Biomolecules

23 pages, 2148 KB

Open AccessArticle

Long-Term Metabolic Responses of Olive to Bacterial and Fungal Inoculation Differ Between Cultivars

by Sergeja Adamič Zamljen, Sara Godena, Nikola Major, Smiljana Goreta Ban, Tvrtko Karlo Kovačević, Marija Polić Pasković and Igor Pasković

Biomolecules 2026, 16(8), 1220; https://doi.org/10.3390/biom16081220 - 21 Aug 2026

Viewed by 383

Abstract

Olive leaves represent a metabolically active tissue that plays an important role in plant responses to biotic stress. The present study comprised two independent experiments investigating biochemical responses of olive leaves to bacterial and fungal challenge under controlled conditions. Changes in primary metabolites [...] Read more.

Olive leaves represent a metabolically active tissue that plays an important role in plant responses to biotic stress. The present study comprised two independent experiments investigating biochemical responses of olive leaves to bacterial and fungal challenge under controlled conditions. Changes in primary metabolites (sugars, organic acids and free amino acids), phenolic compounds and lipid peroxidation were analyzed using chromatographic and spectrophotometric methods. In the bacterial experiment, pronounced differences were observed in primary metabolism. Tryptophan concentrations ranged from approximately 50 mg kg⁻¹ DW to more than 360 mg kg⁻¹ DW in ‘Istarska bjelica’, while sucrose concentrations reached up to 87 g kg⁻¹ DW, demonstrating cultivar-dependent differences in carbohydrate metabolism. Phenolic profiling showed that secoiridoids were the dominant phenolic class, with oleuropein concentrations exceeding 27 g kg⁻¹ DW across bacterial treatments. In the fungal experiment, amino acids showed greater variability than sugars and phenolic compounds, whereas MDA concentrations ranged from approximately 190 to 300 nmol g⁻¹ DW but did not differ significantly among pathogen treatments. Overall, the two experiments showed distinct patterns of metabolite variation associated with bacterial and fungal challenge. These findings contribute to a better understanding of cultivar-dependent metabolic responses and provide a basis for future studies of olive–microbe interactions. Full article

(This article belongs to the Special Issue Plant Secondary Metabolism Engineering and Bioactive Compounds)

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19 pages, 1300 KB

Open AccessArticle

Characterization of Ocular Developmental Disorders in the Israeli Population: Genotype–Phenotype Correlations and Novel Candidate Genes

by Yakov Rabinovich, Yoav Vardizer, Shirley Pincovich, Marva Wolowelsky, Sofia Kulyamzin, Miriam Ehrenberg, Shiri Zayit-Soudry, Inbal Man Peles, Rina Leibu, Nitza Goldenberg-Cohen and Tamar Ben-Yosef

Biomolecules 2026, 16(8), 1219; https://doi.org/10.3390/biom16081219 - 21 Aug 2026

Viewed by 378

Abstract

Microphthalmia, anophthalmia and ocular coloboma (MAC) are rare developmental eye disorders. Although over 100 causative genes have been identified, the molecular spectrum and genotype–phenotype correlations remain incompletely understood, particularly in genetically diverse populations. We set out to molecularly characterize MAC in the Israeli [...] Read more.

Microphthalmia, anophthalmia and ocular coloboma (MAC) are rare developmental eye disorders. Although over 100 causative genes have been identified, the molecular spectrum and genotype–phenotype correlations remain incompletely understood, particularly in genetically diverse populations. We set out to molecularly characterize MAC in the Israeli population. Forty-seven MAC-affected individuals from 43 unrelated families were enrolled. DNA of all probands was subjected to whole exome sequencing. The most common phenotype was microphthalmia (64% of patients). Definite or possible molecular diagnoses were achieved in 13/43 probands (30%) and involved 10 different genes (MFRP, SMO, GJA8, SOX2, RARB, TSPAN12, SHH, PTPN11, BEST1, and TP63). An in vitro splicing assay was used to explore the pathogenicity of a variant in the SMO gene. Following stringent filtering of exome data, 226 rare possibly pathogenic variants were identified in 218 genes not previously associated with MAC. The rate of molecular diagnosis achieved in this Israeli MAC cohort is similar to the reported range in other studies. The results further demonstrate the genetic heterogeneity of MAC, while supporting the involvement of complex inheritance and/or environmental factors in many of the cases. Further studies are required to reveal these underlying etiological factors, and to support the novel genotype–phenotype associations suggested here. Full article

(This article belongs to the Section Molecular Genetics)

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25 pages, 2985 KB

Open AccessReview

The Role of Skeletal Muscle Mitochondria in NLRP3 Inflammasome Signaling

by Jada Sangha and David A. Hood

Biomolecules 2026, 16(8), 1218; https://doi.org/10.3390/biom16081218 - 20 Aug 2026

Viewed by 462

Abstract

Skeletal muscle mitochondria possess the ability to autoregulate their health and functioning by the orchestration of mitochondrial quality control (MQC) pathways. This plasticity allows them to adapt to various stimuli, such as exercise. However, under pathological conditions, mitochondria can become dysfunctional, generating damage-associated [...] Read more.

Skeletal muscle mitochondria possess the ability to autoregulate their health and functioning by the orchestration of mitochondrial quality control (MQC) pathways. This plasticity allows them to adapt to various stimuli, such as exercise. However, under pathological conditions, mitochondria can become dysfunctional, generating damage-associated molecular patterns (DAMPs), such as reactive oxygen species (ROS) and oxidized mitochondrial DNA (mtDNA). These DAMPs can launch an innate immune response, with consequences of widespread inflammation and atrophy. Integral to this is the NLRP3 inflammasome complex. Activation of the NLRP3 inflammasome results in maturation of caspase-1, which processes pro-inflammatory cytokines IL-1β and IL-18, as well as GSDMD. Consequently, the pore-forming GSDMD-N fragment induces pyroptosis, releasing mature IL-1β and IL-18. Exercise training is widely accepted as a potent mechanism to promote skeletal muscle health, particularly by remodeling the mitochondrial network and reducing the production of DAMPs. It has also been shown promote an anti-inflammatory milieu with the release of various myokines. Indeed, the potential of exercise to mitigate NLRP3 inflammasome-mediated inflammation and atrophy is promising. This review will examine the mechanisms underpinning inflammasome priming and activation, as well the effects of exercise, with an emphasis on the skeletal muscle. Full article

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

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15 pages, 1617 KB

Open AccessArticle

Fluorescent Analysis of K_M and V_max Values for Methyl-Dependent Restriction Endonucleases

by Vladislava Martyshova and Sergey Sedykh

Biomolecules 2026, 16(8), 1217; https://doi.org/10.3390/biom16081217 - 20 Aug 2026

Viewed by 305

Abstract

Methyl-dependent restriction endonucleases are promising tools for analyzing eukaryotic DNA methylation patterns. However, quantitative assessment of their substrate specificity requires the determination of the kinetic parameters of enzymatic reactions. Here, we present a method for determining initial reaction rates based on fluorescent probes [...] Read more.

Methyl-dependent restriction endonucleases are promising tools for analyzing eukaryotic DNA methylation patterns. However, quantitative assessment of their substrate specificity requires the determination of the kinetic parameters of enzymatic reactions. Here, we present a method for determining initial reaction rates based on fluorescent probes and real-time monitoring of changes in fluorescence intensity. Initial rates of methyl-dependent GlaI and BlsI restriction endonucleases were determined as the slope of the linear part of the kinetic curves, after which the Michaelis–Menten constants (K_M) and reaction rates (V_max) were calculated using nonlinear regression. For both enzymes, K_M values were determined for the first time, indicating a high affinity of the methyl-dependent restriction endonucleases for methylated sites. K_M values for fully methylated duplexes were in the range of (4.4–7.0)·10² nM for GlaI and 2.4–55 nM for BlsI. K_M values were significantly lower for the hemimethylated duplexes: (1.9–8.0)·10² nM for GlaI and (0.7–15.0)·10² nM for BlsI; and even lower for unmethylated duplexes: (27–46)·10² nM for GlaI and (0.28–23)·10² nM for BlsI. Maximum reaction rates varied within relatively narrow limits: V_max values were in range (4.5–19.5)·10⁻⁴ nM/s for GlaI and (1.4–18)·10⁻⁴ nM/s for BlsI, respectively. V_max values were depended weakly on the degree of methylation compared to the K_M. The proposed fluorescence method was applied to determine the kinetic parameters of methyl-dependent restriction endonucleases for the first time. It may serve as a simpler and more environmentally friendly alternative to traditional electrophoretic approaches that use radioactive labels. Full article

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

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61 pages, 1568 KB

Open AccessReview

Diet and Lipidomics Mediated Regulation of Mesenchymal Stem Cell Function: Diet, Omics and Stem Cell Connection

by Büşra Başar Gökcen, Büşra Atabilen Pınar, Menşure Nur Çelik, Zeynep Büşra Aksoy, Bence Raposa and Duygu Ağagündüz

Biomolecules 2026, 16(8), 1216; https://doi.org/10.3390/biom16081216 - 20 Aug 2026

Viewed by 695

Abstract

Mesenchymal stem/stromal cells (MSCs) are promising candidates in regenerative medicine, but their effectiveness is significantly influenced by the surrounding metabolic and nutritional conditions. Increasing evidence suggests that lipids act not only as energy sources but also as regulators of MSC fate. This review [...] Read more.

Mesenchymal stem/stromal cells (MSCs) are promising candidates in regenerative medicine, but their effectiveness is significantly influenced by the surrounding metabolic and nutritional conditions. Increasing evidence suggests that lipids act not only as energy sources but also as regulators of MSC fate. This review explores how lipid metabolism influences the balance among stemness, immunomodulation, and differentiation into adipogenic or osteogenic lineages. It does so through mechanisms such as fatty acid uptake, β-oxidation, de novo lipogenesis, and membrane remodeling, all orchestrated by CD36, carnitine palmitoyltransferase 1A, PPARγ, AMP-activated protein kinase, and the PI3K/AKT/mTOR pathway. We then examine how diet reshapes the MSC lipidome: obesity and high-fat diets promote adipogenesis and senescence, while omega-3 fatty acids, caloric restriction, micronutrients, and a balanced microbiota help preserve regenerative capacity. Lastly, we discuss how combining lipidomics with multi-omics could uncover lipid-metabolic signatures and regulatory nodes that connect diet to MSC function. Overall, the diet–lipid–MSC axis emerges as a modifiable determinant of MSC function. Full article

(This article belongs to the Special Issue Advancing Innovations in Biomedical Research for Translational Applications: 2nd Edition)

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20 pages, 5966 KB

Open AccessReview

The Enigma of Big Tau Exon 4a: Genomic Architecture, Biophysical Identity, and Unique Evolutionary Mechanisms

by Itzhak Fischer

Biomolecules 2026, 16(8), 1215; https://doi.org/10.3390/biom16081215 - 20 Aug 2026

Viewed by 413

Abstract

The microtubule-associated protein tau, encoded by the MAPT gene, serves as a major component of the neuronal cytoskeleton, facilitating the assembly, stabilization, and spatial organization of microtubules. Much of the work on tau has focused on the low-molecular-weight (LMW) isoforms abundantly expressed in [...] Read more.

The microtubule-associated protein tau, encoded by the MAPT gene, serves as a major component of the neuronal cytoskeleton, facilitating the assembly, stabilization, and spatial organization of microtubules. Much of the work on tau has focused on the low-molecular-weight (LMW) isoforms abundantly expressed in the central nervous system (CNS) and their pathological aggregation in tauopathies. However, a different variant known as “Big tau”, present in the peripheral nervous system (PNS) and selective CNS regions has distinct structural and functional properties and offers a unique perspective on protein evolution. Big tau is characterized by the inclusion of a large, alternatively spliced insert termed exon 4a, which expands the protein’s projection domain by approximately 250 amino acids and increases the molecular weight to 90–110 kDa. The evolutionary trajectory of exon 4a presents a fascinating enigma that challenges conventional models of protein conservation. Across the vertebrate phylogeny, spanning from fishes, amphibians and birds to mammals, the primary amino acid sequence of exon 4a exhibits extreme divergence, often reaching background levels of identity when comparing distant classes. In contrast, the physical length of this domain remains remarkably stable, hovering around the 250-amino acid mark regardless of the species. This pattern suggests that the selective pressure acting on Big tau is not directed toward specific sequence motifs or functional domains, but rather toward the biophysical properties and physical dimensions of the domain. Here, we posit that exon 4a evolved as an essential molecular spacer optimized for the structural demands of long-projection neurons and high-caliber axons as well as a protective structure for the pathologic aggregation of tau. The paper examines the genomic architecture and biophysical identity underlying the stable-size and low sequence identity of exon 4a, presenting two evolutionary mechanisms as working hypotheses: a Prototype Model of neutral drift of an ancient insert, and an Independent Exonization of convergent recruitment of non-coding DNA by transposable elements or intron retention. Finally, we emphasize the need for additional experimental work in vitro and in vivo to resolve unanswered questions about the structure of the 4a exon, the physiological role Big tau and its potential insight into tauopathies therapeutics. Full article

(This article belongs to the Section Molecular Medicine)

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29 pages, 11492 KB

Open AccessArticle

DNA Damage Recognition by Bacterial and Human Adenine-DNA Glycosylases: Insights from Non-Canonical Substrates

by Ulan Sarsenbayeva, Didier Gasparutto, Nicolas Geacintov, Alexander A. Ishchenko, Gulzhan Zhamanbayeva, Kamalidin O. Sharipov, Carlos H. Trasviña-Arenas, Sheila S. David, Dmitry O. Zharkov, Bakhyt T. Matkarimov, Murat Saparbaev and Sabira Taipakova

Biomolecules 2026, 16(8), 1214; https://doi.org/10.3390/biom16081214 - 20 Aug 2026

Viewed by 550

Abstract

The Escherichia coli adenine-DNA glycosylase (MutY) and its human homologue, MUTYH, protect cells against oxygen-free radical-induced mutagenesis by excising regular adenine impaired with 8-oxo-7,8-dihydro-guanine (8oxoG) in the base excision repair (BER) pathway. However, removal of adenine by MutY and MUTYH from an A·8oxoG [...] Read more.

The Escherichia coli adenine-DNA glycosylase (MutY) and its human homologue, MUTYH, protect cells against oxygen-free radical-induced mutagenesis by excising regular adenine impaired with 8-oxo-7,8-dihydro-guanine (8oxoG) in the base excision repair (BER) pathway. However, removal of adenine by MutY and MUTYH from an A·8oxoG pair generated via misincorporation of an oxidized nucleotide during DNA synthesis might induce A·T→C·G transversions. Here, to examine MutY and MUTYH in vitro activities, we used short synthetic DNA duplexes in which the target adenine residue was positioned opposite a variety of DNA base modifications. MUTYH does not excise mismatched adenine in non-canonical DNA substrates, whereas MutY excises adenine mispaired with 1,3-d(GpNpG) cisplatin intra-strand crosslink. In addition, we characterized four MUTYH variants associated with cancer risk, which exhibit the following order of DNA glycosylase deficiency: WT ≥ G169D > G202E ≈ Y165C >> D222N. Human adenine-DNA glycosylase MUTYH and its mutant variants, contrary to bacterial MutY, are not prone to aberrant removal of regular adenine residues opposite modified residues in DNA duplexes. We hypothesize that E. coli MutY is prone to aberrant repair under certain conditions and that this may prevent incorporation of adenine opposite blocking lesions in the template strand. Full article

(This article belongs to the Section Molecular Biology)

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17 pages, 5375 KB

Open AccessArticle

p21 (CDKN1A) Is the Major Driver of Sulforaphane-Mediated Reduction in SAMHD1 T592 Phosphorylation in Macrophages

by Bianka Nicolle Pena Marcelino, Kiersten Girard, Lauren Letourneau, Andrew Lewin, David Lewin, Anna Presicci, Luke Reistrom, Tyler Williams and H. John Sharifi

Biomolecules 2026, 16(8), 1213; https://doi.org/10.3390/biom16081213 - 20 Aug 2026

Viewed by 770

Abstract

Sulforaphane (SFN), a natural compound found in cruciferous vegetables, mobilizes the transcription factor NRF2 to protect macrophages from HIV-1. SFN/NRF2 exerts this protective effect by promoting the reduced phosphorylation of the antiviral protein SAMHD1. Phosphorylation at threonine 592 (T592) potently inhibits the capacity [...] Read more.

Sulforaphane (SFN), a natural compound found in cruciferous vegetables, mobilizes the transcription factor NRF2 to protect macrophages from HIV-1. SFN/NRF2 exerts this protective effect by promoting the reduced phosphorylation of the antiviral protein SAMHD1. Phosphorylation at threonine 592 (T592) potently inhibits the capacity of SAMHD1 to restrict HIV-1. How SFN, and other NRF2 mobilizers reduce SAMHD1 T592 phosphorylation is unclear. p21 (CDKN1A) is an NRF2-responsive protein that accumulates in primary macrophages after SFN treatment. p21 blocks SAMHD1 T592 phosphorylation through the inhibition of several cyclin-dependent kinases. We therefore hypothesized that SFN acts through p21 to reduce SAMHD1 T592 phosphorylation in macrophages. Here, we use RNAi, CRISPR-Cas9, and pharmacological inhibition to deplete or delete p21 in macrophages and demonstrate that p21 is necessary for SFN to efficiently reduce SAMHD1 T592 phosphorylation and restrict HIV-1 transduction. Full article

(This article belongs to the Section Cellular Biochemistry)

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21 pages, 3971 KB

Open AccessArticle

Catalytic Properties of NADP-Reducing Enzymes from Streptococcus cristatus ATCC 51100

by Isabell Schütt, Jonathan Teuffel, Ben H. Hlawatschke, Philip Einwohlt, Bernd Kreikemeyer, Rebecca C. Wade and Tomas Fiedler

Biomolecules 2026, 16(8), 1212; https://doi.org/10.3390/biom16081212 - 20 Aug 2026

Viewed by 371

Abstract

Streptococcus cristatus (S. cristatus) belongs to the viridans group of streptococci and is a commensal of the human upper respiratory tract. With the non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase, GapN, and the oxidative part of the pentose phosphate pathway (oxPPP), S. cristatus can use [...] Read more.

Streptococcus cristatus (S. cristatus) belongs to the viridans group of streptococci and is a commensal of the human upper respiratory tract. With the non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase, GapN, and the oxidative part of the pentose phosphate pathway (oxPPP), S. cristatus can use two different metabolic pathways to provide reduced nicotinamide adenine dinucleotide phosphate (NADPH), an essential cofactor of anabolic reactions such as fatty acid and amino acid biosynthesis. Regarding their NADP-reducing capacity, streptococci can be categorized into three groups: those that have only GapN, those that use only the oxPPP, and those that use both pathways. Here, we report on the experimental and computational characterization of the catalytic properties of the three NADP-reducing enzymes: GapN, glucose-6-phosphate dehydrogenase (G6PDH), and 6-phosphogluconate dehydrogenase (6PGDH) of S. cristatus. Kinetic analyses showed moderate substrate and cofactor affinities, with GapN displaying the tightest substrate binding, followed by 6PGDH and G6PDH, in agreement with structural and computational predictions. All three enzymes preferentially utilized NADP⁺, with only G6PDH exhibiting limited NAD⁺ promiscuity. Growth-phase-dependent activity patterns suggest dynamic adjustment of NADPH-generating pathways, with reduced GapN contribution and sustained oxPPP activity in the stationary phase. Regulatory screening indicated limited allosteric control, though feedback inhibition by NADPH and the ATP sensitivity of G6PDH point to conserved redox regulatory mechanisms. Comparative analysis across streptococci supports the concept that the coexistence of GapN and the oxidative pentose phosphate pathway in S. cristatus may provide metabolic flexibility by offering alternative routes for NADPH generation. Full article

(This article belongs to the Section Enzymology)

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15 pages, 5052 KB

Open AccessArticle

Placental Small Extracellular Vesicles Undetected in Cerebrospinal Fluid of Preeclamptic and Eclamptic Women

by Bryony Davies, Faheem Seedat, Lina Bergman, Catherine Cluver, Angga Wiratama Lokeswara, Michelle Ma, Morganne Wilbourne, Shuhan Jiang, Antonio Galvez, Adam Handel, Andrew Fower, Carlos Escudero, Wei Zhang and Manu Vatish

Biomolecules 2026, 16(8), 1211; https://doi.org/10.3390/biom16081211 - 19 Aug 2026

Viewed by 506

Abstract

Circulating small extracellular vesicles (sEVs) released from the placenta carry bioactive compounds. Placental sEVs (psEVs) have been implicated as drivers of pathology in preeclampsia, a common disorder of pregnancy. This study investigates the hypothesis that psEVs are detectable in cerebrospinal fluid (CSF) during [...] Read more.

Circulating small extracellular vesicles (sEVs) released from the placenta carry bioactive compounds. Placental sEVs (psEVs) have been implicated as drivers of pathology in preeclampsia, a common disorder of pregnancy. This study investigates the hypothesis that psEVs are detectable in cerebrospinal fluid (CSF) during pregnancy, and are present at higher concentrations in preeclamptic and eclamptic pregnancies. Two techniques were used to search for psEVs. Firstly, the ExoCounter assay was performed on neat CSF from normotensive, preeclamptic and eclamptic pregnancies, and non-pregnant controls (n = 11, 12, 10 and 4, respectively). Quantitative PCR was used to search for psEV-associated microRNAs in the CSF of pregnant women. Neither assay found evidence of psEVs in the CSF of pregnant women, regardless of whether they had preeclampsia or eclampsia. This study suggests that psEVs do not reside in CSF during pregnancy and may be more likely to impact central nervous tissues through peripheral changes or interaction with the blood–brain barrier without crossing. Full article

(This article belongs to the Section Molecular Reproduction)

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23 pages, 5396 KB

Open AccessReview

Aerobic Exercise-Mediated Regulation of Ferroptosis in Skeletal Disorders: Molecular Mechanisms and Potential Applications

by Rui Pu, Guo-Pan Gong, Wen-Li Song, Yue Yin, Zi-Yang Chen and Pan Jin

Biomolecules 2026, 16(8), 1210; https://doi.org/10.3390/biom16081210 - 19 Aug 2026

Viewed by 490

Abstract

Skeletal disorders, including osteoporosis, osteoarthritis, rheumatoid arthritis, and osteonecrosis of the femoral head, are common chronic conditions that substantially affect health and quality of life. Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, has increasingly been implicated in abnormal [...] Read more.

Skeletal disorders, including osteoporosis, osteoarthritis, rheumatoid arthritis, and osteonecrosis of the femoral head, are common chronic conditions that substantially affect health and quality of life. Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, has increasingly been implicated in abnormal bone remodeling, cartilage degeneration, synovial pathology, and impaired skeletal homeostasis. Aerobic exercise is an important non-pharmacological approach for maintaining skeletal health, but the role of ferroptosis in its protective effects remains incompletely understood. Previous reviews have mainly discussed ferroptosis in skeletal disorders or the beneficial effects of exercise on skeletal health as separate topics. In contrast, this review places aerobic exercise, ferroptosis, and skeletal disorders within a unified framework and summarizes current evidence across osteoporosis, osteoarthritis, rheumatoid arthritis, and osteonecrosis of the femoral head. We further discuss how aerobic exercise may influence ferroptosis through the regulation of iron homeostasis, lipid peroxidation, antioxidant defense, and inflammatory responses, with attention to recently emerging molecular evidence and to the distinction between direct findings from bone- and joint-related tissues and supportive evidence from non-skeletal systems. Current direct evidence is concentrated mainly in osteoblast-related bone loss and osteoarthritis and is derived predominantly from animal and cellular studies, whereas direct clinical evidence in humans remains limited. Overall, available evidence supports ferroptosis as a potential mechanistic link between aerobic exercise and skeletal protection, but its role in mediating exercise-induced benefits in humans has yet to be established. Further clinical validation of this relationship may help clarify the biological basis of aerobic exercise interventions and support the development of more targeted exercise strategies for the prevention and management of skeletal disorders. Full article

(This article belongs to the Topic Bone-Related Diseases: From Molecular Mechanisms to Therapy Development—2nd Edition)

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14 pages, 12214 KB

Open AccessArticle

An Intact PHD Finger and PHD-BRD Interdomain Linker Are Crucial for Binding of the Chromatin Remodeler Factor TIP5 to the Histone Octamer

by Pavel Čabart

Biomolecules 2026, 16(8), 1209; https://doi.org/10.3390/biom16081209 - 19 Aug 2026

Viewed by 410

Abstract

The bromodomain adjacent to zinc finger (BAZ) family protein TIP5 (transcription termination factor I (TTF-I)/interacting protein 5) contains a plant homeodomain (PHD) zinc finger module that recognizes unmodified histone H3 lysine 4. This study demonstrates that the immobilized PHD domain recruits the histone [...] Read more.

The bromodomain adjacent to zinc finger (BAZ) family protein TIP5 (transcription termination factor I (TTF-I)/interacting protein 5) contains a plant homeodomain (PHD) zinc finger module that recognizes unmodified histone H3 lysine 4. This study demonstrates that the immobilized PHD domain recruits the histone octamer complex. Depletion of zinc cations from the finger or disruption via mutagenesis completely abolished this interaction. Interestingly, the binding ability of the depleted protein was partially recovered under high concentrations of KCl. Extending the PHD domain with a PHD-bromodomain (BRD) interdomain linker led to a substantial increase in binding affinity, with the magnitude progressively dependent on the linker length. To gain insight into these preferential binding interfaces, AlphaFold 3 structure predictions were performed. Within the histone octamer complex, histone H3 was identified as a primary, but not sole, binding partner for TIP5 partial proteins. An increase in predicted total van der Waals interactions correlated with the presence of the linker and its extension; however, an anomaly stemming from the calculated stickiness of the short linker version was encountered. Increased hydrogen-bonding in models with the short linker mirrored the observed affinity. Conversely, the long linker reduced predicted hydrogen (H)-bonds below that for the PHD alone. Finally, structural analysis of the disrupted zinc finger motif revealed the fewest hydrogen bonds. Full article

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

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28 pages, 1390 KB

Open AccessReview

The Prospective Regulatory Functions of lncRNAs and Their ceRNA Networks in the Development of Motor Neurons and Associated Diseases

by Zhenzhen Wang, Yuhan Fu, Siqi Li, Yan Zhang, Tao Sun and Nan Miao

Biomolecules 2026, 16(8), 1208; https://doi.org/10.3390/biom16081208 - 19 Aug 2026

Viewed by 606

Abstract

Motor neurons form a highly specialized network composed of α-, β-, and γ-subtypes that coordinate skeletal muscle activity. Motor neuron diseases (MNDs), including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are characterized by the progressive degeneration of this network, resulting in [...] Read more.

Motor neurons form a highly specialized network composed of α-, β-, and γ-subtypes that coordinate skeletal muscle activity. Motor neuron diseases (MNDs), including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are characterized by the progressive degeneration of this network, resulting in motor dysfunction. Emerging evidence underscores the significant roles of long non-coding RNAs (lncRNAs) in motor neuron development and disease. However, only a few have been experimentally confirmed as true ceRNA regulators, highlighting the need to differentiate validated mechanisms from mere associations or predictions. This review summarizes the regulatory roles of lncRNA-associated ceRNA networks in motor neuron development, evaluates the evidence for their involvement in MNDs, and explores their potential impact on disease progression. It also addresses current challenges, knowledge gaps, and future research directions for understanding ceRNA-mediated mechanisms and developing therapeutic strategies for MNDs. Full article

(This article belongs to the Special Issue Emerging Roles of Non-Coding RNAs in Gene Regulation and Disease)

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29 pages, 10497 KB

Open AccessArticle

Hair Growth-Supporting and Follicle-Protective Potential of a Botanical-Based Supplement Ingredient: In Vitro, Ex Vivo, and Molecular Docking Studies

by Adrián García, Andrea Cavagnino, Pau Navarro, Olivier Gouin, Cristina Guillem, Anaïs Bobier, Cristina Calabuig and Nuria Caturla

Biomolecules 2026, 16(8), 1207; https://doi.org/10.3390/biom16081207 - 18 Aug 2026

Viewed by 1702

Abstract

Hair follicle homeostasis is influenced by hormonal pathways, the scalp microenvironment, and environmental stressors such as pollution, UV radiation, and oxidative stress. Elissara^®, a polyphenol-enriched botanical ingredient, has shown benefits for scalp moisturization, barrier function, sebum regulation, and redness. Building on [...] Read more.

Hair follicle homeostasis is influenced by hormonal pathways, the scalp microenvironment, and environmental stressors such as pollution, UV radiation, and oxidative stress. Elissara^®, a polyphenol-enriched botanical ingredient, has shown benefits for scalp moisturization, barrier function, sebum regulation, and redness. Building on these scalp-level benefits, we investigated Elissara’s effects on follicular signaling, survival-associated biomarkers, oxidative damage, and androgen-related pathways as potential contributors to follicular health, using in silico, in vitro, and ex vivo models. Molecular docking (AutoDock Vina) of the main Elissara bioactives (oleuropein, hydroxytyrosol, verbascoside, carnosic acid, carnosol, and quercetin) identified SRD5A2 as a favorable predicted target, with individual binding energies ranging from −8.70 to −9.73 kcal/mol, approaching finasteride/dutasteride reference values. As an exploratory approach, simultaneous multi-ligand docking showed favorable global docking outputs for several targets, indicating that multiple bioactives could be structurally accommodated within complementary regions of the binding site. In human follicle dermal papilla cells, Elissara significantly increased BrdU incorporation to 245.70% of control at 0.002% and reduced SRD5A2 protein levels by 18.48% at 0.006%. In human scalp explants, Elissara at 200 µg/mL increased β-catenin, Bcl-2, and collagen IV under basal conditions and counteracted acute PM_2.5/UVA-induced alterations in β-catenin, Ki67-positive cells, Bcl-2, IGF-1, collagen IV, and protein carbonylation. Together, these findings support the potential of Elissara as a promising nutricosmetic ingredient for supporting follicular resilience through multiple follicle-relevant pathways. Clinical studies assessing hair growth outcomes are needed to determine whether these preclinical findings translate into measurable benefits. Full article

(This article belongs to the Topic Bioactive Compounds with Application Potentials in Nutraceuticals and Nutricosmetics: Focus on Mechanism of Action and Application Science—2nd Edition)

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16 pages, 1550 KB

Open AccessReview

Shared Major Metabolic Pathways and Potential Targeted Therapies in Malignancies and Systemic Lupus Erythematosus

by Jaron Dalgleish, Maurice Tohme, Michael D. Pisano and Wen-Hai Shao

Biomolecules 2026, 16(8), 1206; https://doi.org/10.3390/biom16081206 - 18 Aug 2026

Viewed by 491

Abstract

Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disease characterized by immune tolerance breakdown, immune cell dysfunction, and chronic inflammation. Cancer is a serious health problem and the second leading cause of mortality worldwide. Emerging evidence underscores the key role of metabolic dysregulation [...] Read more.

Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disease characterized by immune tolerance breakdown, immune cell dysfunction, and chronic inflammation. Cancer is a serious health problem and the second leading cause of mortality worldwide. Emerging evidence underscores the key role of metabolic dysregulation and the association with immunity and immune-related complications in cancer and SLE. Enhanced glycolysis and OXPHOS have been repeatedly reported in both diseases. Metabolic reprogramming is common in cancer cells and immune cells of SLE patients. In many cases, cancer cells and B cells rely on fatty acid oxidation to generate energy. Accordingly, key enzymes in those processes are also upregulated. This review summarizes current findings on major common metabolic dysregulation in cancer and SLE, highlighting the interplay of metabolic disturbances, mitochondrial dysfunction and disease pathogenesis. Furthermore, we explore the potential of targeting metabolic pathways as a therapeutic strategy to mitigate organ damage and improve outcomes in patients with SLE or cancer. We will also discuss the hurdles and prospective developments in metabolism-targeted therapy. We hope this review inspires collaborative work between cancer researchers and SLE clinicians and facilitates clinical application of cancer-metabolism-targeted drug in SLE patients. Full article

(This article belongs to the Special Issue Advancing Innovations in Biomedical Research for Translational Applications: 2nd Edition)

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17 pages, 4279 KB

Open AccessArticle

Inherited Platelet GPIV Deficiency: First Description of a Series of Unrelated Patients with Bleeding Diathesis

by Loredana Bury, Silvia Sorrentino, Emanuela Falcinelli, Giuseppe Guglielmini, Antonietta Ferretti, Paola Concolino, Ana Sánchez-Fuentes, José Rivera, Paolo Gresele and Erica De Candia

Biomolecules 2026, 16(8), 1205; https://doi.org/10.3390/biom16081205 - 18 Aug 2026

Viewed by 543

Abstract

GPIV (CD36) is a multifunctional membrane protein expressed on various cells, including platelets, where it plays a role in adhesion and activation through the interaction with its ligands, including collagen types I and III and thrombospondin 1. Inherited GPIV deficiency, historically recognized in [...] Read more.

GPIV (CD36) is a multifunctional membrane protein expressed on various cells, including platelets, where it plays a role in adhesion and activation through the interaction with its ligands, including collagen types I and III and thrombospondin 1. Inherited GPIV deficiency, historically recognized in anti-Naka alloimmunized East Asian donors, is considered asymptomatic and associated with normal platelet aggregation, although impaired adhesion under high-flow conditions has been reported. Here, we reconsider the molecular basis, epidemiology and functional consequences of GPIV deficiency and report four unrelated patients in whom heterozygous CD36 variants are associated with markedly reduced platelet GPIV expression and a clinically relevant mucocutaneous bleeding diathesis. Patients suffered lifelong bleeding symptoms despite normal light-transmission aggregometry and platelet granule content and release and displayed decreased GPIV expression. Three of them showed slightly decreased VWF. Platelet adhesion to Type I collagen was reduced at high shear. These cases suggest for the first time an association between CD36 gene variants and bleeding and underscore the importance of including GPIV in the diagnostic workup of inherited platelet disorders, particularly when conventional assays do not reveal abnormalities. Full article

(This article belongs to the Collection Feature Papers in Section 'Molecular Medicine')

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15 pages, 10151 KB

Open AccessArticle

Partner of bursicon Regulates Pheromone Gland Development and Sex Pheromone Biosynthesis in Helicoverpa armigera

by Ziling Tang, Yuhao Liu, Huanhuan Zhang, Qing Zhai, Liuyi Fan, Xin Zhang, Du Li, Long Chen and Xiang Li

Biomolecules 2026, 16(8), 1204; https://doi.org/10.3390/biom16081204 - 18 Aug 2026

Viewed by 432

Abstract

Bursicon, a heterodimeric neuropeptide composed of Burs-α and its binding subunit Partner of bursicon (Pburs), is primarily known to regulate insect cuticle tanning and also participates in wing expansion, reproduction and immunity. Pburs is highly expressed during pheromone gland (PG) maturation [...] Read more.

Bursicon, a heterodimeric neuropeptide composed of Burs-α and its binding subunit Partner of bursicon (Pburs), is primarily known to regulate insect cuticle tanning and also participates in wing expansion, reproduction and immunity. Pburs is highly expressed during pheromone gland (PG) maturation in female Helicoverpa armigera, a major agricultural pest, indicating its potential role in PG development and function. In this study, we cloned the full-length coding sequence of HaPburs and verified its high conservation across insects. qPCR revealed PG transcripts peaking at 48 h post-emergence in scotophase. RNAi-mediated knockdown reduced HaPburs transcript levels by 60.01%, resulting in abnormal PG morphology characterized by irregular melanized protrusions. Silencing HaPburs lowered the major sex pheromone component (Z)-11-hexadecenal by 42.66%, reduced male attraction and mating rates to 59.15% and 56.25% of controls, and markedly decreased cumulative fecundity. HaPburs-knockdown significantly downregulated the transcription of HaPKA and HaACC, two key genes involved in sex pheromone biosynthesis. These results suggest that HaPburs mediates PG morphogenesis and sex pheromone biosynthesis, further modulating sex pheromone-mediated reproductive communication in H. armigera. The study expands the known reproductive functions of bursicon and provides a promising molecular target for eco-friendly pest management. Full article

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20 pages, 271 KB

Open AccessSystematic Review

Mare’s Milk for Gut Microbiome Restoration and Immune Recovery After COVID-19 in Children and Pregnant Women: A Hypothesis-Generating Systematic Review

by Zhanna Rakhimbayeva, Abdujalil Mussayev, Ainash Oshibayeva, Gulnaz Nuskabayeva, Saltanat Kyrykbayeva, Lazzat Begimbekova, Saltanat Khudaibergenova, Karlygash Sadykova, Zhanar Zhagiparova and Mohamad Aljofan

Biomolecules 2026, 16(8), 1203; https://doi.org/10.3390/biom16081203 - 17 Aug 2026

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Abstract

Background: Mare’s milk has gained attention as a functional food due to its bioactive compounds and potential microbiome-modulating properties. This systematic review evaluated the evidence on its potential role in gut microbiome restoration and immune modulation following COVID-19, particularly in pediatric and maternal [...] Read more.

Background: Mare’s milk has gained attention as a functional food due to its bioactive compounds and potential microbiome-modulating properties. This systematic review evaluated the evidence on its potential role in gut microbiome restoration and immune modulation following COVID-19, particularly in pediatric and maternal populations. Methods: PubMed/MEDLINE, Scopus, Web of Science, and Embase were systematically searched for studies investigating mare’s milk or koumiss and their effects on gut microbiota, immune responses, inflammatory markers, or gastrointestinal outcomes. Results: Eight studies were included: five examined COVID-19-associated gut microbiome alterations, and three investigated the biological effects of mare’s milk or fermented mare’s milk. COVID-19 was consistently associated with reduced microbial diversity, depletion of beneficial bacteria, and enrichment of opportunistic pathogens, with some changes persisting after recovery. Conclusions: Koumiss demonstrates biologically plausible microbiome-modulating and immunoregulatory properties that may support recovery from COVID-19-associated gut dysbiosis. However, current evidence remains indirect, and clinical studies are needed before recommendations can be made. Full article

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

17 pages, 7645 KB

Open AccessArticle

CD6-Directed Immunotherapy Targets Breast Cancer Stem Cell Function and Enhances Immune-Mediated Cytotoxicity in Triple-Negative Breast Cancer

by Mikel Gurrea-Rubio, Sophie Sloan, Aditya Chada, Camila I. Amarista, Kohei Maeda, Phillip L. Campbell, Pei-Suen Tsou, Laura A. Cooney, Max S. Wicha and David A. Fox

Biomolecules 2026, 16(8), 1202; https://doi.org/10.3390/biom16081202 - 17 Aug 2026

Viewed by 445

Abstract

Triple-negative breast cancer (TNBC) is associated with recurrence, metastasis, and limited durable responses to immunotherapy, in part due to persistence of breast cancer stem cells (BCSCs). We investigated whether CD6-directed immunotherapy with the monoclonal antibody UMCD6 enhances immune-mediated killing and alters function of [...] Read more.

Triple-negative breast cancer (TNBC) is associated with recurrence, metastasis, and limited durable responses to immunotherapy, in part due to persistence of breast cancer stem cells (BCSCs). We investigated whether CD6-directed immunotherapy with the monoclonal antibody UMCD6 enhances immune-mediated killing and alters function of BCSC in stem cell-enriched TNBC models. The SUM-149 and SUM-159 cell lines were analyzed for CD6 ligand expression, cocultured with human peripheral blood mononuclear cells (PBMCs) treated with UMCD6, pembrolizumab, or isotype control, and assessed by live-cell cytotoxicity imaging, flow cytometry, soft agar colony formation, and extreme limiting dilution sphere assays. Both TNBC lines co-expressed the CD6 ligands CD44, CD166/ALCAM, and CD318/CDCP1. UMCD6 significantly increased PBMC-mediated apoptosis and reduced tumor cell survival in both models, with greater activity than pembrolizumab under these in vitro conditions. In surviving SUM-159 cells, UMCD6 reduced the ALDH⁺ population wit×hout significantly altering CD44⁺CD24⁻ frequency, indicating preferential effects on a distinct stem-like compartment. Functionally, UMCD6 decreased anchorage-independent colony formation and reduced sphere-forming frequency from 1/33.6 to 1/68.3 cells (p = 0.0186). These findings identify the CD6 ligand axis as a therapeutic vulnerability in BCSC-enriched TNBC and support further preclinical evaluation of CD6-directed immunotherapy as a strategy to enhance antitumor immunity while limiting tumor-initiating capacity. Full article

(This article belongs to the Special Issue CD5 and CD6 Immunobiology: Multitask Immunomodulatory Molecules in Infection, Cancer and Autoimmunity)

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15 pages, 889 KB

Open AccessFeature PaperArticle

Integrated Analysis of CRY1 Gene Expression and InDel Polymorphism Reveals Associations with Ovarian Morphological Traits in Chinese Holstein Dairy Cattle

by Xuanbo Chen, Enhui Jiang, Yuta Yang, Haotian Zhang, Zhaoyu Liu, Ebadu Areb, Yongsheng Wang and Xianyong Lan

Biomolecules 2026, 16(8), 1201; https://doi.org/10.3390/biom16081201 - 17 Aug 2026

Viewed by 318

Abstract

Clock genes, such as cryptochrome 1 (CRY1), exhibit rhythmic expression in the reproductive organs. This gene is a key component of the circadian clock and is involved in various physiological processes, including reproduction, suggesting that it may be linked to ovarian [...] Read more.

Clock genes, such as cryptochrome 1 (CRY1), exhibit rhythmic expression in the reproductive organs. This gene is a key component of the circadian clock and is involved in various physiological processes, including reproduction, suggesting that it may be linked to ovarian activity via neuroendocrine pathways. However, the association between CRY1 variants and ovarian traits in dairy cows is unclear. In this study we used qRT-PCR to assay the mRNA expression of this gene, and found that CRY1 expression was highest in oocytes in several tissues; subsequently, we found that CRY1 expression was highest in the ovary in Chinese Holstein dairy cattle, followed by muscle and spleen tissues (p < 0.01). Next, we identified a six bp insertion/deletion (indel) locus within the CRY1 gene in Chinese Holstein dairy cattle. Only two genotypes were detected: II (n = 854, 83.7%) and ID (n = 166, 16.3%). Association analysis revealed that the identified indel was significantly associated with dominant follicle and corpus albicans diameters (p < 0.05) during metestrus. Specifically, individuals with the ID genotype exhibited smaller dominant follicles and corpus albicans than those with the II genotype. Our preliminary findings suggest that CRY1 is associated with specific ovarian morphological traits and may serve as a basis for further investigation of its potential role in bovine reproductive function. Full article

(This article belongs to the Special Issue Vertebrate Comparative Genomics)

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20 pages, 410 KB

Open AccessArticle

The Tyrolean Founder MLH1 Variant c.836T>G Causes Lynch Syndrome Due to a Leaky Splice Effect

by Sukanya Horpaopan, Esther Schamschula, Heidelinde Fiegl, Hannes Dapoz, Christina Lutz-Nicoladoni, Simon Schnaiter, Albert Amberger, Ulrich Strasser, Renate Lunzer, Andreas von der Heidt, Katalin Csanaky, Johannes Zschocke and Katharina Wimmer

Biomolecules 2026, 16(8), 1200; https://doi.org/10.3390/biom16081200 - 17 Aug 2026

Viewed by 587

Abstract

The identification of a pathogenic variant (PV) in one of the mismatch repair (MMR) genes confirms the diagnosis of Lynch syndrome (LS). Hence, the correct classification of MMR gene variants is of utmost importance for appropriate counselling, surveillance, and treatment of LS patients [...] Read more.

The identification of a pathogenic variant (PV) in one of the mismatch repair (MMR) genes confirms the diagnosis of Lynch syndrome (LS). Hence, the correct classification of MMR gene variants is of utmost importance for appropriate counselling, surveillance, and treatment of LS patients and their families. In 7/200 unrelated Tyrolean-suspected LS patients, we identified the rare variant MLH1:c.836T>G. Clinical and tumor data strongly indicate that this founder variant is associated with an increased risk for early-onset LS-associated tumors. We also demonstrate that the variant leads to aberrant mRNA splicing. However, the splice effect’s leakiness together with the small effect of the amino acid change p.(Val297Gly) encoded by the residual full-length transcripts in a functional assay preclude its formal classification as (likely) PV according to internationally accepted variant interpretation guidelines. The family histories of the carriers suggest that the obstacles to classify the variant as (likely) PV may be related with a reduced penetrance. Nonetheless, and despite the formal classification of MLH1:c.836T>G as a variant of uncertain significance, we show that carriers should undergo cancer surveillance and predictive testing should be offered to relatives. This variant illustrates the need for an improved classification framework for appropriate categorization of lower-penetrance alleles. Full article

(This article belongs to the Section Molecular Medicine)

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30 pages, 1808 KB

Open AccessReview

MicroRNAs: A Social Network in Diabetic Retinopathy

by Sheila Ngumbi, Mohamed S. Gad, Kara Ye, Sarah Ye, Christie Taylor, Mostafa Mahrous and Manuela Bartoli

Biomolecules 2026, 16(8), 1199; https://doi.org/10.3390/biom16081199 - 17 Aug 2026

Viewed by 578

Abstract

In recent years, the role of non-coding RNAs in human physiology and pathology has emerged as an essential avenue of investigation. Among others, studies identifying the biological role of microRNAs (miRNAs) have paved the way for future inquiries on the importance and biological [...] Read more.

In recent years, the role of non-coding RNAs in human physiology and pathology has emerged as an essential avenue of investigation. Among others, studies identifying the biological role of microRNAs (miRNAs) have paved the way for future inquiries on the importance and biological significance of non-coding RNAs. In this review, we provide an overview of miRNAs’ biology and their contribution to the pathogenesis of diabetic retinopathy (DR). This complication of diabetes is the leading cause of blindness in adults, affecting more than 4 million people in the US alone and over 103 million people worldwide. Despite the tremendous efforts of the scientific community and the pharmaceutical industry, the development of new, more effective therapeutic and diagnostic tools for DR to date remains an unmet need. More than a decade from the initial work assessing miRNA expression profiles in diabetic patients, we have learned the impact of these signaling molecules in DR and garnered knowledge of their complexity and their potential as new diagnostic and therapeutic targets for this potentially blinding condition. Full article

(This article belongs to the Section Molecular Medicine)

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19 pages, 32151 KB

Open AccessArticle

Acquired Resistance to the PRMT5 Inhibitor Confers Collateral Sensitivity to MEK Inhibition in MTAP-Null Non-Small Cell Lung Cancer

by Rongjie Fu, Yalong Wang, Ishita Rehman, Ella Bedford, Sana Sharif, Nghi D. Nguyen, Reid T. Powell, Andrew Adams, Weijun Liu, Shuyue Wang, Wei He, Yue Lu, Bin Liu, Pooja Anil Shah, Jordi Rodon Ahnert, Taiping Chen, Weiyi Peng, Clifford C. Stephan, Xinli Liu, Mark T. Bedford and Han Xu Show full author list Hide full author list

Biomolecules 2026, 16(8), 1198; https://doi.org/10.3390/biom16081198 - 17 Aug 2026

Viewed by 699

Abstract

Protein arginine methyltransferase 5 (PRMT5) is a synthetic lethal target in methylthioadenosine phosphorylase-deleted (MTAP-null) cancers. Second-generation methylthioadenosine (MTA)-cooperative PRMT5 inhibitors preferentially target MTAP-null cells while largely sparing MTAP-wildtype (MTAP-WT) cells, thereby improving tumor selectivity over first-generation PRMT5 [...] Read more.

Protein arginine methyltransferase 5 (PRMT5) is a synthetic lethal target in methylthioadenosine phosphorylase-deleted (MTAP-null) cancers. Second-generation methylthioadenosine (MTA)-cooperative PRMT5 inhibitors preferentially target MTAP-null cells while largely sparing MTAP-wildtype (MTAP-WT) cells, thereby improving tumor selectivity over first-generation PRMT5 inhibitors. Despite encouraging efficacy and safety signals in early clinical studies, the modest objective response rates (ORRs) observed with these inhibitors suggest that intrinsic or acquired resistance may limit their clinical benefit. Here, we investigated acquired resistance to the MTA-cooperative PRMT5 inhibitor BMS-986504/MRTX1719 in MTAP-null non-small cell lung cancer (NSCLC) cells and sought to identify therapeutic vulnerabilities that emerge upon resistance. Using multiple in vitro-derived resistant models, we found that acquired resistance was accompanied by cross-resistance to mechanistically distinct PRMT5 inhibitors. Notably, this phenotype was not fully explained by altered PRMT5 activity or changes in MTA levels. High-throughput drug screening of paired sensitive and resistant cells revealed increased sensitivity to MEK inhibitors following acquisition of MRTX1719 resistance in KRAS-wildtype NSCLC cells. Consistently, resistant cells exhibited rewired MAPK-related transcriptional programs. Together, these findings identify MEK inhibition as a reproducible collateral vulnerability associated with acquired MRTX1719 resistance in MTAP-null NSCLC models and support further evaluation of MEK inhibition as a potential treatment-switching strategy following resistance. Full article

(This article belongs to the Special Issue Protein Arginine Methylation: Functions, Mechanisms, and Therapeutic Implications)

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15 pages, 795 KB

Open AccessReview

Pyrroloquinoline Quinone (PQQ) as a Mitochondrial Rejuvenation Strategy in Aesthetic Dermatology: Mechanisms, Therapeutic Potential, and Future Clinical Applications

by Kyu-Ho Yi

Biomolecules 2026, 16(8), 1197; https://doi.org/10.3390/biom16081197 - 17 Aug 2026

Viewed by 592

Abstract

Background: Mitochondrial dysfunction is increasingly recognized as a central contributor to intrinsic skin aging, photoaging, cellular senescence, impaired extracellular-matrix homeostasis, dysregulated pigmentation, and delayed recovery after energy-based or minimally invasive procedures. Pyrroloquinoline quinone (PQQ) is a redox-active ortho-quinone that has attracted interest because [...] Read more.

Background: Mitochondrial dysfunction is increasingly recognized as a central contributor to intrinsic skin aging, photoaging, cellular senescence, impaired extracellular-matrix homeostasis, dysregulated pigmentation, and delayed recovery after energy-based or minimally invasive procedures. Pyrroloquinoline quinone (PQQ) is a redox-active ortho-quinone that has attracted interest because it can participate in repeated redox cycling, protect mitochondrial function, and activate signaling associated with mitochondrial biogenesis. Objective: This narrative review evaluates the mechanistic basis, available dermatologic evidence, translational opportunities, and major uncertainties surrounding PQQ as a mitochondrial rejuvenation strategy in aesthetic dermatology. Methods: PubMed/MEDLINE and Europe PMC were searched from database inception through 10 August 2026 using PQQ-, mitochondrial-, skin-, delivery-, and safety-related terms; reference lists were also screened. Mechanistic, preclinical, skin-focused, human, and regulatory evidence was synthesized narratively. Results: Experimental studies support PQQ-mediated activation of mitochondrial biogenesis pathways and protection against oxidative injury in several cell and animal systems. Skin-specific evidence includes attenuation of oxidative stress, DNA damage, senescence markers, and matrix metalloproteinases in accelerated-aging mouse models; protection of UVA-exposed human dermal fibroblasts; suppression of UVB-induced caspase-1 release in keratinocytes; a small oral dry-skin study; and a multi-ingredient topical study containing an allyl PQQ derivative. These studies do not establish PQQ-specific clinical aesthetic efficacy. Conclusion: PQQ is a biologically plausible mitochondrial-support compound, but it should currently be regarded as an investigational ingredient rather than an established aesthetic treatment. Carefully designed formulation, toxicology, dose-finding, biomarker, and randomized clinical studies are required before claims regarding wrinkle reduction, pigment improvement, enhanced collagen production, or accelerated post-procedure recovery can be justified. Full article

(This article belongs to the Special Issue Bioactive Compounds in Dermatology)

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15 pages, 1250 KB

Open AccessFeature PaperArticle

Two Faces of the Right Ventricle in Fabry Cardiomyopathy: Septal-Coupled and Atrial-Coupled Strain Patterns and Their Differential Associations with Enzyme Replacement Therapy

by Kuo-Tzu Sung, Dau-Ming Niu, Shu-Fen Hsu, Ming-En Liu, Po-Lin Lin, Yau-Huei Lai, Hsiang-Wei Yang, Yung-Hsiu Lu, Cheng-Ting Tsai, Ta-Chuan Hung, Po-Sheng Chen and Chung-Lieh Hung

Biomolecules 2026, 16(8), 1196; https://doi.org/10.3390/biom16081196 - 17 Aug 2026

Viewed by 367

Abstract

Right ventricular global longitudinal strain (RVGLS) and right ventricular free-wall longitudinal strain (RVFWLS) are both used to assess right ventricular involvement, but they include different myocardial components. We examined their cross-sectional correlates and longitudinal changes associated with enzyme replacement therapy (ERT) in 100 [...] Read more.

Right ventricular global longitudinal strain (RVGLS) and right ventricular free-wall longitudinal strain (RVFWLS) are both used to assess right ventricular involvement, but they include different myocardial components. We examined their cross-sectional correlates and longitudinal changes associated with enzyme replacement therapy (ERT) in 100 patients with genetically confirmed Fabry disease, including 69 with serial echocardiography. RVGLS was independently associated with left ventricular global longitudinal strain (LVGLS; standardized β = 0.466, p < 0.001) and interventricular septal thickness (standardized β = 0.257, p = 0.027), whereas RVFWLS was independently associated with right atrial reservoir strain (standardized β = −0.542, p < 0.001). RVGLS and RVFWLS were not significantly correlated (r = 0.053, p = 0.654). In the paired RV strain subgroup, longitudinal RVGLS change differed between untreated and ERT-treated patients (+2.06 ± 3.94% vs. −1.28 ± 3.64%, p = 0.017), whereas RVFWLS change did not (p = 0.838). In a sensitivity model adjusted for age, sex, genotype, and baseline RVGLS, ERT remained associated with ΔRVGLS (β = −3.28 percentage points, 95% CI −5.25 to −1.32; p = 0.001). These findings identify different correlates of septal-inclusive and free-wall RV strain and require prospective validation. Full article

(This article belongs to the Section Molecular Medicine)

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28 pages, 9970 KB

Open AccessArticle

Domestication-Driven Expansion and Structural Convergence of the Porcine Antiviral Interferon Repertoire

by Jiuyi Li, Niya Tu, Laura C. Miller and Yongming Sang

Biomolecules 2026, 16(8), 1195; https://doi.org/10.3390/biom16081195 - 17 Aug 2026

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Abstract

The porcine interferon (IFN) system is highly diversified, particularly within Type I subfamilies, yet its evolutionary trajectory across domestication and breed formation remains poorly characterized. We performed a comprehensive comparative genomic and structural analysis of 432 IFN sequences spanning all IFN types across [...] Read more.

The porcine interferon (IFN) system is highly diversified, particularly within Type I subfamilies, yet its evolutionary trajectory across domestication and breed formation remains poorly characterized. We performed a comprehensive comparative genomic and structural analysis of 432 IFN sequences spanning all IFN types across 11 Sus scrofa breeds representing commercial, indigenous, and wild/outgroup lineages. Phylogenetic reconstruction, pairwise dN/dS selection pressure analysis, and AlphaFold2-based 3D structure prediction coupled with DALI structural similarity mapping were integrated to resolve repertoire architecture, evolutionary constraints, and domestication-associated divergence. IFN repertoire organization is governed primarily by family identity rather than breed origin, with Type I IFN-α, -δ, and -ω subfamilies showing pronounced gene expansion in domestic breeds. Phylogenetic clustering and structural similarity consistently grouped sequences by subtype, independent of domestication history. Pervasive purifying selection (median ω = 0.48) maintained functional constraints across all lineages. Commercial breeds exhibited significantly higher within-category structural convergence alongside expanded repertoires, while structural conservation was evolutionarily decoupled from sequence-level selective pressure. Domestication potentially drove coordinated IFN repertoire expansion and structural conservation with related purifying selection at the gene level. These findings establish a genomic framework linking breed-specific IFN architecture to antiviral capacity and provide a foundation for immunogenetic-informed breeding strategies in the swine model. Full article

(This article belongs to the Special Issue Natural Products and Their Derivatives with Antiviral Activity)

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3 pages, 141 KB

Open AccessEditorial

Advancing Molecular Regulation in Brain Injury Research: Mechanisms, Diagnosis, and Rehabilitation

by Guanglin Zhang and Pavan Thapak

Biomolecules 2026, 16(8), 1194; https://doi.org/10.3390/biom16081194 - 17 Aug 2026

Viewed by 284

Abstract

Traumatic brain injury (TBI) and non-acquired brain damage represent a catastrophic global health burden, frequently resulting in persistent neurological impairment, long-term cognitive decline, and increased susceptibility to secondary psychiatric disorders [...] Full article

(This article belongs to the Special Issue Advancing Molecular Regulation in Brain Injury Research: Mechanisms, Diagnosis, and Rehabilitation)

19 pages, 5156 KB

Open AccessReview

Advances in Imaging of Plant Ca²⁺ Signaling

by Zhenzhong Tang, Shuangyuan Fan, Guanhong Lin, Tangtao Yuan and Shuang Yang

Biomolecules 2026, 16(8), 1193; https://doi.org/10.3390/biom16081193 - 15 Aug 2026

Viewed by 513

Abstract

Calcium ions (Ca²⁺) function as ubiquitous second messengers that translate environmental and developmental cues into spatially and temporally defined cellular responses in plants. This review summarizes the cellular architecture and molecular mechanisms that generate, shape, and terminate Ca²⁺ signals, with [...] Read more.

Calcium ions (Ca²⁺) function as ubiquitous second messengers that translate environmental and developmental cues into spatially and temporally defined cellular responses in plants. This review summarizes the cellular architecture and molecular mechanisms that generate, shape, and terminate Ca²⁺ signals, with emphasis on plasma-membrane channels, intracellular stores, pumps, exchangers, and organelle-associated transport systems. We also examine the development of live Ca²⁺ indicators, from chemical dyes and aequorin to ratiometric and single-fluorophore genetically encoded calcium indicators, and discuss principles for selecting sensors for different tissues and subcellular compartments. Recent studies have applied these tools to abiotic stress, plant immunity, polar growth, development, symbiosis, and systemic signaling. Accurate quantitative imaging nevertheless requires careful matching of sensor properties to the target cellular environment and rigorous control of motion, spectral interference, and analytical procedures. Combining improved indicators with advanced microscopy, genetic validation, and standardized data analysis should help connect distinct Ca²⁺ signatures with their molecular origins and physiological roles. Full article

(This article belongs to the Section Molecular Biology)

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17 pages, 15440 KB

Open AccessArticle

DNA Methylation Dynamics in Eisenia andrei Regeneration: The Effects of Time, Region, and a Hypomethylating Agent

by Chayeen Brotzki da Costa, Péter Németh and Péter Engelmann

Biomolecules 2026, 16(8), 1192; https://doi.org/10.3390/biom16081192 - 14 Aug 2026

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Abstract

The impact of epigenetic mechanisms on molecular and cellular processes of regeneration remains a less-investigated field, especially concerning earthworm segment restoration. To evaluate distinct methylated cytosines under different conditions, earthworm segments were collected: decitabine-treated and controls; anterior and posterior amputation; intact and regenerated [...] Read more.

The impact of epigenetic mechanisms on molecular and cellular processes of regeneration remains a less-investigated field, especially concerning earthworm segment restoration. To evaluate distinct methylated cytosines under different conditions, earthworm segments were collected: decitabine-treated and controls; anterior and posterior amputation; intact and regenerated (2- and 4-week). 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) distribution in tissues was assessed by immunohistochemistry (IHC), and in genomic DNA by dot blot. DNA-methyltransferase (DNMT) and ten-eleven translocation (TET) dioxygenase activity was determined by immuno-based colorimetry. DNMT1 and TET gene expressions were verified with real-time PCR. Decitabine treatment reduced 5mC levels in most tissues, persisting in the anterior coelomic cavity (intact and blastemas). 5hmC remained elevated in most tissues, remarkably in 2-week blastemas. In the same period, DNMT and TET presented the highest activity in anterior treated samples compared to other treated periods. Concurrently, DNMT1 gene expression increased prominently in anterior segments, while TET showed the highest expression in both anterior and posterior 2-week treated groups. Thus far, our observations indicate that, despite decitabine’s effect on the DNA methylation machinery of the earthworm model, the region of amputation and the regeneration period also interfere with activity and expression of epigenetic enzymes, affecting 5mC and 5hmC distribution. Full article

(This article belongs to the Special Issue Wound Repair and Regeneration: From Molecular and Cellular Mechanisms to New Approaches)

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32 pages, 4645 KB

Open AccessReview

Mechanobiology of Matricellular Proteins in Bladder Cancer: A Narrative Review and Bioinformatics Analysis

by Alim Turgaliyev, Roman Konovalov, Anton Borissenko and Dieter Riethmacher

Biomolecules 2026, 16(8), 1191; https://doi.org/10.3390/biom16081191 - 14 Aug 2026

Viewed by 624

Abstract

The extracellular matrix (ECM) in cancer differs from healthy tissue in structure, composition, and mechanical properties. Matricellular proteins (MCPs) play important roles in shaping ECM architecture during tissue remodeling. This narrative review, combined with a bioinformatics analysis, examines six major MCP families—Fasciclins, Tenascins, [...] Read more.

The extracellular matrix (ECM) in cancer differs from healthy tissue in structure, composition, and mechanical properties. Matricellular proteins (MCPs) play important roles in shaping ECM architecture during tissue remodeling. This narrative review, combined with a bioinformatics analysis, examines six major MCP families—Fasciclins, Tenascins, Thrombospondins, Small Leucine-Rich Proteoglycans, the SPARC family, and the CCN family—through a mechanobiological lens in bladder cancer. It summarizes current knowledge on the mechanical regulation of MCP expression, their effects on matrix stiffness, and their contributions to bladder cancer progression. Analyses of public datasets reveal that stromal cells are the predominant source of MCPs in the tumor microenvironment. Furthermore, mechanical upregulation and involvement in the formation of stiff ECM highlight MCPs as important players in a mechanotransduction feedback loop. While most MCPs exert pro-tumorigenic effects on bladder cancer cells, several display context-dependent or anti-tumorigenic activities. Existing studies have primarily focused on the isolated effects of MCPs on bladder cancer cell lines in two-dimensional systems or simple subcutaneous xenograft models. Both approaches fail to capture the context-dependent nature of MCPs and their involvement in ECM formation. These findings underscore the need for future studies to investigate the complex effects of MCPs on bladder cancer progression. Full article

(This article belongs to the Special Issue Extracellular Matrix Components and Glycobiology in Cancer: From Mechanisms to Therapeutic Targeting)

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