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Keywords = protein sequences

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11 pages, 294 KiB  
Article
Perinatal Outcomes of Chronic Abruption Oligohydramnios Sequence: A Multicenter Retrospective Observational Study
by Yoshifumi Kasuga, Yuka Fukuma, Kaoru Kajikawa, Keisuke Akita, Junko Tamai, Yuya Tanaka, Toshimitsu Otani, Marie Fukutake, Satoru Ikenoue and Mamoru Tanaka
J. Clin. Med. 2025, 14(15), 5523; https://doi.org/10.3390/jcm14155523 - 5 Aug 2025
Abstract
Objective: This study aimed to describe the perinatal and neonatal outcomes of chronic abruption oligohydramnios sequence in the Kanto region of Japan. Methods: This survey was conducted at 123 perinatal centers affiliated to this area. Data on the experience of managing [...] Read more.
Objective: This study aimed to describe the perinatal and neonatal outcomes of chronic abruption oligohydramnios sequence in the Kanto region of Japan. Methods: This survey was conducted at 123 perinatal centers affiliated to this area. Data on the experience of managing chronic abruption oligohydramnios sequence between 1 January 2017, and 31 December 2022, were collected and analyzed. Results: Among the 82 cases of chronic abruption oligohydramnios sequence that were included in this study, there were seven miscarriages, five artificial abortions, and 70 deliveries beyond 22 gestational weeks (singleton: 68; twin: 2). In 82 patients, vaginal bleeding was the initial symptom of chronic abruption oligohydramnios sequence (88%). The mean gestational duration at the initial symptom onset was 17.3 ± 5.0 weeks. Of the 68 singleton pregnancies delivered after 22 gestational weeks, the mean gestational duration at delivery was 25.2 ± 2.8 weeks. In patients with chronic abruption oligohydramnios sequence, the mean white blood cell count at diagnosis and mean of the maximum white blood cell count during pregnancy were 11,589 ± 2885 and 15,357 ± 4745/μL, respectively; and the mean C-reactive protein at diagnosis and mean of the maximum C-reactive protein during pregnancy were 1.0 ± 1.2 and 2.0 ± 2.1 mg/L, respectively. Chorioamnionitis was identified in 43 patients (63%). All neonates were admitted to the neonatal intensive care unit. Of the 68 singleton neonates, 5 died immediately after birth. Conclusions: Chronic abruption oligohydramnios sequence is a rare perinatal complication that is possibly associated with infections, such as chorioamnionitis, and linked to adverse perinatal and neonatal outcomes. Full article
(This article belongs to the Section Obstetrics & Gynecology)
17 pages, 3151 KiB  
Article
Towards a Consensus for the Analysis and Exchange of TFA as a Counterion in Synthetic Peptides and Its Influence on Membrane Permeation
by Vanessa Erckes, Alessandro Streuli, Laura Chamera Rendueles, Stefanie Dorothea Krämer and Christian Steuer
Pharmaceuticals 2025, 18(8), 1163; https://doi.org/10.3390/ph18081163 - 5 Aug 2025
Abstract
Background: With the increasing shift in drug design away from classical drug targets towards the modulation of protein-protein interactions, synthetic peptides are gaining increasing relevance. The synthesis and purification of peptides via solid-phase peptide synthesis (SPPS) strongly rely on trifluoroacetic acid (TFA) as [...] Read more.
Background: With the increasing shift in drug design away from classical drug targets towards the modulation of protein-protein interactions, synthetic peptides are gaining increasing relevance. The synthesis and purification of peptides via solid-phase peptide synthesis (SPPS) strongly rely on trifluoroacetic acid (TFA) as a cleavage agent and ion-pairing reagent, respectively, resulting in peptides being obtained as TFA salts. Although TFA has excellent properties for peptide production, numerous studies highlight the negative impact of using peptides from TFA salts in biological assays. Methods: Investigated peptides were synthesized via SPPS and the TFA counterion was exchanged for Cl via freeze-drying in different concentrations of HCl. Detection and quantification of residual TFA were carried out via FT-IR, 19F-NMR, and HPLC using an evaporative light-scattering detector (ELSD). A liposomal fluorescence assay was used to test for the influence of the counterion on the peptides’ passive membrane permeability. Results: All TFA detection methods were successfully validated according to ICH guidelines. TFA removal with 10 mM HCl was determined to be the optimal condition. No impact on peptide purity was observed at all HCl concentrations. Influences on permeability coefficients depending on peptide sequence and salt form were found. Conclusions: This study presents a systematic investigation of the removal of TFA counterions from synthetic peptides and their replacement with Cl counterions. Detected counterion contents were used to understand the impact of sequence differences, especially positive charges, on the amount and potential localization of counterions. Our findings emphasize the importance of counterion quantification and specification in assays with synthetic peptides. Full article
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14 pages, 1669 KiB  
Article
Guinea Pig X Virus Is a Gammaherpesvirus
by Vy Ngoc Yen Truong, Robert Ellis and Brent A. Stanfield
Viruses 2025, 17(8), 1084; https://doi.org/10.3390/v17081084 - 5 Aug 2025
Abstract
The Guinea Pig X Virus (GPXV), a newly identified gammaherpesvirus, provides an opportunity to study viral evolution and host–virus dynamics. This study characterizes the GPXV genome and investigates its phylogenetic relationships and divergence from related viruses through comparative genomic and phylogenetic analyses. Virus [...] Read more.
The Guinea Pig X Virus (GPXV), a newly identified gammaherpesvirus, provides an opportunity to study viral evolution and host–virus dynamics. This study characterizes the GPXV genome and investigates its phylogenetic relationships and divergence from related viruses through comparative genomic and phylogenetic analyses. Virus propagation was conducted in Vero cells, followed by genomic DNA extraction and pan-herpesvirus nested PCR. Sanger sequencing filled gaps in the initial genome assembly, and whole-genome sequencing was performed using the Illumina MiSeq platform. Phylogenetic analyses focused on ORF8 (glycoprotein B), ORF9 (DNA polymerase catalytic subunit), ORF50 (RTA: replication and transcription activator), and ORF73 (LANA: latency-associated nuclear antigen). Results showed that GPXV ORFs showed variable evolutionary relationships with other gammaherpesviruses, including divergence from primate-associated viruses and clustering with bovine and rodent viruses. In addition to phylogenetics, a comprehensive comparative analysis of protein-coding genes between GPXV and the previously described Guinea Pig Herpes-Like Virus (GPHLV) revealed divergence. Twenty-four non-ORF genomic features were unique to GPXV, while 62 shared ORFs exhibited low to high sequence divergence. These findings highlight GPXV’s distinct evolutionary trajectory and its potential role as a model for studying host-specific adaptations and gammaherpesvirus diversity. Full article
(This article belongs to the Special Issue Animal Herpesvirus 2025)
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18 pages, 5256 KiB  
Article
Impact of Alginate Oligosaccharides on Ovarian Performance and the Gut Microbial Community in Mice with D-Galactose-Induced Premature Ovarian Insufficiency
by Yan Zhang, Hongda Pan, Dao Xiang, Hexuan Qu and Shuang Liang
Antioxidants 2025, 14(8), 962; https://doi.org/10.3390/antiox14080962 (registering DOI) - 5 Aug 2025
Abstract
Premature ovarian insufficiency (POI) is an important factor in female infertility and is often associated with oxidative stress. Alginate oligosaccharides (AOSs), derived from the degradation of alginate, have been demonstrated to have protective effects against various oxidative stress-related diseases. However, the impact of [...] Read more.
Premature ovarian insufficiency (POI) is an important factor in female infertility and is often associated with oxidative stress. Alginate oligosaccharides (AOSs), derived from the degradation of alginate, have been demonstrated to have protective effects against various oxidative stress-related diseases. However, the impact of AOSs on POI has not been previously explored. The current study explored the effects of AOSs on ovarian dysfunction in a mouse model of POI induced by D-galactose (D-gal). Female C57BL/6 mice were randomly divided into five groups: the control (CON), POI model (D-gal), and low-, medium-, and high-dose AOS groups (AOS-L, 100 mg/kg/day; AOS-M, 150 mg/kg/day; AOS-H, 200 mg/kg/day). For 42 consecutive days, mice in the D-gal, AOS-L, AOS-M, and AOS-H groups received daily intraperitoneal injections of D-gal (200 mg/kg/day), whereas those in the CON group received equivalent volumes of sterile saline. Following D-gal injection, AOSs were administered via gavage at the specified doses; mice in the CON and D-gal groups received sterile saline instead. AOS treatment markedly improved estrous cycle irregularities, normalized serum hormone levels, reduced granulosa cell apoptosis, and increased follicle counts in POI mice. Moreover, AOSs significantly reduced ovarian oxidative stress and senescence in POI mice, as indicated by lower levels of malondialdehyde (MDA), higher activities of catalase (CAT) and superoxide dismutase (SOD), and decreased protein expression of 4-hydroxynonenal (4-HNE), nitrotyrosine (NTY), 8-hydroxydeoxyguanosine (8-OHdG), and p16 in ovarian tissue. Analysis of the gut microbiota through 16S rRNA gene sequencing and short-chain fatty acid (SCFA) analysis revealed significant differences in gut microbiota composition and SCFA levels (acetic acid and total SCFAs) between control and D-gal-induced POI mice. These differences were largely alleviated by AOS treatment. AOSs changed the gut microbiota by increasing the abundance of Ligilactobacillus and decreasing the abundance of Clostridiales, Clostridiaceae, Marinifilaceae, and Clostridium_T. Additionally, AOSs mitigated the decline in acetic acid and total SCFA levels observed in POI mice. Notably, the total SCFA level was significantly correlated with the abundance of Ligilactobacillus, Marinifilaceae, and Clostridium_T. In conclusion, AOS intervention effectively mitigates ovarian oxidative stress, restores gut microbiota homeostasis, and regulates the microbiota–SCFA axis, collectively improving D-gal-induced POI. Therefore, AOSs represent a promising therapeutic strategy for POI management. Full article
(This article belongs to the Section Health Outcomes of Antioxidants and Oxidative Stress)
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25 pages, 3822 KiB  
Article
Comparative Transcriptome and MicroRNA Profiles of Equine Mesenchymal Stem Cells, Fibroblasts, and Their Extracellular Vesicles
by Sebastian Sawicki, Monika Bugno-Poniewierska, Jakub Żurowski, Tomasz Szmatoła, Ewelina Semik-Gurgul, Michał Bochenek, Elżbieta Karnas and Artur Gurgul
Genes 2025, 16(8), 936; https://doi.org/10.3390/genes16080936 (registering DOI) - 5 Aug 2025
Abstract
Background: Mesenchymal stem cells (MSCs) are a promising tool in regenerative medicine due to their ability to secrete paracrine factors that modulate tissue repair. Extracellular vesicles (EVs) released by MSCs contain bioactive molecules (e.g., mRNAs, miRNAs, proteins) and play a key role in [...] Read more.
Background: Mesenchymal stem cells (MSCs) are a promising tool in regenerative medicine due to their ability to secrete paracrine factors that modulate tissue repair. Extracellular vesicles (EVs) released by MSCs contain bioactive molecules (e.g., mRNAs, miRNAs, proteins) and play a key role in intercellular communication. Methods: This study compared the transcriptomic profiles (mRNA and miRNA) of equine MSCs derived from adipose tissue (AT-MSCs), bone marrow (BM-MSCs), and ovarian fibroblasts (as a differentiated control). Additionally, miRNAs present in EVs secreted by these cells were characterized using next-generation sequencing. Results: All cell types met ISCT criteria for MSCs, including CD90 expression, lack of MHC II, trilineage differentiation, and adherence. EVs were isolated using ultracentrifugation and validated with nanoparticle tracking analysis and flow cytometry (CD63, CD81). Differential expression analysis revealed distinct mRNA and miRNA profiles across cell types and their secreted EVs, correlating with tissue origin. BM-MSCs showed unique regulation of genes linked to early development and osteogenesis. EVs contained diverse RNA species, including miRNA, mRNA, lncRNA, rRNA, and others. In total, 227 and 256 mature miRNAs were detected in BM-MSCs and AT-MSCs, respectively, including two novel miRNAs per MSC type. Fibroblasts expressed 209 mature miRNAs, including one novel miRNA also found in MSCs. Compared to fibroblasts, 60 and 92 differentially expressed miRNAs were identified in AT-MSCs and BM-MSCs, respectively. Conclusions: The results indicate that MSC tissue origin influences both transcriptomic profiles and EV miRNA content, which may help to interpret their therapeutic potential. Identifying key mRNAs and miRNAs could aid in future optimizing of MSC-based therapies in horses. Full article
(This article belongs to the Section Animal Genetics and Genomics)
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28 pages, 5831 KiB  
Article
An Italian Single-Center Genomic Surveillance Study: Two-Year Analysis of SARS-CoV-2 Spike Protein Mutations
by Riccardo Cecchetto, Emil Tonon, Asia Palmisano, Anna Lagni, Erica Diani, Virginia Lotti, Marco Mantoan, Livio Montesarchio, Francesca Palladini, Giona Turri and Davide Gibellini
Int. J. Mol. Sci. 2025, 26(15), 7558; https://doi.org/10.3390/ijms26157558 (registering DOI) - 5 Aug 2025
Abstract
The repeated occurrence of SARS-CoV-2 variants, largely driven by virus–host interactions, was and will remain a public health concern. Spike protein mutations shaped viral infectivity, transmissibility, and immune escape. From February 2022 to April 2024, a local genomic surveillance program in Verona, Italy, [...] Read more.
The repeated occurrence of SARS-CoV-2 variants, largely driven by virus–host interactions, was and will remain a public health concern. Spike protein mutations shaped viral infectivity, transmissibility, and immune escape. From February 2022 to April 2024, a local genomic surveillance program in Verona, Italy, was conducted on 1333 SARS-CoV-2-positive nasopharyngeal swabs via next generation full-length genome sequencing. Spike protein mutations were classified based on their prevalence over time. Mutations were grouped into five categories: fixed, emerging, fading, transient, and divergent. Notably, some divergent mutations displayed a “Lazarus effect,” disappearing and later reappearing in new lineages, indicating potential adaptive advantages in specific genomic contexts. This two-year surveillance study highlights the dynamic nature of spike protein mutations and their role in SARS-CoV-2 evolution. The findings underscore the need for ongoing mutation-focused genomic monitoring to detect early signals of variant emergence, especially among mutations previously considered disadvantageous. Such efforts are critical for driving public health responses and guiding future vaccine and therapeutic strategies. Full article
(This article belongs to the Special Issue The Interaction Between Cell and Virus, 3rd Edition)
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16 pages, 4746 KiB  
Article
SARS-CoV-2 Nsp1 Is a Major Suppressor of HLA Class I and Class II Expression
by Ivo Schirmeister, Nicolas Eckert, Sebastian Weigang, Jonas Fuchs, Lisa Kern, Georg Kochs and Anne Halenius
Viruses 2025, 17(8), 1083; https://doi.org/10.3390/v17081083 - 5 Aug 2025
Abstract
Human leukocyte antigen class I (HLA-I) molecules present intracellular peptides on the cell surface to enable CD8+ T cells to effectively control viral infections. Many viruses disrupt this antigen presentation pathway to evade immune detection. In this study, we demonstrate that SARS-CoV-2 Nsp1 [...] Read more.
Human leukocyte antigen class I (HLA-I) molecules present intracellular peptides on the cell surface to enable CD8+ T cells to effectively control viral infections. Many viruses disrupt this antigen presentation pathway to evade immune detection. In this study, we demonstrate that SARS-CoV-2 Nsp1 impairs both the constitutive and interferon-γ (IFN-γ)-induced upregulation of HLA-I. Moreover, Nsp1 also blocks IFN-γ-induced expression of HLA-II. We found that, contrary to previously published work, the early SARS-CoV-2 B 1.1.7 Alpha variant lacking the accessory protein ORF8 retained full capacity to downregulate HLA-I, comparable to an ORF8-expressing wild-type isolate. While ectopic overexpression of ORF8 could reduce HLA-I surface levels, this effect was only observed at high expression levels. In contrast, moderate expression of the viral protein Nsp1 was sufficient to potently suppress both basal and IFN-γ-induced HLA-I, as well as HLA-II expression. To probe the underlying mechanism, we analyzed HLA-I-associated genes in previously published RNA-sequencing datasets and confirmed that Nsp1 reduces expression of components required for HLA-I biosynthesis and antigen processing. These findings identify Nsp1 as a key factor that impairs antigen presentation pathways, potentially contributing to the ability of SARS-CoV-2 to modulate immune recognition. Full article
(This article belongs to the Section Coronaviruses)
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19 pages, 5767 KiB  
Article
In Silico Evaluation of Effect and Molecular Modeling of SNPs in Genes Related to Amyotrophic Lateral Sclerosis
by Gustavo Ronconi Roza, Caroline Christine Pincela da Costa, Nayane Soares de Lima, Angela Adamski da Silva Reis and Rodrigo da Silva Santos
Sclerosis 2025, 3(3), 27; https://doi.org/10.3390/sclerosis3030027 - 5 Aug 2025
Abstract
Background: Amyotrophic lateral sclerosis is a systemic, complex, multifactorial, and fatal neurodegenerative disease with various factors involved in its etiology. This study aimed to understand the effects of SNPs in the MTHFR, MTR, SLC19A1, and VAPB genes on protein functionality and structure [...] Read more.
Background: Amyotrophic lateral sclerosis is a systemic, complex, multifactorial, and fatal neurodegenerative disease with various factors involved in its etiology. This study aimed to understand the effects of SNPs in the MTHFR, MTR, SLC19A1, and VAPB genes on protein functionality and structure and their influence on ALS susceptibility. Methods: The dbSNP and ClinVar databases were used for SNP data annotation, while UniProt and PDB provided protein sequences. We performed functional and structural predictions of SNPs using PolyPhen-2 and SNAP2. We modeled mutant proteins using AlphaFold 2 and visualized them in PyMOL to compare native and mutant forms. Results: Our results identified SNP rs74315431 as pathogenic, inducing structural and functional changes and exhibiting visible alterations in the three-dimensional structure. Although predicted as non-pathogenic, SNPs rs1801131, rs1805087, and rs1051266 caused protein structural alterations, a finding confirmed by three-dimensional visualization. SNP rs1801133 diverged from the others, being predicted as pathogenic but without causing changes in protein structure or function. Conclusions: Our study found a strong correlation between SNAP2-predicted alterations and those predicted by AlphaFold 2, whereas PolyPhen-2 results did not directly correlate with three-dimensional structure changes. Full article
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23 pages, 11168 KiB  
Article
Persistent Inflammation, Maladaptive Remodeling, and Fibrosis in the Kidney Following Long COVID-like MHV-1 Mouse Model
by Rajalakshmi Ramamoorthy, Anna Rosa Speciale, Emily M. West, Hussain Hussain, Nila Elumalai, Klaus Erich Schmitz Abe, Madesh Chinnathevar Ramesh, Pankaj B. Agrawal, Arumugam R. Jayakumar and Michael J. Paidas
Diseases 2025, 13(8), 246; https://doi.org/10.3390/diseases13080246 (registering DOI) - 5 Aug 2025
Abstract
Background: Accumulating evidence indicates that SARS-CoV-2 infection results in long-term multiorgan complications, with the kidney being a primary target. This study aimed to characterize the long-term transcriptomic changes in the kidney following coronavirus infection using a murine model of MHV-1-induced SARS-like illness and [...] Read more.
Background: Accumulating evidence indicates that SARS-CoV-2 infection results in long-term multiorgan complications, with the kidney being a primary target. This study aimed to characterize the long-term transcriptomic changes in the kidney following coronavirus infection using a murine model of MHV-1-induced SARS-like illness and to evaluate the therapeutic efficacy of SPIKENET (SPK). Methods: A/J mice were infected with MHV-1. Renal tissues were collected and subjected to immunofluorescence analysis and Next Generation RNA Sequencing to identify differentially expressed genes associated with acute and chronic infection. Bioinformatic analyses, including PCA, volcano plots, and GO/KEGG pathway enrichment, were performed. A separate cohort received SPK treatment, and comparative transcriptomic profiling was conducted. Gene expression profile was further confirmed using real-time PCR. Results: Acute infection showed the upregulation of genes involved in inflammation and fibrosis. Long-term MHV-1 infection led to the sustained upregulation of genes involved in muscle regeneration, cytoskeletal remodeling, and fibrotic responses. Notably, both expression and variability of SLC22 and SLC22A8, key proximal tubule transporters, were reduced, suggesting a loss of segment-specific identity. Further, SLC12A1, a critical regulator of sodium reabsorption and blood pressure, was downregulated and is associated with the onset of polyuria and hydronephrosis. SLC transporters exhibited expression patterns consistent with tubular dysfunction and inflammation. These findings suggest aberrant activation of myogenic pathways and structural proteins in renal tissues, consistent with a pro-fibrotic phenotype. In contrast, SPK treatment reversed the expression of most genes, thereby restoring the gene profiles to those observed in control mice. Conclusions: MHV-1-induced long COVID is associated with persistent transcriptional reprogramming in the kidney, indicative of chronic inflammation, cytoskeletal dysregulation, and fibrogenesis. SPK demonstrates robust therapeutic potential by normalizing these molecular signatures and preventing long-term renal damage. These findings underscore the relevance of the MHV-1 model and support further investigation of SPK as a candidate therapy for COVID-19-associated renal sequelae. Full article
(This article belongs to the Special Issue COVID-19 and Global Chronic Disease 2025: New Challenges)
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13 pages, 2127 KiB  
Article
Assessing SARS-CoV-2 Rare Mutations and Transmission in New York City by NGS
by Dakai Liu, Harlan Pietz, George D. Rodriguez, Yuexiu Wu, Yihan Cao, Vishnu Singh, Hui Li, Eric Konadu, Keither K. James, Calvin Lui, Bright Varghese, Mingyu Shao, Gary Chen, Andrew Schreiner, Jiankun Tong, Carl Urban, Nishant Prasad, Ameer Hassoun, Manish Sharma and William Harry Rodgers
Microorganisms 2025, 13(8), 1821; https://doi.org/10.3390/microorganisms13081821 - 4 Aug 2025
Abstract
SARS-CoV-2 undergoes frequent mutations that drive viral evolution and genomic diversity, influencing transmissibility, immune escape, and disease severity. In this study, we performed whole-genome sequencing on SARS-CoV-2 isolates from patients in New York City and identified several globally rare mutations across multiple viral [...] Read more.
SARS-CoV-2 undergoes frequent mutations that drive viral evolution and genomic diversity, influencing transmissibility, immune escape, and disease severity. In this study, we performed whole-genome sequencing on SARS-CoV-2 isolates from patients in New York City and identified several globally rare mutations across multiple viral lineages. The isolates analyzed for rare mutations belonged to three lineages: B.1.1.7 (Alpha), B.1.526 (Iota), and B.1.623. We identified 16 rare mutations (global incidence <1000) in non-structural protein genes, including nsp2, nsp3, nsp4, nsp6, nsp8, nsp13, nsp14, ORF7a, and ORF8. Three of these mutations—located in nsp2, nsp13, and ORF8—have been reported in fewer than 100 individuals worldwide. We also detected five rare mutations in structural proteins (S, M, and N), including two—one in M and one in N—previously reported in fewer than 100 cases globally. We present clinical profiles of three patients, each infected with genetically distinct viral isolates from the three lineages studied. Furthermore, we illustrate a local transmission chain inferred from unique mutation patterns identified in the Omicron genome. These findings underscore the importance of whole-genome sequencing for detecting rare mutations, tracking community spread, and identifying emerging variants with clinical and public health significance. Full article
(This article belongs to the Special Issue The Molecular Epidemiology of Infectious Diseases)
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26 pages, 1978 KiB  
Article
Fluorescent Peptides Internalize HeLa Cells and Kill Multidrug-Resistant Clinical Bacterial Isolates
by Daniel Castellar-Almonacid, Kelin Johana Cuero-Amu, Jose David Mendoza-Mendoza, Natalia Ardila-Chantré, Fernando José Chavez-Salazar, Andrea Carolina Barragán-Cárdenas, Jhon Erick Rivera-Monroy, Claudia Parra-Giraldo, Zuly Jenny Rivera-Monroy, Javier García-Castañeda and Ricardo Fierro-Medina
Antibiotics 2025, 14(8), 793; https://doi.org/10.3390/antibiotics14080793 (registering DOI) - 4 Aug 2025
Abstract
Palindromic antimicrobial peptides (PAMs) constitute versatile scaffolds for the design and optimization of anticancer agents with applications in therapy, diagnosis, and/or monitoring. In the present study, fluorolabeled peptides derived from the palindromic sequence RWQWRWQWR containing fluorescent probes, such as 2-Aminobenzoyl, 5(6)-Carboxyfluorescein, and Rhodamine [...] Read more.
Palindromic antimicrobial peptides (PAMs) constitute versatile scaffolds for the design and optimization of anticancer agents with applications in therapy, diagnosis, and/or monitoring. In the present study, fluorolabeled peptides derived from the palindromic sequence RWQWRWQWR containing fluorescent probes, such as 2-Aminobenzoyl, 5(6)-Carboxyfluorescein, and Rhodamine B, were obtained. RP-HPLC analysis revealed that the palindromic peptide conjugated to Rhodamine B (RhB-RWQWRWQWR) exhibited the presence of isomers, likely corresponding to the open-ring and spiro-lactam forms of the fluorescent probe. This equilibrium is dependent on the peptide sequence, as the RP-HPLC analysis of dimeric peptide (RhB-RRWQWR-hF-KKLG)2K-Ahx did not reveal the presence of isomers. The antibacterial activity of the fluorescent peptides depends on the probe attached to the sequence and the bacterial strain tested. Notably, some fluorescent peptides showed activity against reference strains as well as sensitive, resistant, and multidrug-resistant clinical isolates of E. coli, S. aureus, and E. faecalis. Fluorolabeled peptides 1-Abz (MIC = 62 µM), RhB-1 (MIC = 62 µM), and Abz-1 (MIC = 31 µM) exhibited significant activity against clinical isolates of E. coli, S. aureus, and E. faecalis, respectively. The RhB-1 (IC50 = 61 µM), Abz-1 (IC50 = 87 µM), and RhB-2 (IC50 = 35 µM) peptides exhibited a rapid, significant, and concentration-dependent cytotoxic effect on HeLa cells, accompanied by morphological changes characteristic of apoptosis. RhB-1 (IC50 = 18 µM) peptide also exhibited significant cytotoxic activity against breast cancer cells MCF-7. These conjugates remain valuable for elucidating the possible mechanisms of action of these novel anticancer peptides. Rhodamine-labeled peptides displayed cytotoxicity comparable to that of their unlabeled analogues, suggesting that cellular internalization constitutes a critical early step in their mechanism of action. These findings suggest that cell death induced by both unlabeled and fluorolabeled peptides proceeds predominantly via apoptosis and is likely contingent upon peptide internalization. Functionalization at the N-terminal end of the palindromic sequence can be evaluated to develop systems for transporting non-protein molecules into cancer cells. Full article
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11 pages, 1293 KiB  
Article
RAB24 Missense Variant in Dogs with Cerebellar Ataxia
by Cleo Schwarz, Jan Wennemuth, Julien Guevar, Francesca Dörn, Vidhya Jagannathan and Tosso Leeb
Genes 2025, 16(8), 934; https://doi.org/10.3390/genes16080934 (registering DOI) - 4 Aug 2025
Abstract
Hereditary ataxias are a highly heterogenous group of diseases characterized by loss of coordination. In this study, we investigated a family of random-bred dogs, in which two siblings were affected by a slowly progressive ataxia. They presented with clinical signs of progressive cerebellar [...] Read more.
Hereditary ataxias are a highly heterogenous group of diseases characterized by loss of coordination. In this study, we investigated a family of random-bred dogs, in which two siblings were affected by a slowly progressive ataxia. They presented with clinical signs of progressive cerebellar ataxia, hypermetria, and absent menace response. The MRI revealed generalized brain atrophy, reduced cortical demarcation, hypoplastic corpus callosum, and cerebellar folia thinning, highly suggestive of a neurodegenerative disorder. We sequenced the genomes of the two affected dogs and their unaffected parents. Filtering for protein-changing variants that had homozygous alternate genotypes in the affected dogs, heterozygous genotypes in the parents, and homozygous reference genotypes in 1576 control genomes yielded a single missense variant in the RAB24 gene, XM_038534663.1:c.239G>T or XP_038390591.1:p.(Gly80Val). Genotypes at this variant showed the expected co-segregation with the ataxia phenotype in the investigated family. The predicted amino acid affects the conserved RabF4 motif. Glycine-80 resides at the protein surface and the introduction of a hydrophobic isopropyl side chain of the mutant valine might impede solvent accessibility. Another missense variant in RAB24, p.Glu38Pro, was previously reported to cause a clinically similar form of cerebellar ataxia in Gordon Setters and Old English Sheepdogs. Taken together, the available data suggest that RAB24:p.Gly80Val represents the causal variant in the studied dogs. To the best of our knowledge, this is only the second report of a potentially pathogenic RAB24 variant in any species and further supports that RAB24 should be considered a candidate gene in human ataxia patients with unclear molecular etiology. Full article
(This article belongs to the Special Issue Hereditary Traits and Diseases in Companion Animals)
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9 pages, 753 KiB  
Article
Combined Genetic and Transcriptional Study Unveils the Role of DGAT1 Gene Mutations in Congenital Diarrhea
by Jingqing Zeng, Jing Ma, Lan Wang, Zhaohui Deng and Ruen Yao
Biomedicines 2025, 13(8), 1897; https://doi.org/10.3390/biomedicines13081897 - 4 Aug 2025
Abstract
Background: Congenital diarrhea is persistent diarrhea that manifests during the neonatal period. Mutations in DGAT1, which is crucial for triglyceride synthesis and lipid absorption in the small intestine, are causal factors for congenital diarrhea. In this study, we aimed to determine [...] Read more.
Background: Congenital diarrhea is persistent diarrhea that manifests during the neonatal period. Mutations in DGAT1, which is crucial for triglyceride synthesis and lipid absorption in the small intestine, are causal factors for congenital diarrhea. In this study, we aimed to determine the value of tissue RNA sequencing (RNA-seq) for assisting with the clinical diagnosis of some genetic variants of uncertain significance. Methods: We clinically evaluated a patient with watery diarrhea, vomiting, severe malnutrition, and total parenteral nutrition dependence. Possible pathogenic variants were detected using whole-exome sequencing (WES). RNA-seq was utilized to explore the transcriptional alterations in DGAT1 variants identified by WES with unknown clinical significance, according to the American College of Medical Genetics guidelines. Systemic examinations, including endoscopic and histopathological examinations of the intestinal mucosa, were conducted to rule out other potential diagnoses. Results: We successfully diagnosed a patient with congenital diarrhea and protein-losing enteropathy caused by a DGAT1 mutation and reviewed the literature of 19 cases of children with DGAT defects. The missense mutation c.620A>G, p.Lys207Arg located in exon 15, and the intronic mutation c.1249-6T>G in DGAT1 were identified by WES. RNA-seq revealed two aberrant splicing events in the DGAT1 gene of the patient’s small intestinal tissue. Both variants lead to loss-of-function consequences and are classified as pathogenic variants of congenital diarrhea. Conclusions: Rare DGAT1 variants were identified as pathogenic evidence of congenital diarrhea, and the detection of tissue-specific mRNA splicing and transcriptional effects can provide auxiliary evidence. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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29 pages, 21916 KiB  
Article
Pentoxifylline and Norcantharidin Synergistically Suppress Melanoma Growth in Mice: A Multi-Modal In Vivo and In Silico Study
by Israel Lara-Vega, Minerva Nájera-Martínez and Armando Vega-López
Int. J. Mol. Sci. 2025, 26(15), 7522; https://doi.org/10.3390/ijms26157522 (registering DOI) - 4 Aug 2025
Abstract
Melanoma is a highly aggressive skin cancer with limited therapeutic response. Targeting intracellular signaling pathways and promoting tumor cell differentiation are promising therapeutic strategies. Pentoxifylline (PTX) and norcantharidin (NCTD) have demonstrated antitumor properties, but their combined mechanisms of action in melanoma remain poorly [...] Read more.
Melanoma is a highly aggressive skin cancer with limited therapeutic response. Targeting intracellular signaling pathways and promoting tumor cell differentiation are promising therapeutic strategies. Pentoxifylline (PTX) and norcantharidin (NCTD) have demonstrated antitumor properties, but their combined mechanisms of action in melanoma remain poorly understood. The effects of PTX (30 and 60 mg/kg) and NCTD (0.75 and 3 mg/kg), administered alone or in combination, in a DBA/2J murine B16-F1 melanoma model via intraperitoneal and intratumoral (IT) routes were evaluated. Tumor growth was monitored, and molecular analyses included RNA sequencing and immunofluorescence quantification of PI3K, AKT1, mTOR, ERBB2, BRAF, and MITF protein levels, and molecular docking simulations were performed. In the final stage of the experiment, combination therapy significantly reduced tumor volume compared to monotherapies, with the relative tumor volume decreasing from 18.1 ± 1.2 (SD) in the IT Control group to 0.6 ± 0.1 (SD) in the IT combination-treated group (n = 6 per group; p < 0.001). RNA-seq revealed over 3000 differentially expressed genes in intratumoral treatments, with enrichment in pathways related to oxidative stress, immune response, and translation regulation (KEGG and Reactome analyses). Minimal transcript-level changes were observed for BRAF and PI3K/AKT/mTOR genes; however, immunofluorescence showed reduced total and phosphorylated levels of PI3K, AKT1, mTOR, BRAF, and ERBB2. MITF protein levels and pigmentation increased, especially in PTX-treated groups, indicating enhanced melanocytic differentiation. Docking analyses predicted direct binding of both drugs to PI3K, AKT1, mTOR, and BRAF, with affinities ranging from −5.7 to −7.4 kcal/mol. The combination of PTX and NCTD suppresses melanoma progression through dual mechanisms: inhibition of PI3K/AKT/mTOR signaling and promotion of tumor cell differentiation. Full article
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15 pages, 550 KiB  
Article
New Insights into the Telomere Structure in Hemiptera (Insecta) Inferred from Chromosome-Level and Scaffold-Level Genome Assemblies
by Desislava Stoianova, Snejana Grozeva, Nadezhda Todorova, Miroslav Rangelov, Vladimir A. Lukhtanov and Valentina G. Kuznetsova
Diversity 2025, 17(8), 552; https://doi.org/10.3390/d17080552 - 4 Aug 2025
Abstract
Telomeres are terminal regions of chromosomes that protect and stabilize chromosome structures. Telomeres are usually composed of specific DNA repeats (motifs) that are maintained by telomerase and a complex of specific proteins. Telomeric DNA sequences are generally highly conserved throughout the evolution of [...] Read more.
Telomeres are terminal regions of chromosomes that protect and stabilize chromosome structures. Telomeres are usually composed of specific DNA repeats (motifs) that are maintained by telomerase and a complex of specific proteins. Telomeric DNA sequences are generally highly conserved throughout the evolution of different groups of eukaryotes. The most common motif in insects is TTAGG, but it is not universal, including in the large order Hemiptera. In particular, several derived telomeric motifs were identified in this order by analyzing chromosome-level genome assemblies or by FISH screening the chromosomes of target species. Here, we analyzed chromosome-level genome assemblies of 16 species from three hemipteran suborders, including Sternorrhyncha (Coccoidea: Planococcus citri, Acanthococcus lagerstroemiae, and Trionymus diminutus; Aphidoidea: Tuberolachnus salignus, Metopolophium dirhodum, Rhopalosiphum padi, and Schizaphis graminum), Auhenorrhyncha (Cicadomorpha: Allygus modestus, Arthaldeus pascuellus, Aphrophora alni, Cicadella viridis, Empoasca decipiens, and Ribautiana ulmi), and Heteroptera (Gerromorpha: Gerris lacustris; Pentatomomorpha: Aradus depressus and A. truncatus). In addition, scaffold-level genome assemblies of three more species of Heteroptera (Gerromorpha: Gerris buenoi, Microvelia longipes, and Hermatobates lingyangjiaoensis) were examined. The presumably ancestral insect motif TTAGG was found at the ends of chromosomes of all species studied using chromosome-level genome assembly analysis, with four exceptions. In Aphrophora alni, we detected sequences of 4 bp repeats of TGAC, which were tentatively identified as a telomeric motif. In Gerris lacustris, from the basal true bug infraorder Gerromorpha, we found a 10 bp motif TTAGAGGTGG, previously unknown not only in Heteroptera or Hemiptera but also in Arthropoda in general. Blast screening of the scaffold-level assemblies showed that TTAGAGGTGG is also likely to be a telomeric motif in G. buenoi and Microvelia. longipes, while the results obtained for H. lingyangjiaoensis were inconclusive. In A. depressus and A. truncatus from the basal for Pentatomomorpha family Aradidae, we found a 10 bp motif TTAGGGATGG. While the available data allowed us to present two alternative hypotheses about the evolution of telomeric motifs in Heteroptera, further data are needed to verify them, especially for the yet unstudied basal infraorders Enicocephalomorpha, Dipsocoromorpha, and Leptopodomorpha. Full article
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