International Journal of Molecular Sciences

20 pages, 7497 KiB

Open AccessArticle

Evaluation of a Novel Mechanical Device for the Production of Microfragmented Adipose Tissue for Veterinary Regenerative Medicine: A Proof-of-Concept

by Priscilla Berni, Valentina Andreoli, Virna Conti, Roberto Ramoni, Giuseppina Basini, Gabriele Scattini, Luisa Pascucci, Martina Pellegrini, Maurizio Del Bue, Gian Paolo Squassino, Francesca Paino, Augusto Pessina, Giulio Alessandri, Paolo Pirazzoli, Antonio Bosetto and Stefano Grolli

Int. J. Mol. Sci. 2024, 25(21), 11854; https://doi.org/10.3390/ijms252111854 - 4 Nov 2024

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Abstract

Therapies based on mesenchymal stromal cells (MSCs) have become one of the most significant advancements in veterinary regenerative medicine. The isolation of MSCs is usually performed by enzymatic digestion and requires variable times for cell expansion. In addition, these procedures need to be [...] Read more.

Therapies based on mesenchymal stromal cells (MSCs) have become one of the most significant advancements in veterinary regenerative medicine. The isolation of MSCs is usually performed by enzymatic digestion and requires variable times for cell expansion. In addition, these procedures need to be performed in specialized laboratory facilities. An alternative approach to in vitro-expanded MSC therapy is the use of microfragmented adipose tissue (microfat), which is a rich source of cells and growth factors from the stromal vascular fraction. Recent clinical studies support its safety and efficacy in the treatment of musculoskeletal disorders and wound healing. The aim of the present work was to characterize the microfragmented adipose tissue obtained by a new mechanical device, which provides sterile tissue that is ready for use in the clinic by the veterinarian, avoiding the need for specialized laboratory facilities. Microfat-derived MSCs were compared with enzymatically isolated MSCs in terms of their phenotypic characterization, growth rate and differentiation potential. Conditioned medium derived from microfat culture was evaluated for its ability to promote MSC vitality. No differences were observed between MSCs obtained through mechanical fragmentation and those derived from collagenase digestion of adipose tissue, suggesting that the device could serve as a practical source of microfragmented adipose tissue for use in veterinary clinics. Full article

(This article belongs to the Special Issue Stem Cells and Selected Papers Associated with 2023 STEMNET MEETING and Related Researchers)

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27 pages, 3602 KiB

Open AccessArticle

Ecto-NOX Disulfide-Thiol Exchanger 2 (ENOX2/tNOX) Is a Potential Prognostic Marker in Primary Malignant Melanoma and May Serve as a Therapeutic Target

by Matti Böcker, Eftychia Chatziioannou, Heike Niessner, Constanze Hirn, Christian Busch, Kristian Ikenberg, Hubert Kalbacher, Rupert Handgretinger and Tobias Sinnberg

Int. J. Mol. Sci. 2024, 25(21), 11853; https://doi.org/10.3390/ijms252111853 - 4 Nov 2024

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Abstract

With an increasing incidence of malignant melanoma, new prognostic biomarkers for clinical decision making have become more important. In this study, we evaluated the role of ecto-NOX disulfide-thiol exchanger 2 (ENOX2/tNOX), a cancer- and growth-associated protein, in the prognosis and therapy of primary [...] Read more.

With an increasing incidence of malignant melanoma, new prognostic biomarkers for clinical decision making have become more important. In this study, we evaluated the role of ecto-NOX disulfide-thiol exchanger 2 (ENOX2/tNOX), a cancer- and growth-associated protein, in the prognosis and therapy of primary malignant melanoma. We conducted a tissue microarray analysis of immunohistochemical ENOX2 protein expression and The Cancer Genome Atlas (TCGA) ENOX2 RNA expression analysis, as well as viability assays and Western blots of melanoma cell lines treated with the ENOX2 inhibitor phenoxodiol (PXD) and BRAF inhibitor (BRAFi) vemurafenib. We discovered that high ENOX2 expression is associated with decreased overall (OS), disease-specific (DSS) and metastasis-free survival (MFS) in primary melanoma (PM) and a reduction in electronic tumor-infiltrating lymphocytes (eTILs). A gradual rise in ENOX2 expression was found with an increase in malignant potential from benign nevi (BNs) via PMs to melanoma metastases (MMs), as well as with an increasing tumor thickness and stage. These results highlight the important role of ENOX2 in cancer growth, progression and metastasis. The ENOX2 expression was not limited to malignant cell lines but could also be found in keratinocytes, fibroblasts and melanocytes. The viability of melanoma cell lines could be inhibited by PXD. A reduced induction of phospho-AKT under PXD could prevent the development of acquired BRAFi resistance. In conclusion, ENOX2 may serve as a potential prognostic marker and therapeutic target in malignant melanoma. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Treatment of Skin Cancer)

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19 pages, 15116 KiB

Open AccessArticle

Analysis of GCRV Pathogenesis and Therapeutic Measures Through Proteomic and Metabolomic Investigations in GCRV-Infected Tissues of Grass Carp (Ctenopharyngodon idella)

by Juhong Xie, Zhihui Jia, Yangyang Li, Lanjie Liao, Zuoyan Zhu, Yaping Wang and Rong Huang

Int. J. Mol. Sci. 2024, 25(21), 11852; https://doi.org/10.3390/ijms252111852 - 4 Nov 2024

Viewed by 607

Abstract

Hemorrhagic disease caused by grass carp reovirus (GCRV) infection is a major problem affecting the grass carp aquaculture industry. Therefore, inhibiting the spread of GCRV infection is of great economic significance. Herein, we sequenced five tissues (gill, liver, intestine, kidney, and muscle) from [...] Read more.

Hemorrhagic disease caused by grass carp reovirus (GCRV) infection is a major problem affecting the grass carp aquaculture industry. Therefore, inhibiting the spread of GCRV infection is of great economic significance. Herein, we sequenced five tissues (gill, liver, intestine, kidney, and muscle) from grass carp before and after GCRV infection using data-independent acquisition proteomic and untargeted metabolomic technologies, and quantitatively identified 10,808 proteins and 4040 metabolites. Then, we analyzed the differentially expressed proteins (DEPs) and metabolites (DEMs) before and after GCRV infection in the five tissues. Gene ontology analysis revealed that the five tissue DEPs were enriched in metabolic, including carbohydrate and lipid metabolic processes. Chemical taxonomy analysis showed that the categories of DEMs mainly included carbohydrates and lipids, such as fatty acids, glycerophospholipids, steroids, and their derivatives. Both the proteomic and the metabolomic data showed that GCRV affected the carbohydrate and lipid metabolism in the host. Shared pathway analysis was performed at both the protein and metabolic levels, showing significant enrichment of the glycolysis and pentose phosphate pathways (p < 0.001). Further analysis of glycolysis and pentose phosphate pathway inhibitors revealed that these two pathways are important for GCRV replication. As the kidney was the most affected among the five tissues, we analyzed the butanoate metabolism in the kidney, which revealed that most of the differentially expressed proteins and differently expressed metabolites in the butanoate metabolism were related to the TCA cycle. Further investigation showed that fumaric acid, an intermediate product in the TCA cycle, significantly inhibited GCRV replication in the CIK cells (p < 0.001), and that this inhibitory effect may be related to its induction of interferon system activation. The addition of fumaric acid to feed increased the survival rate of juvenile grass carp by 19.60% during GCRV infection, and protected the tissues of those infected with GCRV, making it a potential anti-GCRV feed additive. Our results provide new perspectives on GCRV pathogenesis and antiviral strategies for grass carp. Full article

(This article belongs to the Special Issue Molecular Biology of Host and Pathogen Interactions: 2nd Edition)

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18 pages, 4096 KiB

Open AccessArticle

Potential Cryptic Diversity in the Genus Scoliodon (Carcharhiniformes: Carcharhinidae): Insights from Mitochondrial Genome Sequencing

by Peiyuan Ye, Yuanxiang Miao, Chen Wang, Pichai Sonchaeng, Sarawut Siriwong, Shaobo Chen, Junjie Wang and Xiao Chen

Int. J. Mol. Sci. 2024, 25(21), 11851; https://doi.org/10.3390/ijms252111851 - 4 Nov 2024

Viewed by 598

Abstract

Scoliodon is a genus of small placental sharks living in offshore waters. For a long time, the genus was considered a monotypic genus until a valid species, Scoliodon macrorhynchos, was confirmed in 2010. However, S. muelleri in the same study was not [...] Read more.

Scoliodon is a genus of small placental sharks living in offshore waters. For a long time, the genus was considered a monotypic genus until a valid species, Scoliodon macrorhynchos, was confirmed in 2010. However, S. muelleri in the same study was not widely recognized because of the lack of evidence. In this study, we obtained the complete mitochondrial genome of the genus Scoliodon from Ranong, Thailand, and tentatively named it Scoliodon sp. By comparing the complete mitochondrial genome with those of two other Scoliodon species and conducting phylogenetic and divergence time analyses, we determined that Scoliodon sp. diverged from the other species. These findings indicate the potential for a new cryptic species (Scoliodon sp.) in the Scoliodon genus. This conclusion was further supported by a subsequent analysis of the published S. laticaudus control region sequences from previous studies. Finally, based on these conclusions, we used machine learning to derive a new identification method for the cryptic species. This approach may be useful for the discovery of new species or cryptic species in other organisms. Full article

(This article belongs to the Special Issue Mitochondrial Genome of Aquatic Animals: Analysis of Structure, Evolution and Diversity)

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28 pages, 11548 KiB

Open AccessReview

Molecular and Cellular Mechanisms Involved in the Pathophysiology of Retinal Vascular Disease—Interplay Between Inflammation and Oxidative Stress

by Jovana V. Srejovic, Maja D. Muric, Vladimir Lj. Jakovljevic, Ivan M. Srejovic, Suncica B. Sreckovic, Nenad T. Petrovic, Dusan Z. Todorovic, Sergey B. Bolevich and Tatjana S. Sarenac Vulovic

Int. J. Mol. Sci. 2024, 25(21), 11850; https://doi.org/10.3390/ijms252111850 - 4 Nov 2024

Viewed by 954

Abstract

Retinal vascular diseases encompass several retinal disorders, including diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, and retinal vascular occlusion; these disorders are classified as similar groups of disorders due to impaired retinal vascularization. The aim of this review is to address the [...] Read more.

Retinal vascular diseases encompass several retinal disorders, including diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, and retinal vascular occlusion; these disorders are classified as similar groups of disorders due to impaired retinal vascularization. The aim of this review is to address the main signaling pathways involved in the pathogenesis of retinal vascular diseases and to identify crucial molecules and the importance of their interactions. Vascular endothelial growth factor (VEGF) is recognized as a crucial and central molecule in abnormal neovascularization and a key phenomenon in retinal vascular occlusion; thus, anti-VEGF therapy is now the most successful form of treatment for these disorders. Interaction between angiopoietin 2 and the Tie2 receptor results in aberrant Tie2 signaling, resulting in loss of pericytes, neovascularization, and inflammation. Notch signaling and hypoxia-inducible factors in ischemic conditions induce pathological neovascularization and disruption of the blood–retina barrier. An increase in the pro-inflammatory cytokines—TNF-α, IL-1β, and IL-6—and activation of microglia create a persistent inflammatory milieu that promotes breakage of the blood–retinal barrier and neovascularization. Toll-like receptor signaling and nuclear factor-kappa B are important factors in the dysregulation of the immune response in retinal vascular diseases. Increased production of reactive oxygen species and oxidative damage follow inflammation and together create a vicious cycle because each factor amplifies the other. Understanding the complex interplay among various signaling pathways, signaling cascades, and molecules enables the development of new and more successful therapeutic options. Full article

(This article belongs to the Special Issue Innovative Strategies to Target Metabolism, Inflammation, and Oxidative Stress in Human Diseases)

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11 pages, 691 KiB

Open AccessArticle

The Association of TP53, BCL2, BAX and NOXA SNPs and Laryngeal Squamous Cell Carcinoma Development

by Tomas Jakstas, Agne Bartnykaite, Evaldas Padervinskis, Aurelija Vegiene, Elona Juozaityte, Virgilijus Uloza and Rasa Ugenskiene

Int. J. Mol. Sci. 2024, 25(21), 11849; https://doi.org/10.3390/ijms252111849 - 4 Nov 2024

Viewed by 612

Abstract

Head and neck cancer is the seventh leading cancer diagnosis worldwide. One of the most common cancers in the head and neck region is laryngeal cancer. In past years, the incidence of laryngeal squamous cell carcinoma has risen by 23%, and despite progress [...] Read more.

Head and neck cancer is the seventh leading cancer diagnosis worldwide. One of the most common cancers in the head and neck region is laryngeal cancer. In past years, the incidence of laryngeal squamous cell carcinoma has risen by 23%, and despite progress in treatment modalities, the survival rate has not changed. It is well known that genetic alterations may contribute to individuals’ susceptibility to cancer. Research of genetic alterations, such as single nucleotide polymorphisms, is essential to understanding carcinogenesis and susceptibility of laryngeal squamous cell carcinoma. A total of 200 LSCC patients and 200 controls were included in this retrospective case-control study; both groups were matched by age and sex. In the present study, we analyzed six SNPs in genes essential for apoptosis regulation: TP53 (rs9895829, rs17884306), BCL2 (rs1564483, rs4987855), BAX (rs704243), NOXA (PMAIP1) (rs1041978, rs78800940). We evaluated their associations with the risk of LSCC development, its pathomorphological manifestation, and patients’ overall survival rate. Genotyping was carried out using RT-PCR. The AG genotype of rs9895829 was more prevalent in controls than in cancer patients, leading to lower susceptibility to LSCC (OR = 0.301; 95%CI 0.096–0.940; p = 0.039). None of the analyzed SNPs showed an association with pathomorphological features of LSCC, but NOXA rs1041978 T allele carriers were found to be diagnosed with LSCC at an older age (OR = 1.962; 95%CI 1.072–3.592; p = 0.031). There was no statistically significant association between investigated SNPs and patient OS. The present study indicates that the AG genotype of rs9895829 provides a protective effect against LSCC development. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer and Cell Metabolism)

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9 pages, 274 KiB

Open AccessCommunication

Germline Variants in DNA Interstrand-Cross Link Repair Genes May Contribute to Increased Susceptibility for Serrated Polyposis Syndrome

by Patrícia Silva, Inês Francisco, Bruno Filipe, Pedro Lage, Isadora Rosa, Sofia Fernandes, Ricardo Fonseca, Paula Rodrigues, Joana Parreira, Isabel Claro and Cristina Albuquerque

Int. J. Mol. Sci. 2024, 25(21), 11848; https://doi.org/10.3390/ijms252111848 - 4 Nov 2024

Viewed by 683

Abstract

Serrated polyposis syndrome (SPS) is characterized by the development of multiple colorectal serrated polyps and increased predisposition to colorectal cancer (CRC). However, the molecular basis of SPS, especially in cases presenting family history of SPS and/or polyps and/or CRC in first-degree relatives (SPS-FHP/CRC), [...] Read more.

Serrated polyposis syndrome (SPS) is characterized by the development of multiple colorectal serrated polyps and increased predisposition to colorectal cancer (CRC). However, the molecular basis of SPS, especially in cases presenting family history of SPS and/or polyps and/or CRC in first-degree relatives (SPS-FHP/CRC), is still poorly understood. In a previous study, we proposed the existence of two molecular entities amongst SPS-FHP/CRC families, proximal/whole-colon and distal SPS-FHP/CRC, according to the preferential location of lesions and somatic events involved in tumor initiation. In the present study, we aimed to investigate these distinct subgroups of SPS patients in a larger cohort at the germline level and to identify the genetic defects underlying an inherited susceptibility for these two entities. Next-generation sequencing was performed using multigene analysis with a custom-designed panel in a Miseq platform in 60 SPS patients (with and without/unknown FHP/CRC). We found germline pathogenic variants in 6/60 patients (ATM, FANCM, MITF, RAD50, RAD51C, and RNF43). We also found variants of unknown significance (VUS), with prediction of probable damaging effect in 23/60 patients (ATM, BLM, BRCA1, FAN1, ERCC2, ERCC3, FANCA, FANCD2, FANCL, MSH2, MSH6, NTHL1, PALB2, PDGFRA, PMS2, PTCH1, RAD51C, RAD51D, RECQL4, TSC2, WRN, and XRCC5 genes). Most variants were detected in gene coding for proteins of the Fanconi Anemia (FA) pathway involved in the DNA Interstrand-Cross Link repair (ICLR). Notably, variants in ICLR genes were significantly more frequent in the proximal/whole-colon than in the distal subgroup [15/44 (34%) vs 1/16 (6%), p = 0.025], as opposed to the non-ICLR genes that were slightly more frequent in the distal group [8/44 (18%) vs. 5/16 (31%), p > 0.05]. Germline defects in the DNA-ICLR genes may contribute to increased serrated colorectal polyps/carcinoma risk in SPS patients, particularly in proximal/whole-colon SPS. The inclusion of DNA-ICLR genes in the genetic diagnosis of SPS patients, mainly in those with proximal/whole-colon lesions, should be considered and validated by other studies. In addition, patients with germline defects in the DNA-ICLR genes may be more sensitive to treatment with platinum-based therapeutics, which can have implications in the clinical management of these patients. Full article

(This article belongs to the Special Issue DNA Damage and DNA Repair Pathways in Cancer Development)

29 pages, 4568 KiB

Open AccessArticle

AI-Assisted Identification of Primary and Secondary Metabolomic Markers for Postoperative Delirium

by Vladimir A. Ivanisenko, Artem D. Rogachev, Aelita-Luiza A. Makarova, Nikita V. Basov, Evgeniy V. Gaisler, Irina N. Kuzmicheva, Pavel S. Demenkov, Artur S. Venzel, Timofey V. Ivanisenko, Evgenia A. Antropova, Nikolay A. Kolchanov, Victoria V. Plesko, Gleb B. Moroz, Vladimir V. Lomivorotov and Andrey G. Pokrovsky

Int. J. Mol. Sci. 2024, 25(21), 11847; https://doi.org/10.3390/ijms252111847 - 4 Nov 2024

Viewed by 797

Abstract

Despite considerable investigative efforts, the molecular mechanisms of postoperative delirium (POD) remain unresolved. The present investigation employs innovative methodologies for identifying potential primary and secondary metabolic markers of POD by analyzing serum metabolomic profiles utilizing the genetic algorithm and artificial neural networks. The [...] Read more.

Despite considerable investigative efforts, the molecular mechanisms of postoperative delirium (POD) remain unresolved. The present investigation employs innovative methodologies for identifying potential primary and secondary metabolic markers of POD by analyzing serum metabolomic profiles utilizing the genetic algorithm and artificial neural networks. The primary metabolomic markers constitute a combination of metabolites that optimally distinguish between POD and non-POD groups of patients. Our analysis revealed L-lactic acid, inositol, and methylcysteine as the most salient primary markers upon which the prediction accuracy of POD manifestation achieved AUC = 99%. The secondary metabolomic markers represent metabolites that exhibit perturbed correlational patterns within the POD group. We identified 54 metabolites as the secondary markers of POD, incorporating neurotransmitters such as gamma-aminobutyric acid (GABA) and serotonin. These findings imply a systemic disruption in metabolic processes in patients with POD. The deployment of gene network reconstruction techniques facilitated the postulation of hypotheses describing the role of established genomic POD markers in the molecular-genetic mechanisms of metabolic pathways dysregulation, and involving the identified primary and secondary metabolomic markers. This study not only expands the understanding of POD pathogenesis but also introduces a novel technology for the bioinformatic analysis of metabolomic data that could aid in uncovering potential primary and secondary markers in diverse research domains. Full article

(This article belongs to the Special Issue Machine Learning Applications in Bioinformatics and Biomedicine: 2nd Edition)

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36 pages, 1729 KiB

Open AccessReview

Advancements in Therapeutic Approaches for Degenerative Tendinopathy: Evaluating Efficacy and Challenges

by Vivek Kumar Morya, Hamzah Shahid, Jun Lang, Mi Kyung Kwak, Sin-Hye Park and Kyu-Cheol Noh

Int. J. Mol. Sci. 2024, 25(21), 11846; https://doi.org/10.3390/ijms252111846 - 4 Nov 2024

Viewed by 842

Abstract

Degenerative tendinopathy results from the accumulation of minor injuries following unsuccessful tendon repair during acute tendon injuries. The process of tendon repair is prolonged and varies between individuals, making it susceptible to reinjury. Moreover, treating chronic tendinopathy often requires expensive and extensive rehabilitation, [...] Read more.

Degenerative tendinopathy results from the accumulation of minor injuries following unsuccessful tendon repair during acute tendon injuries. The process of tendon repair is prolonged and varies between individuals, making it susceptible to reinjury. Moreover, treating chronic tendinopathy often requires expensive and extensive rehabilitation, along with a variety of combined therapies to facilitate recovery. This condition significantly affects the quality of life of affected individuals, underscoring the urgent need for more efficient and cost-effective treatment options. Although traditional treatments have improved significantly and are being used as substitutes for surgical interventions, the findings have been inconsistent and conflicting. This review aims to clarify these issues by exploring the strengths and limitations of current treatments as well as recent innovations in managing various forms of degenerative tendinopathy. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Tendinopathy: Unraveling the Pathogenesis of Tendon Diseases)

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12 pages, 2735 KiB

Open AccessArticle

Identification of Genes and Long Non-Coding RNAs Putatively Related to Portunus trituberculatus Sex Determination and Differentiation Using Oxford Nanopore Technology Full-Length Transcriptome Sequencing

by Shaoting Jia, Guang Li, Yuchao Huang, Yashi Hou, Baoquan Gao and Jianjian Lv

Int. J. Mol. Sci. 2024, 25(21), 11845; https://doi.org/10.3390/ijms252111845 - 4 Nov 2024

Viewed by 514

Abstract

The swimming crab (Portunus trituberculatus) is an economically important species in China, and its growth traits show obvious sexual dimorphism. Thus, it is important to study the mechanism of sex determination and differentiation in this species. Herein, we identified 2138 differentially [...] Read more.

The swimming crab (Portunus trituberculatus) is an economically important species in China, and its growth traits show obvious sexual dimorphism. Thus, it is important to study the mechanism of sex determination and differentiation in this species. Herein, we identified 2138 differentially expressed genes and 132 differentially expressed long non-coding RNAs (lncRNAs) using Oxford Nanopore Technology full-length transcriptome sequencing. We predicted 561 target genes of the differentially expressed lncRNAs according to their location and base pair complimentary principles. Furthermore, pathways related to sex determination, differentiation, and reproduction were enriched for lncRNAs according to gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses. This indicated that lncRNAs might play regulatory roles in these pathways. Our results could form the basis for future studies of sex determination and differentiation in P. trituberculatus. Full article

(This article belongs to the Special Issue Molecular Advance on Reproduction and Fertility of Aquatic Animals 2.0)

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22 pages, 21689 KiB

Open AccessArticle

Uncovering Metal-Decorated TiO₂ Photocatalysts for Ciprofloxacin Degradation—A Combined Experimental and DFT Study

by Marija Kovačević, Marija Simić, Sanja Živković, Miloš Milović, Ljiljana Tolić Stojadinović, Dubravka Relić and Dragana Vasić Anićijević

Int. J. Mol. Sci. 2024, 25(21), 11844; https://doi.org/10.3390/ijms252111844 - 4 Nov 2024

Viewed by 598

Abstract

Optimization of the efficiency of the photocatalytic degradation of organic and pharmaceutical pollutants represents a matter of fundamental and practical interest. The present experimental and DFT study deals with evaluation of OH radical binding energy as a simple computational descriptor of the catalytic [...] Read more.

Optimization of the efficiency of the photocatalytic degradation of organic and pharmaceutical pollutants represents a matter of fundamental and practical interest. The present experimental and DFT study deals with evaluation of OH radical binding energy as a simple computational descriptor of the catalytic activity of d-metal-decorated TiO₂ photocatalysts for the photodegradation of the widely used antibiotic ciprofloxacin. Five d-metals commonly used in catalytic materials (Zr, Pt, Pd, Fe, and Cu) were deposited on the TiO₂ surface, and the obtained photocatalysts were characterized experimentally (XRPD, ICP-OES, and SEM) and theoretically (DFT). Attention was also paid to the mechanistic insights and degradation byproducts (based on UV-Vis spectrometry and LC/MS analysis) in order to obtain systematic insight into their structure/performance relationships and confirm the proposed model of the degradation process based on OH radical reactivity. Full article

(This article belongs to the Special Issue Advances in the Application of Nanomaterials in Environmental Remediation)

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32 pages, 9671 KiB

Open AccessArticle

Ten Hypermethylated lncRNA Genes Are Specifically Involved in the Initiation, Progression, and Lymphatic and Peritoneal Metastasis of Epithelial Ovarian Cancer

by Eleonora A. Braga, Alexey M. Burdennyy, Leonid A. Uroshlev, Danila M. Zaichenko, Elena A. Filippova, Svetlana S. Lukina, Irina V. Pronina, Iana R. Astafeva, Marina V. Fridman, Tatiana P. Kazubskaya, Vitaly I. Loginov, Alexey A. Dmitriev, Aleksey A. Moskovtsev and Nikolay E. Kushlinskii

Int. J. Mol. Sci. 2024, 25(21), 11843; https://doi.org/10.3390/ijms252111843 - 4 Nov 2024

Viewed by 763

Abstract

Abstract: Our work aimed to evaluate and differentiate the role of ten lncRNA genes (GAS5, HAND2-AS1, KCNK15-AS1, MAGI2-AS3, MEG3, SEMA3B-AS1, SNHG6, SSTR5-AS1, ZEB1-AS1, and ZNF667-AS1) in the development and progression of epithelial [...] Read more.

Abstract: Our work aimed to evaluate and differentiate the role of ten lncRNA genes (GAS5, HAND2-AS1, KCNK15-AS1, MAGI2-AS3, MEG3, SEMA3B-AS1, SNHG6, SSTR5-AS1, ZEB1-AS1, and ZNF667-AS1) in the development and progression of epithelial ovarian cancer (EOC). A representative set of clinical samples was used: 140 primary tumors from patients without and with metastases and 59 peritoneal metastases. Using MS-qPCR, we demonstrated an increase in methylation levels of all ten lncRNA genes in tumors compared to normal tissues (p < 0.001). Using RT-qPCR, we showed downregulation and an inverse relationship between methylation and expression levels for ten lncRNAs (r_s < −0.5). We further identified lncRNA genes that were specifically hypermethylated in tumors from patients with metastases to lymph nodes (HAND2-AS1), peritoneum (KCNK15-AS1, MEG3, and SEMA3B-AS1), and greater omentum (MEG3, SEMA3B-AS1, and ZNF667-AS1). The same four lncRNA genes involved in peritoneal spread were associated with clinical stage and tumor extent (p < 0.001). Interestingly, we found a reversion from increase to decrease in the hypermethylation level of five metastasis-related lncRNA genes (MEG3, SEMA3B-AS1, SSTR5-AS1, ZEB1-AS1, and ZNF667-AS1) in 59 peritoneal metastases. This reversion may be associated with partial epithelial–mesenchymal transition (EMT) in metastatic cells, as indicated by a decrease in the level of the EMT marker, CDH1 mRNA (p < 0.01). Furthermore, novel mRNA targets and regulated miRNAs were predicted for a number of the studied lncRNAs using the NCBI GEO datasets and analyzed by RT-qPCR and transfection of SKOV3 and OVCAR3 cells. In addition, hypermethylation of SEMA3B-AS1, SSTR5-AS1, and ZNF667-AS1 genes was proposed as a marker for overall survival in patients with EOC. Full article

(This article belongs to the Special Issue Molecular Diagnostics and Genomics of Tumors)

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11 pages, 840 KiB

Open AccessCase Report

Prohibited Olympic Medalist with PIEZO1 VUS Who Claims Innocence

by Balázs Sonkodi, Tímea Kováts, Bence Gálik, Márton Tompa, Péter Urbán, Zsófia Flóra Nagy, Pongrác Ács, Miklós Tóth and Attila Gyenesei

Int. J. Mol. Sci. 2024, 25(21), 11842; https://doi.org/10.3390/ijms252111842 - 4 Nov 2024

Viewed by 889

Abstract

Competitive athletes are often exposed to extreme physiological loading, resulting in over excessive mechanotransduction during their acute intensive training sessions and competitions. Individual differences in their genetics often affect how they cope with these challenges, as reflected in their high performances. Olympic Medalists [...] Read more.

Competitive athletes are often exposed to extreme physiological loading, resulting in over excessive mechanotransduction during their acute intensive training sessions and competitions. Individual differences in their genetics often affect how they cope with these challenges, as reflected in their high performances. Olympic Medalists are prohibited from providing atypical values in the Hematological Module of the Athlete Biological Passport. Since there was no aphysiological result and the Athlete maintained his innocence, a whole genome sequence analysis was carried out on him and his parents, with the primary focus on the PIEZO ion channels encoding gene. PIEZO1 is known to participate in homeostatic regulation even on a whole-body level, including the regulation of physical performance, circulatory longevity of red blood cells and cell fate determination of mesenchymal stem cells in relation to hydrostatic pressure. However, PIEZO2 was found to be the principal mechanosensory ion channel for proprioception. These regulatory mechanisms play a pivotal role in mechanotransduction and intensive exercise moments. Interestingly, two variances of uncertain significance of PIEZO1 were found that may explain the atypical values of the Athlete. Furthermore, two additional variances in SDC2, the syndcan-2 encoding gene, were identified in trans position that may influence the crosstalk between PIEZO2 and PIEZO1, with more likely relevance to the detected atypical values. After all, based on the found variances of PIEZO1 and syndecan-2, it cannot be ruled out that these VUS variants may have caused or impacted the exhibited outlier findings of the ABP Hematological Module of the Athlete. Full article

(This article belongs to the Special Issue New Molecular Insights into Red Blood Cell Dynamics)

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12 pages, 5062 KiB

Open AccessArticle

A DFT Study of Band-Gap Tuning in 2D Black Phosphorus via Li⁺, Na⁺, Mg²⁺, and Ca²⁺ Ions

by Liuhua Mu, Jie Jiang, Shiyu Gao, Xiao-Yan Li and Shiqi Sheng

Int. J. Mol. Sci. 2024, 25(21), 11841; https://doi.org/10.3390/ijms252111841 - 4 Nov 2024

Viewed by 694

Abstract

Black phosphorus (BP) and its two-dimensional derivative (2D-BP) have garnered significant attention as promising anode materials for electrochemical energy storage devices, including next-generation fast-charging batteries. However, the interactions between BP and light metal ions, as well as how these interactions influence BP’s electronic [...] Read more.

Black phosphorus (BP) and its two-dimensional derivative (2D-BP) have garnered significant attention as promising anode materials for electrochemical energy storage devices, including next-generation fast-charging batteries. However, the interactions between BP and light metal ions, as well as how these interactions influence BP’s electronic properties, remain poorly understood. Here, we employed density functional theory (DFT) to investigate the effects of monovalent (Li⁺ and Na⁺) and divalent (Mg²⁺ and Ca²⁺) ions on the valence electronic structure of 2D-BP. Molecular orbital analysis revealed that the adsorption of divalent cations can significantly reduce the band gap, suggesting an enhancement in charge transfer rates. In contrast, the adsorption of monovalent cations had minimal impact on the band gap, suggesting the preservation of 2D-BP’s intrinsic electrical properties. Energetic and charge analyses indicated that the extent of charge transfer primarily governs the ability of ions to modulate 2D-BP’s electronic structure, especially under high-pressure conditions where ions are in close proximity to the 2D-BP surface. Moreover, charge polarization calculations revealed that, compared with monovalent cations, divalent cations induced greater polarization, disrupting the symmetry of the pristine 2D-BP and further influencing its electronic characteristics. These findings provide a molecular-level understanding of how ion interactions influence 2D-BP’s electronic properties during ion-intercalation processes, where ions are in close proximity to the 2D-BP surface. Moreover, the calculated diffusion barrier results revealed the potential of 2D-BP as an effective anode material for lithium-ion, sodium-ion, and magnesium-ion batteries, though its performance may be limited for calcium-ion batteries. By extending our understanding of interactions between ions and 2D-BP, this work contributes to the design of efficient and reliable energy storage technologies, particularly for the next-generation fast-charging batteries. Full article

(This article belongs to the Special Issue Adsorption Materials and Adsorption Behavior: 3rd Edition)

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15 pages, 1493 KiB

Open AccessArticle

Gyrophoric Acid, a Secondary Metabolite of Lichens, Exhibits Antidepressant and Anxiolytic Activity In Vivo in Wistar Rats

by Nicol Urbanska, Martina Karasova, Zuzana Jendzelovska, Martin Majerník, Mariana Kolesarova, Dajana Kecsey, Rastislav Jendzelovsky, Peter Bohus and Terezia Kiskova

Int. J. Mol. Sci. 2024, 25(21), 11840; https://doi.org/10.3390/ijms252111840 - 4 Nov 2024

Viewed by 719

Abstract

Gyrophoric acid (GA) is a secondary metabolite of various lichens. It exhibits various biological activities in vitro, but only one study has been carried out in vivo. Because our previous study showed that GA stimulates neurogenesis in healthy rats, the current study aimed [...] Read more.

Gyrophoric acid (GA) is a secondary metabolite of various lichens. It exhibits various biological activities in vitro, but only one study has been carried out in vivo. Because our previous study showed that GA stimulates neurogenesis in healthy rats, the current study aimed to explore the potential of GA during stress-induced depressive-like states in male Wistar rats. In the experiment, pregnant females were used. In the last week of pregnancy, females were subjected to restraint stress. After birth, progeny aged 60 days were stressed repeatedly. The males were divided into three groups: control animals (CTR; n = 10), males with a depression-like state (DEP; n = 10), and GA-treated animals (GA; n = 10). GA males were treated with GA (per os 10 mg/kg) daily for one month, starting from the 60th postnatal day. Our results indicate that GA acts as an antioxidant, as shown by a lowered ROS level in leukocytes (p < 0.01). Moreover, it prolonged the time spent in open arms in the elevated plus maze (p < 0.001). Concomitantly, the stimulation of proliferative activity in hippocampal regions was seen (hilus p < 0.01; subgranular zone p < 0.001) when compared with DEP males. Additionally, the number of mature neurons in the CA1 region of the hippocampus increased markedly (p < 0.01), indicating the role of GA in the maturation process of neurons. Thus, our study points to the potential anxiolytic/antidepressant activity of GA. However, future studies are needed in this complex area. Full article

(This article belongs to the Special Issue Depression: From Molecular Basis to Therapy)

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11 pages, 4471 KiB

Open AccessArticle

Diterpenoid from Croton tonkinensis as a Potential Radiation Sensitizer in Oral Squamous Cell Carcinoma: An In Vitro Study

by Hui-Ming Lee, Ping-Chung Kuo, Wen-Hui Chen, Po-Jen Chen, Sio-Hong Lam, Yu-Chieh Su and Chih-Hao Chen

Int. J. Mol. Sci. 2024, 25(21), 11839; https://doi.org/10.3390/ijms252111839 - 4 Nov 2024

Viewed by 896

Abstract

Radiotherapy combined with a radiosensitizer represents an important treatment for head and neck squamous cell carcinoma (HNSCC). Only a few chemotherapy agents are currently approved as radiosensitizers for targeted therapy. Oral squamous cell carcinoma is one of the deadliest cancers, with approximately ~500,000 [...] Read more.

Radiotherapy combined with a radiosensitizer represents an important treatment for head and neck squamous cell carcinoma (HNSCC). Only a few chemotherapy agents are currently approved as radiosensitizers for targeted therapy. Oral squamous cell carcinoma is one of the deadliest cancers, with approximately ~500,000 new diagnosed cases and 145,000 deaths worldwide per year. The incidence of new cases continues to increase in developing countries. This study aimed to investigate the effect of Croton tonkinensis and Curcuma longa on cell viability in OSCC cells. The HNSCC cell line OML1 and its radiation-resistant clone OML1-R were used. The anticancer effect and the mechanism of action of Croton tonkinensis and Curcuma longa in OSCC cells were analyzed by using cell viability assays, Western blot analysis, and Tranwell migration assays. The results showed that Croton tonkinensis concentration-dependently reduced the viability of OML1 and OML1-R (radioresistant) cells by downregulating the levels of AKT/mTOR mediators, such as p110α, p85, pAKT (ser473), p-mTOR (ser2448), and p-S6 Ribosomal (ser235/236). We found that cotreatment of OML1 and OML1R cells with either zVAD-FMK (apoptosis inhibitor), Ferrostatin-1 (Fer-1, a ferroptosis inhibitor), or chloroquine (CQ, an autophagy inhibitor) markedly reduced cell death. These results demonstrate that Croton tonkinensis exhibits anti-proliferation activity and highlight the therapeutic potential of small-molecule inhibitors against PI3K/mTOR signaling for radiosensitization in HNC treatment. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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34 pages, 424 KiB

Open AccessReview

Blood-Based Biomarkers in Frontotemporal Dementia: A Narrative Review

by Ioannis Liampas, Panagiota Kyriakoulopoulou, Vasiliki Karakoida, Panagiota Andriana Kavvoura, Markos Sgantzos, Dimitrios P. Bogdanos, Polyxeni Stamati, Efthimios Dardiotis and Vasileios Siokas

Int. J. Mol. Sci. 2024, 25(21), 11838; https://doi.org/10.3390/ijms252111838 - 4 Nov 2024

Viewed by 923

Abstract

This narrative review explores the current landscape of blood biomarkers in Frontotemporal dementia (FTD). Neurofilament light chain (NfL) may be useful in the differentiation of behavioral variant FTD from primary psychiatric disorders (PPDs) or dementia with Lewy bodies (DLB). In prodromal FTD and [...] Read more.

This narrative review explores the current landscape of blood biomarkers in Frontotemporal dementia (FTD). Neurofilament light chain (NfL) may be useful in the differentiation of behavioral variant FTD from primary psychiatric disorders (PPDs) or dementia with Lewy bodies (DLB). In prodromal FTD and presymptomatic mutation carriers (GRN, MAPT, C9orf72), elevated NfL may herald pheno-conversion to full-blown dementia. Baseline NfL correlates with steeper neuroanatomical changes and cognitive, behavioral and functional decline, making NfL promising in monitoring disease progression. Phosphorylated neurofilament heavy chain (pNfH) levels have a potential limited role in the demarcation of the conversion stage to full-blown FTD. Combined NfL and pNfH measurements may allow a wider stage stratification. Total tau levels lack applicability in the framework of FTD. p-tau, on the other hand, is of potential value in the discrimination of FTD from Alzheimer’s dementia. Progranulin concentrations could serve the identification of GRN mutation carriers. Glial fibrillary acidic protein (GFAP) may assist in the differentiation of PPDs from behavioral variant FTD and the detection of GRN mutation carriers (additional research is warranted). Finally, TAR DNA-binding protein-43 (TDP-43) appears to be a promising diagnostic biomarker for FTD. Its potential in distinguishing TDP-43 pathology from other FTD-related pathologies requires further research. Full article

(This article belongs to the Section Molecular Neurobiology)

20 pages, 7629 KiB

Open AccessArticle

MgAl-Layered Double Hydroxide-Coated Bio-Silica as an Adsorbent for Anionic Pollutants Removal: A Case Study of the Implementation of Sustainable Technologies

by Muna Abdualatif Abduarahman, Marija M. Vuksanović, Nataša Knežević, Katarina Banjanac, Milena Milošević, Zlate Veličković and Aleksandar Marinković

Int. J. Mol. Sci. 2024, 25(21), 11837; https://doi.org/10.3390/ijms252111837 - 4 Nov 2024

Viewed by 658

Abstract

The adsorption efficiency of Cr(VI) and anionic textile dyes onto MgAl-layered double hydroxides (LDHs) and MgAl-LDH coated on bio-silica (b-SiO₂) nanoparticles (MgAl-LDH@SiO₂) derived from waste rice husks was studied in this work. The material was characterized using field-emission scanning [...] Read more.

The adsorption efficiency of Cr(VI) and anionic textile dyes onto MgAl-layered double hydroxides (LDHs) and MgAl-LDH coated on bio-silica (b-SiO₂) nanoparticles (MgAl-LDH@SiO₂) derived from waste rice husks was studied in this work. The material was characterized using field-emission scanning electron microscopy (FE-SEM/EDS), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopic (XPS) techniques. The adsorption capacities of MgAl-LDH@SiO₂ were increased by 12.2%, 11.7%, 10.6%, and 10.0% in the processes of Cr(VI), Acid Blue 225 (AB-225), Acid Violet 109 (AV-109), and Acid Green 40 (AG-40) dye removal versus MgAl-LDH. The obtained results indicated the contribution of b-SiO₂ to the development of active surface functionalities of MgAl-LDH. A kinetic study indicated lower intraparticle diffusional transport resistance. Physisorption is the dominant mechanism for dye removal, while surface complexation dominates in the processes of Cr(VI) removal. The disposal of effluent water after five adsorption/desorption cycles was attained using enzymatic decolorization, photocatalytic degradation of the dyes, and chromate reduction, satisfying the prescribed national legislation. Under optimal conditions and using immobilized horseradish peroxidase (HRP), efficient decolorization of effluent solutions containing AB-225 and AV-109 dyes was achieved. Exhausted MgAl-LDH@SiO₂ was processed by dissolution/precipitation of Mg and Al hydroxides, while residual silica was used as a reinforcing filler in polyester composites. The fire-proofing properties of composites with Mg and Al hydroxides were also improved, which provides a closed loop with zero waste generation. The development of wastewater treatment technologies and the production of potentially marketable composites led to the successful achievement of both low environmental impacts and circular economy implementation. Full article

(This article belongs to the Section Materials Science)

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19 pages, 5216 KiB

Open AccessArticle

Exploring Genomic Regions Associated with Fruit Traits in Pepper: Insights from Multiple GWAS Models

by Nayoung Ro, Hyeonseok Oh, Ho-Cheol Ko, Jungyoon Yi, Young-Wang Na and Mesfin Haile

Int. J. Mol. Sci. 2024, 25(21), 11836; https://doi.org/10.3390/ijms252111836 - 4 Nov 2024

Viewed by 611

Abstract

This study utilized 303 pepper accessions from diverse Capsicum species to explore fruit traits, including length, width, wall thickness, and weight. Descriptive statistics revealed a mean fruit length of 66.19 mm, width of 23.48 mm, wall thickness of 1.89 mm, and weight of [...] Read more.

This study utilized 303 pepper accessions from diverse Capsicum species to explore fruit traits, including length, width, wall thickness, and weight. Descriptive statistics revealed a mean fruit length of 66.19 mm, width of 23.48 mm, wall thickness of 1.89 mm, and weight of 15.29 g, with significant variability, particularly in fruit weight. Correlation analysis demonstrated strong positive relationships between fruit width, weight, and fruit wall thickness (r = 0.89 and r = 0.86, respectively), while fruit length showed weaker correlations with these traits. Analysis of fruit positions revealed that the majority of accessions had a pendent fruit position (156), followed by erect (85) and intermediate (8). In terms of fruit shape, triangular and narrow triangular shapes were the most common, observed in 102 and 98 accessions, respectively. Genome-wide association studies (GWAS) identified significant single nucleotide polymorphisms (SNPs) associated with fruit traits across four models (Blink, FarmCPU, MLM, MLMM). The number of significantly associated SNPs were as follows: fruit length (89), fruit width (55), fruit weight (63), fruit wall thickness (48), fruit shape (151), and fruit position (51). Several genes were also identified where the SNPs are located or adjacent to, providing candidate genes for further exploration of the genetic basis of fruit morphology. Notably, genes such as E3 ubiquitin-protein ligase RGLG1 (associated with fruit width), Homeobox-leucine zipper protein HDG11 (involved in fruit width), Auxin response factor 23 (linked to fruit shape), and ATP-dependent zinc metalloprotease FtsH (related to fruit weight) were identified. These findings enhance our understanding of the genetic basis of fruit morphology in Capsicum, offering valuable insights for breeding and agricultural practices. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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20 pages, 6875 KiB

Open AccessArticle

Identification of a Novel Biomarker Panel for Breast Cancer Screening

by Maria Vaida, Kamala K. Arumalla, Pavan Kumar Tatikonda, Bharadwaj Popuri, Rashid A. Bux, Paramjit S. Tappia, Guoyu Huang, Jean-François Haince and W. Randolph Ford

Int. J. Mol. Sci. 2024, 25(21), 11835; https://doi.org/10.3390/ijms252111835 - 4 Nov 2024

Viewed by 619

Abstract

Breast cancer remains a major public health concern, and early detection is crucial for improving survival rates. Metabolomics offers the potential to develop non-invasive screening and diagnostic tools based on metabolic biomarkers. However, the inherent complexity of metabolomic datasets and the high dimensionality [...] Read more.

Breast cancer remains a major public health concern, and early detection is crucial for improving survival rates. Metabolomics offers the potential to develop non-invasive screening and diagnostic tools based on metabolic biomarkers. However, the inherent complexity of metabolomic datasets and the high dimensionality of biomarkers complicates the identification of diagnostically relevant features, with multiple studies demonstrating limited consensus on the specific metabolites involved. Unlike previous studies that rely on singular feature selection techniques such as Partial Least Square (PLS) or LASSO regression, this research combines supervised and unsupervised machine learning methods with random sampling strategies, offering a more robust and interpretable approach to feature selection. This study aimed to identify a parsimonious and robust set of biomarkers for breast cancer diagnosis using metabolomics data. Plasma samples from 185 breast cancer patients and 53 controls (from the Cooperative Human Tissue Network, USA) were analyzed. This study also overcomes the common issue of dataset imbalance by using propensity score matching (PSM), which ensures reliable comparisons between cancer and control groups. We employed Univariate Naïve Bayes, L2-regularized Support Vector Classifier (SVC), Principal Component Analysis (PCA), and feature engineering techniques to refine and select the most informative features. Our best-performing feature set comprised 11 biomarkers, including 9 metabolites (SM(OH) C22:2, SM C18:0, C0, C3OH, C14:2OH, C16:2OH, LysoPC a C18:1, PC aa C36:0 and Asparagine), a metabolite ratio (Kynurenine-to-Tryptophan), and 1 demographic variable (Age), achieving an area under the ROC curve (AUC) of 98%. These results demonstrate the potential for a robust, cost-effective, and non-invasive breast cancer screening and diagnostic tool, offering significant clinical value for early detection and personalized patient management. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cancers: Advances and Challenges)

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15 pages, 5395 KiB

Open AccessArticle

Transcriptome and Expression Analysis of Glycerol Biosynthesis-Related Genes in Glenea cantor Fabricius (Cerambycidae: Lamiinae)

by Taihui Lan, Ranran Su, Zishu Dong, Xin Tong, Xialin Zheng and Xiaoyun Wang

Int. J. Mol. Sci. 2024, 25(21), 11834; https://doi.org/10.3390/ijms252111834 - 4 Nov 2024

Viewed by 471

Abstract

Glenea cantor Fabricius (Cerambycidae: Lamiinae) is an important pest that damages kapok trees in Southeast Asia with a wide adaptability to temperature. Glycerol is a protectant and energy source for insects in low-temperature environments. However, glycerol biosynthesis-related genes at the molecular level are [...] Read more.

Glenea cantor Fabricius (Cerambycidae: Lamiinae) is an important pest that damages kapok trees in Southeast Asia with a wide adaptability to temperature. Glycerol is a protectant and energy source for insects in low-temperature environments. However, glycerol biosynthesis-related genes at the molecular level are limited in G. cantor. In this study, the supercooling points and freezing points at different stages were measured, and the cold hardiness of male and female pupae significantly differed. Moreover, a full-length transcriptome of G. cantor was established; glycerol kinase (GK) and glycerol-3-phosphate dehydrogenase (GPDH) genes, which are related to glycerol metabolism, were identified, with a special focus on their expression profiles. A total of 24,476 isoforms stemmed from the full-length transcriptome, along with 568 lncRNAs, 56 transcription factor (TF) families, and 1467 alternative splicing (AS) events. The KEGG pathway enrichment analysis revealed that the isoforms associated with AS were enriched primarily in glycerolipid and glycerophospholipid metabolism. In total, three GK genes and one GPDH gene were identified, and GcGK1 and GcGK3 presented differential sex expression during the pupal stage, which may play a role in thermal adaptability. This study provides a valuable transcriptional database of G. cantor and helps to elucidate the function of glycerol in the thermal adaptation mechanism of longhorn beetles. Full article

(This article belongs to the Special Issue Molecular Ecology, Physiology and Biochemistry of Insects, 5th Edition)

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18 pages, 3987 KiB

Open AccessArticle

Cardioimmunology in Health and Diseases: Impairment of the Cardio-Spleno-Bone Marrow Axis Following Myocardial Infarction in Diabetes Mellitus

by Amankeldi A. Salybekov, Kanat Tashov, Yin Sheng, Ainur Salybekova, Yoshiko Shinozaki, Takayuki Asahara and Shuzo Kobayashi

Int. J. Mol. Sci. 2024, 25(21), 11833; https://doi.org/10.3390/ijms252111833 - 4 Nov 2024

Viewed by 512

Abstract

A comprehensive understanding of the cardio-spleen-bone marrow immune cell axis is essential for elucidating the alterations occurring during the pathogenesis of diabetes mellitus (DM). This study investigates the dynamics of immune cell kinetics in DM after myocardial infarction (MI) over time. MI was [...] Read more.

A comprehensive understanding of the cardio-spleen-bone marrow immune cell axis is essential for elucidating the alterations occurring during the pathogenesis of diabetes mellitus (DM). This study investigates the dynamics of immune cell kinetics in DM after myocardial infarction (MI) over time. MI was induced in diabetic and healthy control groups using C57BL/N6 mice, with sacrifices occurring at days 1, 3, 7, and 28 post-MI to collect heart, peripheral blood (PB), spleen, and bone marrow (BM) samples. Cell suspensions from each organ were isolated and analyzed via flow cytometry. Additionally, the endothelial progenitor cell-colony-forming assay (EPC-CFA) was performed using mononuclear cells derived from BM, PB, and the spleen. The results indicated that, despite normal production in BM and the spleen, CD45+ cells were lower in the PB of DM mice at days 1 to 3. Further analysis revealed a reduction in total and pro-inflammatory neutrophils (N1s) in PB at days 1 to 3 and in the spleen at days 3 to 7 in DM mice, suggesting that DM-induced alterations in splenic neutrophils fail to meet the demand in PB and ischemic tissues. Infiltrating macrophages (total, M1, M2) were reduced at day 3 in the DM-ischemic heart, with total and M1 (days 1–3) and M2 (days 3–7) macrophages being significantly decreased in DM-PB compared to controls, indicating impaired macrophage recruitment and polarization in DM. Myeloid dendritic cells (mDCs) in the heart were higher from days 1 to 7, which corresponded with the enhanced recruitment of CD8+ cells from days 1 to 28 in the DM-infarcted myocardium. Total CD4+ cells decreased in DM-PB at days 1 to 3, suggesting a delayed adaptive immune response to MI. B cells were reduced in PB at days 1 to 3, in myocardium at day 3, and in the spleen at day 7, indicating compromised mobilization from BM. EPC-CFA results showed a marked decrease in definitive EPC colonies in the spleen and BM from days 1 to 28 in DM mice compared to controls in vitro, highlighting that DM severely impairs EPC colony-forming activity by limiting the differentiation of EPCs from primitive to definitive forms. Taking together, this study underscores significant disruptions in the cardio-spleen-bone marrow immune cell axis following MI in DM, revealing delayed innate and adaptive immune responses along with impaired EPC differentiation. Full article

(This article belongs to the Special Issue Cardiac Diseases: Molecular Mechanisms and Therapeutic Strategies)

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14 pages, 2344 KiB

Open AccessArticle

Matrix Background Screening of an ssDNA Aptamer and Its Identification Against Lactopontin

by Chao Zhu, Ziru Feng, Mengmeng Yan, Hongxia Du, Tengfei Li and Jiangsheng Mao

Int. J. Mol. Sci. 2024, 25(21), 11832; https://doi.org/10.3390/ijms252111832 - 4 Nov 2024

Viewed by 575

Abstract

Lactopontin (LPN) is a highly phosphorylated O-glycosylated acidic protein closely associated with infant gut, brain, and immune development, and its recognition is urgent due to its rising application in fortified dairy products and infant formula. In this study, an ssDNA aptamer against LPN [...] Read more.

Lactopontin (LPN) is a highly phosphorylated O-glycosylated acidic protein closely associated with infant gut, brain, and immune development, and its recognition is urgent due to its rising application in fortified dairy products and infant formula. In this study, an ssDNA aptamer against LPN was obtained, among which two kinds of matrix-background-assisted systematic evolution of ligands via exponential enrichment (SELEX) approaches were performed and compared. The direct approach was to utilize the sample matrix as the mixing-incubation background between the ssDNA library and LPN that can theoretically increase screening pressure and simulate practical application scenarios. The indirect approach was to utilize a PBS buffer as a screening background and to include counter-screening steps that adopt the “sample matrix” as a whole as the counter-screening target. Their screening evolutions were monitored through qPCR assays from sequence diversity convergences of each sub-library based on the change in the proportion of hetero- and homo-duplexes from the dissociation curve and melting temperature, which were also verified from the sequence statistics of high-throughput sequencing. The common sequence of Seq.I1II3 from the two approaches was finally fished out as the aptamer through multiple analyses of combining the sequence frequency, secondary structures, homology, and binding assessments, which was demonstrated good specificity and low-nanomolar affinity by qPCR assay (K_D, 5.9 nM). In addition, molecular docking and a dynamics simulation were performed for their binding site prediction and affinity confirmation. This study provides a potential identifying element and a basis for accelerating the development of methods for LPN detection in dairy products. Full article

(This article belongs to the Special Issue Antibodies and Aptamers Used as Molecular Recognition Components in Sensing Platforms)

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24 pages, 2843 KiB

Open AccessArticle

Phytochemical Composition and Functional Properties of Brassicaceae Microgreens: Impact of In Vitro Digestion

by Ivana Šola, Valerija Vujčić Bok, Maja Popović and Sanja Gagić

Int. J. Mol. Sci. 2024, 25(21), 11831; https://doi.org/10.3390/ijms252111831 - 4 Nov 2024

Viewed by 563

Abstract

The aim of this study was to compare the concentration of phenolic compounds, glucosinolates, proteins, sugars and vitamin C between kohlrabi (Brassica oleracea var. acephala gongylodes), Savoy cabbage (B. oleracea sabauda), Brussels sprouts (B. oleracea gemmifera), cauliflower ( [...] Read more.

The aim of this study was to compare the concentration of phenolic compounds, glucosinolates, proteins, sugars and vitamin C between kohlrabi (Brassica oleracea var. acephala gongylodes), Savoy cabbage (B. oleracea sabauda), Brussels sprouts (B. oleracea gemmifera), cauliflower (B. oleracea botrytis), radish (Raphanus sativus) and garden cress (Lepidium sativum) microgreens for their antioxidant and hypoglycemic potential. In addition, we applied an in vitro-simulated system of human digestion in order to track the bioaccessibility of the selected phenolic representatives, and the stability of the microgreens’ antioxidant and hypoglycemic potential in terms of α-amylase and α-glucosidase inhibition after each digestion phase. Using spectrophotometric and RP-HPLC methods with statistical analyses, we found that garden cress had the lowest soluble sugar content, while Savoy cabbage and Brussels sprouts had the highest glucosinolate levels (76.21 ± 4.17 mg SinE/g dm and 77.73 ± 3.33 mg SinE/g dm, respectively). Brussels sprouts were the most effective at inhibiting protein glycation (37.98 ± 2.30% inhibition). A very high positive correlation (r = 0.830) between antiglycation potential and conjugated sinapic acid was recorded. For the first time, the antidiabetic potential of microgreens after in vitro digestion was studied. Kohlrabi microgreens best inhibited α-amylase in both initial and intestinal digestion (60.51 ± 3.65% inhibition and 62.96 ± 3.39% inhibition, respectively), and also showed the strongest inhibition of α-glucosidase post-digestion (19.22 ± 0.08% inhibition). Brussels sprouts, cauliflower, and radish had less stable α-glucosidase than α-amylase inhibitors during digestion. Kohlrabi, Savoy cabbage, and garden cress retained inhibition of both enzymes after digestion. Kohlrabi antioxidant capacity remained unchanged after digestion. The greatest variability was seen in the original samples, while the intestinal phase resulted in the most convergence, indicating that digestion reduced differences between the samples. In conclusion, this study highlights the potential of various microgreens as sources of bioactive compounds with antidiabetic and antiglycation properties. Notably, kohlrabi microgreens demonstrated significant enzyme inhibition after digestion, suggesting their promise in managing carbohydrate metabolism and supporting metabolic health. Full article

(This article belongs to the Special Issue Adaptations of Plant Metabolism and Their Consequences on Nutritive Potential and Bioactivity, 2nd Edition)

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25 pages, 18080 KiB

Open AccessArticle

Comprehensive Analysis and Verification of the Prognostic Significance of Cuproptosis-Related Genes in Colon Adenocarcinoma

by Yixiao Gu, Chengze Li, Yinan Yan, Jingmei Ming, Yuanhua Li, Xiang Chao and Tieshan Wang

Int. J. Mol. Sci. 2024, 25(21), 11830; https://doi.org/10.3390/ijms252111830 - 4 Nov 2024

Viewed by 721

Abstract

Colon adenocarcinoma (COAD) is a frequently occurring and lethal cancer. Cuproptosis is an emerging type of cell death, and the underlying pathways involved in this process in COAD remain poorly understood. Transcriptomic and clinical data for COAD patients were collected from The Cancer [...] Read more.

Colon adenocarcinoma (COAD) is a frequently occurring and lethal cancer. Cuproptosis is an emerging type of cell death, and the underlying pathways involved in this process in COAD remain poorly understood. Transcriptomic and clinical data for COAD patients were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We investigated alterations in DNA and chromatin of cuproptosis-related genes (CRGs) in COAD. In order to identify predictive differentially expressed genes (DEGs) and various molecular subtypes, we used consensus cluster analysis. Through univariate, multivariate, and Lasso Cox regression analyses, four CRGs were identified. A risk prognostic model for cuproptosis characteristics was constructed based on four CRGs. This study also examined the association between the risk score and the tumor microenvironment (TME), the immune landscape, and drug sensitivity. We distinguished two unique molecular subtypes using consensus clustering analysis. We discovered that the clinical characteristics, prognosis, and TME cell infiltration characteristics of patients with multilayer CRG subtypes were all connected. The internal and external evaluations of the predicted accuracy of the prognostic model built using data derived from a cuproptosis risk score were completed at the same time. A nomogram and a clinical pathological analysis make it more useful in the field of medicine. A significant rise in immunosuppressive cells was observed in the high cuproptosis risk score group, with a correlation identified between the cuproptosis risk score and immune cell infiltration. Despite generally poor prognoses, the patients with a high cuproptosis risk but low tumor mutation burden (TMB), cancer stem cell (CSC) index, or microsatellite instability (MSI) may still benefit from immunotherapy. Furthermore, the cuproptosis risk score positively correlated with immune checkpoint gene expression. Analyzing the potential sensitivity to medications could aid in the development of clinical chemotherapy regimens and decision-making. CRGs are the subject of our in-depth study, which exposed an array of regulatory mechanisms impacting TME. In addition, we performed additional data mining into clinical features, prognosis effectiveness, and possible treatment medications. COAD’s molecular pathways will be better understood, leading to more precise treatment options. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer and Cell Metabolism)

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17 pages, 4728 KiB

Open AccessArticle

Nrf2 Deficiency Exacerbates the Decline in Swallowing and Respiratory Muscle Mass and Function in Mice with Aspiration Pneumonia

by Hikaru Hashimoto, Tatsuma Okazaki, Yohei Honkura, Yuzhuo Ren, Peerada Ngamsnae, Takuma Hisaoka, Yasutoshi Koshiba, Jun Suzuki, Satoru Ebihara and Yukio Katori

Int. J. Mol. Sci. 2024, 25(21), 11829; https://doi.org/10.3390/ijms252111829 - 4 Nov 2024

Viewed by 544

Abstract

Aspiration pneumonia exacerbates swallowing and respiratory muscle atrophy. It induces respiratory muscle atrophy through three steps: proinflammatory cytokine production, caspase-3 and calpain, and then ubiquitin–proteasome activations. In addition, autophagy induces swallowing muscle atrophy. Nrf2 is the central detoxifying and antioxidant gene whose function [...] Read more.

Aspiration pneumonia exacerbates swallowing and respiratory muscle atrophy. It induces respiratory muscle atrophy through three steps: proinflammatory cytokine production, caspase-3 and calpain, and then ubiquitin–proteasome activations. In addition, autophagy induces swallowing muscle atrophy. Nrf2 is the central detoxifying and antioxidant gene whose function in aspiration pneumonia is unclear. We explored the role of Nrf2 in aspiration pneumonia by examining swallowing and respiratory muscle mass and function using wild-type and Nrf2-knockout mice. Pepsin and lipopolysaccharide aspiration challenges caused aspiration pneumonia. The swallowing (digastric muscles) and respiratory (diaphragm) muscles were isolated. Quantitative RT-PCR and Western blotting were used to assess their proteolysis cascade. Pathological and videofluoroscopic examinations evaluated atrophy and swallowing function, respectively. Nrf2-knockouts showed exacerbated aspiration pneumonia compared with wild-types. Nrf2-knockouts exhibited more persistent and intense proinflammatory cytokine elevation than wild-types. In both mice, the challenge activated calpains and caspase-3 in the diaphragm but not in the digastric muscles. The digastric muscles showed extended autophagy activation in Nrf2-knockouts compared to wild-types. The diaphragms exhibited autophagy activation only in Nrf2-knockouts. Nrf2-knockouts showed worsened muscle atrophies and swallowing function compared with wild-types. Thus, activation of Nrf2 may alleviate inflammation, muscle atrophy, and function in aspiration pneumonia, a major health problem for the aging population, and may become a therapeutic target. Full article

(This article belongs to the Special Issue Molecular and Neuromuscular Mechanisms in Skeletal Muscle Aging)

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15 pages, 3167 KiB

Open AccessArticle

Anti-Pruritic and Immunomodulatory Effects of Coix [Coix lacryma-jobi L. var. ma-yuen (Rom. Caill.) Stapf.] Sprouts Extract

by Eun-Song Lee, Yong-Il Kim, Jeong-Hoon Lee, Jang-Hoon Kim, Yong-Goo Kim, Kyung-Sook Han, Young-Ho Yoon, Byoung-Ok Cho and Ju-Sung Cho

Int. J. Mol. Sci. 2024, 25(21), 11828; https://doi.org/10.3390/ijms252111828 - 4 Nov 2024

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Abstract

This study explored the anti-pruritic and immunomodulatory effects of Coix sprouts extract, focusing on histamine release and IL-31 cytokine production in HMC-1 cells. The extract significantly inhibited both factors, indicating its potential for pruritus relief. In a pruritus induction mouse model, Coix sprouts [...] Read more.

This study explored the anti-pruritic and immunomodulatory effects of Coix sprouts extract, focusing on histamine release and IL-31 cytokine production in HMC-1 cells. The extract significantly inhibited both factors, indicating its potential for pruritus relief. In a pruritus induction mouse model, Coix sprouts extract outperformed prednisolone in anti-pruritus effectiveness, also improving skin lesions and inhibiting mast cell infiltration. The extract suppressed tryptase expression, reduced release, inhibited mast cell proliferation, and lowered nitric oxide production, suggesting anti-inflammatory properties. Coix sprouts extract shows promise in suppressing inflammation and pruritus, making it a valuable candidate for clinical use. Additionally, the analysis of coixol content in Coix sprouts revealed variations in growth time, indicating their potential as functional materials with anti-pruritus and immune-enhancing applications. Full article

(This article belongs to the Section Molecular Immunology)

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13 pages, 1876 KiB

Open AccessArticle

Development and Evaluation of ABI-171, a New Fluoro-Catechin Derivative, for the Treatment of Idiopathic Pulmonary Fibrosis

by Gian Luca Araldi, Yu-Wen Hwang and Ganesh Raghu

Int. J. Mol. Sci. 2024, 25(21), 11827; https://doi.org/10.3390/ijms252111827 - 4 Nov 2024

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Abstract

The persistent challenge of idiopathic pulmonary fibrosis (IPF), characterized by disease progression and high mortality, underscores the urgent need for innovative therapeutic strategies. We have developed a novel small molecule—catechin derivative ABI-171—selectively targeting dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) and proviral integration site for [...] Read more.

The persistent challenge of idiopathic pulmonary fibrosis (IPF), characterized by disease progression and high mortality, underscores the urgent need for innovative therapeutic strategies. We have developed a novel small molecule—catechin derivative ABI-171—selectively targeting dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) and proviral integration site for Moloney murine leukemia virus 1 (PIM1) kinases, crucial in the pathogenesis of fibrotic processes. We employed the Bleomycin-induced (intratracheal) mouse model of pulmonary fibrosis (PF) to evaluate the therapeutic efficacy of ABI-171. Mice with induced PF were treated QD with ABI-171, either prophylactically or therapeutically, using oral and intranasal routes. Pirfenidone (100 mg/kg, TID) and Epigallocatechin gallate (EGCG, 100 mg/kg, QD), a natural catechin currently in a Phase 1 clinical trial, were used as reference compounds. ABI-171, administered prophylactically, led to a significant reduction in hydroxyproline levels and fibrotic tissue formation compared to the control group. Treatment with ABI-171 improved body weight, indicating mitigation of disease-related weight loss. Additionally, ABI-171 demonstrated anti-inflammatory activity, reducing lymphocyte and neutrophil infiltration. In the therapeutic setting, ABI-171, administered 7 days post-induction, reduced mortality rates (p = 0.04) compared with the bleomycin and EGCG control groups. ABI-171 also ameliorated the severity of lung injuries assessed by improved Masson’s trichrome scores when administered both orally and intranasally. ABI-171 significantly decreases bleomycin-induced PF and improves survival in mice, showcasing promising therapeutic potential beyond current medications like pirfenidone and EGCG for patients with IPF. Based on these results, further studies with ABI-171 are ongoing in preclinical studies. Full article

(This article belongs to the Special Issue Role of Natural Compounds in Human Health and Disease)

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21 pages, 1841 KiB

Open AccessReview

Natural Antimicrobial Agents from Algae: Current Advances and Future Directions

by Antonio Zuorro, Roberto Lavecchia, Jefferson E. Contreras-Ropero, Janet B. García Martínez, Crisóstomo Barajas-Ferreira and Andrés F. Barajas-Solano

Int. J. Mol. Sci. 2024, 25(21), 11826; https://doi.org/10.3390/ijms252111826 - 4 Nov 2024

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Abstract

Infectious diseases have significantly shaped human history, leading to significant advancements in medical science. The discovery and development of antibiotics represented a critical breakthrough, but the rise of antibiotic-resistant pathogens now presents a serious global health threat. Due to the limitations of current [...] Read more.

Infectious diseases have significantly shaped human history, leading to significant advancements in medical science. The discovery and development of antibiotics represented a critical breakthrough, but the rise of antibiotic-resistant pathogens now presents a serious global health threat. Due to the limitations of current synthetic antimicrobials, such as toxicity and environmental concerns, it is essential to explore alternative solutions. Algae, particularly microalgae and cyanobacteria, have emerged as promising sources of bioactive antimicrobial compounds. This review provides a comprehensive analysis of the antimicrobial properties of algal-derived compounds, including polysaccharides, fatty acids, and phenols, which have shown effectiveness against multi-drug-resistant bacteria. A co-occurrence bibliometric analysis using VOSviewer highlighted five key research clusters: antibiotic resistance, algal extracts, biosynthesis, water treatment, and novel pharmacological compounds. Furthermore, the primary mechanisms of action of these bioactive compounds, such as the inhibition of protein synthesis and cell membrane disruption, were identified, demonstrating their potential against both common and multi-resistant pathogens. Future research should prioritize optimizing algal biomass production, utilizing genetic and metabolic engineering, and creating innovative delivery systems to enhance the efficient production of bioactive compounds. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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18 pages, 1603 KiB

Open AccessReview

The Dual Role of B Cells in the Tumor Microenvironment: Implications for Cancer Immunology and Therapy

by Hao Yang, Zhiru Zhang, Jijun Li, Kun Wang, Wanting Zhu and Yingyue Zeng

Int. J. Mol. Sci. 2024, 25(21), 11825; https://doi.org/10.3390/ijms252111825 - 4 Nov 2024

Viewed by 808

Abstract

The tumor microenvironment (TME) is a complex and heterogeneous tissue composed of various cell types, including tumor cells, stromal cells, and immune cells, as well as non-cellular elements. Given their pivotal role in humoral immunity, B cells have emerged as promising targets for [...] Read more.

The tumor microenvironment (TME) is a complex and heterogeneous tissue composed of various cell types, including tumor cells, stromal cells, and immune cells, as well as non-cellular elements. Given their pivotal role in humoral immunity, B cells have emerged as promising targets for anti-tumor therapies. The dual nature of B cells, exhibiting both tumor-suppressive and tumor-promoting functions, has garnered significant attention. Understanding the distinct effects of various B cell subsets on different tumors could pave the way for novel targeted tumor therapies. This review provides a comprehensive overview of the heterogeneous B cell subsets and their multifaceted roles in tumorigenesis, as well as the therapeutic potential of targeting B cells in cancer treatment. To develop more effective cancer immunotherapies, it is essential to decipher the heterogeneity of B cells and their roles in shaping the TME. Full article

(This article belongs to the Section Molecular Immunology)

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Int. J. Mol. Sci., Volume 25, Issue 21 (November-1 2024) – 521 articles

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