome proliferator-activated receptor alpha (PPARα) is a key regulator of lipid metabolism, making its agonists valuable therapeutic targets for various diseases, including chronic peripheral neuropathy. Existing PPARα agonists face limitations such as poor selectivity, sub-optimal bioavailability, and safety concerns. We previously demonstrated that [...] Read more.

Peroxisome proliferator-activated receptor alpha (PPARα) is a key regulator of lipid metabolism, making its agonists valuable therapeutic targets for various diseases, including chronic peripheral neuropathy. Existing PPARα agonists face limitations such as poor selectivity, sub-optimal bioavailability, and safety concerns. We previously demonstrated that A190, a novel, potent, and selective PPARα agonist, effectively alleviates chemotherapy-induced peripheral neuropathy and CFA-induced inflammatory pain as a non-opioid therapeutic agent. However, A190 alone has solubility and permeability issues that limits its oral delivery. To overcome this challenge, in this study, four new-generation ester prodrugs of A190; A190-PD-9 (methyl ester), A190-PD-14 (ethyl ester), A190-PD-154 (isopropyl ester), and A190-PD-60 (cyclic carbonate) were synthesized and evaluated for their enzymatic bioconversion and chemical stability. The lead candidate, A190-PD-60, was further formulated as a microemulsion (A190-PD-60-ME) and optimized via Box–Behnken design. A190-PD-60-ME featured nano-sized droplets (~120 nm), low polydispersity (PDI < 0.3), and high drug loading (>90%) with significant improvement in artificial membrane permeability. Crucially, pharmacokinetic evaluation in rats demonstrated that A190-PD-60-ME reached a 16.6-fold higher Cmax (439 ng/mL) and a 5.9-fold increase in relative oral bioavailability compared with an A190-PD-60 dispersion. These findings support the combined prodrug-microemulsion approach as a promising strategy to overcome oral bioavailability challenges and advance PPARα-targeted therapies. Full article

(This article belongs to the Special Issue Advancing Innovations in Biomedical Research for Translational Applications)

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15 pages, 2101 KiB

Open AccessArticle

Identification of Two Critical Contact Residues in a Pathogenic Epitope from Tetranectin for Monoclonal Antibody Binding and Preparation of Single-Chain Variable Fragments

by Juncheng Wang, Meng Liu, Rukhshan Zahid, Wenjie Zhang, Zecheng Cai, Yan Liang, Die Li, Jiasheng Hao and Yuekang Xu

Biomolecules 2025, 15(8), 1100; https://doi.org/10.3390/biom15081100 - 30 Jul 2025

Abstract

Sepsis is a fetal disease that requires a clear diagnostic biomarker for timely antibiotic treatment. Recent research has identified a pyroptosis-inducing epitope known as P5-5 in tetranectin (TN), a plasma protein produced by monocytes. Previously, we produced a 12F1 monoclonal antibody against the [...] Read more.

Sepsis is a fetal disease that requires a clear diagnostic biomarker for timely antibiotic treatment. Recent research has identified a pyroptosis-inducing epitope known as P5-5 in tetranectin (TN), a plasma protein produced by monocytes. Previously, we produced a 12F1 monoclonal antibody against the P5-5 and discovered that it could not only diagnose the presence but also monitor the progress of sepsis in the clinic. In the current study, we further investigated the structure site of the P5-5 and the recognition mechanism between the 12F1 mAb and the P5-5 epitope. To this end, 10 amino acids (NDALYEYLRQ) in the P5-5 were individually mutated to alanine, and their binding to the mAb was tested to confirm the most significant antigenic recognition sites. In the meanwhile, the spatial conformation of 12F1 mAb variable regions was modeled, and the molecular recognition mechanisms in detail of the mAb to the P5-5 epitope were further studied by molecular docking. Following epitope prediction and experimental verification, we demonstrated that the motif “DALYEYL” in the epitope sequence position 2−8 of TN-P5-5 is the major binding region for mAb recognition, in which two residues (4L and 8L) were essential for the interaction between the P5-5 epitope and the 12F1 mAb. Therefore, our study greatly narrowed down the previously reported motif from ten to seven amino acids and identified two Leu as critical contact residues. Finally, a single-chain variable fragment (scFv) from the 12F1 hybridoma was constructed, and it was confirmed that the identified motif and residues are prerequisites for the strong binding between P5-5 and 12F1. Altogether, the data of the present work could serve as a theoretic guide for the clinical design of biosynthetic drugs by artificial intelligence to treat sepsis. Full article

(This article belongs to the Special Issue Molecular, Cellular, and Blood Biomarkers in Diagnosis, Prognosis, Monitoring, and Treatment)

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11 pages, 471 KiB

Open AccessArticle

The Intestinal Mechanisms in the Excretion of Pepsinogen, Amylase and Lipase in Coprofiltrate in Women During Pregnancy and the Postpartum Period

by Elena Kolodkina and Sergey Lytaev

Biomolecules 2025, 15(8), 1099; https://doi.org/10.3390/biom15081099 - 29 Jul 2025

Abstract

Background: Enzymes secreted by the digestive glands are excreted from the body with urine, sweat and feces, and they are also removed from the blood due to their participation in the enzymatic provision of the secretion entering the gastrointestinal tract. Objective: [...] Read more.

Background: Enzymes secreted by the digestive glands are excreted from the body with urine, sweat and feces, and they are also removed from the blood due to their participation in the enzymatic provision of the secretion entering the gastrointestinal tract. Objective: The aim of this work was to analyze the activity of pepsinogen, amylase and lipase in the coprofiltrate of pregnant women in each trimester of pregnancy and in the postpartum period, taking into account the timing and type of delivery (term, premature, late delivery or cesarean section). Methods: Data from studies of non-pregnant (n = 45) and pregnant (n = 193) women were analyzed. The materials for preparation coprofiltrate were collected during delivery. Pepsinogen activity was determined by proteolytic activity at pH = 1.5–2.0 using the tyrosine spectrophotometric method, while amylase activity was determined by the amyloclastic method of Karavey, and lipolytic activity was determined by a unified kinetic method using olive oil as a substrate. Outcomes: A small amount of pepsinogen was excreted in the coprofiltrate, and while the level of its excretion increased after childbirth, it remained below the control values. At the same time, an increase in the amylolytic activity of the coprofiltrate was observed in all groups of pregnant women examined from the first to the third trimester of pregnancy. In pregnant women, multidirectional changes in lipase activity were observed depending on the timing and type of delivery. Conclusions: At the end of pregnancy, amylolytic activity increased in all women, and pepsinase activity decreased compared to the indicators of non-pregnant women. No reliable differences were found in the lipolytic activity of the coprofiltrate in pregnant women at the end of pregnancy and the indicators of non-pregnant women. Full article

(This article belongs to the Special Issue Digestive Enzymes in Health and Disease)

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16 pages, 1138 KiB

Open AccessReview

Cardiac Myosin Inhibitors in the Treatment of Hypertrophic Cardiomyopathy: Clinical Trials and Future Challenges

by Arnold Kukowka and Marek Droździk

Biomolecules 2025, 15(8), 1098; https://doi.org/10.3390/biom15081098 - 29 Jul 2025

Abstract

Hypertrophic cardiomyopathy (HCM) is a prevalent and often underdiagnosed genetic cardiac disorder characterized by left ventricular hypertrophy and, in many cases, dynamic left ventricular outflow tract obstruction (LVOTO). The development of cardiac myosin inhibitors (CMIs) represents an emerging therapeutic approach in the pharmacological [...] Read more.

Hypertrophic cardiomyopathy (HCM) is a prevalent and often underdiagnosed genetic cardiac disorder characterized by left ventricular hypertrophy and, in many cases, dynamic left ventricular outflow tract obstruction (LVOTO). The development of cardiac myosin inhibitors (CMIs) represents an emerging therapeutic approach in the pharmacological management of obstructive HCM (oHCM). This review offers an integrated and up-to-date synthesis of the cardiac myosin inhibitor class, with a focus on mavacamten, aficamten, and the broader landscape of emerging agents. It also highlights recent clinical trial outcomes, pharmacokinetic and pharmacogenetic considerations, and potential future directions in therapy. Furthermore, we incorporate the most recent data up to May 2025, including late-breaking trial results and real-world safety findings, aiming to provide clinicians with a practical and comprehensive perspective on this evolving drug class. A narrative review was conducted by systematically searching PubMed, Scopus, Google Scholar, and ClinicalTrials.gov for English-language articles and trials published between January 2016 and May 2025. Keywords included “cardiac myosin inhibitor”, mavacamten”, “aficamten”, “MYK-224”, and “hypertrophic cardiomyopathy.” Inclusion criteria encompassed clinical trials and comprehensive reviews specifically addressing CMIs in cardiac applications. CMIs such as mavacamten and aficamten have demonstrated significant clinical benefits in reducing LVOT gradients, improving exercise capacity, and alleviating symptoms in patients with oHCM. Mavacamten is currently approved for clinical use, while aficamten is in advanced regulatory review. Comparative data suggest potential advantages of aficamten in the onset of action, pharmacokinetic profile, and tolerability. Emerging evidence supports the exploration of CMIs in pediatric populations, heart failure with preserved ejection fraction (HFpEF), and non-obstructive HCM (nHCM), although results are still preliminary. Cardiac myosin inhibitors offer a novel, pathophysiology-targeted approach to managing oHCM. While mavacamten has established efficacy, next-generation agents like aficamten may offer improved safety and versatility. Further long-term studies are needed to clarify their role across broader patient populations. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Cardiopathy and Therapeutic Strategies)

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27 pages, 15511 KiB

Open AccessReview

Recent Advances in the Structural Studies of the Proteolytic ClpP/ClpX Molecular Machine

by Astrid Audibert, Jerome Boisbouvier and Annelise Vermot

Biomolecules 2025, 15(8), 1097; https://doi.org/10.3390/biom15081097 - 29 Jul 2025

Abstract

AAA+ ATPases are ring-shaped hexameric protein complexes that operate as elaborate macromolecular motors, driving a variety of ATP-dependent cellular processes. AAA+ ATPases undergo large-scale conformational changes that lead to the conversion of chemical energy from ATP into mechanical work to perform a wide [...] Read more.

AAA+ ATPases are ring-shaped hexameric protein complexes that operate as elaborate macromolecular motors, driving a variety of ATP-dependent cellular processes. AAA+ ATPases undergo large-scale conformational changes that lead to the conversion of chemical energy from ATP into mechanical work to perform a wide range of functions, such as unfolding and translocation of the protein substrate inside a proteolysis chamber of an AAA+-associated protease. Despite extensive biochemical studies on these macromolecular assemblies, the mechanism of substrate unfolding and degradation has long remained elusive. Indeed, until recently, structural characterization of AAA+ protease complexes remained hampered by the size and complexity of the machinery, harboring multiple protein subunits acting together to process proteins to be degraded. Additionally, the major structural rearrangements involved in the mechanism of this complex represent a crucial challenge for structural biology. Here, we report the main advances in deciphering molecular details of the proteolytic reaction performed by AAA+ proteases, based on the remarkable progress in structural biology techniques. Particular emphasis is placed on the latest findings from high-resolution structural analysis of the ClpXP proteolytic complex, using crystallographic and cryo-EM investigations. In addition, this review presents some additional dynamic information obtained using solution-state NMR. This information provides molecular details that help to explain the protein degradation process by such molecular machines. Full article

(This article belongs to the Special Issue Structural Biology of Protein)

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14 pages, 1241 KiB

Open AccessReview

CD4/CD8–p56^lck Induced T-Cell Receptor Signaling and Its Implications for Immunotherapy

by Andres Oroya and Christopher E. Rudd

Biomolecules 2025, 15(8), 1096; https://doi.org/10.3390/biom15081096 - 29 Jul 2025

Abstract

T-cells constitute an essential component of the adaptive immune response, mount a protective response against foreign pathogens and are important regulators of anti-tumor immunotherapy. In this context, the activation of T-cells and chimeric antigen receptor (CAR)-expressing T-cells is orchestrated by various signaling pathways, [...] Read more.

T-cells constitute an essential component of the adaptive immune response, mount a protective response against foreign pathogens and are important regulators of anti-tumor immunotherapy. In this context, the activation of T-cells and chimeric antigen receptor (CAR)-expressing T-cells is orchestrated by various signaling pathways, involving the initiation of a protein tyrosine phosphorylation cascade. For T-cells, this involves initiation of the phosphorylation cascade via src-related protein-tyrosine kinase p56^lck, which we show to associate with the co-receptors CD4 and CD8 for the induction of a phosphorylation cascade needed for the activation of T-cells. Likewise, p56^lck phosphorylation of the antigen receptor immunoreceptor tyrosine-based activation motifs (ITAMs) and key CD28 tyrosine motifs ensures the functionality and the survival of CARs, while their phospho-targets are also inhibited by PD-1, a key component of the immune checkpoint blockade. This review covers historic and current elements of our knowledge of CD4/CD8–p56^lck-induced activation events and their importance to the development of CAR T-cell immunotherapies. Full article

(This article belongs to the Special Issue Molecular Signalling Pathways in Tumorigenesis and Tumor Suppression)

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24 pages, 2145 KiB

Open AccessReview

A New Perspective on Regenerative Medicine: Plant-Derived Extracellular Vesicles

by Yuan Zuo, Jinying Zhang, Bo Sun, Xinxing Wang, Ruiying Wang, Shuo Tian and Mingsan Miao

Biomolecules 2025, 15(8), 1095; https://doi.org/10.3390/biom15081095 - 28 Jul 2025

Abstract

Plant-derived extracellular vesicles (PDEVs) are nanoscale, phospholipid bilayer-enclosed vesicles secreted by living cells through cytokinesis under physiological and pathological conditions. Owing to their high biocompatibility and stability, PDEVs have attracted considerable interest in regenerative medicine applications. They can exhibit the capacity to enhance [...] Read more.

Plant-derived extracellular vesicles (PDEVs) are nanoscale, phospholipid bilayer-enclosed vesicles secreted by living cells through cytokinesis under physiological and pathological conditions. Owing to their high biocompatibility and stability, PDEVs have attracted considerable interest in regenerative medicine applications. They can exhibit the capacity to enhance cellular proliferation, migration, and multi-lineage differentiation through immunomodulation, anti-inflammation effects, antioxidative protection, and tissue regeneration mechanisms. Given their abundant availability, favorable safety profile, and low immunogenicity risks, PDEVs have been successfully employed in therapeutic interventions for skeletal muscle disorders, cardiovascular diseases, neurodegenerative conditions, and tissue regeneration applications. This review mainly provides a comprehensive overview of PDEVs, systematically examining their biological properties, standardized isolation and characterization methodologies, preservation techniques, and current applications in regenerative medicine. Furthermore, we critically discuss future research directions and clinical translation potential, aiming to facilitate the advancement of PDEV-based therapeutic strategies. Full article

(This article belongs to the Section Molecular Medicine)

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33 pages, 1667 KiB

Open AccessSystematic Review

Vitamin D as a Modifiable Risk Factor in Schizophrenia a Systematic Review

by Jadwiga Mosiołek, Bartosz Mosiołek and Agata Szulc

Biomolecules 2025, 15(8), 1094; https://doi.org/10.3390/biom15081094 - 28 Jul 2025

Abstract

The etiology of schizophrenia remains poorly understood. Although certain risk factors have been identified, effective preventive measures are still lacking. This study investigates potential preventive methods while focusing on the role of vitamin D and its status. The role of malnutrition in schizophrenia [...] Read more.

The etiology of schizophrenia remains poorly understood. Although certain risk factors have been identified, effective preventive measures are still lacking. This study investigates potential preventive methods while focusing on the role of vitamin D and its status. The role of malnutrition in schizophrenia risk was first identified in studies on the Dutch Hunger Winter. Vitamin D deficiency was hypothesized as a contributing factor shortly thereafter. This review aims to explore the correlations between vitamin D deficiency at various life stages (maternal, neonatal, adult) and schizophrenia risk, as well as its effects on pharmacokinetics, neurobiology, bone health, and metabolic syndrome. The studies were retrieved from two indexed databases, PubMed and Web of Science, following PRISMA guidelines and included studies published between 2000 and 2024. No correlation was found between maternal vitamin D levels and schizophrenia in offspring while a positive correlation was observed between low neonatal vitamin D levels and schizophrenia in later life. Approximately half of the studies on adults reported mean vitamin D concentrations of below 20 ng/mL which were negatively correlated with gray matter volume and bone health while positively correlated with the prevalence of metabolic syndrome. Additionally, vitamin D levels were also found to correlate with antipsychotic drug concentrations. Full article

(This article belongs to the Special Issue Biomarkers and Molecular Basis of Psychiatry)

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