Biomolecules

31 pages, 1754 KiB

Open AccessReview

V-ATPase and Lysosomal Energy Sensing in Periodontitis and Medicine-Related Osteonecrosis of the Jaw

by Xianrui Yang and Lexie Shannon Holliday

Biomolecules 2025, 15(7), 997; https://doi.org/10.3390/biom15070997 - 11 Jul 2025

Diabetes is a risk factor for periodontitis. Increasing evidence suggests that a central player in this link is the vacuolar H+-ATPase (V-ATPase), which provides a physical and functional core for regulation by the catabolic lysosomal AMP-activated protein kinase complex (L-AMPK) and the anabolic [...] Read more.

Diabetes is a risk factor for periodontitis. Increasing evidence suggests that a central player in this link is the vacuolar H+-ATPase (V-ATPase), which provides a physical and functional core for regulation by the catabolic lysosomal AMP-activated protein kinase complex (L-AMPK) and the anabolic mammalian target of rapamycin complex 1 (mTORC1). These complexes detect levels of various cellular nutrients, including glucose at the lysosome, and promote cellular responses to restore homeostasis. The high-glucose conditions of diabetes foster anabolic mTORC1 signaling that increases inflammation and inflammatory bone resorption in response to periodontal infections. Here, we review the structure and composition of V-ATPase, L-AMPK, mTORC1, and other elements of the energy-sensing platform. Mechanisms by which V-ATPase passes signals to the complexes are examined and recent data are reviewed. Current anti-bone resorptive therapeutics, bisphosphonates and denosumab, enhance the risk of medicine-related osteonecrosis of the jaw (MRONJ) and are not used to treat periodontal bone loss. Accumulating data suggest that it may be possible to target inflammatory bone resorption through agents that stimulate L-AMPK, including metformin and glucagon-like peptide-1 agonists. This approach may reduce inflammatory bone resorption without major effects on overall bone remodeling or increased risk of MRONJ. Full article

(This article belongs to the Special Issue Involved Biomolecules Within Lysosomal Energy Sensing in Health and Disease)

26 pages, 1331 KiB

Open AccessReview

The Role of Alarmins in the Pathogenesis of Asthma

by Paulina Plewa, Julia Pokwicka, Estera Bakinowska, Kajetan Kiełbowski and Andrzej Pawlik

Biomolecules 2025, 15(7), 996; https://doi.org/10.3390/biom15070996 - 11 Jul 2025

Abstract

Asthma is defined as a chronic respiratory disease, the processes of which are mainly related to the hyperreactivity of the immune system. Airway hyperresponsiveness and remodeling are other hallmarks of asthma that are strongly involved in the progression of the disease. Moreover, asthma [...] Read more.

Asthma is defined as a chronic respiratory disease, the processes of which are mainly related to the hyperreactivity of the immune system. Airway hyperresponsiveness and remodeling are other hallmarks of asthma that are strongly involved in the progression of the disease. Moreover, asthma is associated with the occurrence of atopic dermatitis, chronic sinusitis, allergic rhinitis, and a high profile of T2-type cytokines, such as IL-4, IL-5 and IL-13. The hyperresponsiveness of the immune system is a consequence of aberrant levels of alarmins, endogenous molecules that induce pro-inflammatory responses. They are released as a result of a defect or cell death, leading to the initiation of an inflammatory reaction. High-mobility group box 1 (HMGB1), S100 proteins, interleukin-33 (IL-33), thymic stromal lymphopoietin (TSLP), and IL-25 bind to various receptors, influencing the behavior of immune cells, resulting in stimulated migration and activation of these cells. In this review, we will discuss the potential role of alarmins in the pathogenesis of asthma. Full article

(This article belongs to the Special Issue The Role of Alarmins and Innate Lymphoid Cells in Allergic Immune Responses)

21 pages, 2637 KiB

Open AccessArticle

Inhibiting miR-200a-3p Increases Sirtuin 1 and Mitigates Kidney Injury in a Tubular Cell Model of Diabetes and Hypertension-Related Renal Damage

by Olga Martinez-Arroyo, Ana Flores-Chova, Marta Mendez-Debaets, Laia Garcia-Ferran, Lesley Escrivá, Maria Jose Forner, Josep Redón, Raquel Cortes and Ana Ortega

Biomolecules 2025, 15(7), 995; https://doi.org/10.3390/biom15070995 - 11 Jul 2025

Abstract

Hypertension and diabetes mellitus are key contributors to kidney damage, with the renal tubule playing a central role in the progression of kidney disease. MicroRNAs have important regulatory roles in renal injury and are among the most abundant cargos within extracellular vesicles (EVs), [...] Read more.

Hypertension and diabetes mellitus are key contributors to kidney damage, with the renal tubule playing a central role in the progression of kidney disease. MicroRNAs have important regulatory roles in renal injury and are among the most abundant cargos within extracellular vesicles (EVs), emerging as novel kidney disease biomarkers and therapeutic tools. Previously, we identified miR-200a-3p and its target SIRT1 as having a potential role in kidney injury. We aimed to evaluate miR-200a-3p levels in EVs from patient’s urine and delve into its function in causing tubular injury. We quantified miR-200a-3p urinary EV levels in hypertensive patients with and without diabetes (n = 69), 42 of which were with increased urinary albumin excretion (UAE). We analysed miR-200a-3p levels in EVs and cellular pellets, as well as their targets at mRNA and protein levels in renal tubule cells (RPTECs) subjected to high glucose and Angiotensin II treatments, and observed their influence on apoptosis, RPTEC markers and tubular injury markers. We conducted microRNA mimic and inhibitor transfections in treated RPTECs. Our findings revealed elevated miR-200a-3p levels in increased UAE patient urinary EVs, effectively discriminating UAE (AUC of 0.75, p = 0.003). In vitro, miR-200a-3p and renal injury markers increased, while RPTEC markers, SIRT1, and apoptosis decreased under treatments. Experiments using miR-200a-3p mimics and inhibitors revealed a significant impact on SIRT1 and decrease in tubular damage through miR-200a-3p inhibition. Increased levels of miR-200a-3p emerge as a potential disease marker, and its inhibition provides a therapeutic target aimed at reducing renal tubular damage linked to hypertension and diabetes. Full article

(This article belongs to the Special Issue New Insights into Kidney Disease Development and Therapy Strategies)

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20 pages, 9211 KiB

Open AccessArticle

Anionic Lipid Catalyzes the Generation of Cytotoxic Insulin Oligomers

by Jhinuk Saha, Audrey Wolszczak, Navneet Kaur, Malitha C. Dickwella Widanage, Samuel D. McCalpin, Riqiang Fu, Jamel Ali and Ayyalusamy Ramamoorthy

Biomolecules 2025, 15(7), 994; https://doi.org/10.3390/biom15070994 - 11 Jul 2025

Abstract

The misfolding and aggregation of proteins into amyloidogenic assemblies are key features of several metabolic and neurodegenerative diseases. Human insulin has long been known to form amyloid fibrils under various conditions, which affects its bioavailability and function. Clinically, insulin aggregation at recurrent injection [...] Read more.

The misfolding and aggregation of proteins into amyloidogenic assemblies are key features of several metabolic and neurodegenerative diseases. Human insulin has long been known to form amyloid fibrils under various conditions, which affects its bioavailability and function. Clinically, insulin aggregation at recurrent injection sites poses a challenge for diabetic patients who rely on insulin therapy. Furthermore, decreased responsiveness to insulin in type 2 diabetic (T2D) patients may lead to its overproduction and accumulation as aggregates. Earlier reports have reported that various factors such as pH, temperature, agitation, and the presence of lipids or other proteins influence insulin aggregation. Our present study aims to elucidate the effects of non–micellar anionic DMPG (1,2–dimyristoyl–sn–glycero–3–phosphoglycerol) lipids on insulin aggregation. Distinct pathways of insulin aggregation and intermediate formation were observed in the presence of DMPG using a ThT fluorescence assay. The formation of soluble intermediates alongside large insulin fibrils was observed in insulin incubated with DMPG via TEM, DLS, and NMR as opposed to insulin aggregates generated without lipids. ¹³C magic angle spinning solid–state NMR and FTIR experiments indicated that lipids do not alter the conformation of insulin fibrils but do alter the time scale of motion of aromatic and aliphatic side chains. Furthermore, the soluble intermediates were found to be more cytotoxic than fibrils generated with or without lipids. Overall, our study elucidates the importance of anionic lipids in dictating the pathways and intermediates associated with insulin aggregation. These findings could be useful in determining various approaches to avoid toxicity and enhance the effectiveness of insulin in therapeutic applications. Full article

(This article belongs to the Collection Feature Papers in 'Biomacromolecules: Proteins')

36 pages, 1773 KiB

Open AccessReview

Circulating Biomarker Panorama in HIV-Associated Lymphoma: A Bridge from Early Risk Warning to Prognostic Stratification

by Xuejiao Shu, Qing Xiao, Yi Liu, Ya Li, Xiaoqing Xie, Sanxiu He, Jun Li, Xiaomei Zhang and Yao Liu

Biomolecules 2025, 15(7), 993; https://doi.org/10.3390/biom15070993 - 11 Jul 2025

Abstract

HIV-associated lymphoma (HAL) is a heterogeneous and highly aggressive group of malignancies. Although antiretroviral therapy (ART) has significantly prolonged the survival of people living with HIV (PLWH), the risk of malignancy secondary to HIV infection remains higher than in HIV-negative individuals, with HAL [...] Read more.

HIV-associated lymphoma (HAL) is a heterogeneous and highly aggressive group of malignancies. Although antiretroviral therapy (ART) has significantly prolonged the survival of people living with HIV (PLWH), the risk of malignancy secondary to HIV infection remains higher than in HIV-negative individuals, with HAL being among the most frequent. The pathogenesis of HAL is complex, involving multifactorial interactions. In current clinical practice, HAL faces a double challenge: the lack of effective biological risk warning systems and the lack of precise prognostic stratification tools. In recent years, the construction of multidimensional biomarker systems has shown critical value in the comprehensive management of HAL. This review aims to systematically summarize recent advances in circulating biomarkers for HAL, focusing on the potential applications of immune environment indicators, such as inflammatory cytokine profiles and microbial translocation markers, as well as serum protein profiles, lymphocyte subsets, extracellular vesicles (EVs), circulating microRNAs (miRNAs), and viral biomarkers. These biomarkers offer promising avenues for early risk prediction, therapeutic monitoring, and prognostic evaluation. Developing an assessment system based on multidimensional biomarkers will optimize early risk stratification, enable precise prognostic classification, and support personalized therapeutic strategies, thereby providing a novel theoretical basis and practical direction for the clinical management of HAL. Full article

(This article belongs to the Section Molecular Biomarkers)

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18 pages, 2486 KiB

Open AccessArticle

The Unconventional Role of ABHD17A in Increasing the S-Palmitoylation and Antiviral Activity of IFITM1 by Downregulating ABHD16A

by Xuemeng Shi, Shuaiwu Chen, Mingyang Liu, Yali Fan, Xin Wen, Jingyi Wang, Xiaoling Li, Huimin Liu, Lin Mao, Li Yu, Yuxin Hu and Jun Xu

Biomolecules 2025, 15(7), 992; https://doi.org/10.3390/biom15070992 - 11 Jul 2025

Abstract

The broad-spectrum antiviral functions of interferon-inducible transmembrane 1 (IFITM1) rely on S-palmitoylation post-translational modification. α/β-hydrolase domain-containing 17A (ABHD17A) has been reported to be responsible for protein depalmitoylation over the past decade, but whether and how ABHD17A regulates the dynamic S-palmitoylation modification of IFITM1 [...] Read more.

The broad-spectrum antiviral functions of interferon-inducible transmembrane 1 (IFITM1) rely on S-palmitoylation post-translational modification. α/β-hydrolase domain-containing 17A (ABHD17A) has been reported to be responsible for protein depalmitoylation over the past decade, but whether and how ABHD17A regulates the dynamic S-palmitoylation modification of IFITM1 remains unknown. Here, we demonstrated that ABHD17A physically interacts with IFITM1 and increases the S-palmitoylation level of IFITM1. Sequence alignment revealed that ABHD17A lacked the DHHC motif, which is capable of catalyzing the S-palmitoylation modification. Thus, we screened multiple candidate palmitoylating and depalmitoylating enzymes that may contribute to ABHD17A-induced upregulation of IFITM1 S-palmitoylation. The recently discovered depalmitoylase ABHD16A was significantly downregulated by ABHD17A, which counteracted the palmitate-removing reactions of ABHD16A on IFITM1 and subsequently upregulated the S-palmitoylation level and antiviral activity of IFITM1. Our work therefore elucidated the unconventional role of depalmitoylase ABHD17A in elevating the S-palmitoylation modification, expanded the biological functions of ABHD17A in innate immunity, and provided potential targets for viral disease therapy. Full article

(This article belongs to the Special Issue Cancer Epigenetics, Post-Translational Modification, and Drug Discovery)

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15 pages, 959 KiB

Open AccessArticle

Growth Differentiation Factor 15 Predicts Cardiovascular Events in Peripheral Artery Disease

by Ben Li, Farah Shaikh, Houssam Younes, Batool Abuhalimeh, Abdelrahman Zamzam, Rawand Abdin and Mohammad Qadura

Biomolecules 2025, 15(7), 991; https://doi.org/10.3390/biom15070991 - 11 Jul 2025

Abstract

Peripheral artery disease (PAD) is associated with an elevated risk of major adverse cardiovascular events (MACE). Despite this, few reliable biomarkers exist to identify patients at heightened risk of MACE. Growth differentiation factor 15 (GDF15), a stress-responsive cytokine implicated in inflammation, atherosclerosis, and [...] Read more.

Peripheral artery disease (PAD) is associated with an elevated risk of major adverse cardiovascular events (MACE). Despite this, few reliable biomarkers exist to identify patients at heightened risk of MACE. Growth differentiation factor 15 (GDF15), a stress-responsive cytokine implicated in inflammation, atherosclerosis, and thrombosis, has been broadly studied in cardiovascular disease but remains underexplored in PAD. This study aimed to evaluate the prognostic utility of GDF15 for predicting 2-year MACE in PAD patients using explainable statistical and machine learning approaches. We conducted a prospective analysis of 1192 individuals (454 with PAD and 738 without PAD). At study entry, patient plasma GDF15 concentrations were measured using a validated multiplex immunoassay. The cohort was followed for two years to monitor the occurrence of MACE, defined as stroke, myocardial infarction, or death. Baseline GDF15 levels were compared between PAD and non-PAD participants using the Mann–Whitney U test. A machine learning model based on extreme gradient boosting (XGBoost) was trained to predict 2-year MACE using 10-fold cross-validation, incorporating GDF15 and clinical variables including age, sex, comorbidities (hypertension, diabetes, dyslipidemia, congestive heart failure, coronary artery disease, and previous stroke or transient ischemic attack), smoking history, and cardioprotective medication use. The model’s primary evaluation metric was the F1 score, a validated measurement of the harmonic mean of the precision and recall values of the prediction model. Secondary model performance metrics included precision, recall, positive likelihood ratio (LR+), and negative likelihood ratio (LR-). A prediction probability histogram and Shapley additive explanations (SHAP) analysis were used to assess model discrimination and interpretability. The mean participant age was 70 ± SD 11 years, with 32% (n = 386) female representation. Median plasma GDF15 levels were significantly higher in PAD patients compared to the levels in non-PAD patients (1.29 [IQR 0.77–2.22] vs. 0.99 [IQR 0.61–1.63] pg/mL; p < 0.001). During the 2-year follow-up period, 219 individuals (18.4%) experienced MACE. The XGBoost model demonstrated strong predictive performance for 2-year MACE (F1 score = 0.83; precision = 82.0%; recall = 83.7%; LR+ = 1.88; LR− = 0.83). The prediction histogram revealed distinct stratification between those who did vs. did not experience 2-year MACE. SHAP analysis identified GDF15 as the most influential predictive feature, surpassing traditional clinical predictors such as age, cardiovascular history, and smoking status. This study highlights GDF15 as a strong prognostic biomarker for 2-year MACE in patients with PAD. When combined with clinical variables in an interpretable machine learning model, GDF15 supports the early identification of patients at high risk for systemic cardiovascular events, facilitating personalized treatment strategies including multidisciplinary specialist referrals and aggressive cardiovascular risk reduction therapy. This biomarker-guided approach offers a promising pathway for improving cardiovascular outcomes in the PAD population through precision risk stratification. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cardiology 2025)

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31 pages, 1571 KiB

Open AccessReview

Metabolic Dysfunction-Associated Steatotic Liver Disease: From a Very Low-Density Lipoprotein Perspective

by Yan Chen, Kaiwen Lei, Yanglong Liu, Jianshen Liu, Kunhua Wei, Jiao Guo and Zhengquan Su

Biomolecules 2025, 15(7), 990; https://doi.org/10.3390/biom15070990 - 11 Jul 2025

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by excessive accumulation of triglycerides and other lipids within liver cells and is closely associated with cardiovascular disease and metabolic syndrome. Very low-density lipoprotein (VLDL) is a lipoprotein synthesized and secreted by the liver and [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by excessive accumulation of triglycerides and other lipids within liver cells and is closely associated with cardiovascular disease and metabolic syndrome. Very low-density lipoprotein (VLDL) is a lipoprotein synthesized and secreted by the liver and is primarily responsible for transporting triglycerides from the liver to peripheral tissues. Therefore, there is a strong association between MASLD and VLDL. Studies have found that excess production and abnormal metabolism of VLDL can lead to elevated blood triglyceride levels, which in turn promote fat deposition in the liver, leading to MASLD. During the pathophysiological process of MASLD, adipokines and inflammatory mediators secreted by adipose tissue can affect the metabolic network of the liver, further aggravating VLDL metabolic disorders. This paper reviews the effects of VLDL synthesis and metabolism on the development of MASLD, including the changes in VLDL structure and composition, the biosynthesis of VLDL, and the mechanism of underlying VLDL-associated damage, in an attempt to elucidate the intricate crosstalk between MASLD and VLDL, in order to provide new perspectives and methods for the prevention and treatment of related diseases. Full article

(This article belongs to the Section Molecular Medicine)

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25 pages, 2181 KiB

Open AccessArticle

Discovery of a Potent Antimicrobial Peptide Through Rational Design: A New Frontier in Pathogen Control

by Bruna Agrillo, Monica Ambrosio, Rosa Luisa Ambrosio, Marta Gogliettino, Marco Balestrieri, Alessandra Porritiello, Maria Francesca Peruzy, Andrea Mancusi, Luigi Nicolais and Gianna Palmieri

Biomolecules 2025, 15(7), 989; https://doi.org/10.3390/biom15070989 - 11 Jul 2025

Abstract

The increasing circulation of multi-drug-resistant pathogens, coupled with the sluggish development of new antibiotics, is weakening our capacity to combat human infections, resulting in elevated death tolls. To address this worldwide crisis, antimicrobial peptides (AMPs) are viewed as promising substitutes or adjuvants for [...] Read more.

The increasing circulation of multi-drug-resistant pathogens, coupled with the sluggish development of new antibiotics, is weakening our capacity to combat human infections, resulting in elevated death tolls. To address this worldwide crisis, antimicrobial peptides (AMPs) are viewed as promising substitutes or adjuvants for combating bacterial infections caused by multidrug-resistant organisms. Here, the antimicrobial activity and structural characterization of a novel 13-amino acid cationic peptide named RKW (RKWILKWLRTWKK-NH2), designed based on known AMPs sequences and the identification of a key tryptophan-rich structural motif, were described. RKW displayed a broad-spectrum and potent antimicrobial and antibiofilm activity against Gram-positive and Gram-negative pathogens, including ESKAPE bacteria and fungi with minimal inhibitory concentrations (MBC) ranging from 5 µM to 20 μM. Structural results by fluorescence and Circular Dichroism (CD) spectroscopy revealed that the peptide was folded into a regular α-helical conformation in a membrane-like environment, remaining stable in a wide range of pH and temperature for at least 48 h of incubation. Furthermore, RKW showed low toxicity in vitro against mammalian fibroblast cells, indicating its potential as a promising candidate for the development of new antimicrobial or antiseptic strategies. Full article

(This article belongs to the Special Issue Antimicrobial Peptides in Nature: Inspiration for Rationally Designed Antimicrobials)

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16 pages, 3358 KiB

Open AccessArticle

Fatty Acid Metabolism via CPT1A Supports Poll Gland Function and Rutting Activities in Male Bactrian Camels

by Qi Ma, Bohao Zhang, Bin Zhou, Quanwei Zhang and Yuan Gao

Biomolecules 2025, 15(7), 988; https://doi.org/10.3390/biom15070988 - 11 Jul 2025

Abstract

The poll gland, a specialized tissue of male Bactrian camels, undergoes seasonal enlargement and marked metabolic activation during the rutting season. However, the metabolic mechanisms of the poll gland and its role in rutting activities and inducing estrus are still not fully understood. [...] Read more.

The poll gland, a specialized tissue of male Bactrian camels, undergoes seasonal enlargement and marked metabolic activation during the rutting season. However, the metabolic mechanisms of the poll gland and its role in rutting activities and inducing estrus are still not fully understood. This study aimed to investigate the contribution of fatty acid metabolic pathways, specifically those mediated by carnitine palmitoyltransferase 1A (CPT1A), in poll gland activity during the breeding season; poll gland tissue, neck mane, and urine samples were systematically collected from healthy male Bactrian camels stratified into breeding and non-breeding season groups for integrated proteomic, metabolomic, and biochemical assays. Histological and immunohistochemical analyses revealed reduced adipocytes but elevated ATP production in rutting camels, suggesting increased mitochondrial activity and enhanced oxidative phosphorylation. Proteomic analyses identified 119 differentially expressed proteins (DEPs) linked to fatty acid metabolism, with CPT1A, a key regulator of mitochondrial fatty acid oxidation, emerging as a central hub. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis further confirmed enrichment in fatty acid biosynthesis, degradation, and PPAR/AMPK signaling. The metabolomic analysis identified 14 metabolites, including acetylcarnitine and glycine, that were closely correlated with CPT1A expression, suggesting their potential involvement in regulating fatty acid metabolism during the breeding season. Quantitative expression analyses revealed that CPT1A in glandular acini was significantly upregulated in the breeding group compared to the non-breeding group across all assays: qPCR (2.53-fold, p < 0.05), Western blot (3.5-fold, p < 0.05), and immunohistochemistry (1.5-fold, p < 0.05). This demonstrated that CPT1A-mediated fatty acid metabolism plays a pivotal role in energy provision for reproductive activities. The results suggested that CPT1A-mediated fatty acid oxidation sustains poll gland function and reproductive behaviors in male Bactrian camels. This study provided a theoretical basis for understanding the role of CPT1A-mediated fatty acid oxidation in maintaining poll gland function and supporting reproductive activities in male Bactrian camels. Full article

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

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26 pages, 3018 KiB

Open AccessArticle

High Glucose in Diabetic Hyperglycemia Perturbs Lymphocyte SERCA-Regulated Ca²⁺ Stores with Accompanying ER Stress and Signaling Dysfunction

by Md Nasim Uddin, James L. Graham, Peter J. Havel, Roshanak Rahimian and David W. Thomas

Biomolecules 2025, 15(7), 987; https://doi.org/10.3390/biom15070987 - 11 Jul 2025

Abstract

It is well recognized that patients with type 2 diabetes mellitus (T2DM) exhibit significant impairment of immune function resulting in a higher frequency of infections. We hypothesize in this study that a likely contributor to immune dysfunction in T2DM is alteration of T [...] Read more.

It is well recognized that patients with type 2 diabetes mellitus (T2DM) exhibit significant impairment of immune function resulting in a higher frequency of infections. We hypothesize in this study that a likely contributor to immune dysfunction in T2DM is alteration of T lymphocyte signaling functions induced by chronic hyperglycemia. In this study we have utilized the established UC Davis Type 2 Diabetes Mellitus (UCD-T2DM) rat model of human T2DM to investigate whether progressive hyperglycemia diminishes T cell receptor (TCR)-releasable endoplasmic reticulum (ER) Ca²⁺ stores, an essential early antigen-stimulated signal driving T cell activation. Furthermore, results from this study demonstrate that chronic hyperglycemia markedly alters the expression profile of the sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) Ca²⁺ ion pumps, which are the major enzymatic ion transporters maintaining replenished TCR-sensitive Ca²⁺ pools. We conducted companion experiments using Jurkat T lymphocytes exposed to high glucose which allowed finer resolution of early disruptions to ER Ca²⁺ store integrity and greater clarity on SERCA isoform-specific roles in diabetes-induced Ca²⁺ signal dysregulation. In summary, these experiments suggest that hyperglycemia in T2DM drives an ER stress state manifesting in reduced expression of the SERCA pumps, erosion of ER Ca²⁺ stores and culminating in T cell and immune dysfunction. Full article

(This article belongs to the Special Issue T Cell Ca²⁺ Signal Dynamics: An Emerging Landscape for Therapeutic Strategies)

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18 pages, 14857 KiB

Open AccessArticle

Valproic Acid Promotes the Differentiation of Satellite Glial Cells into Neurons via the pH-Dependent Pathway

by Dongyan Wang, Wenrun Kang, Jinhui Zhang, Jianwei Xu, Ruyi Wang, Xiangdan Xiao, Chao Wei, Wenfeng Yu and Junhou Lu

Biomolecules 2025, 15(7), 986; https://doi.org/10.3390/biom15070986 - 11 Jul 2025

Abstract

Valproic acid (VPA) is a widely prescribed antiepileptic agent whose teratogenic potential has been recognized. In recent years, VPA has been shown to promote neuronal regeneration; however, the exact molecular mechanisms are not fully understood. This study elucidates the pH-dependent pathway through which [...] Read more.

Valproic acid (VPA) is a widely prescribed antiepileptic agent whose teratogenic potential has been recognized. In recent years, VPA has been shown to promote neuronal regeneration; however, the exact molecular mechanisms are not fully understood. This study elucidates the pH-dependent pathway through which VPA promotes the differentiation of satellite glial cells (SGCs) into neurons. We observed sustained intracellular pH elevation during the VPA-induced neural differentiation of SGCs, and the modulation of intracellular pH was shown to influence this differentiation process. Then, we found that VPA regulates intracellular pH through NHE1 (sodium–hydrogen exchanger 1), and that the pharmacological inhibition of NHE1 not only attenuated intracellular pH elevation but also substantially impaired VPA-induced neuronal differentiation. Finally, our results showed that the elevated intracellular pH promoted the neuronal differentiation of SGCs by activating β-catenin signaling. These findings provide novel insights into the mechanisms of VPA-induced neurogenesis, advancing our understanding of its pharmacological profile and informing its potential therapeutic application in neuronal regeneration strategies. Full article

(This article belongs to the Section Cellular Biochemistry)

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18 pages, 3292 KiB

Open AccessArticle

Berberine Reveals Anticoccidial Activity by Influencing Immune Responses in Eimeria acervulina-Infected Chickens

by Binh T. Nguyen, Bujinlkham Altanzul, Rochelle A. Flores, Honghee Chang, Woo H. Kim, Suk Kim and Wongi Min

Biomolecules 2025, 15(7), 985; https://doi.org/10.3390/biom15070985 - 10 Jul 2025

Abstract

Serious enteric disease caused by seven species of Eimeira continues to cause significant economic damage to the poultry industry. E. acervulina is one of the most widespread strains in farms and has a significant impact on chicken weight loss. Currently, the use of [...] Read more.

Serious enteric disease caused by seven species of Eimeira continues to cause significant economic damage to the poultry industry. E. acervulina is one of the most widespread strains in farms and has a significant impact on chicken weight loss. Currently, the use of anticoccidial agents to suppress the occurrence of coccidiosis in farms is considerably restricted due to public health and environmental pollution issues. It is important to understand the protective immunity of the host against Eimeria infections with regard to natural products that could be used as alternatives to anticoccidial agents. Berberine chloride is known for its various biological functions, including its anti-parasite activity. However, its impact on intestinal morphology and immune-related activity in broilers infected with Eimeria still remains unclear. The aim of this study is to evaluate the anticoccidial effects of a berberine-based diet in broilers infected with E. acervulina and to monitor the host immune phenomenon using transcriptomic analysis. Administration of berberine to chickens infected with E. acervulina significantly reduced fecal oocyst production and intestinal lesion scores, and increased duodenal villus height, indicating anticoccidial activity and positive effects on intestinal morphology. Transcriptomic analysis of chickens infected with E. acervulina generally observed the down-regulation of metabolism-related genes and the up-regulation of cell integrity-related genes at day 4 post-infection. At day 6 post-infection, an increase in immune-related genes and cellular-homeostasis-related genes was generally observed. Berberine-treated and E. acervulina-infected chickens showed cytokine-cytokine receptor interaction in the second term in a Kyoto Encyclopedia of Genes and Genomes pathway analysis at day 4 post-infection, but not in chickens infected with E. acervulina alone, suggesting host immune changes induced by berberine. These results suggest that berberine, which exhibits anticoccidial effects, may have therapeutic and/or prophylactic potential in protecting the host from infectious and economic-loss-causing diseases, such as Eimeria infection. Full article

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

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25 pages, 2616 KiB

Open AccessArticle

Bio-Fabricated Aluminum Oxide Nanoparticles Derived from Waste Pharmaceutical Packages: Insight into Characterization and Applications

by Jamilah M. Al-Ahmari, Reem M. Alghanmi and Ragaa A. Hamouda

Biomolecules 2025, 15(7), 984; https://doi.org/10.3390/biom15070984 - 10 Jul 2025

Abstract

This study examines the environmental challenges posed by azo-dye pollutants and aluminum industrial waste. Aluminum oxide nanoparticles (P/Al₂O₃-NPs) were produced using a green method that utilized pharmaceutical packaging waste as an aluminum source and marine algae extract (Padina pavonica [...] Read more.

This study examines the environmental challenges posed by azo-dye pollutants and aluminum industrial waste. Aluminum oxide nanoparticles (P/Al₂O₃-NPs) were produced using a green method that utilized pharmaceutical packaging waste as an aluminum source and marine algae extract (Padina pavonica) as reducing and stabilizing agents and that was characterized by XRD, EDX, SEM, TEM, and zeta potential. Batch biosorption studies were performed to assess the effectiveness of P/Al₂O₃-NPs in removing CR dye from aqueous solutions. The results demonstrate that the particle sizes range from 58.63 to 86.70 nm and morphologies vary from spherical to elliptical. FTIR analysis revealed Al–O lattice vibrations at 988 and 570 cm⁻¹. The nanoparticles displayed a negative surface charge (−13 mV) and a pH_zpc of 4.8. Adsorption experiments optimized parameters for CR dye removal, achieving 97.81% efficiency under native pH (6.95), with a dye concentration of 30 mg/L, an adsorbent dosage of 0.1 g/L, and a contact time of 30 min. Thermodynamic studies confirmed that the process is exothermic and spontaneous. Kinetic data fit well with the pseudo-second-order model, while equilibrium data aligned with the Langmuir isotherm. The adsorption mechanism involved van der Waals forces, hydrogen bonding, and π–π interactions, as supported by the influence of pH, isotherm data, and FTIR spectra. Overall, the study demonstrates the potential of eco-friendly P/Al₂O₃-NPs to efficiently remove CR dye from aqueous solutions. Full article

(This article belongs to the Section Bio-Engineered Materials)

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15 pages, 3567 KiB

Open AccessArticle

Role of Charge Density of Polycations in DNA Complexation and Condensation

by Jianxiang Huang, Yangwei Jiang, Dong Zhang, Jingyuan Li, Youqing Shen and Ruhong Zhou

Biomolecules 2025, 15(7), 983; https://doi.org/10.3390/biom15070983 - 10 Jul 2025

Abstract

Polycationic gene vectors have been studied extensively for gene delivery, and the charge density of polycations plays a pivotal role in condensing nucleic acids. Recently, we have synthesized two kinds of polycations with varied charge densities: poly(2-(dimethylamino)ethyl methacrylate) (denoted as A100) and a [...] Read more.

Polycationic gene vectors have been studied extensively for gene delivery, and the charge density of polycations plays a pivotal role in condensing nucleic acids. Recently, we have synthesized two kinds of polycations with varied charge densities: poly(2-(dimethylamino)ethyl methacrylate) (denoted as A100) and a copolymer of 2-(tetramethyleneimino)ethyl methacrylate and 2-(diisopropyl-amino)ethyl methacrylate with a 3:1 feed ratio (denoted as B75D25). Despite its lower charge density, B75D25-based vectors exhibit higher transfection efficiency than A100-based vectors, prompting the hypothesis that hydrophobic interactions, rather than solely high charge density, enhance DNA complexation and gene delivery. This study aims to investigate the molecular mechanisms underlying these differences using molecular dynamics (MD) simulations to study the complexation of DNA with B75D25s and A100s. Our simulations reveal that DNA is quite uniformly covered by B75D25s, and the complexation is not only driven by the electrostatic attraction with DNA but more importantly by the hydrophobic interactions among B75D25s. In contrast, only a small fraction of A100s bind to DNA, which is due to the strong electrostatic repulsion among A100s. Our results reveal the contribution of hydrophobic interactions to the complexation of low-charge-density B75D25s with DNA. These results suggest that high charge density may not be essential for DNA condensation and efficient gene delivery. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Structure and Dynamics and Biophysics in Asia)

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20 pages, 3689 KiB

Open AccessArticle

Active Colitis-Induced Atrial Electrophysiological Remodeling

by Hiroki Kittaka, Edward J. Ouille V, Carlos H. Pereira, Andrès F. Pélaez, Ali Keshavarzian and Kathrin Banach

Biomolecules 2025, 15(7), 982; https://doi.org/10.3390/biom15070982 - 10 Jul 2025

Abstract

Patients with ulcerative colitis exhibit an increased risk for supraventricular arrhythmia during the active disease phase of the disease and show signs of atrial electrophysiological remodeling in remission. The goal of this study was to determine the basis for colitis-induced changes in atrial [...] Read more.

Patients with ulcerative colitis exhibit an increased risk for supraventricular arrhythmia during the active disease phase of the disease and show signs of atrial electrophysiological remodeling in remission. The goal of this study was to determine the basis for colitis-induced changes in atrial excitability. In a mouse model (C57BL/6; 3 months) of dextran sulfate sodium (DSS)-induced active colitis (3.5% weight/volume, 7 days), electrocardiograms (ECG) revealed altered atrial electrophysiological properties with a prolonged P-wave duration and PR interval. ECG changes coincided with a decreased atrial conduction velocity in Langendorff perfused hearts. Action potentials (AP) recorded from isolated atrial myocytes displayed an attenuated maximal upstroke velocity and amplitude during active colitis, as well as a prolonged AP duration (APD). Voltage clamp analysis revealed a colitis-induced shift in the voltage-dependent activation of the Na-current (I_Na) to more depolarizing voltages. In addition, protein levels of Na_v1.5 protein and connexin isoform Cx43 were reduced. APD prolongation depended on a reduction in the transient outward K-current (I_to) mostly generated by K_v4.2 channels. The changes in ECG, atrial conductance, and APD were reversible upon remission. The change in conduction velocity predominantly depended on the reversibility of the reduced Cx43 and Na_v1.5 expression. Treatment of mice with inhibitors of Angiotensin-converting enzyme (ACE) or Angiotensin II (AngII) receptor type 1 (AT1R) prevented the colitis-induced atrial electrophysiological remodeling. Our data support a colitis-induced increase in AngII signaling that promotes atrial electrophysiological remodeling and puts colitis patients at an increased risk for atrial arrhythmia. Full article

(This article belongs to the Special Issue Molecular Advances in Inflammatory Bowel Disease)

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29 pages, 2090 KiB

Open AccessReview

Nematode Pheromones as Key Mediators of Behavior, Development, and Ecological Interactions

by Xi Zheng, Junjie Liu and Xin Wang

Biomolecules 2025, 15(7), 981; https://doi.org/10.3390/biom15070981 - 9 Jul 2025

Abstract

Plant parasitic nematodes cause huge economic losses to agriculture and forestry every year, and chemical insecticides destroy the ecological environment. Researching the mechanism by which small-molecule signaling substances regulate nematode behavior and development is important for developing environmentally friendly biological control agents. Nematode [...] Read more.

Plant parasitic nematodes cause huge economic losses to agriculture and forestry every year, and chemical insecticides destroy the ecological environment. Researching the mechanism by which small-molecule signaling substances regulate nematode behavior and development is important for developing environmentally friendly biological control agents. Nematode pheromones are essential chemicals signaling intraspecies and interspecies communication, regulating development, reproduction, and social behavior. Their structural diversity enables ecological adaptation and cross-kingdom interactions, influencing fungal predation and plant immunity. This review focuses on the classification, function, and regulatory mechanisms of nematode pheromones, interspecific signal transmission, and biosynthesis pathways. We pay special attention to their potential as environmentally friendly biological control agents as well as the challenges currently encountered in their application. Full article

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

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20 pages, 3529 KiB

Open AccessArticle

Evaluating Host Defense Peptides: A Comparative Analysis of Synthetic Peptides and Recombinant Concatemers

by Cristina Saubi, José Vicente Carratalá, Roberto Bello-Madruga, Adrià López-Cano, Susanna Navarro, Anna Arís and Elena Garcia-Fruitós

Biomolecules 2025, 15(7), 980; https://doi.org/10.3390/biom15070980 - 8 Jul 2025

Abstract

The global antibiotic resistance crisis raises concerns about antibiotic use, and alternative strategies are urgently needed. In this context, host defense peptides (HDPs) have rapidly gained interest. However, one of the main obstacles is their production strategy. Chemical synthesis is the most widely [...] Read more.

The global antibiotic resistance crisis raises concerns about antibiotic use, and alternative strategies are urgently needed. In this context, host defense peptides (HDPs) have rapidly gained interest. However, one of the main obstacles is their production strategy. Chemical synthesis is the most widely used, although it is not scalable and has sequence limitations. A possible alternative is recombinant production, but the strategies used so far have limited efficiency. In this study, we aim to compare the activity and main characteristics of different HDPs produced by both chemical synthesis and by recombinant production, using an approach based on tetramers to ameliorate the production process. The results obtained showed that the production of HDPs as tetrameric peptides by recombinant production in Lactococcus lactis enhanced the peptide activity, with HDPs being much more active in terms of antimicrobial activity, more structurally stable, and nanostructured. Thus, the recombinant strategy described herein, fusing four repetitions of the same peptide, can become a real alternative to produce highly active HDPs through a scalable production process. Full article

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

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17 pages, 811 KiB

Open AccessArticle

A Novel GABA-Producing Levilactobacillus brevis Strain Isolated from Organic Tomato as a Promising Probiotic

by Asia Pizzi, Carola Parolin, Davide Gottardi, Arianna Ricci, Giuseppina Paola Parpinello, Rosalba Lanciotti, Francesca Patrignani and Beatrice Vitali

Biomolecules 2025, 15(7), 979; https://doi.org/10.3390/biom15070979 - 8 Jul 2025

Abstract

Gamma-aminobutyric acid (GABA) is a non-protein amino acid playing a significant role in the central nervous system and the gut–brain axis. This study investigated the potential to produce GABA by lactic acid bacteria (LAB) isolated from different varieties of organic tomatoes. The isolated [...] Read more.

Gamma-aminobutyric acid (GABA) is a non-protein amino acid playing a significant role in the central nervous system and the gut–brain axis. This study investigated the potential to produce GABA by lactic acid bacteria (LAB) isolated from different varieties of organic tomatoes. The isolated LAB were taxonomically identified by 16S rRNA gene sequencing, the presence of the gadB gene (glutamate decarboxylase) was detected, and GABA production was quantified using HPLC. Levilactobacillus brevis CRAI showed the highest GABA production under optimised fermentation conditions with 4% monosodium glutamate (MSG). The genome sequencing of L. brevis CRAI revealed the presence of gadA and gadB isoforms and assessed the strain’s safety profile. The gene expression analysis revealed that the gadA and gadB genes were upregulated in the presence of 4% MSG. The probiotic potential of L. brevis CRAI was also assessed by functional assays. The strain showed strong antimicrobial activity against representative enteropathogens, i.e., Escherichia coli ETEC, Salmonella choleraesuis, and Yersinia enterocolitica, and anti-inflammatory effect, reducing nitric oxide production in LPS-stimulated RAW264.7 macrophages. In addition, its ability to adhere to intestinal epithelial Caco-2 cells was demonstrated. These results highlight L. brevis CRAI as a promising candidate for the development of GABA-enriched functional foods or probiotic supplements with the perspective to modulate the gut-brain axis. Full article

(This article belongs to the Special Issue Probiotics and Their Metabolites, 2nd Edition)

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