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Biomolecules
Volume 16
Issue 1
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Biomolecules, Volume 16, Issue 1 (January 2026) – 179 articles

Cover Story (view full-size image): Gal-10 is considered an effective biomarker of eosinophilic and type-2 inflammation and a potential therapeutic target. However, the extracellular crystallization of this protein and its role in the progression of nasal inflammation and mucosa remodeling are not fully understood. The aim of the present study was to evaluate the potential role of Gal-10 in driving nasal mucosa inflammation, epithelial dysfunction, and remodeling in patients with seasonal allergic rhinitis (SAR). Our results indicate that Gal-10 is associated with Th2-type inflammation, mucus overproduction, and epithelial–mesenchymal transition (EMT)-related signaling in the nasal mucosa of children with SAR, potentially predisposing them to structural airway dysfunction and progression of respiratory diseases. View this paper
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17 pages, 2232 KB  
Review
Novel Insights into TSC22D Family Genes in Metabolic Diseases and Cancer
by Wen Shen, Cong Shen, Yang Jiao, Xia Deng, Jue Jia and Guoyue Yuan
Biomolecules 2026, 16(1), 179; https://doi.org/10.3390/biom16010179 - 22 Jan 2026
Viewed by 203
Abstract
Transforming growth factor-beta 1 (TGF-β1)-stimulated clone 22 domain (TSC22D) family genes (including TSC22D1-TSC22D4) were identified as transcription factors. It has been demonstrated that they display multiple functions due to proteins’ isoforms, redundancy, and other factors. Formerly, researchers mainly focused on its functions, [...] Read more.
Transforming growth factor-beta 1 (TGF-β1)-stimulated clone 22 domain (TSC22D) family genes (including TSC22D1-TSC22D4) were identified as transcription factors. It has been demonstrated that they display multiple functions due to proteins’ isoforms, redundancy, and other factors. Formerly, researchers mainly focused on its functions, like controlling cell growth and development, cell apoptosis, and balance of osmotic pressure in vivo. Nowadays, growing evidence indicates that they also play an important role in metabolic regulation and the immune system and are expected to be a new potential target for the treatment of diabetes or obesity. Despite this, it has been shown that TSC22D family genes have an inhibitory effect in multiple tumors. In this review, we significantly synthesized advances in metabolism, showing that TSC22D3 could control lipid accumulation via modulating adipogenesis and adipose differentiation, while TSC22D4 could regulate insulin sensitivity and gluconeogenesis by affecting Akt (serine/threonine kinase, also known as protein kinase B, or PKB) phosphorylation. Moreover, we provide novel insights, including the fact that TSC22D family genes function as a double-edged sword in cancer due to the type of tumor and tumor microenvironment (TME). Full article
(This article belongs to the Section Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates)
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16 pages, 5371 KB  
Article
2-Arylbenzofurans as Selective Cholinesterase Inhibitors: Design, Synthesis, and Evaluation as Alzheimer’s Disease Agents
by Giovanna Lucia Delogu, Michela Begala, Manuel Novás, Maria João Matos, Franca Piras, Sonia Floris, Francesca Pintus, Michele Mancinelli, Benedetta Era and Antonella Fais
Biomolecules 2026, 16(1), 178; https://doi.org/10.3390/biom16010178 - 22 Jan 2026
Viewed by 228
Abstract
New arylbenzofuran derivatives were designed, synthesized, and evaluated as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Five hybrid compounds (31–35) feature a 2-phenylbenzofuran core linked via a heptyloxy spacer to an N-methylbenzylamine moiety, to enhance interactions within [...] Read more.
New arylbenzofuran derivatives were designed, synthesized, and evaluated as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Five hybrid compounds (31–35) feature a 2-phenylbenzofuran core linked via a heptyloxy spacer to an N-methylbenzylamine moiety, to enhance interactions within the active site of BChE. Biological evaluation revealed that brominated derivatives 34 and 35 showed the highest cholinesterases (ChE) inhibition compared to their chlorinated analogs, with compound 34 showing the highest activity for both AChE (IC50 = 27.7 μM) and BChE (IC50 = 0.7 μM). These compounds proved to be non-cytotoxic and demonstrated significant antioxidant activity in SH-SY5Y cells exposed to hydrogen peroxide (H2O2), highlighting their potential to mitigate oxidative stress: a key pathological factor in Alzheimer’s disease. Structural activity analysis suggests that bromine substitution at position 7 and the presence of a seven-carbon linker are critical for dual ChE inhibition and selectivity towards BChE. ADMET prediction indicates favorable pharmacokinetic properties, including drug-likeness and oral bioavailability. Overall, these findings highlight the potential of the 2-arylbenzofuran as a promising scaffold for multitarget-directed ligands in Alzheimer’s disease therapy. Full article
(This article belongs to the Special Issue New Discoveries in the Field of Neuropharmacology)
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25 pages, 3041 KB  
Article
Biological Evaluation and SAR Exploration of Bile Acid–Dihydroartemisinin Hybrids as Potential Anticancer Agents for Colorectal Cancer
by Daniela Perrone, Elisabetta Melloni, Lorenzo Gnudi, Fabio Casciano, Elena Pozza, Francesca Bompan, Paola Secchiero, Elena Marchesi and Maria Luisa Navacchia
Biomolecules 2026, 16(1), 177; https://doi.org/10.3390/biom16010177 - 22 Jan 2026
Viewed by 223
Abstract
Dihydroartemisinin (DHA), a first-line treatment for uncomplicated malaria, has demonstrated antitumor activity against a variety of human cancers, emphasizing its potential for repurposing as an anticancer agent. However, its short half-life and poor bioavailability hinder its application in cancer therapy. We previously demonstrated [...] Read more.
Dihydroartemisinin (DHA), a first-line treatment for uncomplicated malaria, has demonstrated antitumor activity against a variety of human cancers, emphasizing its potential for repurposing as an anticancer agent. However, its short half-life and poor bioavailability hinder its application in cancer therapy. We previously demonstrated that the molecular hybridization of DHA with bile acids (BAs) enhances its anticancer activity by improving stability and reducing toxicity. Based on this rationale, here, we designed and synthesized a library of DHA-based hybrids through conjugation with ursodeoxycholic and chenodeoxycholic bile acids. Different conjugation sites and both cleavable and non-cleavable linkages were explored to enable a comprehensive structure–activity relationship analysis. The resulting BA-DHA hybrids were evaluated in vitro for their anticancer activity against HCT116 and RKO colorectal cancer cell lines. As a result of the synergistic effect of the linker type and conjugation site, the BA-DHA hybrids synthesized via click chemistry emerged as the most active compounds in both cell lines, displaying 2- to 20-fold higher activity than the parent DHA. Mechanistic investigations further revealed that the click-derived BA-DHA hybrids possess enhanced anticancer activity and antimetastatic potential, achieving comparable or even superior efficacy to the parent compound at markedly lower concentrations. Full article
(This article belongs to the Special Issue Molecular Advances in Drug Resistance and Novel Therapies for Cancer)
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20 pages, 2267 KB  
Article
Design and Physicochemical Characterization of Hybrid PLGA–Curcumin/Carbon Dot Nanoparticles for Sustained Galantamine Release: A Proof-of-Concept Study
by Christina Samiotaki, Stavroula Nanaki, Rizos Evangelos Bikiaris, Evi Christodoulou, George Z. Kyzas, Panagiotis Barmpalexis and Dimitrios N. Bikiaris
Biomolecules 2026, 16(1), 176; https://doi.org/10.3390/biom16010176 - 21 Jan 2026
Viewed by 238
Abstract
The present study reports the design and physicochemical characterization of a hybrid nanoparticle system for the potential intranasal delivery of galantamine (GAL), aimed at improving its bioavailability. Carbon dots (CDs) were used to load GAL, enhancing its dissolution and stability, and were subsequently [...] Read more.
The present study reports the design and physicochemical characterization of a hybrid nanoparticle system for the potential intranasal delivery of galantamine (GAL), aimed at improving its bioavailability. Carbon dots (CDs) were used to load GAL, enhancing its dissolution and stability, and were subsequently incorporated into a poly(lactic-co-glycolic acid)–curcumin (PLGA–Cur) conjugate matrix. The successful formation of the PLGA-Cur conjugate was verified via 1H-NMR and FTIR spectroscopy, while the loading of GAL and its physical state in the CDs was assessed via FTIR and pXRD, respectively. The resulting GAL-CD/PLGA–Cur nanoparticles were spherical, with particle sizes varying from 153.7 nm to 256.3 nm, a uniform morphology and a narrow size distribution. In vitro release studies demonstrated a multi-phase sustained release pattern extending up to 12 days. Spectroscopic and thermal analyses confirmed successful conjugation and molecular interactions between GAL and the carrier matrix. This proof-of-concept hybrid system demonstrates promising controlled, multi-phase sustained galantamine release in vitro, highlighting the role of curcumin conjugation in modulating polymer structure and release kinetics and providing a foundation for future biological evaluation. Full article
(This article belongs to the Section Bioinformatics and Systems Biology)
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19 pages, 3239 KB  
Article
Cyclic-FMN Is a Detectable, Putative Intermediate of FAD Metabolism
by Luxene Belfleur, Juha P. Kallio, Wito Richter, Natalie R. Gassman, Mathias Ziegler and Marie E. Migaud
Biomolecules 2026, 16(1), 175; https://doi.org/10.3390/biom16010175 - 21 Jan 2026
Viewed by 291
Abstract
Free flavin adenine dinucleotide (FAD) is metabolized to flavin mononucleotide (FMN) and adenine monophosphate (AMP) by hydrolases and to 4′,5′-cyclic phosphoriboflavin (cFMN) and AMP by the triose kinase FMN cyclase (TKFC). Yet, the lack of analytical standards for cFMN might have resulted in [...] Read more.
Free flavin adenine dinucleotide (FAD) is metabolized to flavin mononucleotide (FMN) and adenine monophosphate (AMP) by hydrolases and to 4′,5′-cyclic phosphoriboflavin (cFMN) and AMP by the triose kinase FMN cyclase (TKFC). Yet, the lack of analytical standards for cFMN might have resulted in the incidence of cFMN in biological specimens being underreported. To address this shortcoming, cFMN was synthesized from either FMN or FAD. The optimization of the FAD to cFMN reaction conditions revealed that an equimolar ratio of ZnSO4 and FAD yielded pure cFMN upon the precipitation of AMP-Zn salts. cFMN is stable to aqueous acidic and basic conditions and is readily extracted from biological samples for detection by liquid chromatography coupled with mass spectrometry. Although cFMN is hydrolyzed by liver tissue extracts to FMN and riboflavin, the mechanisms for this conversion remain elusive. Full article
(This article belongs to the Special Issue Feature Papers in the Natural and Bio-Derived Molecules Section)
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10 pages, 2219 KB  
Communication
Computing the Dissociation Constant from Molecular Dynamics Simulations with Corrections for the Large Pressure Fluctuations—Aquaglyceroporins Have High Affinity for Their Substrate Glycerol
by Md Mohsin, Hans R. Loja and Liao Y. Chen
Biomolecules 2026, 16(1), 174; https://doi.org/10.3390/biom16010174 - 21 Jan 2026
Viewed by 222
Abstract
In this paper, we consider the inevitable large fluctuations of pressure in typical molecular dynamics (MD) simulations of ligand–protein binding problems. In simulations under the constant pressure of one bar, the pressure artifactually fluctuates over the range of ±100 bars or more. [...] Read more.
In this paper, we consider the inevitable large fluctuations of pressure in typical molecular dynamics (MD) simulations of ligand–protein binding problems. In simulations under the constant pressure of one bar, the pressure artifactually fluctuates over the range of ±100 bars or more. This artifact can cause gross inaccuracy in the apparent binding affinity computed as the ratio of the probability for the ligand to be bound inside the protein and the probability for the ligand to be outside the protein. Based on statistical thermodynamics, we derive a correction factor for the ligand–protein binding affinity to compensate for the artifactual pressure fluctuations. The correction factor depends on the change in the system volume between the bound and the unbound states of the ligand. We conducted four sets of MD simulations for glycerol affinities with four aquaglyceroporins: AQP10, AQP3, AQP7, and GlpF. Without the correction factor, the apparent affinity of glycerol with each of these four aquaglyceroporins is computed directly from the simulations to be very low (~1/M). With the correction factor applied, glycerol’s affinity is computed to be 1/mM to 1/µM. In conclusion, glycerol has high affinity for its native facilitator aquaglyceroporins, which is in contrast to the current literature not correcting the artifactual consequences of the large pressure fluctuations in typical in silico experiments. Full article
(This article belongs to the Section Molecular Biophysics: Structure, Dynamics, and Function)
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45 pages, 4315 KB  
Review
A Comprehensive Review of Epigenetic Regulation of Vascular Smooth Muscle Cells During Development and Disease
by Lautaro Natali, Benjamín de la Cruz-Thea, Andrea Godino, Cecilia Conde, Victor I. Peinado and Melina M. Musri
Biomolecules 2026, 16(1), 173; https://doi.org/10.3390/biom16010173 - 21 Jan 2026
Viewed by 623
Abstract
Vascular smooth muscle cells (VSMCs) in the tunica media are essential for maintaining the structure and function of the arterial wall. These cells regulate vascular tone and contribute to vasculogenesis and angiogenesis, particularly during development. Proper control of VSMC differentiation ensures the correct [...] Read more.
Vascular smooth muscle cells (VSMCs) in the tunica media are essential for maintaining the structure and function of the arterial wall. These cells regulate vascular tone and contribute to vasculogenesis and angiogenesis, particularly during development. Proper control of VSMC differentiation ensures the correct size and patterning of vessels. Dysregulation of VSMC behaviour in adulthood, however, is linked to serious cardiovascular diseases, including aortic aneurysm, coronary artery disease, atherosclerosis and pulmonary hypertension. VSMCs are characterised by their phenotypic plasticity, which is the capacity to transition from a contractile to a synthetic, dedifferentiated state in response to environmental cues. This phenotypic switch plays a central role in vascular remodelling, a process that drives the progression of many vascular pathologies. Epigenetic mechanisms, which are defined as heritable but reversible changes in gene expression that do not involve alterations to the DNA sequence, have emerged as key regulators of VSMC identity and behaviour. These mechanisms include DNA methylation, histone modifications, chromatin remodelling, non-coding RNA and RNA modifications. Understanding how these epigenetic processes influence VSMC plasticity is crucial to uncovering the molecular basis of vascular development and disease. This review explores the current understanding of VSMC biology, focusing on epigenetic regulation in health and pathology. Full article
(This article belongs to the Special Issue Epigenetic Regulation of Vascular Smooth Muscle Cells During Development and Disease)
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13 pages, 926 KB  
Article
Dependency of Glucose Homeostasis on Pancreatic Enzymes with Special Reference to Amylase; Study on Healthy and Exocrine Pancreatic Insufficient Pigs
by Piotr Wychowański, Stefan G. Pierzynowski, Kamil Zaworski, Robert Gallotto, Dominika Szkopek, Jarosław Woliński, Janine Donaldson, Tomasz Jacek and Kateryna Pierzynowska
Biomolecules 2026, 16(1), 172; https://doi.org/10.3390/biom16010172 - 20 Jan 2026
Viewed by 328
Abstract
We aimed to highlight the roles of the pancreatic enzymes, with special reference to amylase, on glucose homeostasis in healthy pigs and in pigs with exocrine pancreatic insufficiency (EPI). Healthy pigs fed a high-fat diet (HFD) were subjected to mixed meal tolerance tests [...] Read more.
We aimed to highlight the roles of the pancreatic enzymes, with special reference to amylase, on glucose homeostasis in healthy pigs and in pigs with exocrine pancreatic insufficiency (EPI). Healthy pigs fed a high-fat diet (HFD) were subjected to mixed meal tolerance tests (MMTTs) and pancreatic enzyme treatments, and then blood glucose and insulin concentrations were determined. Following the development of surgically induced EPI, the same experiment was then repeated on the pigs. A significantly lower net postprandial glycemic response was observed in pigs with EPI compared to healthy pigs. Net postprandial glycemic response was not affected by enzyme supplementation during the MMTTs in healthy pigs, but it was affected by adaptation to macronutrient components of the MMTT test meal, both in healthy and EPI pigs. Net postprandial glycemic response and insulin release curves reached higher levels in Creon-treated EPI pigs compared to amylase-treated EPI pigs. In summary, glucose homeostasis mechanisms in EPI pigs were downregulated compared to healthy animals. Creon supplementation during EPI significantly increased postprandial glucose level, while amylase treatment had the opposite effect, which could be explained by its metabolic actions. Full article
(This article belongs to the Special Issue Digestive Enzymes in Health and Disease)
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38 pages, 3246 KB  
Review
Mitochondrial Ca2+ Signaling at the Tripartite Synapse: A Unifying Framework for Glutamate Homeostasis, Metabolic Coupling, and Network Vulnerability
by Mariagrazia Mancuso, Federico Mezzalira, Beatrice Vignoli and Elisa Greotti
Biomolecules 2026, 16(1), 171; https://doi.org/10.3390/biom16010171 - 20 Jan 2026
Viewed by 313
Abstract
Mitochondrial Ca2+ signaling is increasingly recognized as a key integrator of synaptic activity, metabolism, and redox balance within the tripartite synapse. At excitatory synapses, Ca2+ influx through ionotropic glutamate receptors and voltage-gated channels is sensed and transduced by strategically positioned mitochondria, [...] Read more.
Mitochondrial Ca2+ signaling is increasingly recognized as a key integrator of synaptic activity, metabolism, and redox balance within the tripartite synapse. At excitatory synapses, Ca2+ influx through ionotropic glutamate receptors and voltage-gated channels is sensed and transduced by strategically positioned mitochondria, whose Ca2+ uptake and release tune tricarboxylic acid cycle activity, adenosine triphosphate synthesis, and reactive oxygen species (ROS) generation. Through these Ca2+-dependent processes, mitochondria are proposed to help set the threshold at which glutamatergic activity supports synaptic plasticity and homeostasis or, instead, drives hyperexcitability and excitotoxic stress. Here, we synthesize how mitochondrial Ca2+ dynamics in presynaptic terminals, postsynaptic spines, and perisynaptic astrocytic processes regulate glutamate uptake, recycling, and release, and how subtle impairments in these pathways may prime synapses for failure well before overt energetic collapse. We further examine the reciprocal interplay between Ca2+-dependent metabolic adaptations and glutamate homeostasis, the crosstalk between mitochondrial Ca2+ and ROS signals, and the distinct vulnerabilities of neuronal and astrocytic mitochondria. Finally, we discuss how disruption of this Ca2+-centered mitochondria–glutamatergic axis contributes to synaptic dysfunction and circuit vulnerability in neurodegenerative diseases, with a particular focus on Alzheimer’s disease. Full article
(This article belongs to the Special Issue Neuron–Astrocyte Interactions in Neurological Function and Disease)
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19 pages, 1569 KB  
Review
Lactate Metabolism in the Intervertebral Disc: Mechanistic Insights and Pathological Implications
by Ting Zhang, Peng Feng, Peter G. Alexander, Joon Y. Lee, Gwendolyn A. Sowa and Nam V. Vo
Biomolecules 2026, 16(1), 170; https://doi.org/10.3390/biom16010170 - 20 Jan 2026
Viewed by 391
Abstract
The intervertebral disc (IVD) is the largest avascular structure in the human body, and its nucleus pulposus (NP) cells predominantly generate large amounts of lactate through glycolysis, accompanied by an acidic microenvironment—features that represent characteristic metabolic traits of disc cells. In recent years, [...] Read more.
The intervertebral disc (IVD) is the largest avascular structure in the human body, and its nucleus pulposus (NP) cells predominantly generate large amounts of lactate through glycolysis, accompanied by an acidic microenvironment—features that represent characteristic metabolic traits of disc cells. In recent years, knowledge of the biological roles of lactate has undergone a conceptual shift. On the one hand, lactate can serve as a context-dependent auxiliary biofuel in specific regions of the IVD, particularly within annulus fibrosus (AF) regions adjacent to the NP. On the other hand, lactate functions in disc cells as a signaling molecule and a metabolic–epigenetic regulator, influencing transcriptional programs through lactylation and modulating multiple molecular pathways associated with cellular stress adaptation and fate determination. This review summarizes current knowledge on lactate production, transport, and clearance in the intervertebral disc, as well as emerging evidence for the roles of lactate in disc health and pathophysiology. In addition, we outline research perspectives and future directions aimed at advancing our understanding of lactate biology and evaluating its potential as a therapeutic target for intervertebral disc degeneration. Full article
(This article belongs to the Section Molecular Medicine)
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14 pages, 1940 KB  
Article
Transcriptional Profiling Reveals Lineage-Specific Characteristics in ATR/CHK1 Inhibitor-Resistant Endometrial Cancer
by Tzu-Ting Huang and Jung-Min Lee
Biomolecules 2026, 16(1), 169; https://doi.org/10.3390/biom16010169 - 20 Jan 2026
Viewed by 224
Abstract
Recurrent endometrial cancer (EC) has limited therapeutic options beyond platinum-based chemotherapy, highlighting the need to identify exploitable molecular vulnerabilities. Tumors with high genomic instability, including microsatellite instability-high (MSI-h) or copy-number-high (CNH) ECs, rely on the ATR-CHK1 signaling pathway to tolerate replication stress and [...] Read more.
Recurrent endometrial cancer (EC) has limited therapeutic options beyond platinum-based chemotherapy, highlighting the need to identify exploitable molecular vulnerabilities. Tumors with high genomic instability, including microsatellite instability-high (MSI-h) or copy-number-high (CNH) ECs, rely on the ATR-CHK1 signaling pathway to tolerate replication stress and maintain genome integrity, making this pathway an attractive therapeutic target. However, acquired resistance to ATR and CHK1 inhibitors (ATRi/CHK1i) often develops, and the transcriptomic basis of this resistance in EC remains unknown. Here, we established isogenic ATRi- and CHK1i-resistant cell line models from MSI-h (HEC1A) and CNH (ARK2) EC lineages and performed baseline transcriptomic profiling to characterize stable resistance-associated states. MSI-h-derived resistant clones adopted a unified transcriptional state enriched for epithelial-mesenchymal transition, cytokine signaling, and interferon responses, while ATRi-resistant models showing additional enrichment of developmental and KRAS/Notch-associated pathways. In contrast, CNH-derived resistant clones diverged by inhibitor class, with ATRi resistance preferentially enriching proliferation-associated pathways and CHK1i resistance inducing interferon signaling. Notably, THBS1, EDN1, and TENM2 were consistently upregulated across all resistant models relative to parental lines. Together, these findings demonstrate that acquired resistance to ATRi and CHK1i in EC is shaped by both lineage and inhibitor class and provide a transcriptomic framework that may inform future biomarker development and therapeutic strategies. Full article
(This article belongs to the Section Molecular Biomarkers)
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22 pages, 6316 KB  
Article
L-Quebrachitol Attenuates RANKL-Induced Osteoclastogenesis and Bone Resorption in Ovariectomized Rat Model
by Purithat Rattajak, Aratee Aroonkesorn, Thanintorn Yodthong, Acharaporn Issuriya, Siriluk Maskaew, Carl Smythe, Rapepun Wititsuwannakul and Thanawat Pitakpornpreecha
Biomolecules 2026, 16(1), 168; https://doi.org/10.3390/biom16010168 - 20 Jan 2026
Viewed by 290
Abstract
Inositol is a natural carbocyclic sugar that plays an essential role in regulating the vital cellular functions of plants and animals. Existing research has explored methyl derivatives of inositol, reporting on their various biological activities, including antitumor, anti-inflammatory, and anti-osteoporosis activities. Our previous [...] Read more.
Inositol is a natural carbocyclic sugar that plays an essential role in regulating the vital cellular functions of plants and animals. Existing research has explored methyl derivatives of inositol, reporting on their various biological activities, including antitumor, anti-inflammatory, and anti-osteoporosis activities. Our previous study demonstrated that L-quebrachitol, a methyl derivative of inositol, enhances osteoblastogenesis and bone formation; however, its effect on osteoclastogenesis remains unclear. Consequently, we aimed to investigate the effect of L-quebrachitol on receptor activator of nuclear factor-κB ligand-induced osteoclastogenesis in pre-osteoclastic RAW 264.7 cells, and bone resorption in an ovariectomized rat model. The results revealed that L-quebrachitol suppressed RANK-mediated signaling, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Fos proto-oncogene (cFOS) pathways, at both the gene and protein levels. Moreover, the critical transcription factor for osteoclastogenesis, nuclear factor of activated T cells c1 (NFATc1), was downregulated. Inhibition of osteoclast-associated marker genes encoding proteolytic enzymes, such as tartrate-resistant acid phosphatase (TRAP), matrix metallopeptidase 9 (MMP-9), and cathepsin K, led to reduced formation of TRAP-positive multinucleated cells and resorption pits. In addition, proteasome subunit alpha type-5 (PSMA5), which is involved in the degradation of the NF-κB inhibitor, was also suppressed. In particular, the animal study clearly supported the bone homeostasis property of the agent by increasing the BV/TV (bone volume/total volume) and Tb.Th (trabecular thickness) in ovariectomized rats. These findings demonstrate the dose-dependent inhibitory effect of L-quebrachitol on osteoclastogenesis through the modulation of RANK-mediated signaling pathways and prevention of bone loss in an animal model. However, further exploration of the potential of L-quebrachitol as an effective approach for osteoporosis is required. Full article
(This article belongs to the Topic Functional Foods and Nutraceuticals in Health and Disease)
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20 pages, 1726 KB  
Review
CILP2: From ECM Component to a Pleiotropic Modulator in Metabolic Dysfunction, Cancer, and Beyond
by Zheqiong Tan, Suotian Liu and Zhongxin Lu
Biomolecules 2026, 16(1), 167; https://doi.org/10.3390/biom16010167 - 19 Jan 2026
Viewed by 244
Abstract
Initially characterized as a component of the extracellular matrix (ECM) in cartilage, cartilage intermediate layer protein 2 (CILP2) is now recognized as a pleiotropic secretory protein with far-reaching roles in physiology and disease. This review synthesizes evidence establishing CILP2 as a key modulator [...] Read more.
Initially characterized as a component of the extracellular matrix (ECM) in cartilage, cartilage intermediate layer protein 2 (CILP2) is now recognized as a pleiotropic secretory protein with far-reaching roles in physiology and disease. This review synthesizes evidence establishing CILP2 as a key modulator at the nexus of metabolic dysfunction, cancer, and other pathologies. Genomic studies have firmly established the NCAN-CILP2 locus as a hotspot for genetic variants influencing dyslipidemia and cardiovascular risk. Functionally, CILP2 is upregulated by metabolic stress, including high glucose and oxidatively modified LDL (oxLDL), and actively contributes to pathologies such as dyslipidemia, diabetes, and sarcopenia by impairing glucose metabolism and mitochondrial function. Its role extends to fibrosis and neurodevelopment, promoting hypertrophic scar formation and neurogenesis through interactions with ATP citrate lyase (ACLY) and Wnt3a, respectively. More recently, CILP2 has emerged as an oncoprotein, overexpressed in multiple cancers, including pancreatic ductal adenocarcinoma and colorectal cancer. It drives tumor proliferation and metastasis and correlates with tumor microenvironment remodeling through mechanisms involving Akt/EMT signaling and immune infiltration. The dysregulation of CILP2 in patient serum and its correlation with disease severity and poor prognosis highlight it as a promising biomarker and a compelling therapeutic target across a spectrum of human diseases. Full article
(This article belongs to the Section Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates)
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14 pages, 3912 KB  
Article
Immunohistochemical Detection of the Mechano-Gated Piezo Channels in the Normal Endometrium and in Endometriosis
by Angel Sánchez del Rio, Yolanda García-Mesa, Ana Gutiérrez-Palacios, Patricia Cuendias, Eliseo Viña, Graciela Martínez-Barbero, José A. Vega and Olivia García-Suárez
Biomolecules 2026, 16(1), 166; https://doi.org/10.3390/biom16010166 - 19 Jan 2026
Viewed by 306
Abstract
Endometriosis is an inflammatory estrogen-dependent disorder characterized by pain, dyspareunia, dysmenorrhea, and infertility. This is due to the invasion of different organs by endometrial tissue that causes inflammation, angiogenesis, and fibrosis. The ion channels Piezo1 and Piezo2 primarily work as mechanosensors and mechanotransducers [...] Read more.
Endometriosis is an inflammatory estrogen-dependent disorder characterized by pain, dyspareunia, dysmenorrhea, and infertility. This is due to the invasion of different organs by endometrial tissue that causes inflammation, angiogenesis, and fibrosis. The ion channels Piezo1 and Piezo2 primarily work as mechanosensors and mechanotransducers but also have functions that could participate in the clinical hallmarks of endometriosis. Thus, we investigated the occurrence and localization of Piezo1 and Piezo2 in healthy human endometrium and in endometriosis using immunohistochemistry. In healthy endometrium, Piezo1 immunoreactivity was detected in the glands and to a lesser extent in the stroma; Piezo2 was present in the same locations but at low or residual levels. In ectopic endometriosis, there was an increase in the intensity of Piezo1 regardless of location; Piezo2 only showed a net increase in the ovarian and vaginal endometriosis foci. The present results demonstrate the occurrence of Piezo ion channels in the healthy human endometrium for the first time, as well as an increase in Piezo1 in ectopic endometriosis, and no changes in Piezo2 with the exception of the ovary and vagina. However, these results are descriptive and qualitative, although they may serve as the basis for further studies. The role of these ion channels in the endometrium and in the pathogenesis of endometriosis remains to be elucidated, and more precise methods are needed to follow up on this pilot study that can be better analyzed statistically to confirm the results. Full article
(This article belongs to the Special Issue Mechanosensitivity and Ion Channels)
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16 pages, 686 KB  
Article
Development of Mitochondria-Targeted PARP Inhibitors
by Pavels Dimitrijevs, Marina Makrecka-Kuka and Pavel Arsenyan
Biomolecules 2026, 16(1), 165; https://doi.org/10.3390/biom16010165 - 19 Jan 2026
Viewed by 254
Abstract
PARP inhibitors are a clinically validated class of anticancer therapeutics that exploit synthetic lethality to target homologous recombination-deficient tumors, such as those carrying BRCA1/2 mutations. Nevertheless, the rational design of mitochondria-targeted PARP inhibitors capable of selective mitochondrial accumulation and organelle-specific PARP modulation remains [...] Read more.
PARP inhibitors are a clinically validated class of anticancer therapeutics that exploit synthetic lethality to target homologous recombination-deficient tumors, such as those carrying BRCA1/2 mutations. Nevertheless, the rational design of mitochondria-targeted PARP inhibitors capable of selective mitochondrial accumulation and organelle-specific PARP modulation remains an unresolved objective. To enable organelle-specific modulation of PARP activity, we synthesized a series of trialkyl(aryl)phosphonium conjugates of olaparib and rucaparib designed to target mitochondria by cardiolipin binding. Their activity was evaluated by PARP1 inhibition, cardiolipin affinity, and cytotoxicity in BRCA1-deficient HCC1937 breast cancer cells and non-malignant H9C2 cardiomyocytes. All conjugates retained potent PARP1 inhibition (IC50 = 3.4–17 nM), comparable to the parent drugs. Several derivatives, particularly compounds 2d and 6c, exhibited strong cardiolipin binding (EC50 = 12.99 µM and 6.77 µM, respectively) and significantly enhanced cytotoxicity in HCC1937 cells (IC50 = 0.93 and 2.01 µM), outperforming olaparib and rucaparib. Notably, cytotoxicity toward H9C2 cells was lower, indicating a favorable selectivity profile. Phosphonium conjugation preserves PARP1 inhibitory activity while conferring mitochondrial targeting and enhanced anticancer potency. These findings support the development of mitochondria-targeted PARP inhibitors as a next-generation therapeutic strategy with the potential to improve efficacy and overcome resistance in HR-deficient tumors. Full article
(This article belongs to the Special Issue Updates on Mitochondria and Cancer)
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21 pages, 4051 KB  
Article
The Cap-Independent Translation of Survivin 5′UTR and HIV-1 IRES Sequences Is Inhibited by Oxidative Stress Produced by H. pylori Gamma-Glutamyl Transpeptidase Activity
by Mariaignacia Rubilar, Nicolás Carrasco-Véliz, Maritza P. Garrido, María I. Silva, Andrew F. G. Quest, María Fernanda González, Esteban Palacios, Joan Villena, Iván Montenegro and Manuel Valenzuela-Valderrama
Biomolecules 2026, 16(1), 164; https://doi.org/10.3390/biom16010164 - 19 Jan 2026
Viewed by 348
Abstract
Background: Survivin is an anti-apoptotic protein highly expressed during embryonic development and, in adults, mainly in the gastrointestinal epithelium. Its levels decrease in human gastric tissue and cultured cells upon exposure to Helicobacter pylori gamma-glutamyl transpeptidase (GGT), though the underlying mechanism remains unclear. [...] Read more.
Background: Survivin is an anti-apoptotic protein highly expressed during embryonic development and, in adults, mainly in the gastrointestinal epithelium. Its levels decrease in human gastric tissue and cultured cells upon exposure to Helicobacter pylori gamma-glutamyl transpeptidase (GGT), though the underlying mechanism remains unclear. Objective: We aimed to investigate the role of cap-independent translation driven by the Survivin 5′ untranslated region (5′UTR) in response to H. pylori infection in vitro. Methodology: Human cell lines (AGS, GES-1, HeLa, HEK293T) were used alongside bicistronic and monocistronic (Firefly/Renilla luciferases) reporter assays to assess short and long variants of the Survivin 5′UTR and HIV-1 internal ribosome entry site (IRES) sequences. Additional methods included in vitro transcription/translation, RT-qPCR, agarose gel electrophoresis, Western blotting, coupled/uncoupled translation assays, and siRNA silencing. Results: The short variant of the Survivin 5′ UTR supported cap-independent translation, like the HIV-1 IRES. Notably, H. pylori infection suppressed this translation in a GGT-dependent manner in gastric cells, and a similar reduction was observed following treatment with ATO, a known prooxidant. Conclusion: The Survivin 5′UTR exhibits cap-independent translation activity that is inhibited by H. pylori in a GGT-dependent manner, likely via oxidative stress. This mechanism helps to explain the downregulation of Survivin during gastric infection and indicates that oxidative stress can negatively affect both cellular and viral IRES-mediated translation. Full article
(This article belongs to the Special Issue Signal Transduction and Pathway Regulation in Cancer)
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16 pages, 2175 KB  
Article
In Silico Ligand-Based Screening of PDB Database for Searching Unique Motifs Against SARS-CoV-2
by Andrey V. Machulin, Juliya V. Badaeva, Sergei Y. Grishin, Evgeniya I. Deryusheva and Oxana V. Galzitskaya
Biomolecules 2026, 16(1), 163; https://doi.org/10.3390/biom16010163 - 19 Jan 2026
Viewed by 280
Abstract
SARS-CoV-2, the virus responsible for coronavirus disease COVID-19, is a highly transmissible pathogen that has caused substantial global morbidity and mortality. The ongoing COVID-19 pandemic caused by this virus has had a significant impact on public health and the global economy. One approach [...] Read more.
SARS-CoV-2, the virus responsible for coronavirus disease COVID-19, is a highly transmissible pathogen that has caused substantial global morbidity and mortality. The ongoing COVID-19 pandemic caused by this virus has had a significant impact on public health and the global economy. One approach to combating COVID-19 is the development of broadly neutralizing antibodies for prevention and treatment. In this work, we performed an in silico ligand-based screening of the PDB database to search for unique anti-SARS-CoV-2 motifs. The collected data were organized and presented in a classified SARS-CoV-2 Ligands Database, categorized based on the number of ligands and structural components of the spike glycoprotein. The database contains 1797 entries related to the structures of the spike glycoprotein (UniProt ID: P0DTC2), including both full-length molecules and their fragments (individual domains and their combinations) with various ligands, such as angiotensin-converting enzyme II and antibodies. The database’s capabilities allow users to explore various datasets according to the research objectives. To search for motifs in the receptor-binding domain (RBD) most frequently involved in antibody binding sites, antibodies were classified into four classes according to their location on the RBD; for each class, special binding motifs are revealed. In the RBD binding sites, specific tyrosine-containing motifs were found. Data obtained may help speed up the creation of new antibody-based therapies, and guide the rational design of next-generation vaccines. Full article
(This article belongs to the Section Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates)
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23 pages, 2777 KB  
Article
Isolation and Biophysical Characterization of Lipoxygenase-1 from Soybean Seed, a Versatile Biocatalyst for Industrial Applications
by Ioanna Gerogianni, Antiopi Vardaxi, Ilias Matis, Maria Karayianni, Maria Zoumpanioti, Thomas Mavromoustakos, Stergios Pispas and Evangelia D. Chrysina
Biomolecules 2026, 16(1), 162; https://doi.org/10.3390/biom16010162 - 19 Jan 2026
Viewed by 233
Abstract
Lipoxygenases are enzymes found in plants, mammals, and other organisms that catalyse the hydroperoxidation of polyunsaturated fatty acids, such as arachidonic, linoleic, and linolenic acids. They have attracted a lot of attention as molecular targets for industrial and biomedical applications, due to their [...] Read more.
Lipoxygenases are enzymes found in plants, mammals, and other organisms that catalyse the hydroperoxidation of polyunsaturated fatty acids, such as arachidonic, linoleic, and linolenic acids. They have attracted a lot of attention as molecular targets for industrial and biomedical applications, due to their implication in key biological processes, such as plant development and defence, cell growth, as well as immune response and inflammation. Soybean (Glycine max) lipoxygenase (LOX) is a versatile biocatalyst used in biotechnology, pharmaceutical, and food industries. sLOX1, a soybean LOX isoform, is central in various industrial applications; thus, it is of particular interest to develop an efficient sLOX1 isolation process, control its activity, and leverage its potential as an effective industrial biocatalyst, tailoring it to a specific desired outcome. In this study, sLOX1 was extracted and purified from soybean seeds using an optimized protocol that yielded an enzyme preparation with higher activity compared to the commercially available lipoxygenase. Comprehensive biophysical characterization employing dynamic and electrophoretic light scattering, fluorescence, and Fourier-transform infrared spectroscopies revealed that sLOX1 exhibits remarkable structural and functional stability, particularly in sodium borate buffer (pH 9), where it retains activity and integrity up to at least 55 °C and displays minimal aggregation under thermal, ionic, and temporal stress. In contrast, sLOX1 in sodium phosphate buffer (pH 6.8) remained relatively stable against ionic strength and time but showed thermally induced aggregation above 55 °C, while in sodium acetate buffer (pH 4.6), the enzyme exhibited a pronounced aggregation tendency under all tested conditions. Overall, this study provides physicochemical and stability assessments of sLOX1. The combination of enhanced catalytic activity, high purity, and well-defined stability profile across diverse buffer systems highlights sLOX1 as a promising and adaptable biocatalyst for industrial applications, offering valuable insights into optimizing lipoxygenase-based bioprocesses. Full article
(This article belongs to the Section Molecular Biophysics: Structure, Dynamics, and Function)
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21 pages, 15830 KB  
Review
Placenta-Driven Evolution: Viral Gene Acquisition and PEG10’s Essential Roles in Eutherian Placenta
by Hirosuke Shiura, Moe Kitazawa, Tomoko Kaneko-Ishino and Fumitoshi Ishino
Biomolecules 2026, 16(1), 161; https://doi.org/10.3390/biom16010161 - 16 Jan 2026
Viewed by 318
Abstract
Mammalian placentation represents one of the most striking evolutionary innovations among vertebrates, and accumulating evidence indicates that virus-derived genes—particularly the metavirus-derived PEG10 and PEG11/RTL1—have played indispensable but distinct roles: PEG10 in the emergence of therian viviparity and PEG11/RTL1 in the subsequent differentiation [...] Read more.
Mammalian placentation represents one of the most striking evolutionary innovations among vertebrates, and accumulating evidence indicates that virus-derived genes—particularly the metavirus-derived PEG10 and PEG11/RTL1—have played indispensable but distinct roles: PEG10 in the emergence of therian viviparity and PEG11/RTL1 in the subsequent differentiation between marsupial and eutherian placental types. Notably, the metavirus-derived SIRH/RTL gene group, which includes PEG10 and PEG11/RTL1, exhibits unique and diverse functions not only in placenta development but also within microglia of the brain. Because microglia originate from yolk sac progenitors, these findings suggest that extraembryonic tissues such as the placenta and yolk sac provided permissive environments that enabled the retention, expression and functional domestication of virus-derived sequences. Once the placenta itself was established through viral gene integration, it may in turn have acted as a powerful driver of eutherian evolution through recurrent acquisition and co-option of additional virus-derived genes—a process we refer to as “placenta-driven evolution.” This perspective offers a unified framework in which viral gene acquisition is viewed as a key driver of genomic innovation, tightly intertwined with the emergence of viviparity, subsequent divergence at the marsupial–eutherian split, and continued diversification of placental structure and function across eutherian lineages. Full article
(This article belongs to the Special Issue Recent Advances in Retroviruses and Endogenous Retroviruses (ERVs) in Mammalian Placenta and Beyond 2025)
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29 pages, 3250 KB  
Review
Mechanisms of Metabolic Reprogramming Regulating Immunosuppression in the Gastric Cancer Tumor Microenvironment
by Wenting Dong, Xuepeng Qian, Honglin Liu, Jinhai Huo and Weiming Wang
Biomolecules 2026, 16(1), 160; https://doi.org/10.3390/biom16010160 - 16 Jan 2026
Viewed by 638
Abstract
Immunotherapy, especially immune checkpoint inhibitors (ICIs), has become one of the core therapeutic approaches in cancer in recent years. It demonstrates remarkable efficacy in the treatment of melanoma and lung cancer. Conversely, its use in treating gastric cancer (GC) is not associated with [...] Read more.
Immunotherapy, especially immune checkpoint inhibitors (ICIs), has become one of the core therapeutic approaches in cancer in recent years. It demonstrates remarkable efficacy in the treatment of melanoma and lung cancer. Conversely, its use in treating gastric cancer (GC) is not associated with considerable benefits. The high heterogeneity of GC and the tumor microenvironment (TME) may directly influence this phenomenon. This review focuses on the correlation between Helicobacter pylori (H. pylori) infection, gastric physiology, and molecular subtype-specific induction pathways, with emphasis on the unique metabolic features of GC. It explores the connection of H. pylori infection, gastric physiologic functions, and molecular subtype-specific induction mechanism of GC with the special metabolism of GC. It also explains the relationship between immune metabolic reprogramming and the suppressive TME in GC. Crucially, we summarize emerging therapeutic strategies targeting metabolic vulnerabilities. Furthermore, we explore the potential of subtype-guided metabolic therapies to overcome the challenges of the immunosuppressive tumor microenvironment in GC. Full article
(This article belongs to the Collection Recent Advances in Cancer Immunotherapy)
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13 pages, 963 KB  
Article
Effects of Lifelong Low Social Status on Inflammatory Markers in Adult Female Macaques
by Mar M. Sanchez, Kaitlyn Love, Alex van Schoor, Kelly Bailey, Trina Jonesteller, Jocelyne Bachevalier, Maria C. Alvarado, Kelly F. Ethun, Mark E. Wilson and Jessica Raper
Biomolecules 2026, 16(1), 159; https://doi.org/10.3390/biom16010159 - 16 Jan 2026
Viewed by 365
Abstract
Low social status leads to chronic social stress that predicts risk for physical and mental illness, especially when it starts early in life. To examine the longitudinal effects of low social status on the immune system, this study assessed the effects of low [...] Read more.
Low social status leads to chronic social stress that predicts risk for physical and mental illness, especially when it starts early in life. To examine the longitudinal effects of low social status on the immune system, this study assessed the effects of low social status on developmental secretory patterns of pro- and anti-inflammatory markers under baseline conditions, as well as in response to an immune challenge (lipopolysaccharide (LPS)-induced activation of pro- and anti-inflammatory cytokines) in a translational rhesus monkey model of lifelong social subordination stress. Baseline blood samples were collected in 27 socially housed female rhesus monkeys (13 dominants, DOM, and 14 subordinates, SUB) during infancy (6 months), the juvenile pre-pubertal period (16 months), and adulthood (9–10 years) to examine the longitudinal effects of social status on inflammatory markers in unstimulated versus LPS-stimulated conditions mimicking exposure to bacterial infection. Basal levels of the stress hormone cortisol in blood were measured to examine associations between inflammation and activity of the hypothalamic–pituitary–adrenal (HPA) axis throughout the life span. Basal peripheral levels of inflammatory markers (e.g., IL-6) increased across development in both SUB and DOM animals with no significant differences. Basal cortisol levels were significantly higher in infancy as compared to adulthood, but no significant effects of social rank were detected. However, in adulthood, SUB animals showed a cytokine-specific immune response to ex vivo LPS stimulation with significantly higher secretions of IL-1β, IL-2, and IL-10 compared to DOM animals, whereas IL-8 response to LPS was lower in SUB animals than in DOMs. This cytokine-specific response to an immune challenge that mimics bacterial infection could reflect dysregulated immune cells that may have short-term adaptation, but at the cost of longer-term risks for low-grade chronic inflammation and accelerated immune aging for socially subordinate female macaques. Full article
(This article belongs to the Special Issue Early Adversity and the Immune Hypothesis: Call for a Dialogue between Basic and Clinical Neuroscience)
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14 pages, 39400 KB  
Article
Antimicrobial and Antibiofilm Activity of a Lactobacillus reuteri SGL01, Vitamin C and Acerola Probiotic Formulation Against Streptococcus mutans DSM20523
by Adriana Antonina Tempesta, Gaia Vertillo Aluisio, Federica Di Gregorio, Roberta Lucia Pecora, Maria Lina Mezzatesta, Viviana Cafiso, Eleonora Chines, Giovanni Barbagallo and Maria Santagati
Biomolecules 2026, 16(1), 158; https://doi.org/10.3390/biom16010158 - 15 Jan 2026
Viewed by 420
Abstract
Dental caries is a multifactorial chronic infectious disease that impacts healthcare costs globally, caused by alterations of the plaque microbiome and proliferation of cariogenic Streptococcus mutans. Treatments targeting S. mutans, such as alternative strategies using probiotics, might be effective in preventing [...] Read more.
Dental caries is a multifactorial chronic infectious disease that impacts healthcare costs globally, caused by alterations of the plaque microbiome and proliferation of cariogenic Streptococcus mutans. Treatments targeting S. mutans, such as alternative strategies using probiotics, might be effective in preventing the development of dental caries. In this study, the probiotic formulation of Lactobacillus reuteri SGL01, vitamin C, and acerola was tested against S. mutans DSM20523. Antimicrobial activity was assessed by deferred antagonism and spot-on-lawn assays for L. reuteri SGL01. MIC and MBC of L. reuteri SGL01 cell-free supernatant (CFS), vitamin C, and acerola were determined with the microdilution method. Time–kill assays determined the bactericidal kinetics for each compound. The checkerboard method was used to evaluate the potential synergistic activity of CFS–vitamin C or CFS–acerola at scalar dilutions from 1 to 8X MIC. Lastly, antibiofilm activity was tested for each compound. Antimicrobial activity of L. reuteri SGL01 was first assessed by classic methods. MIC and MBC values differed for one dilution for all compounds, with values of 25% and 50% for CFS, 9.3 mg/mL and 18.7 mg/mL for vitamin C, and 18.7 mg/mL and 37.5 mg/mL for acerola, respectively. Moreover, time–kill assays confirmed the bactericidal activity at different timepoints: 4 h for CFS, 6 h for vitamin C, and 24 h for acerola. The fractional inhibitory concentration index (FICI) showed indifference for all combinations, and for associations tested at 2, 4, and 8XMIC. S. mutans biofilm production was impaired for all components, with stronger activity by vitamin C and acerola at lower concentrations. The probiotic formulation containing L. reuteri SGl01, vitamin C, and acerola extract exerts a bactericidal effect, especially strong for the CFS, as well as antibiofilm activity. Thus, the combination of these three components could be advantageous for their complementary effects, with use as a novel treatment against the development of dental caries by S. mutans. Full article
(This article belongs to the Special Issue Prebiotics and Probiotics in Health and Disease: Precision Delivery and Microbiota-Informed Therapeutics)
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14 pages, 2588 KB  
Article
Scavenging for Hydroxybenzoic Acids in Cupriavidus necator: Studying Ligand Sensitivity Using a Biosensor-Based Approach
by Ingrida Sabaliauske, Ernesta Augustiniene, Rizkallah Al Akiki Dit Al Mazraani, Monika Tamasauskaite and Naglis Malys
Biomolecules 2026, 16(1), 157; https://doi.org/10.3390/biom16010157 - 15 Jan 2026
Viewed by 295
Abstract
The increasing demand for rapid identification of bacteria capable of degrading environmentally relevant organic compounds highlights the need for scalable and selective analytical tools. Cupriavidus necator catabolizes several hydroxybenzoic acids, including 2-hydroxybenzoate (salicylate, 2-HBA), 4-hydroxybenzoate (4-HBA), and 3-hydroxybenzoate (3-HBA), funneling them into central [...] Read more.
The increasing demand for rapid identification of bacteria capable of degrading environmentally relevant organic compounds highlights the need for scalable and selective analytical tools. Cupriavidus necator catabolizes several hydroxybenzoic acids, including 2-hydroxybenzoate (salicylate, 2-HBA), 4-hydroxybenzoate (4-HBA), and 3-hydroxybenzoate (3-HBA), funneling them into central aromatic catabolism via monooxygenation to 2,5-dihydroxybenzoate (gentisate, 2,5-dHBA) and 3,4-dihydroxybenzoate (protocatechuate, 3,4-dHBA) followed by the oxidative cleavage reaction, enabling complete conversion to tricarboxylic acid (TCA) cycle intermediates. To quantify how readily C. necator is able to activate catabolic genes in response to hydroxybenzoic acid, an extracellular ligand, we applied an approach centered on a transcription-factor (TF)-based biosensor that combines ligand-bound regulator activity with a fluorescent reporter. This approach allowed to evaluate the ligand sensitivity by determining gene activation threshold ACmin and half-maximal effective concentration EC50. Amongst studied hydroxybenzoic acids, 2-HBA and 4-HBA sensors from C. necator showed very low thresholds 4.8 and 2.4 μM and EC50 values of 19.91 and 13.06 μM, indicating high sensitivity to these compounds and implicating a scavenging characteristic of associated catabolism. This study shows that the TF-based-biosensor approach applied for mapping functional sensing ranges of hydroxybenzoates combined with the research and informatics of catabolism can advance our understanding of how gene expression regulation systems have evolved to respond differentially to the availability and concentration of carbon sources. Furthermore, it can inform metabolic engineering strategies in the prevention of premature pathway activation or in predicting competitive substrate hierarchies in complex mixed environments. Full article
(This article belongs to the Section Biological Factors)
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27 pages, 845 KB  
Review
Microglia, Astrocytes, and Oligodendrocytes in Parkinson’s Disease: Neuroinflammatory Crosstalk and Emerging Therapeutic Strategies
by Dominika Kędzia, Grzegorz Galita, Ireneusz Majsterek and Wioletta Rozpędek-Kamińska
Biomolecules 2026, 16(1), 156; https://doi.org/10.3390/biom16010156 - 15 Jan 2026
Cited by 1 | Viewed by 662
Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by the degeneration of dopaminergic neurons in the substantia nigra, resulting in cardinal motor symptoms such as tremor, rigidity, and bradykinesia. Neuroinflammation is increasingly recognized as a central driver of PD onset and progression [...] Read more.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by the degeneration of dopaminergic neurons in the substantia nigra, resulting in cardinal motor symptoms such as tremor, rigidity, and bradykinesia. Neuroinflammation is increasingly recognized as a central driver of PD onset and progression in which oligodendrocytes, astrocytes, and microglia engage in complex bidirectional crosstalk that shapes the inflammatory milieu of the central nervous system. Pathological activation of glial cells triggers the release of pro-inflammatory cytokines, chemokines, and reactive oxygen species, thereby exacerbating neuronal injury and contributing to sustained disease progression. Modulating maladaptive glial activation states and their intercellular communication represents a promising therapeutic avenue aimed at mitigating neuroinflammation and slowing PD pathology. This review synthesizes current knowledge on neuroinflammation in PD, focusing on the distinct roles of microglia, astrocytes, and oligodendrocytes, their interaction networks, and emerging therapeutic strategies. Full article
(This article belongs to the Special Issue Pathogenesis and Targeted Therapy of Neurodegenerative Diseases)
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11 pages, 1015 KB  
Communication
Duplication of the Antistasin-Like Structure Resulted in a New Anticoagulant Protein in the Medicinal Leech
by Ksenia A. Brovina, Vladislav V. Babenko, Valentin A. Manuvera, Pavel A. Bobrovsky, Daria D. Kharlampieva and Vassili N. Lazarev
Biomolecules 2026, 16(1), 155; https://doi.org/10.3390/biom16010155 - 15 Jan 2026
Viewed by 274
Abstract
Blood-sucking organisms produce various anticoagulant proteins that prevent blood clotting in their prey. Even in well-studied species like Hirudo medicinalis, many such proteins remain unidentified. We previously described a novel cysteine-rich anticoagulant (CRA), a distant homolog of antistasin. Later, we discovered another, [...] Read more.
Blood-sucking organisms produce various anticoagulant proteins that prevent blood clotting in their prey. Even in well-studied species like Hirudo medicinalis, many such proteins remain unidentified. We previously described a novel cysteine-rich anticoagulant (CRA), a distant homolog of antistasin. Later, we discovered another, much larger homolog in the medicinal leech. Its amino acid sequence is also highly cysteine-rich. Analysis of cysteine patterns showed four antistasin-like domain motifs, with one of them strongly disrupted. Since both antistasin and CRA contain two such domains, the new protein represents a duplicated antistasin-like structure. We cloned its cDNA, expressed the recombinant protein in Escherichia coli, purified it by metal-chelate chromatography, refolded it, and tested its anticoagulant properties. Using standard clinical assays—activated partial thromboplastin time, prothrombin time, and thrombin time—we found that the protein inhibited coagulation in all tests, though to varying degrees. These findings suggest that different antistasin-like anticoagulants in the leech enable it to block both intrinsic and extrinsic coagulation pathways, while hirudin inhibits the final step of clot formation. The combination of different anticoagulant proteins allows the leech to effectively prevent the prey’s blood from clotting during feeding. Full article
(This article belongs to the Section Molecular Biology)
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18 pages, 1062 KB  
Article
Evaluating the Antiproliferative Effects of Tri(2-Furyl)- and Triphenylphosphine-Gold(I) Pyridyl- and Pyrimidine-Thiolate Complexes
by Kyle Logan Wilhelm, Shyam Pokhrel, Drew Stolpman, Charli Worth, Sonal Mehta, Raul A. Villacob, Bernd Zechmann, Ahmad A. L. Ahmad, Joseph Taube, Mitchell R. M. Bruce, Alice E. Bruce and Touradj Solouki
Biomolecules 2026, 16(1), 154; https://doi.org/10.3390/biom16010154 - 15 Jan 2026
Viewed by 743
Abstract
Two series of tri(2-furyl)- and triphenylphosphine-gold(I) complexes, with pyridyl- and pyrimidine-thiolate ligands containing electron-donating (-CH3) and electron-withdrawing (-CF3) substituents were synthesized and investigated for cell viability inhibitions. Prior results indicate that several of the gold(I) complexes in these series [...] Read more.
Two series of tri(2-furyl)- and triphenylphosphine-gold(I) complexes, with pyridyl- and pyrimidine-thiolate ligands containing electron-donating (-CH3) and electron-withdrawing (-CF3) substituents were synthesized and investigated for cell viability inhibitions. Prior results indicate that several of the gold(I) complexes in these series have high antifungal properties. The observed link between antifungal and anticancer activity provided motivation to investigate their antiproliferative effects, reported here. The synthesized compounds from both series were characterized by 1H, 13C, and 31P NMR spectroscopy, mass spectrometry (MS), infrared and UV-Vis spectroscopy, and solution stability studies. In addition, an X-ray crystallographic study was conducted on one of the gold(I) complexes. Analyte solubilities in McCoy’s 5A cell media were evaluated by ICP-MS. Initial screening studies were conducted on the two series to evaluate cell viability using the SK-BR-3 cell line. All ten gold(I) complexes exhibited sub-µM cytotoxicity and the most potent representatives, one from each series, were selected for further evaluation in four additional cell lines. Half-maximal effective concentrations (EC50) were determined for the MCF7 and MDA-MB-231 malignant mammary cell lines as well as the two control cell lines, HEK293T and MCF10A, to probe for specificity. Results indicate significant selectivity towards inhibition of cancer cells compared to non-transformed for tri(2-furyl)- and triphenylphosphine-gold(I) complexes with the 3,5-dimethylpyrimidine thiolate ligand when dissolved in cell media. Additional studies including 1% DMSO as a solubilizing agent revealed its significant impact on cellular responses. Full article
(This article belongs to the Special Issue Metal-Based Complexes in Medicine: From Therapeutics to Diagnostics and Theranostics)
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19 pages, 4384 KB  
Article
Study on the Mechanism of Ganoderma lucidum Polysaccharides for Ameliorating Dyslipidemia via Regulating Gut Microbiota and Fecal Metabolites
by Wenshuai Wang, Rui Sun, Jianjun Zhang, Le Jia and Yuanjun Dong
Biomolecules 2026, 16(1), 153; https://doi.org/10.3390/biom16010153 - 14 Jan 2026
Viewed by 395
Abstract
In today’s world, unhealthy living habits have contributed to the rise in metabolic disorders like hyperlipidemia. Recognized as a popular edible and medicinal mushroom in China and various eastern nations, Ganoderma lucidum is a promising high-value functional and medicinal food with multiple biological [...] Read more.
In today’s world, unhealthy living habits have contributed to the rise in metabolic disorders like hyperlipidemia. Recognized as a popular edible and medicinal mushroom in China and various eastern nations, Ganoderma lucidum is a promising high-value functional and medicinal food with multiple biological activities. Our earlier research has demonstrated that G. lucidum polysaccharides (GLP) showed distinct lipid-lowering abilities by enhancing the response to oxidative stress and inflammation, adjusting bile acid production and lipid regulation factors, and facilitating reverse cholesterol transport through Nrf2-Keap1, NF-κB, LXRα-ABCA1/ABCG1, CYP7A1-CYP27A1, and FXR-FGF15 pathways, hence we delved deeper into the effects of GLP on hyperlipidemia, focusing on its structural characterization, gut microbiota, and fecal metabolites. Our findings showed that GLP changed the composition and structure of gut microbiota, and 10 key biomarker strains screened by LEfSe analysis markedly increased the abundance of energy metabolism, and cell growth and death pathways which were found by PICRUSt2. In addition, GLP intervention significantly altered the fecal metabolites, which enriched in amino acid metabolism and lipid metabolism pathways. The results of structural characterization showed that GLP, with the molecular weight of 12.53 kDa, consisted of pyranose rings and was linked by α-type and β-type glycosidic bonds, and its overall morphology appeared as an irregular flaky structure with some flecks and holes in the surface. Collectively, our study highlighted that the protective effects of GLP were closely associated with the modification of gut microbiota and the regulation of metabolites profiles, thus ameliorating dyslipidemia. Full article
(This article belongs to the Special Issue Functions and Mechanisms of Protective Biomolecules in Metabolic Diseases)
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30 pages, 4170 KB  
Article
EruA, a Regulator of Adherent-Invasive E. coli, Enhances Bacterial Pathogenicity by Promoting Adhesion to Epithelial Cells and Survival Within Macrophages
by Zeyan Xu, Chuyu Qin, Ruohan Zhang, Mengting Wu, Anqi Cui, Wei Chen, Lu Chen, Daqing Gao and Ruihua Shi
Biomolecules 2026, 16(1), 152; https://doi.org/10.3390/biom16010152 - 14 Jan 2026
Viewed by 332
Abstract
Adherent-invasive E. coli (AIEC) is closely related to inflammatory bowel disease (IBD). However, its pathogenic mechanism has not yet been fully elucidated. Using a BLASTP search, we discovered that the amino acid sequence of a putative protein (UFP37798.1) in the AIEC LF82 strain [...] Read more.
Adherent-invasive E. coli (AIEC) is closely related to inflammatory bowel disease (IBD). However, its pathogenic mechanism has not yet been fully elucidated. Using a BLASTP search, we discovered that the amino acid sequence of a putative protein (UFP37798.1) in the AIEC LF82 strain is highly homologous to some regulators in the SlyA family. We named it EruA. We displayed the secondary structures of EruA using bioinformatics, overexpressed the His6-tagged EruA protein using SDS-PAGE, and dissected the genetic organization of the eruA chromosomal region using 5′RACE. We constructed an eruA deletion mutant (ΔeruA) and a complementary strain (CΔeruA) of the LF82 strain. The transcriptomes of wild-type (WT) and ΔeruA bacteria were compared using RNA sequencing and qRT-PCR, thereby identifying 32 differentially expressed genes (DEGs). Based on YASARA software and EMSA analysis, EruA directly binds to the consensus sequences (PfimA and PtnaB) in the promoter region of the fimA and tnaB genes from these DEGs. By using a super-resolution confocal microscope (SCM), counting CFUs of colonies on plates, indole quantification, and crystal violet staining of biofilms adhered to tubes or 96-well plates, we found that EruA activates the fimA to promote bacterial adhesion to intestinal epithelial cells and activates the tnaB to enhance bacterial indole production and biofilm formation. Moreover, EruA helps AIEC resist environmental stress and enhances bacterial survival within macrophages as well as loading in mouse tissues. Notably, EruA promotes AIEC colonization in the colons of mice and exacerbates intestinal inflammation caused by bacterial infection in mice with DSS-induced inflammatory colitis, manifested by weight loss, colon length shortening, and pathological changes in colon tissues. Therefore, EruA plays a key role in the pathogenicity of AIEC. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Genetics of Bacteria)
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23 pages, 2955 KB  
Review
Molecular Mechanisms and Therapeutic Potential of Baicalein in Acute Pancreatitis: A Comprehensive Review
by Linbo Yao, Shiyu Liu, Wei Huang and Xinmin Yang
Biomolecules 2026, 16(1), 151; https://doi.org/10.3390/biom16010151 - 14 Jan 2026
Viewed by 378
Abstract
Acute pancreatitis (AP) is a severe inflammatory disorder characterized by a complex molecular pathophysiology involving premature zymogen activation, organelle dysfunction, and systemic immune dysregulation. Current therapeutic strategies remain largely supportive, underscoring the critical need for specific molecular-targeted interventions. Baicalein, a bioactive flavonoid derived [...] Read more.
Acute pancreatitis (AP) is a severe inflammatory disorder characterized by a complex molecular pathophysiology involving premature zymogen activation, organelle dysfunction, and systemic immune dysregulation. Current therapeutic strategies remain largely supportive, underscoring the critical need for specific molecular-targeted interventions. Baicalein, a bioactive flavonoid derived from Scutellaria baicalensis Georgi, has emerged as a potent pleiotropic agent. This review comprehensively synthesizes the molecular mechanisms underlying baicalein’s therapeutic efficacy in AP. Its capacity to intercept the pathological cascade at multiple checkpoints is elucidated, from mitigating the initiating cytosolic calcium overload and preserving mitochondrial integrity to suppressing the cytokine storm via the TLR4/NF-κB/MAPK signaling axis. Crucially, baicalein modulates the pancreatic immune microenvironment by driving the phenotypic polarization of macrophages from pro-inflammatory M1 to reparative M2 states and regulating neutrophil dynamics, specifically by inhibiting infiltration and neutrophil extracellular trap formation. Furthermore, its role in orchestrating regulated cell death pathways is highlighted, specifically by blocking pyroptosis and ferroptosis while modulating apoptosis, and its function as a biophysical scavenger of circulating histones and pancreatic lipase to neutralize systemic toxins. Consequently, this review emphasizes the multi-target biological activities of baicalein, providing a mechanistic rationale for its development as a precision therapeutic candidate for AP. Full article
(This article belongs to the Special Issue Advances in Pharmacognosy and Phytochemistry: From Molecular to Pre-Clinical Insights)
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17 pages, 3542 KB  
Article
Mechanobiological Regulation of Alveolar Bone Remodeling: A Finite Element Study and Molecular Pathway Interpretation
by Anna Ewa Kuc, Magdalena Sulewska, Kamil Sybilski, Jacek Kotuła, Grzegorz Hajduk, Szymon Saternus, Jerzy Małachowski, Julia Bar, Joanna Lis, Beata Kawala and Michał Sarul
Biomolecules 2026, 16(1), 150; https://doi.org/10.3390/biom16010150 - 14 Jan 2026
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Abstract
Background: Mechanical loading is a fundamental regulator of bone remodelling; however, the mechanotransduction mechanisms governing alveolar bone adaptation under tensile-dominant orthodontic loading remain insufficiently defined. In particular, the molecular pathways associated with tension-driven cortical modelling in the periodontal ligament (PDL)–bone complex have not [...] Read more.
Background: Mechanical loading is a fundamental regulator of bone remodelling; however, the mechanotransduction mechanisms governing alveolar bone adaptation under tensile-dominant orthodontic loading remain insufficiently defined. In particular, the molecular pathways associated with tension-driven cortical modelling in the periodontal ligament (PDL)–bone complex have not been systematically interpreted in the context of advanced biomechanical simulations. Methods: A nonlinear finite element model of the alveolar bone–PDL–tooth complex was developed using patient-specific CBCT data. Three loading configurations were analysed: (i) conventional orthodontic loading, (ii) loading combined with corticotomy alone, and (iii) a translation-dominant configuration generated by the Bone Protection System (BPS). Pressure distribution, displacement vectors, and stress polarity within the PDL and cortical plate were quantified across different bone density conditions. The mechanical outputs were subsequently interpreted in relation to established mechanotransductive molecular pathways involved in osteogenesis and angiogenesis. Results: Conventional loading generated compression-dominant stress fields within the marginal PDL, frequently exceeding physiological thresholds and producing moment-driven root displacement. Corticotomy alone reduced local stiffness but did not substantially alter stress polarity. The BPS configuration redirected loads toward a tensile-favourable mechanical environment characterised by reduced peak compressive pressures and parallel (translation-dominant) displacement vectors. The predicted tensile stress distribution is compatible with activation profiles of key mechanosensitive pathways, including integrin–FAK signalling, Wnt/β-catenin–mediated osteogenic differentiation and HIF-1α/VEGF-driven angiogenic coupling, suggesting a microenvironment that may be more conducive to cortical apposition than to resorption. Conclusions: This study presents a computational–molecular framework linking finite element–derived tensile stress patterns with osteogenic and angiogenic signalling pathways relevant to alveolar bone remodelling. The findings suggestthat controlled redirection of orthodontic loading toward tensile domains may shift the mechanical environment of the PDL–bone complex toward conditions associated with osteogenic than resorptive responses providing a mechanistic basis for tension-induced cortical modelling. This mechanobiological paradigm advances the understanding of load-guided alveolar bone adaptation at both the tissue and molecular levels. Full article
(This article belongs to the Section Molecular Biology)
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