Biomolecules

15 pages, 1404 KiB

Open AccessArticle

Physiologically Based Pharmacokinetic Modeling for Predicting Drug Levels After Bariatric Surgery: Vardenafil Exposure Before vs. After Gastric Sleeve/Bypass

by Daniel Porat, Oleg Dukhno, Sandra Cvijić and Arik Dahan

Biomolecules 2025, 15(7), 975; https://doi.org/10.3390/biom15070975 (registering DOI) - 7 Jul 2025

Abstract

Bariatric surgery involves major changes in the anatomy and physiology of the gastrointestinal tract, which may alter oral drug bioavailability and efficacy. Phosphodiesterase-5 inhibitor (PDE5i) drugs are the first-line treatment of erectile dysfunction, a condition associated with a higher BMI. In this paper, [...] Read more.

Bariatric surgery involves major changes in the anatomy and physiology of the gastrointestinal tract, which may alter oral drug bioavailability and efficacy. Phosphodiesterase-5 inhibitor (PDE5i) drugs are the first-line treatment of erectile dysfunction, a condition associated with a higher BMI. In this paper, we examine the PDE5i vardenafil for possible post-bariatric changes in solubility/dissolution and absorption. Vardenafil solubility was determined in vitro, as well as ex vivo using aspirated gastric contents from patients prior to vs. following bariatric procedures. Dissolution was tested in vitro under unoperated stomach vs. post-gastric sleeve/bypass conditions. Lastly, the gathered solubility/dissolution data were used to produce an in silico physiologically based pharmacokinetic (PBPK) model (GastroPlus^®), where gastric volume, pH, and transit time, as well as proximal GI bypass (when relevant) were all adjusted for, evaluating vardenafil dissolution, gastrointestinal compartmental absorption, and pharmacokinetics before vs. after different bariatric procedures. pH-dependent solubility was demonstrated for vardenafil with low (pH 7) vs. high solubility (pH 1–5), which was confirmed ex vivo. The impaired dissolution of all vardenafil doses under post-gastric bypass conditions was demonstrated, contrary to complete (100%) dissolution under pre-surgery and post-sleeve gastrectomy conditions. Compared to unoperated individuals, PBPK simulations revealed altered pharmacokinetics post-gastric bypass (but not after sleeve gastrectomy), with 30% lower peak plasma concentration (C_max) and 40% longer time to C_max (T_max). Complete absorption after gastric bypass is predicted for vardenafil, which is attributable to significant absorption from the large intestine. The biopharmaceutics and PBPK analysis indicate that vardenafil may be similarly effective after sleeve gastrectomy as before the procedure. However, results after gastric bypass question the effectiveness of this PDE5i. Specifically, vardenafil’s onset of action might be delayed and unpredictable, negatively affecting the practicality of the intended use. Full article

(This article belongs to the Section Molecular Medicine)

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29 pages, 2523 KiB

Open AccessReview

Viscum coloratum (Komar.) Nakai: A Review of Botany, Phytochemistry, Pharmacology, Pharmacokinetics and Toxicology

by Han Di, Congcong Shen, Shengyu Zhang, Yanhong Wang and Feng Guan

Biomolecules 2025, 15(7), 974; https://doi.org/10.3390/biom15070974 (registering DOI) - 7 Jul 2025

Abstract

Viscum coloratum (Komar.) Nakai (V. coloratum) is a traditional Chinese herbal medicine. It is used in treating rheumatism and paralysis, lumbar and knee soreness, weakness of the muscles and bones, excessive leakage of menstruation, leakage of blood in pregnancy, restlessness of [...] Read more.

Viscum coloratum (Komar.) Nakai (V. coloratum) is a traditional Chinese herbal medicine. It is used in treating rheumatism and paralysis, lumbar and knee soreness, weakness of the muscles and bones, excessive leakage of menstruation, leakage of blood in pregnancy, restlessness of the fetus, dizziness and vertigo. All information about V. coloratum was collected through databases such as PubMed, Google Scholar, Web of Science, and the China National Knowledge Infrastructure and supplemented by consulting classical Chinese medical books. To date, 111 compounds have been isolated and identified from V. coloratum, including flavonoids, phenylpropanoids, terpenoids, diarylheptanoids, alkaloids, other components, and macromolecular compounds, such as polysaccharides and lectins. These chemical components exhibit anti-inflammatory, anticancer, antioxidant, and anti-cardiovascular disease effects, among other beneficial effects. According to the reports, alkaloids, lectins, and other chemical components present in V. coloratum may induce toxicity due to excessive intake or accidental ingestion. However, there are few reports on the toxicology of V. coloratum, and there is a lack of studies on the toxicity of V. coloratum with known in vitro or preclinical activity. It is suggested that further studies on the toxicology of V. coloratum should be conducted in the future. In this paper, the botany, traditional uses, phytochemistry, pharmacology, and pharmacokinetics of V. coloratum are summarized, and the progress and shortcomings in toxicology are discussed, so as to provide a possible direction for future research on V. coloratum. Full article

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

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21 pages, 26512 KiB

Open AccessArticle

Insights into Membrane Damage by α-Helical and β-Sheet Peptides

by Warin Rangubpit, Hannah E. Distaffen, Bradley L. Nilsson and Cristiano L. Dias

Biomolecules 2025, 15(7), 973; https://doi.org/10.3390/biom15070973 (registering DOI) - 7 Jul 2025

Abstract

Peptide-induced disruption of lipid membranes is central to both amyloid diseases and the activity of antimicrobial peptides. Here, we combine all-atom molecular dynamics simulations with biophysical experiments to investigate how four amphipathic peptides interact with lipid bilayers. All peptides adsorb on the membrane [...] Read more.

Peptide-induced disruption of lipid membranes is central to both amyloid diseases and the activity of antimicrobial peptides. Here, we combine all-atom molecular dynamics simulations with biophysical experiments to investigate how four amphipathic peptides interact with lipid bilayers. All peptides adsorb on the membrane surface. Peptide M01 [Ac-(FKFE)₂-NH₂] self-assembles into

β

-sheet nanofibrils that span both leaflets of the membrane, creating water-permeable channels. The other three peptides adopt

α

-helical structures at the water–lipid interface. Peptide M02 [Ac-FFKKFFEE-NH₂], a sequence isomer of M01, does not form

β

-sheet aggregates and is too short to span the bilayer, resulting in no observable water permeation across the membrane. Peptides M03 and M04 are

α

-helical isomers long enough to span the bilayer, with a polar face that allows the penetration of water deep inside the membrane. For the M03 peptide [Ac-(FFKKFFEE)₂-NH₂], insertion into the bilayer starts with the nonpolar N-terminal amino acids penetrating the hydrophobic core of the bilayer, while electrostatic interactions hold negative residues at the C-terminus on the membrane surface. The M04 peptide, [Ac-FFKKFFEEFKKFFEEF-NH₂], is made by relocating a single nonpolar residue from the central region of M03 to the C-terminus. This nonpolar residue becomes unfavorably exposed to the solvent upon insertion of the N-terminal region of the peptide into the membrane. Consequently, higher concentrations of M04 peptides are required to induce water permeation compared to M03. Overall, our comparative analysis reveals how subtle rearrangements of polar and nonpolar residues modulate peptide-induced water permeation. This provides mechanistic insights relevant to amyloid pathology and antimicrobial peptide design. Full article

(This article belongs to the Special Issue New Insights into Protein Aggregation in Condensed and Amyloid States)

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16 pages, 2249 KiB

Open AccessArticle

Elucidating the Role of Toxoplama gondii’s Mitochondrial Superoxide Dismutase

by James Alexander Tirtorahardjo, Christopher I-H. Ma, Areej Shaikh and Rosa M. Andrade

Biomolecules 2025, 15(7), 972; https://doi.org/10.3390/biom15070972 (registering DOI) - 7 Jul 2025

Abstract

Toxoplasma gondii is an Apicomplexan parasite that possesses a well-developed system of scavengers of reactive oxygen species (ROS). Among its components, T. gondii mitochondrial superoxide dismutase (TgSOD2) is essential, as predicted by the CRISPR phenotype index and evidenced by the non-viability of its [...] Read more.

Toxoplasma gondii is an Apicomplexan parasite that possesses a well-developed system of scavengers of reactive oxygen species (ROS). Among its components, T. gondii mitochondrial superoxide dismutase (TgSOD2) is essential, as predicted by the CRISPR phenotype index and evidenced by the non-viability of its constitutive knockouts. As an obligate intracellular parasite, TgSOD2 is upregulated during extracellular stages. Herein, we generated a viable TgSOD2 knockdown mutant using an inducible auxin–degron system to explore the biological role of TgSOD2 in T. gondii. Depletion of TgSOD2 led to impaired parasite growth and replication, reduced mitochondrial membrane potential (MMP), abnormalities in the distribution of ATP synthase within its mitochondrial electron transport chain (mETC), and increased susceptibility to mETC inhibitors. Through a proximal biotinylation approach, we identified the interactions of TgSOD2 with complexes IV and V of its mETC, suggesting that these sites are sensitive to ROS. Our study provides the first insights into the role of TgSOD2 in maintaining its mitochondrial redox homeostasis and subsequent parasite replication fitness. Significance: Toxoplasma gondii infects nearly a third of the world population and can cause fetal miscarriages or life-threatening complications in vulnerable patients. Current therapies do not eradicate the parasite from the human hosts, rendering them at risk of recurrence during their lifetimes. T. gondii has a single mitochondrion, which is well-known for its susceptibility to oxidative damage that leads to T. gondii’s death. Therefore, targeting T. gondii mitochondrion remains an attractive therapeutic strategy for drug development. T. gondii’s mitochondrial superoxide dismutase is an antioxidant protein in the parasite mitochondrion and is essential for its survival. Understanding its biological role could reveal mitochondrial vulnerabilities in T. gondii and provide new leads for the development of effective treatments for T. gondii infections. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Infectious Pathogen Adaptation, Emergence, and Re-emergence)

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32 pages, 4364 KiB

Open AccessArticle

Predictive and Prognostic Relevance of ABC Transporters for Resistance to Anthracycline Derivatives

by Rümeysa Yücer, Rossana Piccinno, Ednah Ooko, Mona Dawood, Gerhard Bringmann and Thomas Efferth

Biomolecules 2025, 15(7), 971; https://doi.org/10.3390/biom15070971 (registering DOI) - 6 Jul 2025

Abstract

Anthracyclines have been clinically well established in cancer chemotherapy for decades. The main limitations of this drug class are the development of resistance and severe side effects. In the present investigation, we analyzed 30 anthracyclines in a panel of 59 cell lines of [...] Read more.

Anthracyclines have been clinically well established in cancer chemotherapy for decades. The main limitations of this drug class are the development of resistance and severe side effects. In the present investigation, we analyzed 30 anthracyclines in a panel of 59 cell lines of the National Cancer Institute, USA. The log₁₀IC₅₀ values varied from −10.49 M (3′-deamino-3′-(4″-(3″-cyano)morpholinyl)-doxorubicin, 1) to −4.93 M (N,N-dibenzyldaunorubicin hydrochloride, 30). Multidrug-resistant NCI-ADR-Res ovarian cancer cells revealed a high degree of resistance to established anthracyclines (between 18-fold to idarubicin (4) and 166-fold to doxorubicin (13) compared to parental, drug-sensitive OVCAR8 cells). The resistant cells displayed only low degrees of resistance (1- to 5-fold) to four other anthracyclines (7, 18, 28, 30) and were even hypersensitive (collaterally sensitive) to two compounds (1, 26). Live cell time-lapse microscopy proved the cross-resistance of the three chosen anthracyclines (4, 7, 9) on sensitive CCRF/CEM and multidrug-resistant CEM/ADR5000 cells. Structure–activity relationships showed that the presence of tertiary amino functions is helpful in avoiding resistance, while primary amines rather increased resistance development. An α-aminonitrile function as in compound 1 was favorable. Investigating the mRNA expression of 49 ATP-binding cassette (ABC) transporter genes showed that ABCB1/MDR1 encoding P-glycoprotein was the most important one for acquired and inherent resistance to anthracyclines. Molecular docking demonstrated that all anthracyclines bound to the same binding domain at the inner efflux channel side of P-glycoprotein with high binding affinities. Kaplan–Meier statistics of RNA sequencing data of more than 8000 tumor biopsies of TCGA database revealed that out of 23 tumor entities high ABCB1 expression was significantly correlated with worse survival times for acute myeloid leukemia, multiple myeloma, and hepatocellular carcinoma patients. This indicates that ABCB1 may serve as a prognostic marker in anthracycline-based chemotherapy regimens in these tumor types and a target for the development of novel anthracycline derivatives. Full article

(This article belongs to the Special Issue Current Advances in ABC Transporters in Physiology and Disease)

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Graphical abstract

24 pages, 1289 KiB

Open AccessReview

Targeting Mitochondrial Quality Control for the Treatment of Triple-Negative Breast Cancer: From Molecular Mechanisms to Precision Therapy

by Wanjuan Pei, Ling Dai, Mingxiao Li, Sihui Cao, Yili Xiao, Yan Yang, Minghao Ma, Minjie Deng, Yang Mo and Mi Liu

Biomolecules 2025, 15(7), 970; https://doi.org/10.3390/biom15070970 (registering DOI) - 5 Jul 2025

Abstract

Breast cancer is the leading threat to the health of women, with a rising global incidence linked to social and psychological factors. Among its subtypes, triple-negative breast cancer (TNBC), which lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth [...] Read more.

Breast cancer is the leading threat to the health of women, with a rising global incidence linked to social and psychological factors. Among its subtypes, triple-negative breast cancer (TNBC), which lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, is highly heterogeneous with early metastasis and a poor prognosis, making it the most challenging subtype. Mounting evidence shows that the mitochondrial quality control (MQC) system is vital for maintaining cellular homeostasis. Dysfunction of the MQC is tied to tumor cell invasiveness, metastasis, and chemoresistance. This paper comprehensively reviews the molecular link between MQC and TNBC development. We focused on how abnormal MQC affects TNBC progression by influencing chemoresistance, immune evasion, metastasis, and cancer stemness. On the basis of current studies, new TNBC treatment strategies targeting key MQC nodes have been proposed. These findings increase the understanding of TNBC pathogenesis and offer a theoretical basis for overcoming treatment challenges, providing new research angles and intervention targets for effective precision therapy for TNBC. Full article

(This article belongs to the Section Cellular Biochemistry)

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19 pages, 2139 KiB

Open AccessArticle

Methionine Restriction Differentially Modulates Expression of Genes in the Base Excision Repair Pathway in Rat Brain and Liver

by Ricardo Gredilla, Monica Lopez-Torres and Ines Sanchez-Roman

Biomolecules 2025, 15(7), 969; https://doi.org/10.3390/biom15070969 (registering DOI) - 5 Jul 2025

Abstract

Methionine restriction (MetR) is a dietary intervention that extends mean and maximum life span in rodents, at least in part, by reducing oxidative stress and promoting DNA stability in different tissues. Regarding DNA stability, DNA repair pathways play a critical role, both in [...] Read more.

Methionine restriction (MetR) is a dietary intervention that extends mean and maximum life span in rodents, at least in part, by reducing oxidative stress and promoting DNA stability in different tissues. Regarding DNA stability, DNA repair pathways play a critical role, both in the nuclear and mitochondrial fractions. Base excision repair (BER) is the main one involved in the repair of oxidative damage, as well as the main one in mitochondria. Despite the relevance of DNA repair in DNA maintenance, it is not known whether MetR regulates BER as a mechanism of preserving genomic stability. In this study we analyzed, for the first time, the effect of 40% MetR for 7 weeks on BER in rat brain cortex and liver, focusing on the expression of several key BER genes. In the brain cortex, MetR significantly increased the gene expression of the DNA glycosylase Ogg1 and the DNA endonuclease Ape1 while reducing DNA polymerase γ gene expression. Conversely, MetR led to a general reduction in the expression of BER genes in the liver. Our findings highlight a tissue-specific regulation of the BER gene expression in response to MetR. Different potential mechanisms underlying these changes in BER, such as DNA methylation or activation of signaling pathways, are discussed. Full article

(This article belongs to the Special Issue Mitochondrial ROS in Health and Disease)

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22 pages, 881 KiB

Open AccessReview

The Regulatory Role of LncRNAs in Modulating Autophagy and Drug Resistance in Non-Small-Cell Lung Cancer: Focus on Targeted Therapeutic Approaches

by Shuncai Dai, Yuxin Zhong, Jianfu Lu and Linjiang Song

Biomolecules 2025, 15(7), 968; https://doi.org/10.3390/biom15070968 (registering DOI) - 5 Jul 2025

Abstract

Lung cancer remains one of the leading causes of death associated with cancer globally, with non-small cell lung cancer (NSCLC) accounting for 80–85% of all lung cancer cases. Despite its high prevalence, the underlying mechanisms of NSCLC have not been completely clarified, and [...] Read more.

Lung cancer remains one of the leading causes of death associated with cancer globally, with non-small cell lung cancer (NSCLC) accounting for 80–85% of all lung cancer cases. Despite its high prevalence, the underlying mechanisms of NSCLC have not been completely clarified, and current therapeutic strategies face significant limitations. Recent research has revealed the important role of long non-coding RNAs (lncRNAs) in NSCLC, particularly in regulating processes such as autophagy and drug resistance. LncRNAs are a class of non-coding RNA molecules, typically with transcript lengths exceeding 200 nucleotides, and have been the subject of extensive investigation in recent years. Their involvement in critical cellular processes has opened up new research avenues for precision medicine in NSCLC. This review aims to offer a comprehensive analysis of the mechanisms by which lncRNAs regulate autophagy and drug resistance in NSCLC, explore their potential clinical applications as diagnostic biomarkers and therapeutic targets, and provide both theoretical foundations and practical guidance to advance precision medicine in this area. By deepening our understanding of the role of lncRNAs in NSCLC, this article also highlights the promising potential of lncRNA-based approaches for the diagnosis and treatment of this disease. Full article

(This article belongs to the Section Cellular Biochemistry)

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16 pages, 1810 KiB

Open AccessReview

A Review of Desmopressin Use in Bleeding Disorders: An Unsung Hero?

by Benjamin Reardon, Leonardo Pasalic and Emmanuel J. Favaloro

Biomolecules 2025, 15(7), 967; https://doi.org/10.3390/biom15070967 (registering DOI) - 5 Jul 2025

Abstract

As a synthetic analogue of vasopressin, desmopressin or DDAVP has well established hemostatic properties. We present a review of DDAVP and summarize the clinical and laboratory evidence for its use in hemophilia A, von Willebrand disease (VWD), platelet function disorders, uremia, liver cirrhosis, [...] Read more.

As a synthetic analogue of vasopressin, desmopressin or DDAVP has well established hemostatic properties. We present a review of DDAVP and summarize the clinical and laboratory evidence for its use in hemophilia A, von Willebrand disease (VWD), platelet function disorders, uremia, liver cirrhosis, and pregnancy, followed by illustrative examples of its broad efficacy from our local practice. In brief, DDAVP acts to release von Willebrand factor (VWF) and factor VIII from endogenously stored reserves, thereby correcting plasma deficiencies present in mild to moderately affected patients with hemophilia A and VWD. Thus, DDAVP represents a non-transfusional therapy for these disorders. Typically, a trial of DDAVP is arranged to assess individual responsiveness before employing DDAVP clinically, since there is individual variation in responsiveness. Thereafter, DDAVP can be utilized in responsive patients for clinical use and provides a factor replacement sparing strategy in these patients for some clinical situations. Nevertheless, DDAVP is best applied as a factor replacement sparing strategy, especially for minor procedures or short-term use. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms in Anti-Thrombosis)

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19 pages, 3824 KiB

Open AccessArticle

Identification of a Novel Antibacterial Function of Mammalian Calreticulin

by Yichao Ma, Jiachen Liu, Xinming Qin, Xiaojing Cui and Qian Yang

Biomolecules 2025, 15(7), 966; https://doi.org/10.3390/biom15070966 (registering DOI) - 4 Jul 2025

Abstract

Calreticulin is a highly conserved and multifunctional molecular chaperone ubiquitously expressed in humans and animals. Beyond its well-established roles in calcium homeostasis, protein folding, and immune regulation, recent studies in aquatic species have suggested a previously unrecognized antimicrobial function of calreticulin. These findings [...] Read more.

Calreticulin is a highly conserved and multifunctional molecular chaperone ubiquitously expressed in humans and animals. Beyond its well-established roles in calcium homeostasis, protein folding, and immune regulation, recent studies in aquatic species have suggested a previously unrecognized antimicrobial function of calreticulin. These findings raise the question of whether calreticulin also exerts antibacterial activity in terrestrial mammals, which has not been systematically investigated to date. To address this knowledge gap, we successfully constructed and expressed recombinant goat calreticulin using the Pichia pastoris expression system, yielding a protein of over 99% purity that predominantly exists in dimeric form. Functional assays demonstrated that both recombinant goat and human calreticulin exhibited preliminary inhibitory activity against Escherichia coli, Salmonella typhimurium, and Pasteurella multocida. Calreticulin was capable of binding to these three bacterial species as well as bacterial lipopolysaccharides (LPS). Notably, in the presence of Ca²⁺, calreticulin induced bacterial aggregation, indicating a potential mechanism for limiting bacterial dissemination and proliferation. Given the high anatomical, genetic, and physiological similarity between goats and humans—particularly in respiratory tract structure and mucosal immune function—neonatal goats were selected as a relevant model for evaluating the in vivo antimicrobial efficacy of calreticulin. Accordingly, we established an intranasal infection model using Pasteurella multocida to assess the protective role of calreticulin against respiratory bacterial challenge. Following infection, calreticulin expression was markedly upregulated in the nasal mucosa, trachea, and lung tissues. Moreover, intranasal administration of exogenous calreticulin significantly alleviated infection-induced pathological injury to the respiratory system and effectively decreased bacterial loads in infected tissues. Collectively, this study systematically elucidates the antimicrobial activity of calreticulin in a mammalian model and highlights its potential as a natural immune effector, providing novel insights for the development of host-targeted antimicrobial strategies. Full article

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

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45 pages, 10640 KiB

Open AccessReview

Endogenous Ribonucleases: Therapeutic Targeting of the Transcriptome Through Oligonucleotide-Triggered RNA Inactivation

by Daria A. Chiglintseva, Olga A. Patutina and Marina A. Zenkova

Biomolecules 2025, 15(7), 965; https://doi.org/10.3390/biom15070965 (registering DOI) - 4 Jul 2025

Abstract

The selective regulation of gene expression at the RNA level represents a rapidly evolving field offering substantial clinical potential. This review examines the molecular mechanisms of intracellular enzymatic systems that utilize single-stranded nucleic acids to downregulate specific RNA targets. The analysis encompasses antisense [...] Read more.

The selective regulation of gene expression at the RNA level represents a rapidly evolving field offering substantial clinical potential. This review examines the molecular mechanisms of intracellular enzymatic systems that utilize single-stranded nucleic acids to downregulate specific RNA targets. The analysis encompasses antisense oligonucleotides and synthetic mimics of small interfering RNA (siRNA), microRNA (miRNA), transfer RNA-derived small RNA (tsRNA), and PIWI-interacting RNA (piRNA), elucidating their intricate interactions with crucial cellular machinery, specifically RNase H1, RNase P, AGO, and PIWI proteins, mediating their biological effects. The functional and structural characteristics of these endonucleases are examined in relation to their mechanisms of action and resultant therapeutic outcomes. This comprehensive analysis illuminates the interactions between single-stranded nucleic acids and their endonuclease partners, covering antisense inhibition pathways as well as RNA interference processes. This field of research has important implications for advancing targeted RNA modulation strategies across various disease contexts. Full article

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

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13 pages, 1433 KiB

Open AccessArticle

Lipid Profile Characterization of Human Micro-Fragmented Adipose Tissue via Untargeted Lipidomics

by Camillo Morano, Michele Dei Cas, Giulio Alessandri, Valentina Coccè, Francesca Paino, Monica Bignotto, Luisa Doneda, Carlo Tremolada, Augusto Pessina and Rita Paroni

Biomolecules 2025, 15(7), 964; https://doi.org/10.3390/biom15070964 (registering DOI) - 4 Jul 2025

Abstract

Mesenchymal stem cells (MSCs) exhibit low immunogenicity, multipotency, and are abundantly present in adipose tissue, making this tissue an easily accessible resource for regenerative medicine. Different commercial procedures have been developed to micro-fragment the adipose tissue aspirate from patients before its reinjection. We [...] Read more.

Mesenchymal stem cells (MSCs) exhibit low immunogenicity, multipotency, and are abundantly present in adipose tissue, making this tissue an easily accessible resource for regenerative medicine. Different commercial procedures have been developed to micro-fragment the adipose tissue aspirate from patients before its reinjection. We explored a commercial device which mechanically micro-fragments human lipoaspirate (LA) resulting in a homogeneous micro-fragmentation of fat tissue (MFAT). This device has been successfully employed in several clinical applications involving autologous adipose tissue transplantation. Here, we compare the untargeted/targeted lipidomic profile of LA and MFAT looking for differences in terms of qualitative modifications occurring during the handling of the original LA material. In MFAT, different lipid subclasses such as diacylglycerols, triacylglycerols, phospholipids, and sphingolipids are more represented than in LA. In addition, via targeted fatty acids analysis, we found a lower abundance of monounsaturated fatty acids in MFAT. The biological implications of these findings must be better investigated to contribute to a better understanding of the clinical efficacy of MFAT and for its potential use as a scaffold for drug delivery applications. Full article

(This article belongs to the Section Lipids)

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19 pages, 1805 KiB

Open AccessArticle

A Hybrid Sequential Feature Selection Approach for Identifying New Potential mRNA Biomarkers for Usher Syndrome Using Machine Learning

by Rama Krishna Thelagathoti, Wesley A. Tom, Dinesh S. Chandel, Chao Jiang, Gary Krzyzanowski, Appolinaire Olou and M. Rohan Fernando

Biomolecules 2025, 15(7), 963; https://doi.org/10.3390/biom15070963 (registering DOI) - 4 Jul 2025

Abstract

Usher syndrome, a rare genetic disorder causing both hearing and vision loss, presents significant diagnostic and therapeutic challenges due to its complex genetic basis. The identification of reliable biomarkers for early detection and intervention is crucial for improving patient outcomes. In this study, [...] Read more.

Usher syndrome, a rare genetic disorder causing both hearing and vision loss, presents significant diagnostic and therapeutic challenges due to its complex genetic basis. The identification of reliable biomarkers for early detection and intervention is crucial for improving patient outcomes. In this study, we present a machine learning-based hybrid sequential feature selection approach to identify key mRNA biomarkers associated with Usher syndrome. Beginning with a dataset of 42,334 mRNA features, our approach successfully reduced dimensionality and identified 58 top mRNA biomarkers that distinguish Usher syndrome from control samples. We employed a combination of feature selection techniques, including variance thresholding, recursive feature elimination, and Lasso regression, integrated within a nested cross-validation framework. The selected biomarkers were further validated using multiple machine learning models, including Logistic Regression, Random Forest, and Support Vector Machines, demonstrating robust classification performance. To assess the biological relevance of the computationally identified mRNA biomarkers, we experimentally validated candidates from the top 10 selected mRNAs using droplet digital PCR (ddPCR). The ddPCR results were consistent with expression patterns observed in the integrated transcriptomic metadata, reinforcing the credibility of our machine learning-driven biomarker discovery framework. Our findings highlight the potential of machine learning-driven biomarker discovery to enhance the detection of Usher syndrome. Full article

(This article belongs to the Special Issue Artificial Intelligence (AI) in Biomedicine: 2nd Edition)

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22 pages, 1565 KiB

Open AccessArticle

Levels of Zinc, Iron, and Copper in the Aqueous Humor of Patients with Primary Glaucoma

by Yangjiani Li, Zhe Liu, Zhidong Li, Yingting Zhu, Shuxin Liang, Hongtao Liu, Jingfei Xue, Jicheng Lin, Ye Deng, Caibin Deng, Simei Zeng, Yehong Zhuo and Yiqing Li

Biomolecules 2025, 15(7), 962; https://doi.org/10.3390/biom15070962 (registering DOI) - 4 Jul 2025

Abstract

Background: This case–control study evaluated the concentrations of zinc (Zn), iron (Fe), and copper (Cu) in the aqueous humor (AH) of patients with primary glaucoma, and their relationships with clinical factors. Methods: This study enrolled 100 patients with primary glaucoma and categorized them [...] Read more.

Background: This case–control study evaluated the concentrations of zinc (Zn), iron (Fe), and copper (Cu) in the aqueous humor (AH) of patients with primary glaucoma, and their relationships with clinical factors. Methods: This study enrolled 100 patients with primary glaucoma and categorized them into subtypes: acute angle-closure crisis (AACC), primary angle-closure glaucoma (PACG), and primary open-angle glaucoma (POAG). A total of 67 patients with senile cataract were enrolled as controls. Their AH samples and clinical information were obtained. Results: In primary glaucoma, Zn, Fe, and Cu concentrations increased, especially in AACC group; Zn, Fe, and Cu were positively correlated mutually; and decreased Zn/Fe and increased Fe/Cu were observed. The number of quadrants with closed anterior chamber angle on gonioscopy was positively associated with Fe and Cu levels in AACC and with Zn and Cu levels in PACG. In POAG, we found negative associations between Zn and the number of quadrants with retinal nerve fiber layer thinning on optical coherence tomography, Fe and age, and Cu and the cup-to-disc ratio. Trace metals showed high efficiency in discriminating primary glaucoma from controls. Conclusions: Zn, Fe, and Cu concentrations in patients with primary glaucoma increased and were associated with clinical factors, acting as potential biomarkers. Full article

(This article belongs to the Section Chemical Biology)

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13 pages, 1760 KiB

Open AccessReview

The Role of Myeloid Differentiation Factor 2 in Stroke: Mechanisms and Therapeutic Potential

by Deyuan Zhu, Jihu Zhao, Qian Chen, Qiong Liu and Yibin Fang

Biomolecules 2025, 15(7), 961; https://doi.org/10.3390/biom15070961 (registering DOI) - 4 Jul 2025

Abstract

Stroke represents a significant public health burden, ranking as a leading cause of death and disability globally. The prevalence of stroke increases with age, with ischemic stroke accounting for nearly 87% of cases globally. The pathophysiology of stroke is characterized by neuronal injury, [...] Read more.

Stroke represents a significant public health burden, ranking as a leading cause of death and disability globally. The prevalence of stroke increases with age, with ischemic stroke accounting for nearly 87% of cases globally. The pathophysiology of stroke is characterized by neuronal injury, neuroinflammation, and oxidative stress, which exacerbate brain damage and hinder recovery. Myeloid Differentiation Factor 2 (MD2), an accessory protein of Toll-like receptor 4 (TLR4), has emerged as a key player in mediating inflammatory responses in stroke. This short review discusses the molecular mechanisms by which MD2 contributes to neuroinflammation and neuronal death following stroke and highlights MD2 as a promising therapeutic target for stroke treatment. Subsequently, we investigate the potential of MD2 inhibitors, their underlying mechanisms, and the therapeutic prospects of such inhibitors in reducing stroke-induced brain damage. Full article

(This article belongs to the Section Molecular Medicine)

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14 pages, 875 KiB

Open AccessReview

Quiescence Multiverse

by Damien Laporte and Isabelle Sagot

Biomolecules 2025, 15(7), 960; https://doi.org/10.3390/biom15070960 - 4 Jul 2025

Abstract

Cellular quiescence is operationally defined as a temporary and reversible cessation of proliferation. This state encompasses a wide range of physiological situations since most cells, from microbes to cells composing complex tissues, spend most of their lives non-dividing, waiting for signals to reproliferate. [...] Read more.

Cellular quiescence is operationally defined as a temporary and reversible cessation of proliferation. This state encompasses a wide range of physiological situations since most cells, from microbes to cells composing complex tissues, spend most of their lives non-dividing, waiting for signals to reproliferate. As such, individual quiescent cells must withstand the effects of time not only to survive but also to maintain their ability to divide. These capacities are shaped by a combination of deterministic factors relying on cell history and cumulative stochastic events linked to the environment but also to time. In addition, with time, quiescence deepens, the quiescence exit process being extended. Yet, this deepening is not necessarily sensed evenly by each individual quiescent cell, and some cells exit quiescence faster than others. Hence, time generates heterogeneity within quiescent cell populations, heterogeneity that, in turn, increases cell population resilience and robustness to time. In this review, we discuss some of the loops that link quiescence and time. Full article

(This article belongs to the Special Issue Cellular Quiescence and Dormancy)

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14 pages, 2845 KiB

Open AccessArticle

Heparin-Binding Hemagglutinin-Induced Trained Immunity in Macrophages: Implications for Antimycobacterial Defense

by Yongqiang Li, Xiuping Jia, Jinhua Tang, Huilian Qiao, Jiani Zhou and Yueyun Ma

Biomolecules 2025, 15(7), 959; https://doi.org/10.3390/biom15070959 - 4 Jul 2025

Abstract

Tuberculosis (TB) is a major global health threat, with the current Bacillus Calmette–Guérin (BCG) vaccine having limited efficacy against adult pulmonary disease. Trained immunity (TI) is a form of innate immune memory that enhances antimicrobial defense. It is characterized by the epigenetic and [...] Read more.

Tuberculosis (TB) is a major global health threat, with the current Bacillus Calmette–Guérin (BCG) vaccine having limited efficacy against adult pulmonary disease. Trained immunity (TI) is a form of innate immune memory that enhances antimicrobial defense. It is characterized by the epigenetic and metabolic reprogramming of innate immune cells and holds promise as a promising approach to prevent TB. In this study, we investigated the capacity of heparin-binding hemagglutinin (HBHA), a methylated antigen of Mycobacterium tuberculosis, to induce TI in murine RAW264.7 macrophages, human-derived THP-1 macrophages, and human peripheral blood mononuclear cells (hPBMCs). HBHA-trained macrophages exhibited the enhanced expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) following secondary lipopolysaccharide stimulation. The epigenetic profiling indicated elevated levels of H3K4me1 and H3K4me3 histone marks at cytokine gene loci. Further, metabolic analysis revealed heightened lactate production and the increased expression of glycolytic enzymes. Functionally, HBHA-trained macrophages exhibited improved control of intracellular mycobacteria, as evidenced by a significant reduction in colony-forming units following BCG infection. These findings elucidate that HBHA induces a functional TI phenotype via coordinated epigenetic and metabolic changes, and suggest HBHA may serve as a valuable tool for studying TI and its relevance to host defense against mycobacterial infections, pending further in vivo and clinical validation. Full article

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

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28 pages, 2642 KiB

Open AccessArticle

The Proteomic Landscape of Parkin-Deficient and Parkin-Overexpressing Rat Nucleus Accumbens: An Insight into the Role of Parkin in Methamphetamine Use Disorder

by Akhil Sharma, Tarek Atasi, Florine Collin, Weiwei Wang, TuKiet T. Lam, Rolando Garcia-Milian, Tasnim Arroum, Lucynda Pham, Maik Hüttemann and Anna Moszczynska

Biomolecules 2025, 15(7), 958; https://doi.org/10.3390/biom15070958 - 3 Jul 2025

Abstract

In recent years, methamphetamine (METH) misuse in the US has been rapidly increasing, and there is no FDA-approved pharmacotherapy for METH use disorder (MUD). We previously determined that ubiquitin-protein ligase parkin is involved in the regulation of METH addictive behaviors in rat models [...] Read more.

In recent years, methamphetamine (METH) misuse in the US has been rapidly increasing, and there is no FDA-approved pharmacotherapy for METH use disorder (MUD). We previously determined that ubiquitin-protein ligase parkin is involved in the regulation of METH addictive behaviors in rat models of MUD. Parkin is not yet a “druggable” drug target; therefore, this study aimed to determine which biological processes, pathways, and proteins downstream of parkin are likely drug targets against MUD. Employing young adult Long Evans male rats with parkin deficit or excess in the nucleus accumbens (NAc), label-free proteomics, and molecular biology, we determined that the pathways downstream of parkin that are candidates for regulating METH addictive behaviors in young adult male rats are mitochondrial respiration, oxidative stress, AMPA receptor trafficking, GABAergic neurotransmission, and actin cytoskeleton dynamics. Full article

(This article belongs to the Special Issue Advances in Neuroproteomics)

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14 pages, 2345 KiB

Open AccessArticle

Transcript PHF19-207 May Be a Long Non-Coding RNA with Tumor-Promoting Role in Colon Cancer

by Dunja Pavlovic, Tamara Babic, Sofija Ignjatovic, Katarina Pavlovic, Sandra Dragicevic and Aleksandra Nikolic

Biomolecules 2025, 15(7), 957; https://doi.org/10.3390/biom15070957 - 2 Jul 2025

Abstract

Recent pan-cancer transcriptome analysis has revealed differential activity of two alternative PHF19 gene promoters in malignant versus non-malignant gut mucosa. One of these promoters upregulated in colon cancer leads to the expression of the PHF19-207 transcript, suggesting its potential role in tumor promotion. [...] Read more.

Recent pan-cancer transcriptome analysis has revealed differential activity of two alternative PHF19 gene promoters in malignant versus non-malignant gut mucosa. One of these promoters upregulated in colon cancer leads to the expression of the PHF19-207 transcript, suggesting its potential role in tumor promotion. The objective of this study was to investigate the function of PHF19-207 using in silico tools and publicly available data, as well as to assess its expression in colon cancer. Expression analyses were conducted via qPCR and RNA sequencing on RNA extracted from the immortalized colonic epithelial cell line HCEC-1CT, as well as a series of colon cancer cell lines cultured in both 2D and 3D environments. The expression of PHF19-207 was found to be elevated in all malignant cell lines compared to the non-malignant HCEC-1CT cell line in both culture conditions, with the most prominent increase observed in cell lines derived from advanced stages of the disease and in the HCEC-1CT cell line overexpressing KRAS. Furthermore, the PHF19-207 transcript was detected in exosomes derived from malignant cells. These findings suggest that PHF19-207 holds potential as a diagnostic biomarker. In addition, in silico analyses indicate that this transcript may function as a long non-coding RNA involved in the regulation of gene expression. Further functional investigations are required to elucidate its precise role in colon carcinogenesis. Full article

(This article belongs to the Special Issue Colorectal and Gastric Cancers: Molecular Mechanisms and Potential Biomarkers)

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