International Journal of Molecular Sciences

20 pages, 4836 KiB

Open AccessArticle

Analysis of the Mechanism of Wood Vinegar and Butyrolactone Promoting Rapeseed Growth and Improving Low-Temperature Stress Resistance Based on Transcriptome and Metabolomics

by Kunmiao Zhu, Jun Liu, Ang Lyu, Tao Luo, Xin Chen, Lijun Peng and Liyong Hu

Int. J. Mol. Sci. 2024, 25(17), 9757; https://doi.org/10.3390/ijms25179757 - 9 Sep 2024

Cited by 1 | Viewed by 821

Abstract

Rapeseed is an important oil crop in the world. Wood vinegar could increase the yield and abiotic resistance of rapeseed. However, little is known about the underlying mechanisms of wood vinegar or its valid chemical components on rapeseed. In the present study, wood [...] Read more.

Rapeseed is an important oil crop in the world. Wood vinegar could increase the yield and abiotic resistance of rapeseed. However, little is known about the underlying mechanisms of wood vinegar or its valid chemical components on rapeseed. In the present study, wood vinegar and butyrolactone (γ-Butyrolactone, one of the main components of wood vinegar) were applied to rapeseed at the seedling stage, and the molecular mechanisms of wood vinegar that affect rapeseed were studied by combining transcriptome and metabolomic analyses. The results show that applying wood vinegar and butyrolactone increases the biomass of rapeseed by increasing the leaf area and the number of pods per plant, and enhances the tolerance of rapeseed under low temperature by reducing membrane lipid oxidation and improving the content of chlorophyll, proline, soluble sugar, and antioxidant enzymes. Compared to the control, 681 and 700 differentially expressed genes were in the transcriptional group treated with wood vinegar and butyrolactone, respectively, and 76 and 90 differentially expressed metabolites were in the metabolic group. The combination of transcriptome and metabolomic analyses revealed the key gene-metabolic networks related to various pathways. Our research shows that after wood vinegar and butyrolactone treatment, the amino acid biosynthesis pathway of rapeseed may be involved in mediating the increase in rapeseed biomass, the proline metabolism pathway of wood vinegar treatment may be involved in mediating rapeseed’s resistance to low-temperature stress, and the sphingolipid metabolism pathway of butyrolactone treatment may be involved in mediating rapeseed’s resistance to low-temperature stress. It is suggested that the use of wood vinegar or butyrolactone are new approaches to increasing rapeseed yield and low-temperature resistance. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Plant Biostimulants)

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16 pages, 1589 KiB

Open AccessArticle

GWAS Enhances Genomic Prediction Accuracy of Caviar Yield, Caviar Color and Body Weight Traits in Sturgeons Using Whole-Genome Sequencing Data

by Hailiang Song, Tian Dong, Wei Wang, Xiaoyu Yan, Chenfan Geng, Song Bai and Hongxia Hu

Int. J. Mol. Sci. 2024, 25(17), 9756; https://doi.org/10.3390/ijms25179756 - 9 Sep 2024

Viewed by 643

Abstract

Caviar yield, caviar color, and body weight are crucial economic traits in sturgeon breeding. Understanding the molecular mechanisms behind these traits is essential for their genetic improvement. In this study, we performed whole-genome sequencing on 673 Russian sturgeons, renowned for their high-quality caviar. [...] Read more.

Caviar yield, caviar color, and body weight are crucial economic traits in sturgeon breeding. Understanding the molecular mechanisms behind these traits is essential for their genetic improvement. In this study, we performed whole-genome sequencing on 673 Russian sturgeons, renowned for their high-quality caviar. With an average sequencing depth of 13.69×, we obtained approximately 10.41 million high-quality single nucleotide polymorphisms (SNPs). Using a genome-wide association study (GWAS) with a single-marker regression model, we identified SNPs and genes associated with these traits. Our findings revealed several candidate genes for each trait: caviar yield: TFAP2A, RPS6KA3, CRB3, TUBB, H2AFX, morc3, BAG1, RANBP2, PLA2G1B, and NYAP1; caviar color: NFX1, OTULIN, SRFBP1, PLEK, INHBA, and NARS; body weight: ACVR1, HTR4, fmnl2, INSIG2, GPD2, ACVR1C, TANC1, KCNH7, SLC16A13, XKR4, GALR2, RPL39, ACVR2A, ADCY10, and ZEB2. Additionally, using the genomic feature BLUP (GFBLUP) method, which combines linkage disequilibrium (LD) pruning markers with GWAS prior information, we improved genomic prediction accuracy by 2%, 1.9%, and 3.1% for caviar yield, caviar color, and body weight traits, respectively, compared to the GBLUP method. In conclusion, this study enhances our understanding of the genetic mechanisms underlying caviar yield, caviar color, and body weight traits in sturgeons, providing opportunities for genetic improvement of these traits through genomic selection. Full article

(This article belongs to the Special Issue Molecular Biology and the Genetic Breeding of Aquatic Animals: Breakthroughs and Challenges)

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14 pages, 268 KiB

Open AccessReview

Prostate-Specific Membrane Antigen Biology and Pathophysiology in Prostate Carcinoma, an Update: Potential Implications for Targeted Imaging and Therapy

by Justine Maes, Simon Gesquière, Anton De Spiegeleer, Alex Maes and Christophe Van de Wiele

Int. J. Mol. Sci. 2024, 25(17), 9755; https://doi.org/10.3390/ijms25179755 - 9 Sep 2024

Viewed by 677

Abstract

Prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein, was shown to be expressed 100–1000 fold higher in prostate adenocarcinoma as compared to normal prostate epithelium. Given the enzymatic function of PSMA with the presence of an internalization triggering motif, various Glu-urea-Lys-based inhibitors have been [...] Read more.

Prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein, was shown to be expressed 100–1000 fold higher in prostate adenocarcinoma as compared to normal prostate epithelium. Given the enzymatic function of PSMA with the presence of an internalization triggering motif, various Glu-urea-Lys-based inhibitors have been developed and, amongst others, radiolabeled with positron emitters for targeted positron emission tomography imaging such as ⁶⁸Ga-PSMA-HBED-CC Glu-urea-Lys(Ahx) as well as with beta and alpha-emitting radioisotopes for targeted therapy, e.g., ¹⁷⁷Lu-PSMA-617. In this paper, we review and discuss the potential implications for targeted imaging and therapy of altered PSMA-glycosylation, of PSMA-driven activation of the P13K/Akt/mTOR, of the evolution over time and the relationship with androgen signaling and changes in DNA methylation of PSMA, and of androgen deprivation therapy (ADT) in prostate carcinoma. Full article

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

17 pages, 1353 KiB

Open AccessCase Report

Identification of SYNJ1 in a Complex Case of Juvenile Parkinsonism Using a Multiomics Approach

by Ester Leno-Durán, Luisa Arrabal, Susana Roldán, Inmaculada Medina, Clara Alcántara-Domínguez, Victor García-Cabrera, Jorge Saiz, Coral Barbas, Maria José Sánchez, Carmen Entrala-Bernal, Francisco Fernández-Rosado, Jose Antonio Lorente, Purificacion Gutierrez-Ríos and Luis Javier Martínez-Gonzalez

Int. J. Mol. Sci. 2024, 25(17), 9754; https://doi.org/10.3390/ijms25179754 - 9 Sep 2024

Viewed by 784

Abstract

This study aimed to elucidate the genetic causes underlying the juvenile parkinsonism (JP) diagnosed in a girl with several family members diagnosed with spinocerebellar ataxia type 2 (SCA2). To achieve this, whole-exome sequencing, analysis of CAG repeats, RNA sequencing analysis on fibroblasts, and [...] Read more.

This study aimed to elucidate the genetic causes underlying the juvenile parkinsonism (JP) diagnosed in a girl with several family members diagnosed with spinocerebellar ataxia type 2 (SCA2). To achieve this, whole-exome sequencing, analysis of CAG repeats, RNA sequencing analysis on fibroblasts, and metabolite identification were performed. As a result, a homozygous missense mutation SNP T>C (rs2254562) in synaptojamin 1 (SYNJ1), which has been implicated in the regulation of membrane trafficking in the synaptic vesicles, was identified. Additionally, we observed overexpression of L1 cell adhesion molecule (L1CAM), Cdc37, GPX1, and GPX4 and lower expression of ceruloplasmin in the patient compared to the control. We also found changes in sphingolipid, inositol, and inositol phosphate metabolism. These findings help to clarify the mechanisms of JP and suggest that the etiology of JP in the patient may be multifactorial. This is the first report of the rs2254562 mutation in the SYNJ gene identified in a JP patient with seizures and cognitive impairment. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 4.0)

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16 pages, 3526 KiB

Open AccessArticle

Toxicity and Metabolomic Dysfunction Invoked by Febrifugin, a Harmful Component of Edible Nut of Swietenia macrophylla

by Xiaoyue Zhang, Qinyang Song, Hanghang Zheng, Rui Wang and Qiang Zhang

Int. J. Mol. Sci. 2024, 25(17), 9753; https://doi.org/10.3390/ijms25179753 - 9 Sep 2024

Viewed by 580

Abstract

Swietenia macrophylla fruit is a valuable and historically significant medicinal plant with anti-hypertension and anti-diabetes. We identified a toxic component, Febrifugin, from the edible part of the nut following zebrafish toxicity-guided isolation. Febrifugin is a mexicanolide-type limonoid compound. The toxic factor induced acute [...] Read more.

Swietenia macrophylla fruit is a valuable and historically significant medicinal plant with anti-hypertension and anti-diabetes. We identified a toxic component, Febrifugin, from the edible part of the nut following zebrafish toxicity-guided isolation. Febrifugin is a mexicanolide-type limonoid compound. The toxic factor induced acute toxicity in zebrafish, including yolk sac edema and pericardial edema, reduced body length, decreased melanin deposition, and presented acute skeletal developmental issues. Further exploration of the acute toxicity mechanism through metabolomics revealed that Febrifugin caused significant changes in 13 metabolites in zebrafish larvae, which are involved in the pentose phosphate, tricarboxylic acid (TCA) cycle, and amino acid biosynthesis. The bioassay of oxidative stress capacity and qRT-PCR measurement showed that the compound significantly affected the h6pd gene in the pentose phosphate pathway and the mRNA expression of cs, idh3a, fh, and shda genes in the TCA cycle, leading to reactive oxygen species (ROS) accumulation and a notable decrease in glutathione (GSH) activity in zebrafish. These findings provide a basis for the rational use of S. macrophylla as a medicinal plant and raise awareness of the safety of medicinal plants. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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21 pages, 2536 KiB

Open AccessReview

Establishing Treatment Effectiveness in Fabry Disease: Observation-Based Recommendations for Improvement

by Bram C. F. Veldman, Daphne H. Schoenmakers, Laura van Dussen, Mareen R. Datema and Mirjam Langeveld

Int. J. Mol. Sci. 2024, 25(17), 9752; https://doi.org/10.3390/ijms25179752 - 9 Sep 2024

Viewed by 863

Abstract

Fabry disease (FD, OMIM #301500) is caused by pathogenic GLA gene (OMIM #300644) variants, resulting in a deficiency of the α-galactosidase A enzyme with accumulation of its substrate globotriaosylceramide and its derivatives. The phenotype of FD is highly variable, with distinctive disease features [...] Read more.

Fabry disease (FD, OMIM #301500) is caused by pathogenic GLA gene (OMIM #300644) variants, resulting in a deficiency of the α-galactosidase A enzyme with accumulation of its substrate globotriaosylceramide and its derivatives. The phenotype of FD is highly variable, with distinctive disease features and course in classical male patients but more diverse and often nonspecific features in non-classical and female patients. FD-specific therapies have been available for approximately two decades, yet establishing robust evidence for long-term effectiveness remains challenging. This review aims to identify the factors contributing to this lack of robust evidence for the treatment of FD with enzyme replacement therapy (ERT) (agalsidase-alfa and -beta and pegunigalsidase alfa) and chaperone therapy (migalastat). Major factors that have been identified are study population heterogeneity (concerning sex, age, phenotype, disease stage) and differences in study design (control groups, outcomes assessed), as well as the short duration of studies. To address these challenges, we advocate for patient matching to improve control group compatibility in future FD therapy studies. We recommend international collaboration and harmonization, facilitated by an independent FD registry. We propose a stepwise approach for evaluating the effectiveness of novel treatments, including recommendations for surrogate outcomes and required study duration. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Pathophysiology, Molecular Mechanism and Therapeutic Strategies)

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22 pages, 14482 KiB

Open AccessArticle

by Kawthar S. Alghamdi, Rahaf H. Kassar, Wesam F. Farrash, Ahmad A. Obaid, Shakir Idris, Alaa Siddig, Afnan M. Shakoori, Sallwa M. Alshehre, Faisal Minshawi and Abdulrahman Mujalli

Int. J. Mol. Sci. 2024, 25(17), 9751; https://doi.org/10.3390/ijms25179751 - 9 Sep 2024

Viewed by 888

Abstract

Inflammatory Bowel Diseases (IBD), which encompass ulcerative colitis (UC) and Crohn’s disease (CD), are characterized by chronic inflammation and tissue damage of the gastrointestinal tract. This study aimed to uncover novel disease-gene signatures, dysregulated pathways, and the immune cell infiltration landscape of inflamed [...] Read more.

Inflammatory Bowel Diseases (IBD), which encompass ulcerative colitis (UC) and Crohn’s disease (CD), are characterized by chronic inflammation and tissue damage of the gastrointestinal tract. This study aimed to uncover novel disease-gene signatures, dysregulated pathways, and the immune cell infiltration landscape of inflamed tissues. Eight publicly available transcriptomic datasets, including inflamed and non-inflamed tissues from CD and UC patients were analyzed. Common differentially expressed genes (DEGs) were identified through meta-analysis, revealing 180 DEGs. DEGs were implicated in leukocyte transendothelial migration, PI3K-Akt, chemokine, NOD-like receptors, TNF signaling pathways, and pathways in cancer. Protein–protein interaction network and cluster analysis identified 14 central IBD players, which were validated using eight external datasets. Disease module construction using the NeDRex platform identified nine out of 14 disease-associated genes (CYBB, RAC2, GNAI2, ITGA4, CYBA, NCF4, CPT1A, NCF2, and PCK1). Immune infiltration profile assessment revealed a significantly higher degree of infiltration of neutrophils, activated dendritic cells, plasma cells, mast cells (resting/activated), B cells (memory/naïve), regulatory T cells, and M0 and M1 macrophages in inflamed IBD tissue. Collectively, this study identified the immune infiltration profile and nine disease-associated genes as potential modulators of IBD pathogenesis, offering insights into disease molecular mechanisms, and highlighting potential disease modulators and immune cell dynamics. Full article

(This article belongs to the Special Issue Immunoanalytical and Bioinformatics Methods in Immunology Research)

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24 pages, 1646 KiB

Open AccessArticle

The Impact of ARMS2 (rs10490924), VEGFA (rs3024997), TNFRSF1B (rs1061622), TNFRSF1A (rs4149576), and IL1B1 (rs1143623) Polymorphisms and Serum Levels on Age-Related Macular Degeneration Development and Therapeutic Responses

by Dzastina Cebatoriene, Alvita Vilkeviciute, Greta Gedvilaite-Vaicechauskiene, Monika Duseikaite, Akvile Bruzaite, Loresa Kriauciuniene, Dalia Zaliuniene and Rasa Liutkeviciene

Int. J. Mol. Sci. 2024, 25(17), 9750; https://doi.org/10.3390/ijms25179750 - 9 Sep 2024

Viewed by 586

Abstract

Age-related macular degeneration (AMD) is a major global health problem as it is the leading cause of irreversible loss of central vision in the aging population. Anti-vascular endothelial growth factor (anti-VEGF) therapies are effective but do not respond optimally in all patients. This [...] Read more.

Age-related macular degeneration (AMD) is a major global health problem as it is the leading cause of irreversible loss of central vision in the aging population. Anti-vascular endothelial growth factor (anti-VEGF) therapies are effective but do not respond optimally in all patients. This study investigates the genetic factors associated with susceptibility to AMD and response to treatment, focusing on key polymorphisms in the ARMS2 (rs10490924), IL1B1 (rs1143623), TNFRSF1B (rs1061622), TNFRSF1A (rs4149576), VEGFA (rs3024997), ARMS2, IL1B1, TNFRSF1B, TNFRSF1A, and VEGFA serum levels in AMD development and treatment efficacy. This study examined the associations of specific genetic polymorphisms and serum protein levels with exudative and early AMD and the response to anti-VEGF treatment. The AA genotype of VEGFA (rs3024997) was significantly associated with a 20-fold reduction in the odds of exudative AMD compared to the GG + GA genotypes. Conversely, the TT genotype of ARMS2 (rs10490924) was linked to a 4.2-fold increase in the odds of exudative AMD compared to GG + GT genotypes. In females, each T allele of ARMS2 increased the odds by 2.3-fold, while in males, the TT genotype was associated with a 5-fold increase. Lower serum IL1B levels were observed in the exudative AMD group compared to the controls. Early AMD patients had higher serum TNFRSF1B levels than controls, particularly those with the GG genotype of TNFRSF1B rs1061622. Exudative AMD patients with the CC genotype of TNFRSF1A rs4149576 had lower serum TNFRSF1A levels compared to the controls. Visual acuity (VA) analysis showed that non-responders had better baseline VA than responders but experienced decreased VA after treatment, whereas responders showed improvement. Central retinal thickness (CRT) reduced significantly in responders after treatment and was lower in responders compared to non-responders after treatment. The T allele of TNFRSF1B rs1061622 was associated with a better response to anti-VEGF treatment under both dominant and additive genetic models. These findings highlight significant genetic and biochemical markers associated with AMD and treatment response. This study found that the VEGFA rs3024997 AA genotype reduces the odds of exudative AMD, while the ARMS2 rs10490924 TT genotype increases it. Lower serum IL1B levels and variations in TNFRSF1B and TNFRSF1A levels were linked to AMD. The TNFRSF1B rs1061622 T allele was associated with better anti-VEGF treatment response. These markers could potentially guide risk assessment and personalized treatment for AMD. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Retinal Degeneration and How to Avoid It—2nd Edition)

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15 pages, 5040 KiB

Open AccessArticle

Transcriptome Analysis Reveals the Effect of Oyster Mushroom Spherical Virus Infection in Pleurotus ostreatus

by Yifan Wang, Junjie Yan, Guoyue Song, Zhizhong Song, Matthew Shi, Haijing Hu, Lunhe You, Lu Zhang, Jianrui Wang, Yu Liu, Xianhao Cheng and Xiaoyan Zhang

Int. J. Mol. Sci. 2024, 25(17), 9749; https://doi.org/10.3390/ijms25179749 - 9 Sep 2024

Viewed by 504

Abstract

Oyster mushroom spherical virus (OMSV) is a mycovirus that inhibits mycelial growth, induces malformation symptoms, and decreases the yield of fruiting bodies in Pleurotus ostreatus. However, the pathogenic mechanism of OMSV infection in P. ostreatus is poorly understood. In this study, RNA [...] Read more.

Oyster mushroom spherical virus (OMSV) is a mycovirus that inhibits mycelial growth, induces malformation symptoms, and decreases the yield of fruiting bodies in Pleurotus ostreatus. However, the pathogenic mechanism of OMSV infection in P. ostreatus is poorly understood. In this study, RNA sequencing (RNA-seq) was conducted, identifying 354 differentially expressed genes (DEGs) in the mycelium of P. ostreatus during OMSV infection. Verifying the RNA-seq data through quantitative real-time polymerase chain reaction on 15 DEGs confirmed the consistency of gene expression trends. Both Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses highlighted the pivotal role of primary metabolic pathways in OMSV infection. Additionally, significant changes were noted in the gene expression levels of carbohydrate-active enzymes (CAZymes), which are crucial for providing the carbohydrates needed for fungal growth, development, and reproduction by degrading renewable lignocellulose. The activities of carboxymethyl cellulase, laccase, and amylase decreased, whereas chitinase activity increased, suggesting a potential mechanism by which OMSV influenced mycelial growth through modulating CAZyme activities. Therefore, this study provided insights into the pathogenic mechanisms triggered by OMSV in P. ostreatus. Full article

(This article belongs to the Special Issue Advances in Plant Virus Diseases and Virus-Induced Resistance)

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21 pages, 6576 KiB

Open AccessArticle

Impact of Methylated Cyclodextrin KLEPTOSE^® CRYSMEB on Inflammatory Responses in Human In Vitro Models

by Damien Truffin, Flora Marchand, Mathias Chatelais, Gérald Chêne, Laure Saias, Frauke Herbst, Justin Lipner and Alastair J. King

Int. J. Mol. Sci. 2024, 25(17), 9748; https://doi.org/10.3390/ijms25179748 - 9 Sep 2024

Viewed by 606

Abstract

KLEPTOSE^® CRYSMEB methylated cyclodextrin derivative displays less methylated group substitution than randomly methylated cyclodextrin. It has demonstrated an impact on atherosclerosis and neurological diseases, linked in part to cholesterol complexation and immune response, however, its impact on inflammatory cascade pathways is not [...] Read more.

KLEPTOSE^® CRYSMEB methylated cyclodextrin derivative displays less methylated group substitution than randomly methylated cyclodextrin. It has demonstrated an impact on atherosclerosis and neurological diseases, linked in part to cholesterol complexation and immune response, however, its impact on inflammatory cascade pathways is not clear. Thus, the impact of KLEPTOSE^® CRYSMEB on various pharmacological targets was assessed using human umbilical vein endothelial cells under physiological and inflammatory conditions, followed by screening against twelve human primary cell-based systems designed to model complex human tissue and disease biology of the vasculature, skin, lung, and inflammatory tissues using the BioMAP^® Diversity PLUS^® panel. Finally, its anti-inflammatory mechanism was investigated on peripheral blood mononuclear cells to evaluate anti-inflammatory or pro-resolving properties. The results showed that KLEPTOSE^® CRYSMEB can modulate the immune system in vitro and potentially manage vascular issues by stimulating the expression of molecules involved in the crosstalk between immune cells and other cell types. It showed anti-inflammatory effects that were driven by the inhibition of pro-inflammatory cytokine secretion and could have different impacts on different tissue types. Moreover, this cyclodextrin showed no clear impact on pro-resolving lipid mediators. Additionally, it appeared that the mechanism of action of KLEPTOSE^® CRYSMEB seems to not be shared by other well-known anti-inflammatory molecules. Finally, KLEPTOSE^® CRYSMEB may have an anti-inflammatory impact, which could be due to its effect on receptors such as TLR or direct complexation with LPS or PGE2, and conversely, this methylated cyclodextrin could stimulate a pro-inflammatory response involving lipid mediators and on proteins involved in communication with immune cells, probably via interaction with membrane cholesterol. Full article

(This article belongs to the Special Issue Research on Cyclodextrin)

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18 pages, 1569 KiB

Open AccessReview

Experimental Cell Models for Investigating Neurodegenerative Diseases

by Cecilia Evangelisti, Sherin Ramadan, Antonio Orlacchio and Emanuele Panza

Int. J. Mol. Sci. 2024, 25(17), 9747; https://doi.org/10.3390/ijms25179747 - 9 Sep 2024

Viewed by 744

Abstract

Experimental models play a pivotal role in biomedical research, facilitating the understanding of disease mechanisms and the development of novel therapeutics. This is particularly true for neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and motor neuron disease, [...] Read more.

Experimental models play a pivotal role in biomedical research, facilitating the understanding of disease mechanisms and the development of novel therapeutics. This is particularly true for neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and motor neuron disease, which present complex challenges for research and therapy development. In this work, we review the recent literature about experimental models and motor neuron disease. We identified three main categories of models that are highly studied by scientists. In fact, experimental models for investigating these diseases encompass a variety of approaches, including modeling the patient’s cell culture, patient-derived induced pluripotent stem cells, and organoids. Each model offers unique advantages and limitations, providing researchers with a range of tools to address complex biological questions. Here, we discuss the characteristics, applications, and recent advancements in terms of each model system, highlighting their contributions to advancing biomedical knowledge and translational research. Full article

(This article belongs to the Special Issue Genetic Bases of Neurodegenerative Disease)

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11 pages, 759 KiB

Open AccessReview

The Role of the Endometrium in Implantation: A Modern View

by Pavel I. Deryabin and Aleksandra V. Borodkina

Int. J. Mol. Sci. 2024, 25(17), 9746; https://doi.org/10.3390/ijms25179746 - 9 Sep 2024

Viewed by 630

Abstract

According to the current data, the endometrium acts as a “sensor” of embryo quality, which promotes the implantation of euploid embryos and prevents the implantation and/or subsequent development of genetically abnormal embryos. The present review addresses the nature of the “sensory function” of [...] Read more.

According to the current data, the endometrium acts as a “sensor” of embryo quality, which promotes the implantation of euploid embryos and prevents the implantation and/or subsequent development of genetically abnormal embryos. The present review addresses the nature of the “sensory function” of the endometrium and highlights the necessity for assessing its functional status. The first section examines the evolutionary origin of the “sensory” ability of the endometrium as a consequence of spontaneous decidualization that occurred in placental animals. The second section details the mechanisms for implementing this function at the cellular level. In particular, the recent findings of the appearance of different cell subpopulations during decidualization are described, and their role in implantation is discussed. The pathological consequences of an imbalance among these subpopulations are also discussed. Finally, the third section summarizes information on currently available clinical tools to assess endometrial functional status. The advantages and disadvantages of the approaches are emphasized, and possible options for developing more advanced technologies for assessing the “sensory” function of the endometrium are proposed. Full article

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

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13 pages, 1019 KiB

Open AccessArticle

Identification of SNPs and Candidate Genes Associated with Monocyte/Lymphocyte Ratio and Neutrophil/Lymphocyte Ratio in Duroc × Erhualian F₂ Population

by Jiakun Qiao, Minghang Xu, Fangjun Xu, Zhaoxuan Che, Pingping Han, Xiangyu Dai, Na Miao and Mengjin Zhu

Int. J. Mol. Sci. 2024, 25(17), 9745; https://doi.org/10.3390/ijms25179745 - 9 Sep 2024

Viewed by 496

Abstract

Understanding the pig immune function is crucial for disease-resistant breeding and potentially for human health research due to shared immune system features. Immune cell ratios, like monocyte/lymphocyte ratio (MLR) and neutrophil/lymphocyte ratio (NLR), offer a more comprehensive view of immune status compared to [...] Read more.

Understanding the pig immune function is crucial for disease-resistant breeding and potentially for human health research due to shared immune system features. Immune cell ratios, like monocyte/lymphocyte ratio (MLR) and neutrophil/lymphocyte ratio (NLR), offer a more comprehensive view of immune status compared to individual cell counts. However, research on pig immune cell ratios remains limited. This study investigated MLR and NLR in a Duroc × Erhualian F₂ resource population. Heritability analysis revealed high values (0.649 and 0.688 for MLR and NLR, respectively), suggesting a strong genetic component. Furthermore, we employed an ensemble-like GWAS (E-GWAS) strategy and functional annotation analysis to identify 11 MLR-associated and 6 NLR-associated candidate genes. These genes were significantly enriched in immune-related biological processes. These findings provide novel genetic markers and candidate genes associated with porcine immunity, thereby providing valuable insights for addressing biosecurity and animal welfare concerns in the pig industry. Full article

(This article belongs to the Section Molecular Immunology)

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29 pages, 5961 KiB

Open AccessArticle

Synthesis of Ethyl Pyrimidine-Quinolincarboxylates Selected from Virtual Screening as Enhanced Lactate Dehydrogenase (LDH) Inhibitors

by Iván Díaz, Sofía Salido, Manuel Nogueras and Justo Cobo

Int. J. Mol. Sci. 2024, 25(17), 9744; https://doi.org/10.3390/ijms25179744 - 9 Sep 2024

Viewed by 560

Abstract

The inhibition of the hLDHA (human lactate dehydrogenase A) enzyme has been demonstrated to be of great importance in the treatment of cancer and other diseases, such as primary hyperoxalurias. In that regard, we have designed, using virtual docking screening, a novel family [...] Read more.

The inhibition of the hLDHA (human lactate dehydrogenase A) enzyme has been demonstrated to be of great importance in the treatment of cancer and other diseases, such as primary hyperoxalurias. In that regard, we have designed, using virtual docking screening, a novel family of ethyl pyrimidine-quinolinecarboxylate derivatives (13–18)(a–d) as enhanced hLDHA inhibitors. These inhibitors were synthesised through a convergent pathway by coupling the key ethyl 2-aminophenylquinoline-4-carboxylate scaffolds (7–12), which were prepared by Pfitzinger synthesis followed by a further esterification, to the different 4-aryl-2-chloropyrimidines (VIII(a–d)) under microwave irradiation at 150–170 °C in a green solvent. The values obtained from the hLDHA inhibition were in line with the preliminary of the preliminary docking results, the most potent ones being those with U-shaped disposition. Thirteen of them showed IC₅₀ values lower than 5 μM, and for four of them (16a, 18b, 18c and 18d), IC₅₀ ≈ 1 μM. Additionally, all compounds with IC₅₀ < 10 μM were also tested against the hLDHB isoenzyme, resulting in three of them (15c, 15d and 16d) being selective to the A isoform, with their hLDHB IC₅₀ > 100 μM, and the other thirteen behaving as double inhibitors. Full article

(This article belongs to the Special Issue Drug Discovery: Design, Synthesis and Activity Evaluation)

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12 pages, 5157 KiB

Open AccessArticle

Comparative Analysis of the Mitochondrial Genome of Eggplant (Solanum melongena L.) to Identify Cytoplasmic Male Sterility Candidate Genes

by Wentao Deng, Guiyun Gan, Weiliu Li, Chuying Yu, Yaqin Jiang, Die Li, Qihong Yang, Wenjia Li, Peng Wang and Yikui Wang

Int. J. Mol. Sci. 2024, 25(17), 9743; https://doi.org/10.3390/ijms25179743 - 9 Sep 2024

Viewed by 563

Abstract

Cytoplasmic male sterility (CMS) is important for commercial hybrid seed production. However, it is still not used in eggplant (Solanum melongena L.), and corresponding regulatory genes and mechanisms of action have not been reported. We report CMS line 327A, which was derived [...] Read more.

Cytoplasmic male sterility (CMS) is important for commercial hybrid seed production. However, it is still not used in eggplant (Solanum melongena L.), and corresponding regulatory genes and mechanisms of action have not been reported. We report CMS line 327A, which was derived from the hybridization between cultivated and wild eggplants. By looking at different stages of anther development under a microscope, we saw that the 327A anther’s tapetum layer vacuolized during meiosis, which caused abortion. To investigate the 327A CMS regulatory genes, the mitochondrial genomes of 327A and its maintainer line 327B were assembled de novo. It was found that 15 unique ORFs (Open Reading Frame) were identified in 327A. RT-PCR and RT-QPCAR tests confirmed that orf312a and orf172a, 327A-specific ORFs with a transmembrane domain, were strongly expressed in sterile anthers of 327A. In addition, orf312a has a chimeric structure with the ribosomal protein subunit rpl16. Therefore, orf312a and orf172a can be considered strong candidate genes for CMS. Concurrently, we analyzed the characteristics of CMS to develop a functional molecular marker, CMS312, targeting a future theoretical basis for eggplant CMS three-line molecular breeding. Full article

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

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19 pages, 2994 KiB

Open AccessArticle

Role of CD44-Positive Extracellular Vesicles Derived from Highly Metastatic Mouse Mammary Carcinoma Cells in Pre-Metastatic Niche Formation

by Ayana Ikari, Yuko Ito, Kohei Taniguchi, Masa-Aki Shibata, Kosei Kimura, Mitsuhiko Iwamoto and Sang-Woong Lee

Int. J. Mol. Sci. 2024, 25(17), 9742; https://doi.org/10.3390/ijms25179742 - 9 Sep 2024

Viewed by 579

Abstract

Malignant breast cancers pose a notable challenge when it comes to treatment options. Recently, research has implicated extracellular vesicles (EVs) secreted by cancer cells in the formation of a pre-metastatic niche. Small clumps of CD44-positive breast cancer cells are efficiently transferred through CD44–CD44 [...] Read more.

Malignant breast cancers pose a notable challenge when it comes to treatment options. Recently, research has implicated extracellular vesicles (EVs) secreted by cancer cells in the formation of a pre-metastatic niche. Small clumps of CD44-positive breast cancer cells are efficiently transferred through CD44–CD44 protein homophilic interaction. This study aims to examine the function of CD44-positive EVs in pre-metastatic niche formation in vitro and to suggest a more efficacious EV formulation. We used mouse mammary carcinoma cells, BJMC3879 Luc2 (Luc2 cells) as the source of CD44-positive EVs and mouse endothelial cells (UV2 cells) as the recipient cells in the niche. Luc2 cells exhibited an enhanced secretion of EVs expressing CD44 and endothelial growth factors (VEGF-A, -C) under 20% O₂ (representative of the early stage of tumorigenesis) compared to its expression under 1% O₂ (in solid tumor), indicating that pre-metastatic niche formation occurs in the early stage. Furthermore, UV2 endothelial cells expressing CD44 demonstrated a high level of engulfment of EVs that had been supplemented with hyaluronan, and the proliferation of UV2 cells occurred following the engulfment of EVs. These results suggest that anti-VEGF-A and -C encapsulated, CD44-expressing, and hyaluronan-coated EVs are more effective for tumor metastasis. Full article

(This article belongs to the Section Molecular Oncology)

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13 pages, 2345 KiB

Open AccessArticle

Metabolic Engineering of Escherichia coli for Production of a Bioactive Metabolite of Bilirubin

by Huaxin Chen, Peng Xiong, Ning Guo and Zhe Liu

Int. J. Mol. Sci. 2024, 25(17), 9741; https://doi.org/10.3390/ijms25179741 - 9 Sep 2024

Viewed by 603

Abstract

Bilirubin (BR) is an important ingredient of a valuable Chinese medicine, Calculus bovis. Over recent decades, increasing evidence has confirmed that BR offers health benefits in cardiovascular health, stroke, diabetes, and metabolic syndrome. However, BR is mainly produced by extraction from pig bile. [...] Read more.

Bilirubin (BR) is an important ingredient of a valuable Chinese medicine, Calculus bovis. Over recent decades, increasing evidence has confirmed that BR offers health benefits in cardiovascular health, stroke, diabetes, and metabolic syndrome. However, BR is mainly produced by extraction from pig bile. In this study, we assembled an efficient pathway for BR production by metabolic engineering of Escherichia coli. First, heme oxygenase (HO1) and biliverdin reductase were co-expressed in E. coli. HPLC and LC–MS confirmed the accumulation of BR in the recombinant E. coli cells. To improve BR production, the catalytic abilities of HO1 from different species were investigated. In addition, the outermembrane-bound heme receptor (ChuA) and the enzymes involved in heme biosynthesis were overexpressed among which ChuA, 5-aminolevulinic acid dehydratase (HemB), protoporphyrin oxidase (HemG), and ferrochelatase (HemH) were found to enhance BR accumulation in E. coli. In addition, expression of ferredoxin (Fd) was shown to contribute to efficient conversion of heme to BR in E. coli. To increase supply of NADPH, isocitrate dehydrogenase (IDH), NAD kinase (nadK), NADP-specific glutamate dehydrogenase (gdhA), and glucose-6-phosphate 1-dehydrogenase (ZWF) were overexpressed and were found to enhance BR accumulation when these proteins were expressed with a low-copy plasmid pACYCduet-1. Modular optimization of the committed genes led to a titer of 17.2 mg/L in strain M1BHG. Finally, fed-batch fermentation was performed for the strains M1BHG and M1, resulting in accumulation of 75.5 mg/L and 25.8 mg/L of BR, respectively. This is the first report on biosynthesis of BR through metabolic engineering in a heterologous host. Full article

(This article belongs to the Special Issue The Role of Bioactive Compounds in Human Health and Disease: 2nd Edition)

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25 pages, 18859 KiB

Open AccessArticle

DNA Methylation and Subgenome Dominance Reveal the Role of Lipid Metabolism in Jinhu Grouper Heterosis

by Yang Liu, Linna Wang, Zhentong Li, Linlin Li, Shuai Chen, Pengfei Duan, Xinyi Wang, Yishu Qiu, Xiaoyu Ding, Jinzhi Su, Yuan Deng and Yongsheng Tian

Int. J. Mol. Sci. 2024, 25(17), 9740; https://doi.org/10.3390/ijms25179740 - 9 Sep 2024

Viewed by 407

Abstract

Heterosis of growth traits in economic fish has benefited the production of aquaculture for many years, yet its genetic and molecular basis has remained obscure. Nowadays, a new germplasm of hybrid Jinhu grouper (Epinephelus fuscoguttatus ♀ × E. tukula ♂), abbreviated as [...] Read more.

Heterosis of growth traits in economic fish has benefited the production of aquaculture for many years, yet its genetic and molecular basis has remained obscure. Nowadays, a new germplasm of hybrid Jinhu grouper (Epinephelus fuscoguttatus ♀ × E. tukula ♂), abbreviated as EFT, exhibiting paternal-biased growth heterosis, has provided an excellent model for investigating the potential regulatory mechanisms of heterosis. We integrated transcriptome and methylome to unravel the changes of gene expression, epigenetic modification, and subgenome dominance in EFT compared with maternal E. fuscoguttatus. Integration analyses showed that the heterotic hybrids showed lower genomic DNA methylation levels than the purebred parent, and the up-regulated genes were mostly DNA hypomethylation. Furthermore, allele-specific expression (ASE) detected paternal subgenome dominance-regulated paternal-biased heterosis, and paternal bias differentially expressed genes (DEGs) were wholly up-regulated in the muscle. Multi-omics results highlighted the role of lipid metabolism, particularly “Fatty acid synthesis”, “EPA biosynthesis”, and “Signaling lipids”, in EFT heterosis formation. Coherently, our studies have proved that the eicosapentaenoic acid (EPA) of EFT was greater than that of maternal E. fuscoguttatus (8.46% vs. 7.46%). Finally, we constructed a potential regulatory network for control of the heterosis formation in EFT. Among them, fasn, pparg, dgat1, igf1, pomca, fgf8a, and fgfr4 were identified as key genes. Our results provide new and valuable clues for understanding paternal-biased growth heterosis in EFT, taking a significant step towards the molecular basis of heterosis. Full article

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

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13 pages, 1746 KiB

Open AccessReview

Gene Therapy for Achromatopsia

by Megan F. Baxter and Grace A. Borchert

Int. J. Mol. Sci. 2024, 25(17), 9739; https://doi.org/10.3390/ijms25179739 - 9 Sep 2024

Viewed by 768

Abstract

Achromatopsia is the most common cone dysfunction syndrome, affecting 1 in 30,000 people. It is an autosomal recessive disorder with a heterogeneous genetic background with variants reported in CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6. Up to 90% [...] Read more.

Achromatopsia is the most common cone dysfunction syndrome, affecting 1 in 30,000 people. It is an autosomal recessive disorder with a heterogeneous genetic background with variants reported in CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6. Up to 90% of achromatopsia patients harbour mutations in CNGA3 or CNB3, which encode for the alpha and beta subunits of the cone cyclic nucleotide-gated (CNG) channel in cone-specific phototransduction. The condition presents at birth or early infancy with poor visual acuity, nystagmus, photophobia, and colour vision loss in all axes. Multimodal retinal imaging has provided insightful information to characterise achromatopsia patients based on their genotype. There is no FDA-approved treatment for achromatopsia; however, studies have reported several preclinical gene therapies with anatomical and functional improvements reported in vivo. There are currently five gene therapy clinical trials registered for human patients at the phase I/II stage and for CNGA3 or CNGB3 causing achromatopsia. This review aims to discuss the genetics of achromatopsia, genotypic and phenotypic correlations in multimodal retinal imaging, and the developments and challenges in gene therapy clinical trials. Full article

(This article belongs to the Special Issue Advances in Gene and Cell Therapy—2nd Edition)

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17 pages, 9964 KiB

Open AccessArticle

L-Fucose-Rich Sulfated Glycans from Edible Brown Seaweed: A Promising Functional Food for Obesity and Energy Expenditure Improvement

by Jimin Hyun, Hyo-Geun Lee, Jun-Geon Je, Yun-Sang Choi, Kyung-Mo Song, Tae-Kyung Kim, Bomi Ryu, Min-Cheol Kang and You-Jin Jeon

Int. J. Mol. Sci. 2024, 25(17), 9738; https://doi.org/10.3390/ijms25179738 - 9 Sep 2024

Viewed by 578

Abstract

The global obesity epidemic, exacerbated by the sedentary lifestyle fostered by the COVID-19 pandemic, presents a growing socioeconomic burden due to decreased physical activity and increased morbidity. Current obesity treatments show promise, but they often come with expensive medications, frequent injections, and potential [...] Read more.

The global obesity epidemic, exacerbated by the sedentary lifestyle fostered by the COVID-19 pandemic, presents a growing socioeconomic burden due to decreased physical activity and increased morbidity. Current obesity treatments show promise, but they often come with expensive medications, frequent injections, and potential side effects, with limited success in improving obesity through increased energy expenditure. This study explores the potential of a refined sulfated polysaccharide (SPSL), derived from the brown seaweed Scytosiphon lomentaria (SL), as a safe and effective anti-obesity treatment by promoting energy expenditure. Chemical characterization revealed that SPSL, rich in sulfate and L-fucose content, comprises nine distinct sulfated glycan structures. In vitro analysis demonstrated potent anti-lipogenic properties in adipocytes, mediated by the downregulation of key adipogenic modulators, including 5′ adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor γ (PPARγ) pathways. Inhibiting AMPK attenuated the anti-adipogenic effects of SPSL, confirming its involvement in the mechanism of action. Furthermore, in vivo studies using zebrafish models showed that SPSL increased energy expenditure and reduced lipid accumulation. These findings collectively highlight the therapeutic potential of SPSL as a functional food ingredient for mitigating obesity-related metabolic dysregulation by promoting energy expenditure. Further mechanistic and preclinical investigations are warranted to fully elucidate its mode of action and evaluate its efficacy in obesity management, potentially offering a novel, natural therapeutic avenue for this global health concern. Full article

(This article belongs to the Special Issue New Insights into Adipose Tissue Metabolic Function and Dysfunction, 3rd Edition)

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16 pages, 5192 KiB

Open AccessArticle

The Immunosuppressive Receptor CD32b Regulation of Macrophage Polarization and Its Implications in Tumor Progression

by Hong-Jing Chuang, Ying-Yin Chen, Yi-Da Chung, Evelyn Huang, Cadence Yoshang Huang, Jrhau Lung, Chung-Yu Chen and Hui-Fen Liao

Int. J. Mol. Sci. 2024, 25(17), 9737; https://doi.org/10.3390/ijms25179737 - 9 Sep 2024

Viewed by 549

Abstract

Macrophages, pivotal components of the immune system, orchestrate host defense mechanisms in humans and mammals. Their polarization into classically activated macrophages (CAMs or M1) and alternatively activated macrophages (AAMs or M2) dictates distinct functional roles in immunity and tissue homeostasis. While the negative [...] Read more.

Macrophages, pivotal components of the immune system, orchestrate host defense mechanisms in humans and mammals. Their polarization into classically activated macrophages (CAMs or M1) and alternatively activated macrophages (AAMs or M2) dictates distinct functional roles in immunity and tissue homeostasis. While the negative regulatory role of CD32b within the FC gamma receptor (FCγR) family is recognized across various immune cell types, its influence on macrophage polarization remains elusive. This study aimed to elucidate the regulatory role of CD32b in macrophage polarization and discern the differential expression markers between the M1 and M2 phenotypes following CD32b siRNA transfection. The results revealed a decrease in the CD32b levels in lipopolysaccharide (LPS)-treated M1 and an increase in interleukin-4 (IL-4)-treated M2 macrophages, as observed in macrophage Raw264.7 cells. Furthermore, CD32b siRNA transfection significantly downregulated the M2 markers (IL-10, VEGF, Arg-1, and STAT6), while upregulating the M1 markers (IL-6, NF-κB, NOS2, and STAT1) in the Raw264.7 cells. Similar findings were recapitulated in macrophage-rich adherent cells isolated from mouse spleens. Additionally, the cytopathological analysis of pleural effusions and ascitic fluids from patients with cancer revealed a positive correlation between advanced tumor stages, metastasis, and elevated CD32b levels. In conclusion, this study highlights the regulatory influence of CD32b in suppressing M1 expression and promoting M2 polarization. Moreover, heightened M2 activation and CD32b levels appear to correlate with tumor progression. A targeted CD32b blockade may serve as a novel therapeutic strategy to inhibit M2 macrophage polarization and is promising for anti-tumor intervention. Full article

(This article belongs to the Special Issue Molecular Insights into Cancer Metabolism, Metastasis, and Immune Evasion)

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21 pages, 3444 KiB

Open AccessReview

Safety and Efficacy of Bispecific Antibodies in Adults with Large B-Cell Lymphomas: A Systematic Review of Clinical Trial Data

by Elena Bayly-McCredie, Maxine Treisman and Salvatore Fiorenza

Int. J. Mol. Sci. 2024, 25(17), 9736; https://doi.org/10.3390/ijms25179736 - 9 Sep 2024

Viewed by 1250

Abstract

Bispecific antibodies (bsAbs) are an emerging therapy in the treatment of large B-cell lymphomas (LBCLs). There is a gap in the research on the safety and efficacy of bsAbs in adults with LBCL, with current research focusing on the wider non-Hodgkin’s lymphoma population. [...] Read more.

Bispecific antibodies (bsAbs) are an emerging therapy in the treatment of large B-cell lymphomas (LBCLs). There is a gap in the research on the safety and efficacy of bsAbs in adults with LBCL, with current research focusing on the wider non-Hodgkin’s lymphoma population. To address this research gap, we conducted a systematic review aiming to evaluate the safety and efficacy outcomes of bsAbs in adults with LBCL. A systematized search was conducted in PubMed, EMBASE, and CENTRAL on 10 April 2024. Interventional clinical trials were eligible for inclusion. Observational studies, reviews, and meta-analyses were excluded. According to the Revised Risk of Bias Assessment Tool for Nonrandomized Studies, the included studies were largely of a high quality for safety outcome reporting, but of mixed quality for efficacy outcome reporting. Due to the heterogeneity of the included studies, the results were discussed as a narrative synthesis. Nineteen early phase studies were evaluated in the final analysis, with a pooled sample size of 1332 patients. Nine bsAbs were investigated across the studies as monotherapy (nine studies) or in combination regimes (10 studies). The rates of cytokine release syndrome were variable, with any grade events ranging from 0 to 72.2%. Infection rates were consistently high across the reporting studies (38–60%). Cytopenias were found to be common, in particular, anemia (4.4–62%), thrombocytopenia (3.3–69%), and neutropenia (4.4–70%). Immune effector cell-associated neurotoxicity syndrome (ICANS) and grade ≥3 adverse events were not commonly reported. Promising efficacy outcomes were reported, with median overall response rates of 95–100% in the front-line and 36–91% in terms of relapsed/refractory disease. The results of this systematic review demonstrate that bsAbs are generally well-tolerated and effective in adults with LBCL. BsAbs appear to have superior tolerability, but inferior efficacy to CAR T-cell therapies in adults with LBCL. Future research on safety and efficacy should focus on evaluating adverse event timing and management, the impact on the patient’s quality of life, the burden on the healthcare system, and overall survival outcomes. Full article

(This article belongs to the Special Issue Antibody Therapy for Hematologic Malignancies)

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21 pages, 1682 KiB

Open AccessArticle

Neutrophil Biomarkers Can Predict Cardiotoxicity of Anthracyclines in Breast Cancer

by Valentina K. Todorova, Gohar Azhar, Annjanette Stone, Sindhu J. Malapati, Yingni Che, Wei Zhang, Issam Makhoul and Jeanne Y. Wei

Int. J. Mol. Sci. 2024, 25(17), 9735; https://doi.org/10.3390/ijms25179735 - 9 Sep 2024

Viewed by 664

Abstract

Doxorubicin (DOX), a commonly used anticancer agent, causes cardiotoxicity that begins with the first dose and may progress to heart failure years after treatment. An inflammatory response associated with neutrophil recruitment has been recognized as a mechanism of DOX-induced cardiotoxicity. This study aimed [...] Read more.

Doxorubicin (DOX), a commonly used anticancer agent, causes cardiotoxicity that begins with the first dose and may progress to heart failure years after treatment. An inflammatory response associated with neutrophil recruitment has been recognized as a mechanism of DOX-induced cardiotoxicity. This study aimed to validate mRNA expression of the previously identified biomarkers of DOX-induced cardiotoxicity, PGLYRP1, CAMP, MMP9, and CEACAM8, and to assay their protein expression in the peripheral blood of breast cancer patients. Blood samples from 40 breast cancer patients treated with DOX-based chemotherapy were collected before and after the first chemotherapy cycle and > 2 years after treatment. The protein and gene expression of PGLYRP1/Tag7, CAMP/LL37, MMP9/gelatinase B, and CEACAM8/CD66b were determined using ELISA and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Receiver operating characteristic (ROC) curve analysis was used to determine the diagnostic value of each candidate biomarker. Patients with cardiotoxicity (n = 20) had significantly elevated levels of PGLYRP1, CAMP, MMP9, and CEACAM8 at baseline, after the first dose of DOX-based chemotherapy, and at > 2 years after treatment relative to patients without cardiotoxicity (n = 20). The first dose of DOX induced significantly higher levels of all examined biomarkers in both groups of patients. At > 2 years post treatment, the levels of all but MMP9 dropped below the baseline. There was a good correlation between the expression of mRNA and the target proteins. We demonstrate that circulating levels of PGLYRP1, CAMP, MMP9, and CEACAM8 can predict the cardiotoxicity of DOX. This novel finding may be of value in the early identification of patients at risk for cardiotoxicity. Full article

(This article belongs to the Special Issue Research Progress on the Mechanism and Treatment of Cardiomyopathy)

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11 pages, 1453 KiB

Open AccessArticle

The Study of the Inheritance Mechanisms of Myotonic Dystrophy Type 1 (DM1) in Families from the Republic of North Ossetia-Alania

by Sofya A. Ionova, Aysylu F. Murtazina, Andrey A. Marakhonov, Olga A. Shchagina, Nina V. Ryadninskaya, Inna S. Tebieva, Vitaly V. Kadyshev, Artem O. Borovikov, Evgeny K. Ginter, Sergey I. Kutsev and Rena A. Zinchenko

Int. J. Mol. Sci. 2024, 25(17), 9734; https://doi.org/10.3390/ijms25179734 - 9 Sep 2024

Viewed by 501

Abstract

Myotonic dystrophy type 1 (DM1) is a multisystem disorder with progressive myopathy and myotonia. The clinical study was conducted in the Republic of North Ossetia-Alania (RNOA), and in it 39 individuals from 17 unrelated families were identified with DM1. Clinical presentations varied, including [...] Read more.

Myotonic dystrophy type 1 (DM1) is a multisystem disorder with progressive myopathy and myotonia. The clinical study was conducted in the Republic of North Ossetia-Alania (RNOA), and in it 39 individuals from 17 unrelated families were identified with DM1. Clinical presentations varied, including muscle weakness, fatigue, intellectual disability, hypersomnia, ophthalmological abnormalities, and alopecia. Using clinical and genotyping data, we confirmed the diagnosis and enabled the study of CTG-repeat anticipation and DM1 prevalence in the Ossetian and Ingush populations. CTG expansion correlated with age of onset, with clinical severity, and with offspring showing more severe symptoms than parents. In many families, the youngest child had a more severe DM1 phenotype than older siblings. The prevalence was 14.17 per 100,000 in Ossetians and 18.74 per 100,000 in Ingush people, aligning with global data. Segregation analysis showed a higher frequency of maternal transmission. The study highlights the clinical and genetic heterogeneity of DM1 and its dependence on repeat expansion and paternal and maternal age. Full article

(This article belongs to the Special Issue Genes and Human Diseases 2.0)

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28 pages, 462 KiB

Open AccessReview

Oral Health and Nutraceutical Agents

by Mariantonietta Leo, Floriana D’Angeli, Carlo Genovese, Antonella Spila, Chiara Miele, Dania Ramadan, Patrizia Ferroni and Fiorella Guadagni

Int. J. Mol. Sci. 2024, 25(17), 9733; https://doi.org/10.3390/ijms25179733 - 9 Sep 2024

Viewed by 905

Abstract

Oral health is essential for both overall health and quality of life. The mouth is a window into the body’s health, and nutrition can strongly impact the state of general and oral health. A healthy diet involves the synergistic effect of various nutraceutical [...] Read more.

Oral health is essential for both overall health and quality of life. The mouth is a window into the body’s health, and nutrition can strongly impact the state of general and oral health. A healthy diet involves the synergistic effect of various nutraceutical agents, potentially capable of conferring protective actions against some inflammatory and chronic-degenerative disorders. Nutraceuticals, mostly present in plant-derived products, present multiple potential clinical, preventive, and therapeutic benefits. Accordingly, preclinical and epidemiological studies suggested a protective role for these compounds, but their real preventive and therapeutic effects in humans still await confirmation. Available evidence suggests that plant extracts are more effective than individual constituents because they contain different phytochemicals with multiple pharmacological targets and additive/synergistic effects, maximizing the benefits for oral health. Moreover, nutritional recommendations for oral health should be personalized and aligned with valid suggestions for overall health. This review is aimed to: introduce the basic concepts of nutraceuticals, including their main food sources; examine the logic that supports their relationship with oral health, and summarize and critically discuss clinical trials testing the utility of nutraceuticals in the prevention and treatment of oral diseases. Full article

(This article belongs to the Special Issue Oral Microbiota and Bone Regeneration)

16 pages, 4980 KiB

Open AccessCommunication

Short Communication: Novel Di- and Triselenoesters as Effective Therapeutic Agents Inhibiting Multidrug Resistance Proteins in Breast Cancer Cells

by Dominika Radomska, Robert Czarnomysy, Krzysztof Marciniec, Justyna Nowakowska, Enrique Domínguez-Álvarez and Krzysztof Bielawski

Int. J. Mol. Sci. 2024, 25(17), 9732; https://doi.org/10.3390/ijms25179732 - 8 Sep 2024

Viewed by 792

Abstract

Breast cancer has the highest incidence rate among all malignancies worldwide. Its high mortality is mainly related to the occurrence of multidrug resistance, which significantly limits therapeutic options. In this regard, there is an urgent need to develop compounds that would overcome this [...] Read more.

Breast cancer has the highest incidence rate among all malignancies worldwide. Its high mortality is mainly related to the occurrence of multidrug resistance, which significantly limits therapeutic options. In this regard, there is an urgent need to develop compounds that would overcome this phenomenon. There are few reports in the literature that selenium compounds can modulate the activity of P-glycoprotein (MDR1). Therefore, we performed in silico studies and evaluated the effects of the novel selenoesters EDAG-1 and EDAG-8 on BCRP, MDR1, and MRP1 resistance proteins in MCF-7 and MDA-MB-231 breast cancer cells. The cytometric analysis showed that the tested compounds (especially EDAG-8) are inhibitors of BCRP, MDR1, and MRP1 efflux pumps (more potent than the reference compounds—novobiocin, verapamil, and MK-571). An in silico study correlates with these results, suggesting that the compound with the lowest binding energy to these transporters (EDAG-8) has a more favorable spatial structure affecting its anticancer activity, making it a promising candidate in the development of a novel anticancer agent for future breast cancer therapy. Full article

(This article belongs to the Special Issue Multidrug Resistance in Cancer: Molecular Mechanisms and Therapeutic Implications)

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14 pages, 1113 KiB

Open AccessArticle

The 5:2 Diet Affects Markers of Insulin Secretion and Sensitivity in Subjects with and without Type 2 Diabetes—A Non-Randomized Controlled Trial

by Neda Rajamand Ekberg, Anton Hellberg, Michaela Linn Sundqvist, Angelica Lindén Hirschberg, Sergiu-Bogdan Catrina and Kerstin Brismar

Int. J. Mol. Sci. 2024, 25(17), 9731; https://doi.org/10.3390/ijms25179731 - 8 Sep 2024

Viewed by 1121

Abstract

This non-randomized controlled trial aimed to compare the effect of the 5:2 diet on insulin levels as a primary outcome and markers of insulin secretion (connecting peptide (C-peptide) and insulin-like growth factor binding protein-1 (IGFBP-1)) and sensitivity (Homeostatic Model Assessment for Insulin Resistance [...] Read more.

This non-randomized controlled trial aimed to compare the effect of the 5:2 diet on insulin levels as a primary outcome and markers of insulin secretion (connecting peptide (C-peptide) and insulin-like growth factor binding protein-1 (IGFBP-1)) and sensitivity (Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)), as well as body composition as secondary outcomes in overweight/obese individuals with and without type 2 diabetes (T2D). Ninety-seven participants (62% women), 35 with T2D and 62 BMI- and waist-matched controls without T2D, followed the 5:2 diet (two days per week of fasting) for six months with a 12-month follow-up. At six months, there was no loss to follow-up in the T2D group, whereas four controls discontinued this study. Overall, 82% attended the 12-month follow-up. After the intervention, insulin levels decreased in the control group and glucose decreased in the T2D group, while C-peptide, HOMA-IR, waist circumference, BMI, trunk, and total fat% decreased in both groups. Furthermore, low IGFBP-1, indicating hyperinsulinemia, improved in the T2D group. The changes in fasting glucose and waist measurement were significantly more improved in the T2D group than in the controls. Persistent positive effects were observed at the 12-month follow-up. The 5:2 diet for six months was feasible and efficient to reduce markers of insulin secretion and resistance and therefore holds promise as management of overweight/obesity in subjects with and without T2D. Full article

(This article belongs to the Special Issue Molecular Diagnosis and Treatments of Diabetes Mellitus)

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17 pages, 4498 KiB

Open AccessArticle

8-Prenylgenistein Isoflavone in Cheonggukjang Acts as a Novel AMPK Activator Attenuating Hepatic Steatosis by Enhancing the SIRT1-Mediated Pathway

by Radha Arulkumar, Hee Jin Jung, Sang Gyun Noh, Hyun Woo Kim and Hae Young Chung

Int. J. Mol. Sci. 2024, 25(17), 9730; https://doi.org/10.3390/ijms25179730 - 8 Sep 2024

Viewed by 783

Abstract

8-Prenylgenistein (8PG), a genistein derivative, is present in fermented soybeans (Glycine max), including cheonggukjang (CGJ), and exhibits osteoprotective, osteogenic, and antiadipogenic properties. However, the hepatoprotective effects of 8PG and its underlying molecular mechanisms remain largely unexplored. Here, we identified the high binding affinity [...] Read more.

8-Prenylgenistein (8PG), a genistein derivative, is present in fermented soybeans (Glycine max), including cheonggukjang (CGJ), and exhibits osteoprotective, osteogenic, and antiadipogenic properties. However, the hepatoprotective effects of 8PG and its underlying molecular mechanisms remain largely unexplored. Here, we identified the high binding affinity of 8PG with AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), which acts as a potent AMPK activator that counteracts hepatic steatosis. Notably, 8PG exhibited better pharmacokinetics with greater absorption and higher plasma binding than the positive controls for the target proteins. Moreover, 8PG exerted non-carcinogenic activity in rats and significantly increased AMPK phosphorylation. Compound C, an AMPK inhibitor, did not antagonize 8PG-activated AMPK in HepG2 cells. 8PG significantly attenuated palmitate-induced lipid accumulation and enhanced phosphorylated AMPK and its downstream target, acetyl-CoA carboxylase. Further, 8PG activated nuclear SIRT1 at the protein level, which promoted fatty acid oxidation in palmitate-treated HepG2 cells. Overall, 8PG acts as a potent AMPK activator, further attenuating hepatic steatosis via the SIRT1-mediated pathway and providing new avenues for dietary interventions to treat metabolic dysfunction-associated steatotic liver disease (MASLD). Full article

(This article belongs to the Special Issue The Role of Natural Products in Non-alcoholic Fatty Liver Disease)

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13 pages, 1365 KiB

Open AccessArticle

Efficient Solution-Phase Dipeptide Synthesis Using Titanium Tetrachloride and Microwave Heating

by Palmira Alessia Cavallaro, Marzia De Santo, Rocco Marinaro, Emilia Lucia Belsito, Angelo Liguori and Antonella Leggio

Int. J. Mol. Sci. 2024, 25(17), 9729; https://doi.org/10.3390/ijms25179729 - 8 Sep 2024

Viewed by 506

Abstract

Microwaves have been successfully employed in the Lewis acid titanium tetrachloride-assisted synthesis of peptide systems. Dipeptide systems with their amino function differently protected with urethane protecting groups have been synthesized in short periods of time and with high yields. The formation of the [...] Read more.

Microwaves have been successfully employed in the Lewis acid titanium tetrachloride-assisted synthesis of peptide systems. Dipeptide systems with their amino function differently protected with urethane protecting groups have been synthesized in short periods of time and with high yields. The formation of the peptide bond between the two reacting amino acids was achieved in pyridine by using titanium tetrachloride as a condensing agent and heating the reaction mixture with a microwave reactor. The reaction conditions are compatible with amino acids featuring various side chains and different protecting groups on both the amino function and side chains. Additionally, the substrates retain their chiral integrity after reaction. Full article

(This article belongs to the Section Physical Chemistry and Chemical Physics)

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19 pages, 24465 KiB

Open AccessArticle

Identification and Characterization of Shaker Potassium Channel Gene Family and Response to Salt and Chilling Stress in Rice

by Quanxiang Tian, Tongyuan Yu, Mengyuan Dong, Yue Hu, Xiaoguang Chen, Yuan Xue, Yunxia Fang, Jian Zhang, Xiaoqin Zhang and Dawei Xue

Int. J. Mol. Sci. 2024, 25(17), 9728; https://doi.org/10.3390/ijms25179728 - 8 Sep 2024

Viewed by 586

Abstract

Shaker potassium channel proteins are a class of voltage-gated ion channels responsible for K⁺ uptake and translocation, playing a crucial role in plant growth and salt tolerance. In this study, bioinformatic analysis was performed to identify the members within the Shaker gene [...] Read more.

Shaker potassium channel proteins are a class of voltage-gated ion channels responsible for K⁺ uptake and translocation, playing a crucial role in plant growth and salt tolerance. In this study, bioinformatic analysis was performed to identify the members within the Shaker gene family. Moreover, the expression patterns of rice Shaker(OsShaker) K⁺ channel genes were analyzed in different tissues and salt treatment by RT–qPCR. The results revealed that there were eight OsShaker K⁺ channel genes distributed on chromosomes 1, 2, 5, 6 and 7 in rice, and their promoters contained a variety of cis-regulatory elements, including hormone-responsive, light-responsive, and stress-responsive elements, etc. Most of the OsShaker K⁺ channel genes were expressed in all tissues of rice, but at different levels in different tissues. In addition, the expression of OsShaker K⁺ channel genes differed in the timing, organization and intensity of response to salt and chilling stress. In conclusion, our findings provide a reference for the understanding of OsShaker K⁺ channel genes, as well as their potential functions in response to salt and chilling stress in rice. Full article

(This article belongs to the Special Issue Gene Mining and Germplasm Innovation for the Important Traits in Rice)

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Int. J. Mol. Sci., Volume 25, Issue 17 (September-1 2024) – 624 articles

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