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17 pages, 7038 KiB  
Article
Polyploidy Induction of Wild Diploid Blueberry V. fuscatum
by Emily Walter, Paul M. Lyrene and Ye Chu
Horticulturae 2025, 11(8), 921; https://doi.org/10.3390/horticulturae11080921 (registering DOI) - 5 Aug 2025
Abstract
Diploid Vaccinium fuscatum is a wild blueberry species with a low chilling requirement, an evergreen growth habit, and soil adaptability to southeast US growing regions. Regardless of its potential to improve the abiotic and biotic resilience of cultivated blueberries, this species has rarely [...] Read more.
Diploid Vaccinium fuscatum is a wild blueberry species with a low chilling requirement, an evergreen growth habit, and soil adaptability to southeast US growing regions. Regardless of its potential to improve the abiotic and biotic resilience of cultivated blueberries, this species has rarely been used for blueberry breeding. One hurdle is the ploidy barrier between diploid V. fuscatum and tetraploid cultivated highbush blueberries. To overcome the ploidy barrier, vegetative shoots micro-propagated from one genotype of V. fuscatum, selected because it grew vigorously in vitro and two southern highbush cultivars, ‘Emerald’ and ‘Rebel,’ were treated with colchicine. While shoot regeneration was severely repressed in ‘Emerald’ and ‘Rebel,’ shoot production from the V. fuscatum clone was not compromised at either 500 µM or 5000 µM colchicine concentrations. Due to the high number of shoots produced in vitro via the V. fuscatum clone shoots of this clone that had an enlarged stem diameter in vitro were subjected to flow cytometer analysis to screen for induced polyploidy. Sixteen synthetic tetraploid V. fuscatum, one synthetic octoploid ‘Emerald,’ and three synthetic octoploid ‘Rebel’ were identified. Growth rates of the polyploid-induced mutants were reduced compared to their respective wildtype controls. The leaf width and length of synthetic tetraploid V. fuscatum and synthetic octoploid ‘Emerald’ was increased compared to the wildtypes, whereas the leaf width and length of synthetic octoploid ‘Rebel’ were reduced compared to the wildtype controls. Significant increases in stem thickness and stomata guard cell length were found in the polyploidy-induced mutant lines compared to the wildtypes. In the meantime, stomata density was reduced in the mutant lines. These morphological changes may improve drought tolerance and photosynthesis in these mutant lines. Synthetic tetraploid V. fuscatum can be used for interspecific hybridization with highbush blueberries to expand the genetic base of cultivated blueberries. Full article
(This article belongs to the Section Propagation and Seeds)
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15 pages, 1636 KiB  
Article
The Immunoproteasome Is Expressed but Dispensable for a Leukemia Infected Cell Vaccine
by Delphine Béland, Victor Mullins-Dansereau, Karen Geoffroy, Mélissa Viens, Kim Leclerc Desaulniers and Marie-Claude Bourgeois-Daigneault
Vaccines 2025, 13(8), 835; https://doi.org/10.3390/vaccines13080835 (registering DOI) - 5 Aug 2025
Abstract
Background/Objectives: Leukemia is associated with high recurrence rates and cancer vaccines are emerging as a promising immunotherapy against the disease. Here, we investigate the mechanism of action by which a personalized vaccine made from leukemia cells infected with an oncolytic virus (ICV) induces [...] Read more.
Background/Objectives: Leukemia is associated with high recurrence rates and cancer vaccines are emerging as a promising immunotherapy against the disease. Here, we investigate the mechanism of action by which a personalized vaccine made from leukemia cells infected with an oncolytic virus (ICV) induces anti-tumor immunity. Methods: Using the L1210 murine model, leukemia cells were infected and irradiated to create the ICV. The CRISPR-Cas9 system was used to engineer knockout cells to test in treatment efficacy studies. Results: We found that pro-inflammatory interferons (IFNs) that are produced by infected vaccine cells induce the immunoproteasome (ImP), a specialized proteasome subtype that is found in immune cells. Interestingly, we show that while a vaccine using the oncolytic vesicular stomatitis virus (oVSV) completely protects against tumor challenge, the wild-type (wt) virus, which does not induce the ImP, is not as effective. To delineate the contribution of the ImP for vaccine efficacy, we generated ImP-knockout cell lines and found no differences in treatment efficacy compared to wild-type cells. Furthermore, an ICV using another murine leukemia model that expresses the ImP only when infected by an IFN gamma-encoding variant of the virus demonstrated similar efficacy as the parental virus. Conclusions: Taken together, our data show that ImP expression by vaccine cells was not required for the efficacy of leukemia ICVs. Full article
(This article belongs to the Special Issue Personalised Cancer Vaccines)
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17 pages, 1747 KiB  
Article
Rasagiline Inhibits Human Melanoma Cell Viability and Interacts Synergistically with Mitoxantrone and Antagonistically with Cisplatin—In Vitro Isobolographic Studies
by Danuta Krasowska, Paula Wróblewska-Łuczka, Michał Chojnacki, Katarzyna Załuska-Ogryzek, Jacek Kurzepa and Jarogniew J. Łuszczki
Cancers 2025, 17(15), 2563; https://doi.org/10.3390/cancers17152563 - 3 Aug 2025
Viewed by 271
Abstract
Background: The increased incidence of malignant melanoma is observed in patients with Parkinson’s disease. Methods: The anti-proliferative effects of carbidopa and rasagiline on four human malignant melanoma cell lines (A375, SK-MEL28, FM55P and FM55M2) were determined in MTT assay. The interaction profiles of [...] Read more.
Background: The increased incidence of malignant melanoma is observed in patients with Parkinson’s disease. Methods: The anti-proliferative effects of carbidopa and rasagiline on four human malignant melanoma cell lines (A375, SK-MEL28, FM55P and FM55M2) were determined in MTT assay. The interaction profiles of rasagiline in combinations with cisplatin (CDDP) and mitoxantrone (MTX) in four human melanoma cell lines (A375, SK-MEL28, FM55P and FM55M2) were assessed by means of the isobolographic analysis in the MTT test; Results: Rasagiline, but not carbidopa, produced clear-cut anti-proliferative effects on various melanoma cell lines. The median inhibitory concentrations (IC50 values) of rasagiline in the MTT were 280.69 µM for A375, 402.89 µM for SK-MEL28, 349.44 µM for FM55P, and 117.45 µM for FM55M2, respectively. The experimentally-derived selectivity index for rasagiline ranged from 8.22 to 28.18. Flow cytometry assay revealed, in two melanoma cell lines (FM55P and A375), a significant increase in the number of cells in the G0/G1 (up to 76.48% and 75.46% for cell lines, respectively), accompanied by a decrease in the percentage of cells in the S phase (decrease to 9.91% and 10.83% for cell lines, respectively), which may indicate potential cytostatic properties of rasagiline. The combinations of rasagiline with CDDP (at the fixed-ratio of 1:1) exerted either antagonistic interactions (p < 0.05) in the A375 and SK-MEL28, or additive interactions, with a tendency toward antagonism in the FM55P and FM55M2 cell lines in the MTT test. In contrast, the combinations of rasagiline with MTX (ratio of 1:1) produced either synergistic interaction (p < 0.05) in the FM55P cell line or additive interactions with a tendency toward synergy in the FM55M2, SK-MEL28, and A375 cell lines in the MTT test. Conclusions: Rasagiline combined with MTX exerted the most desirable synergistic interactions in relation to the anti-proliferative effects in four malignant melanoma cell lines, as assessed isobolographically. In contrast, rasagiline should not be combined with CDDP during the treatment of malignant melanoma due to the antagonistic interactions in the MTT assay. Full article
(This article belongs to the Special Issue Research on New Drugs and Drug Targets in Melanoma)
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12 pages, 1650 KiB  
Communication
Salsolinol-Containing Senna silvestris Exerts Antiviral Activity Against Hepatitis B Virus
by Alberto Quintero, Maria Maillo, Nelson Gomes, Angel Fernández, Hector R. Rangel, Fabian Michelangeli and Flor H. Pujol
Plants 2025, 14(15), 2372; https://doi.org/10.3390/plants14152372 - 1 Aug 2025
Viewed by 186
Abstract
Several natural products have been shown to display antiviral activity against the hepatitis B virus (HBV), among a number of other viruses. In a previous study, the hydro-alcoholic extracts (n = 66) of 31 species from the Venezuelan Amazonian rain forest were tested [...] Read more.
Several natural products have been shown to display antiviral activity against the hepatitis B virus (HBV), among a number of other viruses. In a previous study, the hydro-alcoholic extracts (n = 66) of 31 species from the Venezuelan Amazonian rain forest were tested on the hepatoma cell line HepG2.2.15, which constitutively produces HBV. One of the species that exerted inhibitory activity on HBV replication was Senna silvestris. The aim of this study was the bioassay-guided purification of the ethanol fraction of leaves of S. silvestris, which displayed the most significant inhibitory activity against HBV. After solvent extraction and two rounds of reverse-phase HPLC purification, NMR analysis identified salsolinol as the compound that may exert the desired antiviral activity. The purified compound exerted inhibition of both HBV DNA and core HBV DNA. Pure salsolinol obtained from a commercial source also displayed anti-HBV DNA inhibition, with an approximate MIC value of 12 µM. Although salsolinol is widely used in Chinese traditional medicine to treat congestive heart failure, it has also been associated with Parkinson’s disease. More studies are warranted to analyze the effect of changes in its chemical conformation, searching for potent antiviral, perhaps dual agents against HBV and HIV, with reduced toxicity. Full article
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13 pages, 1809 KiB  
Perspective
Specific Low/Endogenous Replication Stress Response Protects Genomic Stability via Controlled ROS Production in an Adaptive Way and Is Dysregulated in Transformed Cells
by Bernard S. Lopez
Cells 2025, 14(15), 1183; https://doi.org/10.3390/cells14151183 - 31 Jul 2025
Viewed by 182
Abstract
Cells are assaulted daily by stresses that jeopardize genome integrity. Primary human cells adapt their response to the intensity of replication stress (RS) in a diphasic manner: below a stress threshold, the canonical DNA damage response (cDDR) is not activated, but a noncanonical [...] Read more.
Cells are assaulted daily by stresses that jeopardize genome integrity. Primary human cells adapt their response to the intensity of replication stress (RS) in a diphasic manner: below a stress threshold, the canonical DNA damage response (cDDR) is not activated, but a noncanonical cellular response, low-level stress-DDR (LoL-DDR), has recently been described. LoL-DDR prevents the accumulation of premutagenic oxidized bases (8-oxoguanine) through the production of ROS in an adaptive way. The production of RS-induced ROS (RIR) is tightly controlled: RIR are excluded from the nucleus and are produced by the NADPH oxidases DUOX1/DUOX2, which are controlled by NF-κB and PARP1; then, RIR activate the FOXO1-detoxifying pathway. Increasing the intensity of RS suppresses RIR via p53 and ATM. Notably, LoL-DDR is dysregulated in cancer cell lines, in which RIR are not produced by NADPH oxidases, are not detoxified under high-level stress, and favor the accumulation of 8-oxoguanine. LoL-DDR dysregulation occurred at an early stage of cancer progression in an in vitro model. Since, conversely, ROS trigger RS, this establishes a vicious cycle that continuously jeopardizes genome integrity, fueling tumorigenesis. These data reveal a novel type of ROS-controlled DNA damage response and demonstrate the fine-tuning of the cellular response to stress. The effects on genomic stability and carcinogenesis are discussed here. Full article
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26 pages, 9475 KiB  
Article
Microalgae-Derived Vesicles: Natural Nanocarriers of Exogenous and Endogenous Proteins
by Luiza Garaeva, Eugene Tolstyko, Elena Putevich, Yury Kil, Anastasiia Spitsyna, Svetlana Emelianova, Anastasia Solianik, Eugeny Yastremsky, Yuri Garmay, Elena Komarova, Elena Varfolomeeva, Anton Ershov, Irina Sizova, Evgeny Pichkur, Ilya A. Vinnikov, Varvara Kvanchiani, Alina Kilasoniya Marfina, Andrey L. Konevega and Tatiana Shtam
Plants 2025, 14(15), 2354; https://doi.org/10.3390/plants14152354 - 31 Jul 2025
Viewed by 315
Abstract
Extracellular vesicles (EVs), nanoscale membrane-enclosed particles, are natural carriers of proteins and nucleic acids. Microalgae are widely used as a source of bioactive substances in the food and cosmetic industries and definitely have a potential to be used as the producers of EVs [...] Read more.
Extracellular vesicles (EVs), nanoscale membrane-enclosed particles, are natural carriers of proteins and nucleic acids. Microalgae are widely used as a source of bioactive substances in the food and cosmetic industries and definitely have a potential to be used as the producers of EVs for biomedical applications. In this study, the extracellular vesicles isolated from the culture medium of two unicellular microalgae, Chlamydomonas reinhardtii (Chlamy-EVs) and Parachlorella kessleri (Chlore-EVs), were characterized by atomic force microscopy (AFM), cryo-electronic microscopy (cryo-EM), and nanoparticle tracking analysis (NTA). The biocompatibility with human cells in vitro (HEK-293T, DF-2 and A172) and biodistribution in mouse organs and tissues in vivo were tested for both microalgal EVs. An exogenous therapeutic protein, human heat shock protein 70 (HSP70), was successfully loaded to Chlamy- and Chlore-EVs, and its efficient delivery to human glioma and colon carcinoma cell lines has been confirmed. Additionally, in order to search for potential therapeutic biomolecules within the EVs, their proteomes have been characterized. A total of 105 proteins were identified for Chlamy-EVs and 33 for Chlore-EVs. The presence of superoxide dismutase and catalase in the Chlamy-EV constituents allows for considering them as antioxidant agents. The effective delivery of exogenous cargo to human cells and the possibility of the particle yield optimization by varying the microalgae growth conditions make them favorable producers of EVs for biotechnology and biomedical application. Full article
(This article belongs to the Section Plant Cell Biology)
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12 pages, 1773 KiB  
Article
Low-Frequency rTMS and Diazepam Exert Synergistic Effects on the Excitability of an SH-SY5Y Model of Epileptiform Activity
by Ioannis Dardalas, Efstratios K. Kosmidis, Roza Lagoudaki, Vasilios K. Kimiskidis, Theodoros Samaras, Theodoros Moysiadis, Dimitrios Kouvelas and Chryssa Pourzitaki
Biomedicines 2025, 13(8), 1857; https://doi.org/10.3390/biomedicines13081857 - 30 Jul 2025
Viewed by 312
Abstract
Background/Objectives: Epilepsy is a brain condition that affects millions of people worldwide. Although there are many antiepileptic drugs with different mechanisms of action, many patients still fail to control their agonizing symptoms, a situation that highlights the need for more strategies to address [...] Read more.
Background/Objectives: Epilepsy is a brain condition that affects millions of people worldwide. Although there are many antiepileptic drugs with different mechanisms of action, many patients still fail to control their agonizing symptoms, a situation that highlights the need for more strategies to address this issue. In this in vitro study, we elucidated and characterized the alterations in intracellular Ca2+ levels in cell cultures where diazepam and repetitive transcranial magnetic stimulation were implemented, alone or in combination. Methods: Using the differentiated human-derived neuroblastoma cell line SH-SY5Y, we measured the alterations in intracellular Ca2+ levels under the impact of either low-frequency repetitive transcranial magnetic stimulation (1 Hz), diazepam (14 μM), or their combination. We used the Ca2+-sensitive fluorescent indicator Fluo-4 acetoxymethyl ester for calcium imaging, while neuronal excitation was achieved with 50 mM KCl. Results: The highest median fluorescence intensity increase (%ΔF/F = 24.80) was observed in control cell cultures, followed by rTMS cultures (%ΔF/F = 16.96) and diazepam cultures (%ΔF/F = 11.46). The lowest median fluorescence intensity value (%ΔF/F =−0.44) was observed when diazepam was used concomitantly with repetitive transcranial magnetic stimulation. Post hoc analysis assessed pairwise differences, showing statistically significant differentiation between the control group and all other groups. Additionally, statistically significant results were observed between repetitive transcranial magnetic stimulation or diazepam and their combination, but not between them. Conclusions: The combination of diazepam and repetitive transcranial magnetic stimulation resulted in the most significant reduction in intracellular Ca2+ levels, as indicated by the lowest fluorescence values compared with the control group. Individually, each treatment produced a notable but less pronounced effect. We conclude that both diazepam and low-frequency repetitive transcranial magnetic stimulation can control epileptiform activity in vitro, while their combination is the most effective treatment. Full article
(This article belongs to the Special Issue Epilepsy: From Mechanisms to Therapeutic Approaches)
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31 pages, 23068 KiB  
Article
Heparan Sulfate Proteoglycans as Potential Markers for In Vitro Human Neural Lineage Specification
by Chieh Yu, Duy L. B. Nguyen, Martina Gyimesi, Ian W. Peall, Son H. Pham, Lyn R. Griffiths, Rachel K. Okolicsanyi and Larisa M. Haupt
Cells 2025, 14(15), 1158; https://doi.org/10.3390/cells14151158 - 26 Jul 2025
Viewed by 368
Abstract
Heparan sulfate proteoglycans (HSPGs) within the neuronal niche are expressed during brain development, contributing to multiple aspects of neurogenesis, yet their roles in glial lineage commitment remain elusive. This study utilised three human cell models expanded under basal culture conditions followed by media-induced [...] Read more.
Heparan sulfate proteoglycans (HSPGs) within the neuronal niche are expressed during brain development, contributing to multiple aspects of neurogenesis, yet their roles in glial lineage commitment remain elusive. This study utilised three human cell models expanded under basal culture conditions followed by media-induced lineage induction to identify a reproducible and robust model of gliogenesis. SH-SY5Y human neuroblastoma cells (neuronal control), ReNcell CX human neural progenitor cells (astrocyte inductive) and ReNcell VM human neural progenitor (mixed neural induction) models were examined. The cultures were characterised during basal and inductive states via Q-PCR, Western Blotting, immunocytochemistry (ICC) and calcium signalling activity analyses. While the ReNcell lines did not produce fully mature or homogeneous astrocyte cultures, the ReNcell CX cultures most closely resembled an astrocytic phenotype with ReNcell VM cells treated with platelet-derived growth factor (PDGF) biased toward an oligodendrocyte lineage. The glycated variant of surface-bound glypican-2 (GPC2) was found to be associated with lineage commitment, with GPC6 and 6-O HS sulfation upregulated in astrocyte lineage cultures. Syndecan-3 (SDC3) emerged as a lineage-sensitive proteoglycan, with its cytoplasmic domain enriched in progenitor-like states and lost upon differentiation, supporting a role in maintaining neural plasticity. Conversely, the persistence of transmembrane-bound SDC3 in astrocyte cultures suggest continued involvement in extracellular signalling and proteoglycan secretion, demonstrated by increased membrane-bound HS aggregates. This data supports HSPGs and HS GAGs as human neural lineage differentiation and specification markers that may enable better isolation of human neural lineage-specific cell populations and improve our understanding of human neurogenesis. Full article
(This article belongs to the Collection Feature Papers in 'Cells of the Nervous System' Section)
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23 pages, 2161 KiB  
Review
Recent Advances in Engineering the Unfolded Protein Response in Recombinant Chinese Hamster Ovary Cell Lines
by Dyllan Rives, Tara Richbourg, Sierra Gurtler, Julia Martone and Mark A. Blenner
Int. J. Mol. Sci. 2025, 26(15), 7189; https://doi.org/10.3390/ijms26157189 - 25 Jul 2025
Viewed by 333
Abstract
Chinese hamster ovary (CHO) cells are the most common protein production platform for glycosylated biopharmaceuticals due to their relatively efficient secretion systems, post-translational modification (PTM) machinery, and quality control mechanisms. However, high productivity and titer demands can overburden these processes. In particular, the [...] Read more.
Chinese hamster ovary (CHO) cells are the most common protein production platform for glycosylated biopharmaceuticals due to their relatively efficient secretion systems, post-translational modification (PTM) machinery, and quality control mechanisms. However, high productivity and titer demands can overburden these processes. In particular, the endoplasmic reticulum (ER) can become overwhelmed with misfolded proteins, triggering the unfolded protein response (UPR) as evidence of ER stress. The UPR increases the expression of multiple genes/proteins, which are beneficial to protein folding and secretion. However, if the stressed ER cannot return to a state of homeostasis, a prolonged UPR results in apoptosis. Because ER stress poses a substantial bottleneck for secreting protein therapeutics, CHO cells are both selected for and engineered to improve high-quality protein production through optimized UPR and ER stress management. This is vital for optimizing industrial CHO cell fermentation. This review begins with an overview of common ER-stress related markers. Next, the optimal UPR profile of high-producing CHO cells is discussed followed by the context-dependency of a UPR profile for any given recombinant CHO cell line. Recent efforts to control and engineer ER stress-related responses in CHO cell lines through the use of various bioprocess operations and activation/inhibition strategies are elucidated. Finally, this review concludes with a discussion on future directions for engineering the CHO cell UPR. Full article
(This article belongs to the Special Issue New Insights into the Molecular Mechanisms of the UPR and Cell Stress)
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19 pages, 3112 KiB  
Article
Development of a Lentiviral Vector for High-Yield Production of Synthetic and Recombinant GCase for Gaucher Disease Therapy
by Ana Carolina Coelho, Claudia Emília Vieira Wiezel, Alline Cristina de Campos, Lílian Louise Souza Figueiredo, Gabriela Aparecida Marcondes Suardi, Juliana de Paula Bernardes, Daniela Pretti da Cunha Tirapelli, Vitor Marcel Faça, Kuruvilla Joseph Abraham, Carlos Gilberto Carlotti-Júnior, Velia Siciliano, Ron Weiss, Stanton Gerson and Aparecida Maria Fontes
Int. J. Mol. Sci. 2025, 26(15), 7089; https://doi.org/10.3390/ijms26157089 - 23 Jul 2025
Viewed by 308
Abstract
Gaucher disease (GD) is an autosomal recessive disorder caused by the deficient activity of the lysosomal enzyme glucocerebrosidase (GCase). Although enzyme replacement therapy (ERT) remains the standard of care for non-neuropathic GD patients, its high cost significantly limits accessibility. To enhance production efficiency, [...] Read more.
Gaucher disease (GD) is an autosomal recessive disorder caused by the deficient activity of the lysosomal enzyme glucocerebrosidase (GCase). Although enzyme replacement therapy (ERT) remains the standard of care for non-neuropathic GD patients, its high cost significantly limits accessibility. To enhance production efficiency, we developed a lentiviral system encoding a codon-optimized GCase gene driven by the human elongation factor 1a (hEF1α) promoter for stable production in human cell lines. A functional lentiviral vector, LV_EF1α_GBA_Opt, was generated at a titer of 7.88 × 108 LV particles/mL as determined by qPCR. Six transduction cycles were performed at a multiplicity of infection of 30–50. The transduced heterogeneous human cell population showed GCase-specific activity of 307.5 ± 53.49 nmol/mg protein/h, which represents a 3.21-fold increase compared to wild-type 293FT cells (95.58 ± 16.5 nmol/mg protein/h). Following single-cell cloning, two clones showed specific activity of 763.8 ± 135.1 and 752.0 ± 152.1 nmol/mg/h (clones 15 and 16, respectively). These results show that codon optimization, a lentiviral delivery system, and clonal selection together enable the establishment of stable human cell lines capable of producing high levels of biologically active, synthetic recombinant GCase in vitro. Further studies are warranted for the functional validation in GD patient-derived fibroblasts and animal models. Full article
(This article belongs to the Special Issue Gaucher Disease: From Molecular Mechanisms to Treatments)
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19 pages, 2360 KiB  
Article
Novel N-Alkyl 3-(3-Benzyloxyquinoxalin-2-yl) Propanamides as Antiproliferative Agents: Design, Synthesis, In Vitro Testing, and In Silico Mechanistic Study
by Samar A. Abubshait
Molecules 2025, 30(14), 3025; https://doi.org/10.3390/molecules30143025 - 18 Jul 2025
Viewed by 497
Abstract
A series of eleven new N-alkyl 3-(3-benzyloxyquinoxalin-2-yl) propanamides were prepared based on the azide coupling of 3-(3-benzyloxyquinoxalin-2-yl) propanhydrazide with a variety of primary and secondary amines and the consequent conjunction of a broad spectrum of lipophile and hydrophile characters to a quinoxaline [...] Read more.
A series of eleven new N-alkyl 3-(3-benzyloxyquinoxalin-2-yl) propanamides were prepared based on the azide coupling of 3-(3-benzyloxyquinoxalin-2-yl) propanhydrazide with a variety of primary and secondary amines and the consequent conjunction of a broad spectrum of lipophile and hydrophile characters to a quinoxaline ring system. 3-(3-benzyloxyquinoxalin-2-yl) propanhydrazide was produced in a two-step reaction of methyl 3-(3-oxo-3,4-dihydroquinoxalin-2-yl) propanoate with benzyl chloride followed by the hydrazinolysis of the corresponding ester. The antiproliferative activity of the compounds was tested in various cancer cell lines, including PC-3, Hela, HCT-116, and MCF-7; they showed a wide spectrum of activity for most of the tested compounds. Compound 6k exhibited the highest activity, which was comparable to that of doxorubicin, with IC50 (µM) values of 12.17 ± 0.9, 9.46 ± 0.7, 10.88 ± 0.8, and 6.93 ± 0.4 µM compared to 8.87 ± 0.6, 5.57 ± 0.4, 5.23 ± 0.3, and 4.17 ± 0.2 µM for doxorubicin against Hela, HCT-116, and MCF-7, respectively. The in silico mechanistic study revealed the inhibition of HDAC-6 through the binding of the unique zinc finger ubiquitin-binding domain (HDAC6 Zf-UBD). The docking results showed a specific binding pattern that emphasized the crucial role of the quinoxaline ring and its substituents. The newly developed derivatives were evaluated for antitumor effects against four cancer cell lines PC-3, HeLa, HCT-116, and MCF-7. This research led to the identification of a quinoxaline-based scaffold exhibiting broad-spectrum antiproliferative activity and a distinct mechanism involving binding to HDAC6 Zf-UBD. The findings highlight its potential for further optimization and preclinical studies to support future anticancer drug development. Full article
(This article belongs to the Special Issue Molecular Docking in Drug Discovery, 2nd Edition)
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17 pages, 3046 KiB  
Article
Therapeutic Use of Parerythrobacter sp. M20A3S10, a Marine Bacterium, Targeting Influenza Viruses and Flaviviruses
by Kyeong-Seo Moon, Ji-Young Chung, Hyeon Jeong Moon, Gun Lee, Chung-Do Lee, Su-Bin Jung, Hyo-Jin Kim, Jun-Gyu Park, Yeong-Bin Baek and Sang-Ik Park
Animals 2025, 15(14), 2125; https://doi.org/10.3390/ani15142125 - 18 Jul 2025
Viewed by 268
Abstract
Emerging RNA viruses such as influenza A virus (IAV), Zika virus (ZIKV), and dengue virus (DENV) continue to pose major challenges to animal and public health due to their high mutation rates, wide host ranges, and immune evasion strategies. In this study, we [...] Read more.
Emerging RNA viruses such as influenza A virus (IAV), Zika virus (ZIKV), and dengue virus (DENV) continue to pose major challenges to animal and public health due to their high mutation rates, wide host ranges, and immune evasion strategies. In this study, we evaluated the in vitro antiviral activity of a marine bacterial extract derived from Parerythrobacter sp. M20A3S10 against IAV (H1N1; H3N2), influenza B virus (IBV), ZIKV, and DENV2. The extract demonstrated broad-spectrum antiviral effects with favorable selectivity indices across multiple host-derived epithelial cell lines. Notably, post-infection treatment significantly suppressed viral replication, suggesting a host-modulating or replication-inhibiting mechanism. While the extract’s active components have yet to be identified, bacteria from the Erythrobacteraceae family are known producers of bioactive metabolites with potential antiviral properties. These findings provide preliminary insight into the potential of marine-derived bacterial compounds in veterinary antiviral development and highlight the need for further characterization and in vivo validation. This work contributes to the understanding of virus–host interactions and the exploration of novel therapeutic strategies targeting the pathogenesis and immune modulation of veterinary RNA viruses. Full article
(This article belongs to the Special Issue Pathogenesis, Immunology and Epidemiology of Veterinary Viruses)
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18 pages, 2563 KiB  
Article
The Potential Anti-Cancer Effects of Polish Ethanolic Extract of Propolis and Quercetin on Glioma Cells Under Hypoxic Conditions
by Małgorzata Kłósek, Anna Kurek-Górecka, Radosław Balwierz, Grażyna Pietsz and Zenon P. Czuba
Molecules 2025, 30(14), 3008; https://doi.org/10.3390/molecules30143008 - 17 Jul 2025
Viewed by 649
Abstract
Tissue hypoxia is commonly observed in head cancers and contributes to both molecular and functional changes in tumour cells. It is known to stimulate erythropoiesis, angiogenesis, and metabolic alterations within tumour cells. Glioblastoma, a type of brain tumour, is characterized by rapid proliferation [...] Read more.
Tissue hypoxia is commonly observed in head cancers and contributes to both molecular and functional changes in tumour cells. It is known to stimulate erythropoiesis, angiogenesis, and metabolic alterations within tumour cells. Glioblastoma, a type of brain tumour, is characterized by rapid proliferation and aggressive growth. Recent studies have indicated that natural products may hold potential as components of cancer therapy. Among these, Polish propolis and its active compound, quercetin, have demonstrated promising anti-cancer properties. The aim of this study was to evaluate the concentrations of selected cytokines—specifically IL-6, IL-9, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF-BB), interferon gamma-induced protein 10 (IP-10), and monocyte chemoattractant protein-1 (MCP-1)—produced by astrocytes of the CCF-STTG1 cell line. The cytotoxic effects of ethanolic extract of propolis (EEP) and quercetin were assessed using the MTT assay. Astrocytes were stimulated with lipopolysaccharide (LPS, 200 ng/mL) and/or IFN-α (100 U/mL), followed by treatment with EEP or quercetin (25–50 µg/mL) under hypoxic conditions for two hours. Cytokine concentrations were measured using the xMAP Luminex Multiplex Immunoassay and the Multiplex Bead-Based Cytokine Kit. Our study demonstrated that Polish propolis and its component quercetin modulate the tumour microenvironment in vitro, primarily by altering the levels of specific cytokines. The HCA analysis revealed that IL-6 and MCP-1 formed a distinct cluster at the highest linkage distance (approximately 100% of Dmax), suggesting that their expression patterns are significantly different from those of the other cytokines and that they are more similar to each other than to the rest. PCA analysis showed that EEP-PL (50 μg/mL) with IFN-α and EEP-PL (50 μg/mL) with LPS exert similar activities on cytokine secretion by astrocytes. Similar effects were demonstrated for EEP-PL 50 μg/mL + LPS + IFN-α, EEP-PL 25 μg/mL + IFN-α and EEP-PL 25 μg/mL + LPS + IFN-α. Our findings suggest that Polish propolis and quercetin may serve as promising natural agents to support the treatment of stage IV malignant astrocytoma. Nonetheless, further research is needed to confirm these results. Full article
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18 pages, 7149 KiB  
Article
Co-Inhibition of PARP and STAT3 as a Promising Approach for Triple-Negative Breast Cancer
by Changyou Shi, Li Pan, Satomi Amano, Mei-Yi Wu, Chenglong Li and Jiayuh Lin
Biomolecules 2025, 15(7), 1035; https://doi.org/10.3390/biom15071035 - 17 Jul 2025
Viewed by 413
Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive subtype known for its rapid metastatic potential. Despite its severity, treatment options for TNBC remain limited. Olaparib, an FDA-approved PARP inhibitor, has been used to treat germline BRCA-mutated TNBC in both metastatic and high-risk [...] Read more.
Triple-negative breast cancer (TNBC) is a highly aggressive subtype known for its rapid metastatic potential. Despite its severity, treatment options for TNBC remain limited. Olaparib, an FDA-approved PARP inhibitor, has been used to treat germline BRCA-mutated TNBC in both metastatic and high-risk early-stage settings. However, acquired resistance to PARP inhibitors and their limited applicability in non-BRCA TNBCs are now two major growing clinical problems. Activation of the IL-6/STAT3 signaling cascade has been implicated in therapeutic resistance. In this study, we evaluated the combined effects of the PARP inhibitor olaparib and the STAT3 inhibitor LLL12B in human TNBC cell lines with both BRCA mutations and wild-type BRCA status. Our results demonstrate that the PARP inhibitor olaparib can induce increased interleukin-6 (IL-6) in TNBC cells, with ELISA showing a 2- to 39-fold increase across five cell lines. MTT assays revealed that knocking down or inhibiting STAT3, a key downstream effector of the IL-6/GP130 pathway, sensitizes TNBC cells to olaparib. Treatment with either olaparib or LLL12B alone reduced TNBC cell viability, migration, and invasion. Notably, their combined administration produced a markedly enhanced inhibitory effect compared to individual treatments, regardless of BRCA mutation status. These findings highlight the potential of dual PARP and STAT3 inhibition as a novel targeted therapeutic strategy for both BRCA-mutant and BRCA-proficient TNBC. Full article
(This article belongs to the Special Issue PARPs in Cell Death and PARP Inhibitors in Cancers: 2nd Edition)
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26 pages, 3044 KiB  
Article
Optimization of YF17D-Vectored Zika Vaccine Production by Employing Small-Molecule Viral Sensitizers to Enhance Yields
by Sven Göbel, Tilia Zinnecker, Ingo Jordan, Volker Sandig, Andrea Vervoort, Jondavid de Jong, Jean-Simon Diallo, Peter Satzer, Manfred Satzer, Kai Dallmeier, Udo Reichl and Yvonne Genzel
Vaccines 2025, 13(7), 757; https://doi.org/10.3390/vaccines13070757 - 16 Jul 2025
Viewed by 852
Abstract
Background: Modern viral vector production needs to consider process intensification for higher yields from smaller production volumes. However, innate antiviral immunity triggered in the producer cell may limit virus replication. While commonly used cell lines (e.g., Vero or E1A-immortalised cells) are already compromised [...] Read more.
Background: Modern viral vector production needs to consider process intensification for higher yields from smaller production volumes. However, innate antiviral immunity triggered in the producer cell may limit virus replication. While commonly used cell lines (e.g., Vero or E1A-immortalised cells) are already compromised in antiviral pathways, the redundancy of innate signaling complicates host cell optimization by genetic engineering. Small molecules that are hypothesized to target antiviral pathways (Viral Sensitizers, VSEs) added to the culture media offer a versatile alternative to genetic modifications to increase permissiveness and, thus, viral yields across multiple cell lines. Methods: To explore how the yield for a chimeric Zika vaccine candidate (YF-ZIK) could be further be increased in an intensified bioprocess, we used spin tubes or an Ambr15 high-throughput microbioreactor system as scale-down models to optimize the dosing for eight VSEs in three host cell lines (AGE1.CR.pIX, BHK-21, and HEK293-F) based on their tolerability. Results: Addition of VSEs to an already optimized infection process significantly increased infectious titers by up to sevenfold for all three cell lines tested. The development of multi-component VSE formulations using a design of experiments approach allowed further synergistic titer increases in AGE1.CR.pIX cells. Scale-up to 1 L stirred-tank bioreactors and 3D-printed mimics of 200 or 2000 L reactors resulted in up to threefold and eightfold increases, respectively. Conclusions: Addition of single VSEs or combinations thereof allowed a further increase in YF-ZIK titers beyond the yield of an already optimized, highly intensified process. The described approach validates the use of VSEs and can be instructive for optimizing other virus production processes. Full article
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