Biomolecules

17 pages, 665 KB

Open AccessReview

Molecular Health Effects of Electronic Cigarettes

by Paweł Sutkowy, Igor Hadryś, Wiktor Gmys, Przemysław Grzempa, Aleksandra Sobieszczańska, Weronika Tuska, Karolina Błachnio and Alina Woźniak

Biomolecules 2026, 16(2), 264; https://doi.org/10.3390/biom16020264 (registering DOI) - 7 Feb 2026

Abstract

Electronic cigarettes (e-cigarettes) have emerged as a prevalent substitute for conventional cigarettes, garnering perceptions of being a safer option for health. Nicotine addicts use e-cigarettes to cease smoking. These products have also become common among young people because of their taste, smell, and [...] Read more.

Electronic cigarettes (e-cigarettes) have emerged as a prevalent substitute for conventional cigarettes, garnering perceptions of being a safer option for health. Nicotine addicts use e-cigarettes to cease smoking. These products have also become common among young people because of their taste, smell, and attractive appearance. However, accumulating experimental and clinical evidence indicates that e-cigarette use is not risk-free. The inhalation of e-cigarette aerosols exposes users and their non-using peers to a complex mixture of chemical compounds, including aldehydes, heavy metals, and flavoring agents, many of which possess pro-oxidative and pro-inflammatory properties. This review summarizes and critically analyzes current evidence on the molecular and cellular mechanisms underlying the biological effects of e-cigarette aerosols. Particular attention is given to excessive production of reactive oxygen species, mitochondrial dysfunction, DNA damage, and the activation of redox-sensitive signaling pathways, including NF-κB and NRF2. These molecular alterations may trigger acute and, with prolonged exposure, chronic oxidative stress and inflammation, which in turn can affect gene expression, protein function, and metabolic pathways. While molecular and experimental studies often demonstrate adverse biological responses to e-cigarette aerosols, the translation of these findings into long-term clinical outcomes remains an area of ongoing investigation. Full article

(This article belongs to the Section Biological Factors)

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17 pages, 12141 KB

Open AccessArticle

Chemokine Receptor Profile of Circulating Leukocyte Subsets in Response to Acute High-Intensity Interval Training

by Katharina Leuchte, Sara Fresnillo Saló, Anne Rahbech, Mikkel Byrdal, Anders Vinther and Gitte Holmen Olofsson

Biomolecules 2026, 16(2), 263; https://doi.org/10.3390/biom16020263 (registering DOI) - 7 Feb 2026

Abstract

Physically active individuals demonstrate enhanced immune competence. Efficient execution of effector function relies on chemokine receptor-regulated immune cell trafficking along chemokine gradients to sites of inflammation, infection, tumors, or tissue damage. This study investigates the impact of acute high-intensity interval training (HIIT) on [...] Read more.

Physically active individuals demonstrate enhanced immune competence. Efficient execution of effector function relies on chemokine receptor-regulated immune cell trafficking along chemokine gradients to sites of inflammation, infection, tumors, or tissue damage. This study investigates the impact of acute high-intensity interval training (HIIT) on chemokine receptor expression in leukocytes. Sixteen healthy participants completed a single HIIT session, and peripheral blood was collected before exercise (Bsl), immediately after (Ex02), and one hour later (Ex60). Surface expression of selected chemokine receptors was measured using flow cytometry on CD4⁺ T cells, γδ T cells, NK cells, and monocytes, followed by FlowSOM clustering. NK cells, CD4⁺ T cells, and γδ T cells were strongly mobilized at Ex02 and returned to or below baseline at Ex60. HIIT preferentially mobilized CX3CR1⁺ CXCR2⁺ CD56^dim NK cells, CD4⁺ T cells expressing CX3CR1^hi and CCR5⁺, and CX3CR1⁺ CD56⁺ γδ T cells, indicating mobilization of immune cells phenotypically associated with migratory and cytotoxic potential. Proportions of intermediate and non-classical monocytes increased at Ex02 and decreased at Ex60. In conclusion, HIIT induced a rapid redistribution of leukocyte subsets with chemokine receptor profiles suggesting enhanced endothelial interaction and migratory capacity toward effector tissues. Full article

(This article belongs to the Special Issue Exercise Immunology: Molecular Mechanisms and Health Applications)

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18 pages, 6817 KB

Open AccessArticle

Structural and Biophysical Analyses of Human Prostamide/Prostaglandin F Synthase with Two Active Form-Mimicking Mutations

by Sang Won Cheon, Yen Thi Kim Nguyen, Jin Mo Kang, Youngbeom Yu, Yoonyoung Heo, Hyoun Sook Kim and Byung Woo Han

Biomolecules 2026, 16(2), 262; https://doi.org/10.3390/biom16020262 (registering DOI) - 7 Feb 2026

Abstract

Human prostamide/prostaglandin F synthase (PGFS) catalyzes the NADPH-dependent conversion of prostaglandin H₂ (PGH2) to prostaglandin F₂α that plays a key role in regulating intraocular pressure and labor. Despite its physiological importance, structural and biochemical information of the human PGFS has [...] Read more.

Human prostamide/prostaglandin F synthase (PGFS) catalyzes the NADPH-dependent conversion of prostaglandin H₂ (PGH2) to prostaglandin F₂α that plays a key role in regulating intraocular pressure and labor. Despite its physiological importance, structural and biochemical information of the human PGFS has been limited because of difficulties in obtaining sufficient quality of PGFS wild-type crystal and short half-life of PGH2. Here, we report the crystal structure of human PGFS with two active site mutations, C44S/C47S double mutant (DM), which mimics the reduced active form of the CXXC motif of human PGFS. Structural analysis revealed that PGFS DM adopts a typical thioredoxin (Trx)-like fold. Analysis of B-factors and MD simulations reveals that Tyr108–Asp124 is an intrinsically flexible region, devoid of any stabilizing crystal contacts. Unlike canonical Trx-like proteins, Pro167 in PGFS adopts a trans-conformation, inducing a specific Arg40 side chain localization that creates a positive charge near the CXXC motif. Activation of PGFS by reduction of disulfide bond in the CXXC motif enhanced the thermal stability via core stabilization, yet an unexpected increase in the structural disorder was detected with CD spectroscopy, especially upon ligand binding. These findings collectively establish PGFS as a structurally distinct and redox-regulated enzyme. Our results provide novel molecular insights into PGFS as an underexplored but promising therapeutic target. Full article

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

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11 pages, 503 KB

Open AccessArticle

Perioperative Inflammatory Cytokines in Parkinson’s Disease

by Jong-Woan Kim, Seung-ah Yoo, Yemi Choi, Gi Heon Jeong, Jaeseung Lee and Jin Joo

Biomolecules 2026, 16(2), 261; https://doi.org/10.3390/biom16020261 - 5 Feb 2026

Abstract

Background: Neuroinflammation is increasingly recognized as an important contributor to Parkinson’s disease (PD), yet perioperative immune responses in this population remain incompletely characterized. This study investigated perioperative cytokine dynamics in patients with PD compared with healthy controls (HCs) undergoing orthopedic surgery under [...] Read more.

Background: Neuroinflammation is increasingly recognized as an important contributor to Parkinson’s disease (PD), yet perioperative immune responses in this population remain incompletely characterized. This study investigated perioperative cytokine dynamics in patients with PD compared with healthy controls (HCs) undergoing orthopedic surgery under general anesthesia. Methods: In this prospective pilot observational study, 50 patients scheduled for lower limb orthopedic surgery were enrolled (25 PD patients, 25 HCs). Serum cytokines (IL-6, IL-8, VEGF, MCP-1, HMGB1, S100B, and PARK7) were measured immediately after anesthesia induction (PRE) and 24 h postoperatively (POST). Between-group comparisons were performed using independent t-tests, and within-group perioperative changes were assessed using paired t-tests. Absolute (Δ = POST − PRE) and relative perioperative changes were analyzed. Results: IL-6 increased significantly after surgery in both groups, with no significant differences in absolute or relative perioperative changes between the PD and HC group. IL-8 concentrations were numerically higher in PD patients at both time points, but perioperative changes did not differ significantly between groups. VEGF decreased modestly within the PD group, whereas no significant change was observed in HCs; however, between-group differences in perioperative VEGF changes were not significant. S100B and PARK7 increased postoperatively in HCs but not in PD patients, while MCP-1 and HMGB1 showed no significant perioperative changes. Conclusions: In this pilot study, perioperative cytokine responses in patients with PD were largely comparable to those in HCs. Despite evidence of chronic low-grade inflammation in the PD group, no disease-specific amplification of acute perioperative inflammatory responses was observed. These findings suggest that perioperative immune activation in PD may be selective rather than global. Full article

17 pages, 1681 KB

Open AccessArticle

Distinct Biomarker Patterns Reveal Metabolic–Inflammatory Profiles Across Mental Disorders

by Krissia F. Godoy, Joice M. A. Rodolpho, Jaqueline Bianchi, Bruna D. L. Fragelli, Fernanda O. Duarte, Luciana Camillo, Gustavo B. Silva, Juliana A. Prado, Carlos Speglich and Fernanda F. Anibal

Biomolecules 2026, 16(2), 260; https://doi.org/10.3390/biom16020260 - 5 Feb 2026

Abstract

Mental disorders, including anxiety, depression, and bipolar disorder, are frequently associated with metabolic, inflammatory, and behavioral alterations that modulate their clinical expression and increase the risk of physical comorbidities. This cross-sectional study aimed to characterize the profile of inflammatory, metabolic, and cardiac biomarkers [...] Read more.

Mental disorders, including anxiety, depression, and bipolar disorder, are frequently associated with metabolic, inflammatory, and behavioral alterations that modulate their clinical expression and increase the risk of physical comorbidities. This cross-sectional study aimed to characterize the profile of inflammatory, metabolic, and cardiac biomarkers in individuals with mental disorders compared to healthy controls, also considering anthropometric and lifestyle indicators. Fifty volunteers were evaluated and distributed into four groups: control, anxiety, depression, and bipolar disorder. All participants completed the Depression, Anxiety, and Stress Scale—21 items (DASS-21) and underwent blood collection for the assessment of inflammatory biomarkers such as C-Reactive Protein and its high-sensitivity detection (CRP/hs-CRP), Interleukins (IL-6, IL-1β) and Tumor Necrosis Factor alpha (TNF-α), metabolic biomarkers (vitamin D, cortisol, and D-dimer), and cardiac biomarkers such as N-terminal pro-B-type Natriuretic Peptide (NT-proBNP), Creatine Kinase—MB (CK-MB), troponin I (cTnI), and myoglobin (Myo). The results showed a significantly higher body mass index (BMI) in clinical groups, particularly in groups with anxiety and depression. Biomarker analyses revealed significant differences in groups with mental disorders. Elevated levels of CRP (p = 0.0038), hs-CRP (p = 0.0048), and IL-6 (p = 0.0030) were identified in the anxiety group, while the depression group was characterized by reduced vitamin D levels (p = 0.0302). Individuals with bipolar disorder presented significantly higher levels of CK-MB (p = 0.0016), CRP (p < 0.0001), IL-6 (p = 0.0198), and IL-1β (p = 0.0067). It was also observed that most individuals with mental disorders did not engage in physical activity. This inactivity was associated with worse emotional scores, higher systemic inflammation, and vitamin D deficiency. These findings reinforce the existence of an integrated axis between metabolism, inflammation, and behavior, in which excess weight, sedentary lifestyle, and nutritional deficiencies synergistically contribute to the maintenance of psychiatric symptoms and metabolic vulnerability. Integrating biomarkers, BMI, and behavioral factors may aid in identifying clinical subphenotypes and guiding more precise and individualized therapeutic strategies. Full article

(This article belongs to the Section Molecular Biomarkers)

12 pages, 1144 KB

Open AccessArticle

Distinct Domains Contribute to the Subcellular Localization of Human cGAS in Yeast

by Sara López-Montesino, Julia María Coronas-Serna, Humberto Martín, María Molina and Víctor J. Cid

Biomolecules 2026, 16(2), 259; https://doi.org/10.3390/biom16020259 - 5 Feb 2026

Abstract

Cyclic GMP-AMP synthase (cGAS) functions as a DNA sensor in the cytoplasm, triggering immune responses, but it is also translocated to the nucleus, where it is kept catalytically inactive. It consists of an unstructured N-terminal domain of around 160 amino acids, and a [...] Read more.

Cyclic GMP-AMP synthase (cGAS) functions as a DNA sensor in the cytoplasm, triggering immune responses, but it is also translocated to the nucleus, where it is kept catalytically inactive. It consists of an unstructured N-terminal domain of around 160 amino acids, and a larger C-terminal fold comprising the catalytic and DNA-binding domains. Subcellular localization of cGAS is thought to play a key role in its regulation. Here, we make use of heterologous expression in the eukaryotic model Saccharomyces cerevisiae to study cGAS localization in a neutral cellular environment. cGAS-eGFP was mostly found in aggregates at the endoplasmic reticulum–mitochondria encounter structure (ERMES) and juxtanuclear protein quality compartments (JUNQs), although some cells displayed an association between cGAS-eGFP and the plasma membrane. The N-terminus of cGAS fused to eGFP was unable to associate with the plasma membrane by itself, but its deletion dramatically promoted nuclear localization of cGAS-eGFP and decreased cytoplasmic aggregates. A mutant in the DNA-binding Zn-thumb motif of cGAS also showed a more prominent nuclear localization. Thus, both the N-terminal and C-terminal domains of cGAS seem to cooperate to prevent nuclear localization and to maintain cytoplasmic reservoirs of the protein. Heterologous cGAS expression in yeast is a valuable tool for modeling aspects of its subcellular localization and aggregative features. Full article

(This article belongs to the Section Cellular Biochemistry)

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34 pages, 970 KB

Open AccessSystematic Review

Sexually Dimorphic Neuroimmune Pathways in Chronic Pain: A Comprehensive Systematic Review of Cellular and Molecular Mechanisms

by Nebojsa Brezic, Strahinja Gligorevic, Aleksandar Sič, Vasilis-Spyridon Tseriotis and Nebojsa Nick Knezevic

Biomolecules 2026, 16(2), 258; https://doi.org/10.3390/biom16020258 - 5 Feb 2026

Abstract

Chronic pain is a highly prevalent and disabling condition with a well-documented female predominance in incidence, severity and persistence. These sex differences are driven by sexually dimorphic neuroimmune mechanisms rather than psychosocial factors alone. This systematic review was conducted to comprehensively synthesize human [...] Read more.

Chronic pain is a highly prevalent and disabling condition with a well-documented female predominance in incidence, severity and persistence. These sex differences are driven by sexually dimorphic neuroimmune mechanisms rather than psychosocial factors alone. This systematic review was conducted to comprehensively synthesize human clinical and translational evidence on sex-specific neuroimmune and glial cell pathways underlying chronic pain. Scientific literature was systematically searched from database inception to December 2025 across multiple biomedical databases to identify relevant clinical and translational studies. Across pain conditions, convergent evidence demonstrated that chronic pain mechanisms diverge by sex at cellular and molecular levels. Male-predominant pathways were characterized by microglial activation, particularly P2X4 receptor–mediated signaling and brain-derived neurotrophic factor–dependent neuronal disinhibition, supported by neuroimaging, transcriptomic, and pharmacological data. In contrast, female-predominant mechanisms involved adaptive immune processes, including CD4⁺ and CD8⁺ T cell infiltration, pannexin-1–dependent leptin release, chemokine signaling, and astrocyte-mediated neuroimmune crosstalk. Sex-specific cytokine and chemokine profiles, differential glial activation patterns, and divergent neuroimmune–endocrine interactions further distinguished pain pathways between males and females. Despite consistent mechanistic trends, substantial heterogeneity within each sex, limited sex-stratified power in many studies, and variability in outcome measures constrained quantitative synthesis and generalizability. The findings indicate that chronic pain is not a unitary disorder but rather a collection of mechanistically distinct conditions shaped by biological sex. These results highlight the limitations of sex-neutral therapeutic strategies and support the development of precision medicine approaches incorporating sex-informed neuroimmune biomarkers and mechanism-matched interventions. Future studies should prioritize adequately powered sex-stratified analyses, integration of neuroimmune biomarkers and clinical trial designs capable of detecting sex-by-treatment interactions. Full article

(This article belongs to the Special Issue Endocrine, Immune and Molecular Biomarkers in Pain and Psychosomatic Disorders: Bridging Mechanisms and Medical Application)

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33 pages, 4149 KB

Open AccessReview

OGG1 and MUTYH DNA Glycosylases, the Dynamic Duo Against 8-Oxoguanine DNA Lesion: Structure, Regulation, and Novel Emerging Roles

by Ana P. Gómez-Ramírez, Melody Malek, Estela G. García-González, Sergio E. Campos, Luis G. Brieba, Sheila S. David and Carlos H. Trasviña-Arenas

Biomolecules 2026, 16(2), 257; https://doi.org/10.3390/biom16020257 - 5 Feb 2026

Abstract

OGG1 and MUTYH are base excision repair (BER) DNA glycosylases (DGs) from the Helix–hairpin–Helix superfamily responsible for initiating and coordinating the repair of 8-oxo-7,8-dihydroguanine (OG), and its replication-derived mispair with adenine (OG:A), respectively. The DNA repair activities of these DGs are pivotal to [...] Read more.

OGG1 and MUTYH are base excision repair (BER) DNA glycosylases (DGs) from the Helix–hairpin–Helix superfamily responsible for initiating and coordinating the repair of 8-oxo-7,8-dihydroguanine (OG), and its replication-derived mispair with adenine (OG:A), respectively. The DNA repair activities of these DGs are pivotal to safeguarding nuclear and mitochondrial genomes. Indeed, DG functional impairment is associated with numerous pathologies, including neurodegenerative diseases, metabolic syndromes, and cancer. The timely and precise localization and processing of oxidized nucleobases carried out by these DGs are modulated by a complex regulatory network at both transcriptional and posttranslational levels, as well as intricate protein–protein interaction networks. In the absence of regulation, inappropriate and imbalanced DG activity may trigger telomeric instability, changes in transcriptional profiles and cell death. This review focuses on summarizing key features of OGG1 and MUTYH function, with a special emphasis on structure, regulation, and novel emerging roles. Full article

(This article belongs to the Special Issue Molecular Mechanisms in DNA and RNA Damage and Repair)

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18 pages, 1420 KB

Open AccessReview

Nasopharyngeal Carcinoma at the Virology Precision Oncology Nexus: Decoding Molecular Alterations for Early Intervention and Therapeutic Innovation

by Na Liu, Bin Meng, Yueshuo Li, Min Tang, Ya Cao, Li Shang and Feng Shi

Biomolecules 2026, 16(2), 256; https://doi.org/10.3390/biom16020256 - 5 Feb 2026

Abstract

Nasopharyngeal carcinoma (NPC) represents an Epstein–Barr virus (EBV)-associated malignancy showing elevated incidence in East and Southeast Asia. Early detection remains vital, as molecular abnormalities precede visible histological changes during tumor development. This review summarizes recent progress in decoding NPC’s molecular profile, including genetic [...] Read more.

Nasopharyngeal carcinoma (NPC) represents an Epstein–Barr virus (EBV)-associated malignancy showing elevated incidence in East and Southeast Asia. Early detection remains vital, as molecular abnormalities precede visible histological changes during tumor development. This review summarizes recent progress in decoding NPC’s molecular profile, including genetic mutations, epigenetic alterations, non-coding RNA networks and proteomic alterations. Importantly, these molecular discoveries are increasingly informing clinical approaches to disease management. Modern diagnostic integration of histopathology, EBV biomarkers and advanced imaging has improved detection, yet locoregional recurrence and distant metastasis remain major causes of mortality. Immunotherapy shows promising efficacy in recurrent/metastatic NPC, underscoring the potential of molecular insights to guide therapeutic innovation. Full article

(This article belongs to the Special Issue Tumor Biomarkers and Precision Therapy: Epigenetic, Immune, and Proteomic Strategies)

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20 pages, 3442 KB

Open AccessArticle

Opposing Roles for ATP13A2 and ATP13A3 in Breast Cancer Subtype-Specific Polyamine Homeostasis

by Emily Meeus, Jan Eggermont, Sarah van Veen and Peter Vangheluwe

Biomolecules 2026, 16(2), 255; https://doi.org/10.3390/biom16020255 - 5 Feb 2026

Abstract

Polyamine homeostasis is essential for normal cellular function and is maintained through coordinated regulation of polyamine biosynthesis, catabolism, and transport. This balance is frequently disrupted in breast cancer, a biologically heterogeneous disease comprising distinct molecular subtypes. However, whether polyamine metabolism and transport are [...] Read more.

Polyamine homeostasis is essential for normal cellular function and is maintained through coordinated regulation of polyamine biosynthesis, catabolism, and transport. This balance is frequently disrupted in breast cancer, a biologically heterogeneous disease comprising distinct molecular subtypes. However, whether polyamine metabolism and transport are differentially regulated across breast cancer subtypes remains poorly defined. Here, we systematically interrogate polyamine homeostasis across representative breast cancer subtypes by integrating cell line profiling combined with analysis of publicly available patient datasets. We found subtype-associated differences across the polyamine pathway and identify polyamine transport as a key contributor to inter- and intra-subtype heterogeneity. Notably, ATP13A3 emerges as a previously unrecognized adverse prognostic marker, particularly in basal-like breast cancer, where its expression associates with proliferative and oncogenic signaling programs. In contrast, ATP13A2 shows an opposing association with patient survival, suggesting divergent functional roles for these closely related transporters. Together, our findings demonstrate that polyamine regulation in breast cancer is highly subtype dependent and highlight the importance of molecular stratification when considering polyamine-directed therapeutic strategies in breast cancer. Full article

(This article belongs to the Special Issue Emerging Insights into the Role of Polyamines in Cellular Metabolism and Function)

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21 pages, 995 KB

Open AccessReview

The Gut Microbiota–Mast Cell Axis in Intestinal Homeostasis and Food Allergy Pathogenesis

by Alessia Carnevale, Caterina Marangio, Erisa Putro, Rosa Molfetta and Rossella Paolini

Biomolecules 2026, 16(2), 254; https://doi.org/10.3390/biom16020254 - 5 Feb 2026

Abstract

Food allergy is an increasing global health burden, particularly in industrialized countries, with rising prevalence in both pediatric and adult populations. It is characterized by exaggerated immune responses to innocuous dietary antigens, leading to clinical manifestations ranging from mild gastrointestinal symptoms to life-threatening [...] Read more.

Food allergy is an increasing global health burden, particularly in industrialized countries, with rising prevalence in both pediatric and adult populations. It is characterized by exaggerated immune responses to innocuous dietary antigens, leading to clinical manifestations ranging from mild gastrointestinal symptoms to life-threatening anaphylaxis. Mast cells are central effectors in the pathophysiology of food allergy, initiating and amplifying allergic inflammation through the release of a broad array of mediators upon activation. Recent studies have revealed that the intestinal microbiota plays a critical role in shaping immune responses, including the regulation of mast cell development, maturation, and activation. Moreover, dysbiosis has been associated with increased susceptibility to allergic sensitization and heightened mast cell reactivity. This review explores the molecular mechanisms underlying the microbiota–mast cell axis in the context of intestinal homeostasis and food allergy with a particular emphasis on the regulation of mast cell effector functions by TLR signaling and microbial metabolites. We also discuss the therapeutic potential of targeting the microbiota–mast cell axis as novel strategies to restore immune tolerance. Understanding this complex crosstalk opens new avenues for translational approaches in the prevention and treatment of food allergy. Full article

(This article belongs to the Special Issue Molecular Basis of Mast Cells Activation and Medical Implications)

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18 pages, 6073 KB

Open AccessArticle

Absence of Neuromuscular Dysfunction in Mice with Gut Epithelium-Restricted Expression of ALS Mutation hSOD1^G93A

by Li Dong, Xuejun Li, Ang Li, Jianxun Yi, Yanan Vockery, Yan Chang, Zui Pan, Marco Brotto and Jingsong Zhou

Biomolecules 2026, 16(2), 253; https://doi.org/10.3390/biom16020253 - 5 Feb 2026

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a devastating neuromuscular disorder characterized by the progressive loss of motor neurons and skeletal muscle, ultimately leading to respiratory failure and death, typically within 3–5 years following diagnosis. While the death of motor neurons is the pathological hallmark, [...] Read more.

Amyotrophic Lateral Sclerosis (ALS) is a devastating neuromuscular disorder characterized by the progressive loss of motor neurons and skeletal muscle, ultimately leading to respiratory failure and death, typically within 3–5 years following diagnosis. While the death of motor neurons is the pathological hallmark, ALS is increasingly recognized as a systemic disorder involving non-motor systems. Gastrointestinal dysfunction has been widely observed in both ALS patients and animal models. However, because gut abnormalities and neuromuscular degeneration are intertwined during ALS disease progression, it remains unclear whether these gut abnormalities are merely a consequence of neuromuscular degeneration or whether they play a crucial role in initiating it. In this study, we investigated whether an ALS-associated mutation expressed exclusively in the gut can directly affect neuromuscular function. We generated a novel transgenic mouse model, Gut-hG93A, which overexpresses the human ALS mutation hSOD1^G93A specifically in the epithelial cells of the intestine at a level comparable to the endogenous mouse SOD1. We found that the specific overexpression of hSOD1^G93A in gut epithelial cells did not cause abnormalities in the structure of the tight junctions or in gut permeability. Furthermore, there were no significant differences between Gut-hG93A and control mice regarding lifespan, body weight, or neuromuscular activities, including grip strength, daily travel distance and in vivo muscle contractility. These findings suggest that the ALS-associated hSOD1^G93A mutation, when expressed solely in the gut epithelium, is not sufficient to initiate neuromuscular degeneration of systemic ALS-like pathology. Full article

(This article belongs to the Special Issue Exploring Novel Molecular Pathways and Emerging Treatments for Neuromuscular Disorders)

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28 pages, 6765 KB

Open AccessArticle

Elucidating the Mechanisms of SA–4–1BBL-Mediated Cancer Immunoprevention Through Advanced Informatics Approaches

by Mohit Verma, Feyza Nur Arguc, Mohammad T. Malik, Pallav Singh, Sameep Dhakal, Yen On Chan, Manish Sridhar Immadi, Sabin Dahal, Vahap Ulker, Mohammad Tarique, Lalit Batra, Esma S. Yolcu, Haval Shirwan and Trupti Joshi

Biomolecules 2026, 16(2), 252; https://doi.org/10.3390/biom16020252 - 4 Feb 2026

Abstract

Cancer immunoprevention leverages the immune system’s surveillance mechanisms to mitigate tumor development. Vaccines that constitute a tumor antigen and an immune adjuvant are perceived as immunoprevention modalities. However, relevant tumor antigens are unknown for non-viral cancers, which constitute most human cancers. Our group [...] Read more.

Cancer immunoprevention leverages the immune system’s surveillance mechanisms to mitigate tumor development. Vaccines that constitute a tumor antigen and an immune adjuvant are perceived as immunoprevention modalities. However, relevant tumor antigens are unknown for non-viral cancers, which constitute most human cancers. Our group has recently shown that SA–4–1BBL, a novel agonist of CD137 receptor, but not antibodies, shows immunoprevention efficacy against various tumors. Advanced bioinformatics analyses of bulk RNA-seq data were conducted to elucidate mechanisms underlying cancer immunoprevention. Mice received subcutaneous injections of SA–4–1BBL or agonistic 3H3 antibody, and the injection-site tissue (IS) and draining lymph nodes (LN) were analyzed for differential gene expression. SA–4–1BBL induced a compartmentalized and temporally dynamic immune program characterized by early effector activation at IS and sustained immune regulation in draining LN. K-means clustering of 4564 DEGs identified eight functionally distinct clusters. IS-enriched clusters contained activation genes for CD4⁺ T and NK cells, including Cd28, Klra1, Cd4, Cd40, and Cd40l, while LN clusters were enriched for regulatory genes (Tnfaip3, Irf5, Col1a2) that ensure immune priming and homeostatic restraint for a balanced response. SA–4–1BBL generated a more selective and durable activation of adaptive immunity, TCR signaling, Th1/Th2 differentiation, and NK cytotoxicity. 3H3 activated broader innate inflammatory programs, including Toll-like receptor and neurodegeneration-linked pathways. IMPRes analysis showed that SA–4–1BBL activates sequential immune-regulatory circuits centered on Stat1, Cd247, and Ifng and modulates the CD151–TGF-β axis. These findings demonstrate that SA–4–1BBL elicits a balanced immune response, ensuring both safety and efficacy in preventing cancer development. Full article

(This article belongs to the Collection Feature Papers in Bioinformatics and Systems Biology Section)

18 pages, 739 KB

Open AccessReview

Metabolic Drivers of Valve Calcification and Atrial Remodeling in Calcific Aortic Stenosis

by Simina Mariana Moroz, Alina Gabriela Negru, Silvia Luca, Mihaela Valcovici, Mirela Baba, Alina Maria Lupu, Ana Lascu, Daniel Florin Lighezan and Ioana Mozos

Biomolecules 2026, 16(2), 251; https://doi.org/10.3390/biom16020251 - 4 Feb 2026

Abstract

AS, one of the most common forms of valvular heart disease, requiring intervention in aging populations in Europe and North America, has traditionally been viewed as a passive, degenerative condition. However, growing evidence supports a paradigm shift toward recognizing AS as an active [...] Read more.

AS, one of the most common forms of valvular heart disease, requiring intervention in aging populations in Europe and North America, has traditionally been viewed as a passive, degenerative condition. However, growing evidence supports a paradigm shift toward recognizing AS as an active metabolic and inflammatory disorder. This narrative review synthesizes experimental, translational, and clinical evidence published between 2015 and 2025 examining metabolic mechanisms linking valvular calcification and atrial remodeling in AS and discusses their clinical relevance in the context of transcatheter aortic valve replacement (TAVR). We discussed classical pathways involving mineral metabolism and vitamin signaling, alongside emerging roles of lipid oxidation, mitochondrial dysfunction, epigenetic regulation, and gut microbiome-derived metabolites. Further, metabolomic signatures associated with disease severity and post-TAVR outcomes were reviewed, highlighting the predominantly associative nature and current limitations of these data. Although valve replacement remains the only effective therapy for advanced AS, metabolic and multi-omics insights may improve future risk stratification and mechanistic understanding. Metabolomic profiling could be integrated at multiple points in the clinical pathway for aortic stenosis and TAVR—most promisingly for pre-procedural risk stratification. The present paper focuses on an integrative framework in which valvular calcification and atrial remodeling are viewed within a broader context of metabolic dysregulation. Future research should aim to translate molecular biomarkers into real-world diagnostics and targeted interventions. Full article

(This article belongs to the Special Issue New Insights into Mechanisms and Therapeutics for Cardiovascular Disorders: 2nd Edition)

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20 pages, 3988 KB

Open AccessArticle

Transcriptome Analysis of the Brain and Gnathal Ganglion Reveals Feeding-Mediated Genes in Helicoverpa armigera Larvae

by Longlong Sun, Rongmei Lin, Shuting Chen, Guiying Xie, Xincheng Zhao, Wenbo Chen and Qingbo Tang

Biomolecules 2026, 16(2), 250; https://doi.org/10.3390/biom16020250 - 4 Feb 2026

Abstract

Despite the central role of the gustatory nervous system in regulating feeding behavior in the larvae of the major agricultural pest Helicoverpa armigera, the systemic molecular basis of this process is largely unknown. To investigate the molecular basis, we performed RNA-seq on [...] Read more.

Despite the central role of the gustatory nervous system in regulating feeding behavior in the larvae of the major agricultural pest Helicoverpa armigera, the systemic molecular basis of this process is largely unknown. To investigate the molecular basis, we performed RNA-seq on dissected brains and gnathal ganglion (GNG) from fifth-instar larvae, revealing 944 differentially expressed genes (DEGs) that are potentially involved in feeding behaviors. Bioinformatic analyses revealed significant enrichment of these DEGs in pathways including “taste transduction”, “neuroactive ligand–receptor interaction”, and “feeding behavior”. Furthermore, 41 candidate genes closely associated with feeding behaviors were screened, including neuropeptides, neuropeptide receptors, gustatory receptors, and feeding-mediated proteins. Phylogenetic analyses demonstrated that these key genes are evolutionarily conserved. Quantitative real-time PCR (qPCR) results confirmed that most of these candidate genes were significantly upregulated during the fifth instar stage, and their expression was further enhanced under starvation conditions (p < 0.05). Our study presents the first systemic feeding-mediated transcriptomic profile in the insect central nervous system and identifies key feeding-mediated genes in H. armigera larvae. These findings advance our understanding of the molecular basis of feeding in Lepidopteran pests and offer potential target genes for developing gustatory-based pest control strategies. Full article

(This article belongs to the Section Molecular Biology)

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15 pages, 10421 KB

Open AccessArticle

Distinct Modulation of Helicobacter pylori HtrA Activity by Divalent Transition Metals, Impacting HtrA Stability, Oligomerization and E-Cadherin Shedding

by Sebastian Diechler, Sabine Bernegger, Gernot Posselt, Hans Brandstetter and Silja Wessler

Biomolecules 2026, 16(2), 249; https://doi.org/10.3390/biom16020249 - 4 Feb 2026

Abstract

The Group-1 carcinogen Helicobacter pylori (H. pylori) secretes the serine protease high-temperature requirement A (HtrA), which is directly involved in the disruption of the epithelial barrier in the stomach. HtrA cleaves the extracellular domains of junctional proteins, including E-cadherin (CDH1), claudin-8, [...] Read more.

The Group-1 carcinogen Helicobacter pylori (H. pylori) secretes the serine protease high-temperature requirement A (HtrA), which is directly involved in the disruption of the epithelial barrier in the stomach. HtrA cleaves the extracellular domains of junctional proteins, including E-cadherin (CDH1), claudin-8, occludin, or desmoglein-2, to open intercellular adhesions, allowing H. pylori to transmigrate to subepithelial regions of the gastric mucosa. In our previous work, we found that Zn²⁺ and Cu²⁺ ions efficiently blocked the HtrA activity. However, the impact of other divalent ions on HtrA activity is rather unknown. In this report, we unexpectedly found a stimulating effect through Mn²⁺, Ni²⁺ and Co²⁺ ions on HtrA oligomerization and activity. In contrast to other tested ions, increasing concentrations of Mn²⁺, Ni²⁺ and Co²⁺ strongly enhanced HtrA multimerization as determined in SDS-PAGE under non-reducing conditions and in casein zymography. Increased proteolytic activity of HtrA was further assessed in in vitro cleavage experiments using casein and CDH1 as substrates. Mechanistically, divalent ions bound to HtrA and induced an active conformation, which strongly increased CDH1 cleavage in vitro. The importance of enhanced HtrA activity was finally underlined by the analysis of CDH1 cleavage in H. pylori infection experiments, showing that Ni²⁺ potentiated HtrA-mediated CDH1 shedding. In summary, this study demonstrates that divalent ions exhibit different effects on HtrA activity and that Ni²⁺ and Co²⁺ enhance proteolytic activity by promoting oligomerization, suggesting that metal availability in the gastric environment affects H. pylori virulence. Full article

(This article belongs to the Section Biological Factors)

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23 pages, 4671 KB

Open AccessArticle

Impaired TGFβ Signaling in Plaque-Associated Microglia

by Oliver Krzyzan, Angela Kuhla, Björn Spittau and Natascha Vidovic

Biomolecules 2026, 16(2), 248; https://doi.org/10.3390/biom16020248 - 4 Feb 2026

Abstract

Aging and Alzheimer’s disease (AD) are associated with profound changes in glial cell morphology and signaling. This study investigates the three-dimensional morphology of microglia and the intracellular localization of phosphorylated SMAD proteins as downstream effectors of transforming growth factor β (TGF-β) signaling in [...] Read more.

Aging and Alzheimer’s disease (AD) are associated with profound changes in glial cell morphology and signaling. This study investigates the three-dimensional morphology of microglia and the intracellular localization of phosphorylated SMAD proteins as downstream effectors of transforming growth factor β (TGF-β) signaling in the amyloid precursor protein and presenilin-1 (APP/PS1) transgenic mouse model of Alzheimer’s disease. Using confocal microscopy and Simple Neurite Tracer software, we reconstructed and quantitatively analyzed glial cell morphology in aged wild-type and APP/PS1 mice. Immunofluorescence staining revealed altered pSMAD2 distribution in microglia, suggesting impaired canonical TGF-β signaling. Our findings indicate a disturbed glial morphology and dysfunctional TGF-β signaling cascade in the APP/PS1 model, underlining their potential role in Alzheimer’s disease pathogenesis. Full article

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32 pages, 1468 KB

Open AccessReview

The Landscape of SERCA2 in Cardiovascular Diseases: Expression Regulation, Therapeutic Applications, and Emerging Roles

by Jianmin Wu, Mengting Liao, Tengkun Dai, Guiyan Liu, Jiayi Zhang, Yiling Zhu, Lin Xu and Juanjuan Zhao

Biomolecules 2026, 16(2), 247; https://doi.org/10.3390/biom16020247 - 4 Feb 2026

Abstract

Driven by rapid socioeconomic progress and changing lifestyles, the global burden of cardiovascular diseases (CVDs) continues to escalate, with surging morbidity and mortality rates imposing a severe threat to public health. Clinical treatments are focused on the alleviation of treatments, highlighting the need [...] Read more.

Driven by rapid socioeconomic progress and changing lifestyles, the global burden of cardiovascular diseases (CVDs) continues to escalate, with surging morbidity and mortality rates imposing a severe threat to public health. Clinical treatments are focused on the alleviation of treatments, highlighting the need for a deeper understanding of CVDs pathogenesis and the development of targeted therapies. Recent studies have identified imbalances in intracellular Ca²⁺ homeostasis as a key pathological mechanism in the progression of CVDs. Notably, sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase 2 (SERCA2), a membrane protein encoded by the ATP2A2 gene and ranging from 97 to 115 kDa in molecular weight, plays a pivotal role in regulating intracellular Ca²⁺ levels. Extensive evidence links abnormal SERCA2 function to various CVDs, including heart failure, cardiac hypertrophy, atherosclerosis, and diabetic cardiomyopathy. This review systematically explores the regulatory mechanisms of SERCA2 expression and its functional regulation—including transcriptional regulation, post-translational modifications, and protein–protein interactions—and further investigates its pathological roles in cardiovascular diseases as well as its potential as a therapeutic target. By synthesizing current knowledge, this article aims to provide new insights for future basic research and establish a theoretical foundation for clinical applications. Full article

(This article belongs to the Special Issue Advances in Membrane Proteins: From Structure to Function and Molecular Engineering)

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28 pages, 2042 KB

Open AccessReview

Advances in Next-Generation Immunotherapies for Ovarian Cancer: Mechanisms of Immune Evasion and Novel Therapeutic Targets

by Md Ataur Rahman, Maroua Jalouli, Mohammed Al-Zharani and Abdel Halim Harrath

Biomolecules 2026, 16(2), 246; https://doi.org/10.3390/biom16020246 - 4 Feb 2026

Abstract

Ovarian cancer (OC) is a particularly lethal gynecological malignancy with few treatment options due to its late-stage diagnosis, extensive genetic heterogeneity, and frequent development of resistance to existing therapies. Immunotherapy has revolutionized the management and clinical outcome of numerous solid tumors, but its [...] Read more.

Ovarian cancer (OC) is a particularly lethal gynecological malignancy with few treatment options due to its late-stage diagnosis, extensive genetic heterogeneity, and frequent development of resistance to existing therapies. Immunotherapy has revolutionized the management and clinical outcome of numerous solid tumors, but its clinical benefit for OC has been limited, in part due to an extremely immunosuppressive tumor microenvironment (TME) and diverse, overlapping immune evasion mechanisms. In this review, we present a comprehensive and timely synthesis of next-generation immunotherapeutic approaches for ovarian cancer, emphasizing strategies that overcome the immunosuppressive tumor microenvironment and improve clinical responsiveness. We describe the emerging molecular mechanisms of immune evasion in OC, including altered antigen presentation, inhibition of T-cell activation (e.g., via immunological checkpoints, metabolic reprogramming), polarization of tumor-associated macrophages (TAMs), and dysfunction of natural killer (NK) cells. We also critically examine several emerging therapeutic approaches, including combination immune checkpoint blockade (ICB), bispecific T-cell engagers (BiTEs), neoantigen-based vaccines, chimeric antigen receptor (CAR)-T- and CAR-NK-cell therapies, oncolytic viruses (OVs), and nanoparticle-mediated immunomodulation. In addition, we highlight recent advances in tumor microenvironment–targeted therapies for ovarian cancer, focusing on strategies that modulate non-lymphoid components such as cancer-associated fibroblasts (CAFs), hypoxia-driven signaling, and the PI3K/AKT/mTOR axis to enhance antitumor immune responsiveness. Finally, we discuss how predictive biomarkers, multi-omics systems, and patient-derived organoid models are accelerating the development and deployment of precision immunotherapies for OC. We would like to highlight the translational promise of next-generation immunotherapies and identify novel molecular targets that may be leveraged to achieve durable responses in OC. Full article

(This article belongs to the Special Issue Ovarian Cancer and Breast Cancer: Molecular Mechanisms, and Therapeutic Targets)

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