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Int. J. Mol. Sci., Volume 25, Issue 3 (February-1 2024) – 584 articles

Cover Story (view full-size image): For a long time, RBCs were considered to be passive carriers of respiratory gases; however, emerging evidence highlights a more complex physiological role. In recent years, clinical and epidemiological studies have associated quantitative and qualitative abnormalities of RBCs with thrombosis in PV and ET patients. Increased RBC counts and hematocrit, which modulate blood rheology by increasing viscosity, as well as qualitative changes, such as abnormal deformability, aggregation, increased expression of adhesion proteins and phosphatidylserine, and the release of extracellular microvesicles, are contributing to the occurrence of prothrombotic events in these patients. This highlights the active contribution of RBCs to thrombosis, paving the way for new therapeutical strategies. View this paper
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14 pages, 6874 KiB  
Article
PgDDS Changes the Plant Growth of Transgenic Aralia elata and Improves the Production of Re and Rg3 in Its Leaves
by Wenhua Guo, Yue Zhao, Honghao Xu, Yuxin Xia, Lei Tao and Xiangling You
Int. J. Mol. Sci. 2024, 25(3), 1945; https://doi.org/10.3390/ijms25031945 - 5 Feb 2024
Viewed by 1355
Abstract
Aralia elata (Miq.) Seem is a medicinal plant that shares a common pathway for the biosynthesis of triterpenoid saponins with Panax ginseng. Here, we transferred the dammarenediol-II synthase gene from P. ginseng (PgDDS; GenBank: AB122080.1) to A. elata. The [...] Read more.
Aralia elata (Miq.) Seem is a medicinal plant that shares a common pathway for the biosynthesis of triterpenoid saponins with Panax ginseng. Here, we transferred the dammarenediol-II synthase gene from P. ginseng (PgDDS; GenBank: AB122080.1) to A. elata. The growth of 2-year-old transgenic plants (L27; 9.63 cm) was significantly decreased compared with wild-type plants (WT; 74.97 cm), and the leaflet shapes and sizes of the transgenic plants differed from those of the WT plants. Based on a terpene metabolome analysis of leaf extracts from WT, L13, and L27 plants, a new structural skeleton for ursane-type triterpenoid saponins was identified. Six upregulated differentially accumulated metabolites (DAMs) were detected, and the average levels of Rg3 and Re in the leaves of the L27 plants were 42.64 and 386.81 μg/g, respectively, increased significantly compared with the WT plants (15.48 and 316.96 μg/g, respectively). Thus, the expression of PgDDS in A. elata improved its medicinal value. Full article
(This article belongs to the Special Issue Omics Study to Uncover Signalling and Gene Regulation in Plants 2.0)
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20 pages, 2431 KiB  
Article
Hypervirulent Capsular Serotypes K1 and K2 Klebsiella pneumoniae Strains Demonstrate Resistance to Serum Bactericidal Activity and Galleria mellonella Lethality
by Basaier AL-Busaidi, Muna AL-Muzahmi, Zahra AL-Shabibi, Meher Rizvi, Azza AL-Rashdi, Amina AL-Jardani, Robeena Farzand and Zaaima AL-Jabri
Int. J. Mol. Sci. 2024, 25(3), 1944; https://doi.org/10.3390/ijms25031944 - 5 Feb 2024
Viewed by 2215
Abstract
Hypervirulent Klebsiella pneumoniae (hvKp) is a variant that has been increasingly linked to severe, life-threatening infections including pyogenic liver abscess and bloodstream infections. HvKps belonging to the capsular serotypes K1 and K2 have been reported worldwide, however, very scarce studies are available on [...] Read more.
Hypervirulent Klebsiella pneumoniae (hvKp) is a variant that has been increasingly linked to severe, life-threatening infections including pyogenic liver abscess and bloodstream infections. HvKps belonging to the capsular serotypes K1 and K2 have been reported worldwide, however, very scarce studies are available on their genomics and virulence. In the current study, we report four hypermucoviscous extended-spectrum β-lactamase-producing hvKp clinical strains of capsular serotype K1 and K2 isolated from pus and urine of critically ill patients in tertiary care hospitals in Oman. These strains belong to diverse sequence types (STs), namely ST-23(K1), ST-231(K2), ST-881(K2), and ST-14(K2). To study their virulence, a Galleria mellonella model and resistance to human serum killing were used. The G. mellonella model revealed that the K1/ST-23 isolate was the most virulent, as 50% of the larvae died in the first day, followed by isolate K2/ST-231 and K2/ST-14, for which 75% and 50% of the larvae died in the second day, respectively. Resistance to human serum killing showed there was complete inhibition of bacterial growth of all four isolates by the end of the first hour and up to the third hour. Whole genome sequencing (WGS) revealed that hvKp strains display a unique genetic arrangement of k-loci. Whole-genome single-nucleotide polymorphism-based phylogenetic analysis revealed that these hvKp isolates were phylogenetically distinct, belonging to diverse clades, and belonged to different STs in comparison to global isolates. For ST-23(K1), ST-231(K2), ST-881(K2), and ST-14(K2), there was a gradual decrease in the number of colonies up to the second to third hour, which indicates neutralization of bacterial cells by the serum components. However, this was followed by a sudden increase of bacterial growth, indicating possible resistance of bacteria against human serum bactericidal activity. This is the first report from Oman detailing the WGS of hvKp clinical isolates and assessing their resistance and virulence genomics, which reinforce our understanding of their epidemiology and dissemination in clinical settings. Full article
(This article belongs to the Special Issue Diverse Responses of Immune Cells to Bacterial Infections)
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19 pages, 9207 KiB  
Article
Genetic Diversity in Bronchial Asthma Susceptibility: Exploring the Role of Vitamin D Receptor Gene Polymorphisms in Varied Geographic Contexts
by Natalia Paramonova, Ilva Trapina, Brigita Gradauskiene (Sitkauskiene), Samanta Plavina, Laura Tamasauskiene, Daina Bastyte, Ingrida Rumba-Rozenfelde, Sandra Tapina, Ieva Stakaitiene, Rasa Ugenskiene, Lawrence Shih-Hsin Wu, Jiu-Yao Wang, Miao-Hsi Hsieh, Pei-Chi Chen and Nikolajs Sjakste
Int. J. Mol. Sci. 2024, 25(3), 1943; https://doi.org/10.3390/ijms25031943 - 5 Feb 2024
Viewed by 1499
Abstract
Bronchial asthma (BA) exhibits varying prevalence across global populations, prompting a comprehensive investigation into genetic and environmental determinants. Vitamin D is a potent immunomodulator capable of suppressing inflammatory signals in several cell types involved in the asthmatic response; it exerts effects on the [...] Read more.
Bronchial asthma (BA) exhibits varying prevalence across global populations, prompting a comprehensive investigation into genetic and environmental determinants. Vitamin D is a potent immunomodulator capable of suppressing inflammatory signals in several cell types involved in the asthmatic response; it exerts effects on the immune system by binding to the nuclear vitamin D receptor (VDR). VDR gene genetic variations are affecting serum vitamin D levels with a possible role in the BA risk. The current study aimed to examine the complex interaction of various factors (genetic background, serum vitamin D levels, and geographic location) to identify differences in the influence of these factors on the susceptibility to asthma between populations at different latitudes. Focusing on Eastern European cohorts from Latvia and Lithuania and comparing them with published data on East Asian populations, we explore the impact of VDR gene polymorphisms on BA susceptibility. Genotyping four key VDR SNPs and assessing their association with 25-hydroxyvitamin D levels, our study unveils significant associations of the studied loci with the risk of asthma—both risk-reducing and increasing effects, differently distributed between Baltic and East Asian populations. The functional effects of in silico VDR gene genetic variations are also identified and discussed. Full article
(This article belongs to the Special Issue Molecular Advances and Perspectives of Lung Disease)
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28 pages, 968 KiB  
Review
Role of microRNAs in Immune Regulation with Translational and Clinical Applications
by Zsuzsanna Gaál
Int. J. Mol. Sci. 2024, 25(3), 1942; https://doi.org/10.3390/ijms25031942 - 5 Feb 2024
Cited by 7 | Viewed by 3056
Abstract
MicroRNAs (miRNAs) are 19–23 nucleotide long, evolutionarily conserved noncoding RNA molecules that regulate gene expression at the post-transcriptional level. In this review, involvement of miRNAs is summarized in the differentiation and function of immune cells, in anti-infective immune responses, immunodeficiencies and autoimmune diseases. [...] Read more.
MicroRNAs (miRNAs) are 19–23 nucleotide long, evolutionarily conserved noncoding RNA molecules that regulate gene expression at the post-transcriptional level. In this review, involvement of miRNAs is summarized in the differentiation and function of immune cells, in anti-infective immune responses, immunodeficiencies and autoimmune diseases. Roles of miRNAs in anticancer immunity and in the transplantation of solid organs and hematopoietic stem cells are also discussed. Major focus is put on the translational clinical applications of miRNAs, including the establishment of noninvasive biomarkers for differential diagnosis and prediction of prognosis. Patient selection and response prediction to biological therapy is one of the most promising fields of application. Replacement or inhibition of miRNAs has enormous therapeutic potential, with constantly expanding possibilities. Although important challenges still await solutions, evaluation of miRNA fingerprints may contribute to an increasingly personalized management of immune dysregulation with a remarkable reduction in toxicity and treatment side effects. More detailed knowledge of the molecular effects of physical exercise and nutrition on the immune system may facilitate self-tailored lifestyle recommendations and advances in prevention. Full article
(This article belongs to the Special Issue Epigenetic Regulation in Human Disease)
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16 pages, 5553 KiB  
Article
A Cancer-Specific Monoclonal Antibody against HER2 Exerts Antitumor Activities in Human Breast Cancer Xenograft Models
by Mika K. Kaneko, Hiroyuki Suzuki, Tomokazu Ohishi, Takuro Nakamura, Tomohiro Tanaka and Yukinari Kato
Int. J. Mol. Sci. 2024, 25(3), 1941; https://doi.org/10.3390/ijms25031941 - 5 Feb 2024
Cited by 5 | Viewed by 4470
Abstract
Monoclonal antibody (mAb)-based and/or cell-based immunotherapies provide innovative approaches to cancer treatments. However, safety concerns over targeting normal cells expressing reactive antigens still exist. Therefore, the development of cancer-specific mAbs (CasMabs) that recognize cancer-specific antigens with in vivo antitumor efficacy is required to [...] Read more.
Monoclonal antibody (mAb)-based and/or cell-based immunotherapies provide innovative approaches to cancer treatments. However, safety concerns over targeting normal cells expressing reactive antigens still exist. Therefore, the development of cancer-specific mAbs (CasMabs) that recognize cancer-specific antigens with in vivo antitumor efficacy is required to minimize the adverse effects. We previously screened anti-human epidermal growth factor receptor 2 (HER2) mAbs and successfully established a cancer-specific anti-HER2 mAb, H2Mab-250/H2CasMab-2 (IgG1, kappa). In this study, we showed that H2Mab-250 reacted with HER2-positive breast cancer cells but did not show reactivity to normal epithelial cells in flow cytometry. In contrast, a clinically approved anti-HER2 mAb, trastuzumab, recognized both breast cancer and normal epithelial cells. We further compared the affinity, effector activation, and antitumor effect of H2Mab-250 with trastuzumab. The results showed that H2Mab-250 exerted a comparable antitumor effect with trastuzumab in the mouse xenograft models of BT-474 and SK-BR-3, although H2Mab-250 possessed a lower affinity and effector activation than trastuzumab in vitro. H2Mab-250 could contribute to the development of chimeric antigen receptor-T or antibody–drug conjugates without adverse effects for breast cancer therapy. Full article
(This article belongs to the Special Issue Targeted Cancer Therapy Using Monoclonal Antibodies)
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16 pages, 5381 KiB  
Article
Identification of Candidate Male-Reproduction-Related Genes from the Testis and Androgenic Gland of Macrobrachium nipponense, Regulated by PDHE1, through Transcriptome Profiling Analysis
by Shubo Jin, Yiwei Xiong, Wenyi Zhang, Hui Qiao, Yan Wu, Sufei Jiang and Hongtuo Fu
Int. J. Mol. Sci. 2024, 25(3), 1940; https://doi.org/10.3390/ijms25031940 - 5 Feb 2024
Cited by 2 | Viewed by 1368
Abstract
The previous publication identified that pyruvate dehydrogenase E1 (PDHE1) positively regulated the process of male reproduction in M. nipponense through affecting the expressions of insulin-like androgenic gland hormone. The present study aimed to identify the potential male-reproduction-related genes that were regulated [...] Read more.
The previous publication identified that pyruvate dehydrogenase E1 (PDHE1) positively regulated the process of male reproduction in M. nipponense through affecting the expressions of insulin-like androgenic gland hormone. The present study aimed to identify the potential male-reproduction-related genes that were regulated by PDHE1 through performing the transcriptome profiling analysis in the testis and androgenic gland after the knockdown of the expressions of PDHE1 by the injection of dsPDHE1. Both RNA-Seq and qPCR analysis identified the significant decreases in PDHE1 expressions in the testis and androgenic gland in dsPDHE1-injected prawns compared to those in dsGFP-injected prawns, indicating the efficiency of dsPDHE1 in the present study. Transcriptome profiling analysis identified 56 and 127 differentially expressed genes (DEGs) in the testis and androgenic gland, respectively. KEGG analysis revealed that the energy-metabolism-related pathways represented the main enriched metabolic pathways of DEGs in both the testis and androgenic gland, including pyruvate metabolism, the Citrate cycle (TCA cycle), Glycolysis/Gluconeogenesis, and the Glucagon signaling pathway. Thus, it is predicted that these metabolic pathways and the DEGs from these metabolic pathways regulated by PDHE1 may be involved in the regulation of male reproduction in M. nipponense. Furthermore, four genes were found to be differentially expressed in both the testis and androgenic gland, of which ribosomal protein S3 was down-regulated and uncharacterized protein LOC113829596 was up-regulated in both the testis and androgenic gland in dsPDHE1-injected prawns. The present study provided valuable evidence for the establishment of an artificial technique to regulate the process of male reproduction in M. nipponense. Full article
(This article belongs to the Section Molecular Biology)
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37 pages, 6614 KiB  
Review
Hyperpolarized Xenon-129 Chemical Exchange Saturation Transfer (HyperCEST) Molecular Imaging: Achievements and Future Challenges
by Viktoriia Batarchuk, Yurii Shepelytskyi, Vira Grynko, Antal Halen Kovacs, Aaron Hodgson, Karla Rodriguez, Ruba Aldossary, Tanu Talwar, Carson Hasselbrink, Iulian C. Ruset, Brenton DeBoef and Mitchell S. Albert
Int. J. Mol. Sci. 2024, 25(3), 1939; https://doi.org/10.3390/ijms25031939 - 5 Feb 2024
Cited by 1 | Viewed by 2312
Abstract
Molecular magnetic resonance imaging (MRI) is an emerging field that is set to revolutionize our perspective of disease diagnosis, treatment efficacy monitoring, and precision medicine in full concordance with personalized medicine. A wide range of hyperpolarized (HP) 129Xe biosensors have been recently [...] Read more.
Molecular magnetic resonance imaging (MRI) is an emerging field that is set to revolutionize our perspective of disease diagnosis, treatment efficacy monitoring, and precision medicine in full concordance with personalized medicine. A wide range of hyperpolarized (HP) 129Xe biosensors have been recently developed, demonstrating their potential applications in molecular settings, and achieving notable success within in vitro studies. The favorable nuclear magnetic resonance properties of 129Xe, coupled with its non-toxic nature, high solubility in biological tissues, and capacity to dissolve in blood and diffuse across membranes, highlight its superior role for applications in molecular MRI settings. The incorporation of reporters that combine signal enhancement from both hyperpolarized 129Xe and chemical exchange saturation transfer holds the potential to address the primary limitation of low sensitivity observed in conventional MRI. This review provides a summary of the various applications of HP 129Xe biosensors developed over the last decade, specifically highlighting their use in MRI. Moreover, this paper addresses the evolution of in vivo applications of HP 129Xe, discussing its potential transition into clinical settings. Full article
(This article belongs to the Special Issue Molecular Probe: Recent Research and Future Challenges)
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16 pages, 842 KiB  
Article
Evolutionary Analysis of Six Gene Families Part of the Reactive Oxygen Species (ROS) Gene Network in Three Brassicaceae Species
by Thomas Horst Berthelier, Sébastien Christophe Cabanac, Caroline Callot, Arnaud Bellec, Catherine Mathé, Elisabeth Jamet and Christophe Dunand
Int. J. Mol. Sci. 2024, 25(3), 1938; https://doi.org/10.3390/ijms25031938 - 5 Feb 2024
Viewed by 1327
Abstract
Climate change is expected to intensify the occurrence of abiotic stress in plants, such as hypoxia and salt stresses, leading to the production of reactive oxygen species (ROS), which need to be effectively managed by various oxido-reductases encoded by the so-called ROS gene [...] Read more.
Climate change is expected to intensify the occurrence of abiotic stress in plants, such as hypoxia and salt stresses, leading to the production of reactive oxygen species (ROS), which need to be effectively managed by various oxido-reductases encoded by the so-called ROS gene network. Here, we studied six oxido-reductases families in three Brassicaceae species, Arabidopsis thaliana as well as Nasturtium officinale and Eutrema salsugineum, which are adapted to hypoxia and salt stress, respectively. Using available and new genomic data, we performed a phylogenomic analysis and compared RNA-seq data to study genomic and transcriptomic adaptations. This comprehensive approach allowed for the gaining of insights into the impact of the adaptation to saline or hypoxia conditions on genome organization (gene gains and losses) and transcriptional regulation. Notably, the comparison of the N. officinale and E. salsugineum genomes to that of A. thaliana highlighted changes in the distribution of ohnologs and homologs, particularly affecting class III peroxidase genes (CIII Prxs). These changes were specific to each gene, to gene families subjected to duplication events and to each species, suggesting distinct evolutionary responses. The analysis of transcriptomic data has allowed for the identification of genes related to stress responses in A. thaliana, and, conversely, to adaptation in N. officinale and E. salsugineum. Full article
(This article belongs to the Special Issue Plant Response to Abiotic Stress 2.0)
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14 pages, 9055 KiB  
Article
Multifunctional Biomass-Based Ionic Liquids/CuCl-Catalyzed CO2-Promoted Hydration of Propargylic Alcohols: A Green Synthesis of α-Hydroxy Ketones
by Ye Yuan, Siqi Zhang, Kang Duan, Yong Xu, Kaixuan Guo, Cheng Chen, Somboon Chaemchuen, Dongfeng Cao and Francis Verpoort
Int. J. Mol. Sci. 2024, 25(3), 1937; https://doi.org/10.3390/ijms25031937 - 5 Feb 2024
Viewed by 1326
Abstract
α-Hydroxy ketones are a class of vital organic skeletons that generally exist in a variety of natural products and high-value chemicals. However, the traditional synthetic route for their production involves toxic Hg salts and corrosive H2SO4 as catalysts, resulting in [...] Read more.
α-Hydroxy ketones are a class of vital organic skeletons that generally exist in a variety of natural products and high-value chemicals. However, the traditional synthetic route for their production involves toxic Hg salts and corrosive H2SO4 as catalysts, resulting in harsh conditions and the undesired side reaction of Meyer–Schuster rearrangement. In this study, CO2-promoted hydration of propargylic alcohols was achieved for the synthesis of various α-hydroxy ketones. Notably, this process was catalyzed using an environmentally friendly and cost-effective biomass-based ionic liquids/CuCl system, which effectively eliminated the side reaction. The ionic liquids utilized in this system are derived from natural biomass materials, which exhibited recyclability and catalytic activity under 1 bar of CO2 pressure without volatile organic solvents or additives. Evaluation of the green metrics revealed the superiority of this CuCl/ionic liquid system in terms of environmental sustainability. Further mechanistic investigation attributed the excellent performance to the ionic liquid component, which exhibited multifunctionality in activating substrates, CO2 and the Cu component. Full article
(This article belongs to the Special Issue Molecular Research on Chemical, Physical and Optical Properties of Materials)
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32 pages, 3685 KiB  
Article
Association of Alpha-Crystallin with Human Cortical and Nuclear Lens Lipid Membrane Increases with the Grade of Cortical and Nuclear Cataract
by Preston Hazen, Geraline Trossi-Torres, Raju Timsina, Nawal K. Khadka and Laxman Mainali
Int. J. Mol. Sci. 2024, 25(3), 1936; https://doi.org/10.3390/ijms25031936 - 5 Feb 2024
Cited by 1 | Viewed by 1514
Abstract
Eye lens α-crystallin has been shown to become increasingly membrane-bound with age and cataract formation; however, to our knowledge, no studies have investigated the membrane interactions of α-crystallin throughout the development of cataracts in separated cortical membrane (CM) and nuclear membrane (NM) from [...] Read more.
Eye lens α-crystallin has been shown to become increasingly membrane-bound with age and cataract formation; however, to our knowledge, no studies have investigated the membrane interactions of α-crystallin throughout the development of cataracts in separated cortical membrane (CM) and nuclear membrane (NM) from single human lenses. In this study, four pairs of human lenses from age-matched male and female donors and one pair of male lenses ranging in age from 64 to 73 years old (yo) were obtained to investigate the interactions of α-crystallin with the NM and CM throughout the progression of cortical cataract (CC) and nuclear cataract (NC) using the electron paramagnetic resonance spin-labeling method. Donor health history information (diabetes, smoker, hypertension, radiation treatment), sex, and race were included in the data analysis. The right eye lenses CM and NM investigated were 64 yo male (CC: 0), 68 yo male (CC: 3, NC: 2), 73 yo male (CC: 1, NC: 2), 68 yo female (CC: 3, NC: 2), and 73 yo female (CC: 1, NC: 3). Similarly, left eye lenses CM and NM investigated were 64 yo male (CC: 0), 68 yo male (CC: 3, NC: 2), 73 yo male (CC: 2, NC: 3), 68 yo female (CC: 3, NC: 2), and 73 yo female (CC: 1, NC: 3). Analysis of α-crystallin binding to male and female eye lens CM and NM revealed that the percentage of membrane surface occupied (MSO) by α-crystallin increases with increasing grade of CC and NC. The binding of α-crystallin resulted in decreased mobility, increased order, and increased hydrophobicity on the membrane surface in male and female eye lens CM and NM. CM mobility decreased with an increase in cataracts for both males and females, whereas the male lens NM mobility showed no significant change, while female lens NM showed increased mobility with an increase in cataract grade. Our data shows that a 68 yo female donor (long-term smoker, pre-diabetic, and hypertension; grade 3 CC) showed the largest MSO by α-crystallin in CM from both the left and right lens and had the most pronounced mobility changes relative to all other analyzed samples. The variation in cholesterol (Chol) content, size and amount of cholesterol bilayer domains (CBDs), and lipid composition in the CM and NM with age and cataract might result in a variation of membrane surface mobility, membrane surface hydrophobicity, and the interactions of α-crystallin at the surface of each CM and NM. These findings provide insight into the effect of decreased Chol content and the reduced size and amount of CBDs in the cataractous CM and NM with an increased binding of α-crystallin with increased CC and NC grade, which suggests that Chol and CBDs might be a key component in maintaining lens transparency. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Eye Diseases: 2nd Edition)
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14 pages, 1438 KiB  
Review
Hydrogen Sulfide in the Oxidative Stress Response of Plants: Crosstalk with Reactive Oxygen Species
by Zhiya Liu, Yayu Liu and Weibiao Liao
Int. J. Mol. Sci. 2024, 25(3), 1935; https://doi.org/10.3390/ijms25031935 - 5 Feb 2024
Cited by 3 | Viewed by 1608
Abstract
Growing evidence suggests that exposure of plants to unfavorable environments leads to the accumulation of hydrogen sulfide (H2S) and reactive oxygen species (ROS). H2S interacts with the ROS-mediated oxidative stress response network at multiple levels. Therefore, it is essential [...] Read more.
Growing evidence suggests that exposure of plants to unfavorable environments leads to the accumulation of hydrogen sulfide (H2S) and reactive oxygen species (ROS). H2S interacts with the ROS-mediated oxidative stress response network at multiple levels. Therefore, it is essential to elucidate the mechanisms by which H2S and ROS interact. The molecular mechanism of action by H2S relies on the post-translational modification of the cysteine sulfur group (-SH), known as persulfidation. H2S cannot react directly with -SH, but it can react with oxidized cysteine residues, and this oxidation process is induced by H2O2. Evidently, ROS is involved in the signaling pathway of H2S and plays a significant role. In this review, we summarize the role of H2S-mediated post-translational modification mechanisms in oxidative stress responses. Moreover, the mechanism of interaction between H2S and ROS in the regulation of redox reactions is focused upon, and the positive cooperative role of H2S and ROS is elucidated. Subsequently, based on the existing evidence and clues, we propose some potential problems and new clues to be explored, which are crucial for the development of the crosstalk mechanism of H2S and ROS in plants. Full article
(This article belongs to the Special Issue The Role and Mechanism of Hydrogen Sulfide and ROS in Plants)
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17 pages, 2985 KiB  
Article
Analysis of the Effects of Pentose Phosphate Pathway Inhibition on the Generation of Reactive Oxygen Species and Epileptiform Activity in Hippocampal Slices
by Daria Ponomareva, Anton Ivanov and Piotr Bregestovski
Int. J. Mol. Sci. 2024, 25(3), 1934; https://doi.org/10.3390/ijms25031934 - 5 Feb 2024
Cited by 1 | Viewed by 1761
Abstract
The pentose phosphate pathway (PPP) is one of three major pathways involved in glucose metabolism, which is regulated by glucose-6-phosphate dehydrogenase (G6PD) controls NADPH formation. NADPH, in turn, regulates the balance of oxidative stress and reactive oxygen species (ROS) levels. G6PD dysfunction, affecting [...] Read more.
The pentose phosphate pathway (PPP) is one of three major pathways involved in glucose metabolism, which is regulated by glucose-6-phosphate dehydrogenase (G6PD) controls NADPH formation. NADPH, in turn, regulates the balance of oxidative stress and reactive oxygen species (ROS) levels. G6PD dysfunction, affecting the PPP, is implicated in neurological disorders, including epilepsy. However, PPP’s role in epileptogenesis and ROS production during epileptic activity remains unclear. To clarify these points, we conducted electrophysiological and imaging analyses on mouse hippocampal brain slices. Using the specific G6PD inhibitor G6PDi−1, we assessed its effects on mouse hippocampal slices, examining intracellular ROS, glucose/oxygen consumption, the NAD(P)H level and ROS production during synaptic stimulation and in the 4AP epilepsy model. G6PDi−1 increased basal intracellular ROS levels and reduced synaptically induced glucose consumption but had no impact on baselevel of NAD(P)H and ROS production from synaptic stimulation. In the 4AP model, G6PDi−1 did not significantly alter spontaneous seizure frequency or H2O2 release amplitude but increased the frequency and peak amplitude of interictal events. These findings suggest that short-term PPP inhibition has a minimal impact on synaptic circuit activity. Full article
(This article belongs to the Special Issue Molecular Research in Hippocampal Neurogenesis and Brain Dysfunctions)
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44 pages, 2300 KiB  
Review
Mucus Structure, Viscoelastic Properties, and Composition in Chronic Respiratory Diseases
by Michela Abrami, Alice Biasin, Fabiana Tescione, Domenico Tierno, Barbara Dapas, Annalucia Carbone, Gabriele Grassi, Massimo Conese, Sante Di Gioia, Domenico Larobina and Mario Grassi
Int. J. Mol. Sci. 2024, 25(3), 1933; https://doi.org/10.3390/ijms25031933 - 5 Feb 2024
Cited by 9 | Viewed by 5860
Abstract
The respiratory mucus, a viscoelastic gel, effectuates a primary line of the airway defense when operated by the mucociliary clearance. In chronic respiratory diseases (CRDs), such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF), the mucus is overproduced and its [...] Read more.
The respiratory mucus, a viscoelastic gel, effectuates a primary line of the airway defense when operated by the mucociliary clearance. In chronic respiratory diseases (CRDs), such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF), the mucus is overproduced and its solid content augments, changing its structure and viscoelastic properties and determining a derangement of essential defense mechanisms against opportunistic microbial (virus and bacteria) pathogens. This ensues in damaging of the airways, leading to a vicious cycle of obstruction and infection responsible for the harsh clinical evolution of these CRDs. Here, we review the essential features of normal and pathological mucus (i.e., sputum in CF, COPD, and asthma), i.e., mucin content, structure (mesh size), micro/macro-rheology, pH, and osmotic pressure, ending with the awareness that sputum biomarkers (mucins, inflammatory proteins and peptides, and metabolites) might serve to indicate acute exacerbation and response to therapies. There are some indications that old and novel treatments may change the structure, viscoelastic properties, and biomarker content of sputum; however, a wealth of work is still needed to embrace these measures as correlates of disease severity in association with (or even as substitutes of) pulmonary functional tests. Full article
(This article belongs to the Collection Feature Papers in Molecular Pathology, Diagnostics, and Therapeutics)
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14 pages, 1765 KiB  
Review
The Ubiquitin-Associated and SH3 Domain-Containing Proteins (UBASH3) Family in Mammalian Development and Immune Response
by Katarina Vukojević, Violeta Šoljić, Vlatka Martinović, Fila Raguž and Natalija Filipović
Int. J. Mol. Sci. 2024, 25(3), 1932; https://doi.org/10.3390/ijms25031932 - 5 Feb 2024
Cited by 2 | Viewed by 1545
Abstract
UBASH3A and UBASH3B are protein families of atypical protein tyrosine phosphatases that function as regulators of various cellular processes during mammalian development. As UBASH3A has only mild phosphatase activity, its regulatory effects are based on the phosphatase-independent mechanisms. On the contrary, UBASH3B has [...] Read more.
UBASH3A and UBASH3B are protein families of atypical protein tyrosine phosphatases that function as regulators of various cellular processes during mammalian development. As UBASH3A has only mild phosphatase activity, its regulatory effects are based on the phosphatase-independent mechanisms. On the contrary, UBASH3B has strong phosphatase activity, and the suppression of its receptor signalling is mediated by Syk and Zap-70 kinases. The regulatory functions of UBASH3A and UBASH3B are particularly evident in the lymphoid tissues and kidney development. These tyrosine phosphatases are also known to play key roles in autoimmunity and neoplasms. However, their involvement in mammalian development and its regulatory functions are largely unknown and are discussed in this review. Full article
(This article belongs to the Special Issue Role of Tula-Family Proteins in Cell Signaling and Activation: Advances and Challenges)
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15 pages, 2960 KiB  
Article
Tyrosine Sulfation at Antibody Light Chain CDR-1 Increases Binding Affinity and Neutralization Potency to Interleukine-4
by Aaron M. D’Antona, Julie M. Lee, Melvin Zhang, Clarence Friedman, Tao He, Lidia Mosyak, Eric Bennett, Laura Lin, Maddison Silverman, Funi Cometa, Caryl Meade, Tyler Hageman, Eric Sousa, Justin Cohen, Kimberly Marquette, Darren Ferguson and Xiaotian Zhong
Int. J. Mol. Sci. 2024, 25(3), 1931; https://doi.org/10.3390/ijms25031931 - 5 Feb 2024
Cited by 2 | Viewed by 1788
Abstract
Structure and function of therapeutic antibodies can be modulated by a variety of post-translational modifications (PTM). Tyrosine (Tyr) sulfation is a type of negatively charged PTM that occurs during protein trafficking through the Golgi. In this study, we discovered that an anti-interleukin (IL)-4 [...] Read more.
Structure and function of therapeutic antibodies can be modulated by a variety of post-translational modifications (PTM). Tyrosine (Tyr) sulfation is a type of negatively charged PTM that occurs during protein trafficking through the Golgi. In this study, we discovered that an anti-interleukin (IL)-4 human IgG1, produced by transiently transfected HEK293 cells, contained a fraction of unusual negatively charged species. Interestingly, the isolated acidic species exhibited a two-fold higher affinity to IL-4 and a nearly four-fold higher potency compared to the main species. Mass spectrometry (MS) showed the isolated acidic species possessed an +80-Dalton from the expected mass, suggesting an occurrence of Tyr sulfation. Consistent with this hypothesis, we show the ability to control the acidic species during transient expression with the addition of Tyr sulfation inhibitor sodium chlorate or, conversely, enriched the acidic species from 30% to 92% of the total antibody protein when the IL-4 IgG was co-transfected with tyrosylprotein sulfotransferase genes. Further MS and mutagenesis analysis identified a Tyr residue at the light chain complementarity-determining region-1 (CDRL-1), which was sulfated specifically. These results together have demonstrated for the first time that Tyr sulfation at CDRL-1 could modulate antibody binding affinity and potency to a human immune cytokine. Full article
(This article belongs to the Section Biochemistry)
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12 pages, 2847 KiB  
Article
E3 Ubiquitin Ligase PUB23 in Kiwifruit Interacts with Trihelix Transcription Factor GT1 and Negatively Regulates Immune Responses against Pseudomonas syringae pv. actinidiae
by Tao Wang, Gang Wang, Jiyu Zhang and Jiping Xuan
Int. J. Mol. Sci. 2024, 25(3), 1930; https://doi.org/10.3390/ijms25031930 - 5 Feb 2024
Cited by 3 | Viewed by 1403
Abstract
Kiwifruit bacterial canker caused by Pseudomonas syringae pv. actinidiae (Psa) is the most serious disease threatening kiwifruit production. Our previous study found genes encoding the U-box containing proteins were significantly regulated by Psa infection. Here, we report a U-box type E3 ubiquitin ligase [...] Read more.
Kiwifruit bacterial canker caused by Pseudomonas syringae pv. actinidiae (Psa) is the most serious disease threatening kiwifruit production. Our previous study found genes encoding the U-box containing proteins were significantly regulated by Psa infection. Here, we report a U-box type E3 ubiquitin ligase PUB23 in kiwifruit which acts as a negative regulator of immune responses against Psa. PUB23 was found to physically interact with GT1, a trihelix transcription factor, in vitro and in vivo. The expression of GT1 was up-regulated in PUB23-silenced plants, indicating that interacting with PUB23 may directly or indirectly suppress GT1 expression. The silencing of PUB23 led to enhanced immune responses of PAMP-triggered immunity (PTI), including a higher expression level of defense marker genes PR1 and RIN4, and increased accumulation of hydrogen peroxide and superoxide anion. Our results reveal a negative role PUB23 plays in kiwifruit immune responses against Psa and may regulate gene expression by interacting with GT1. Full article
(This article belongs to the Section Molecular Plant Sciences)
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4 pages, 191 KiB  
Editorial
Emerging Therapeutic Options in Pancreatic Cancer Management
by Donatella Delle Cave
Int. J. Mol. Sci. 2024, 25(3), 1929; https://doi.org/10.3390/ijms25031929 - 5 Feb 2024
Viewed by 1247
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate of <8% [...] Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer)
40 pages, 8470 KiB  
Article
Neuropharmacological Evidence Implicating Drug-Induced Glutamate Receptor Dysfunction in Affective and Cognitive Sequelae of Subchronic Methamphetamine Self-Administration in Mice
by Christopher J. E. Denning, Lauren E. Madory, Jessica N. Herbert, Ryan A. Cabrera and Karen K. Szumlinski
Int. J. Mol. Sci. 2024, 25(3), 1928; https://doi.org/10.3390/ijms25031928 - 5 Feb 2024
Cited by 2 | Viewed by 1636
Abstract
Methamphetamine (MA) is a highly addictive drug, and MA use disorder is often comorbid with anxiety and cognitive impairment. These comorbid conditions are theorized to reflect glutamate-related neurotoxicity within the frontal cortical regions. However, our prior studies of MA-sensitized mice indicate that subchronic, [...] Read more.
Methamphetamine (MA) is a highly addictive drug, and MA use disorder is often comorbid with anxiety and cognitive impairment. These comorbid conditions are theorized to reflect glutamate-related neurotoxicity within the frontal cortical regions. However, our prior studies of MA-sensitized mice indicate that subchronic, behaviorally non-contingent MA treatment is sufficient to dysregulate glutamate transmission in mouse brain. Here, we extend this prior work to a mouse model of high-dose oral MA self-administration (0.8, 1.6, or 3.2 g/L; 1 h sessions × 7 days) and show that while female C57BL/6J mice consumed more MA than males, MA-experienced mice of both sexes exhibited some signs of anxiety-like behavior in a behavioral test battery, although not all effects were concentration-dependent. No MA effects were detected for our measures of visually cued spatial navigation, spatial learning, or memory in the Morris water maze; however, females with a history of 3.2 g/L MA exhibited reversal-learning deficits in this task, and mice with a history of 1.6 g/L MA committed more working-memory incorrect errors and relied upon a non-spatial navigation strategy during the radial-arm maze testing. Relative to naïve controls, MA-experienced mice exhibited several changes in the expression of certain glutamate receptor-related proteins and their downstream effectors within the ventral and dorsal areas of the prefrontal cortex, the hippocampus, and the amygdala, many of which were sex-selective. Systemic pretreatment with the mGlu1-negative allosteric modulator JNJ 162596858 reversed the anxiety-like behavior expressed by MA-experienced mice in the marble-burying test, while systemic pretreatment with NMDA or the NMDA antagonist MK-801 bi-directionally affected the MA-induced reversal-learning deficit. Taken together, these data indicate that a relatively brief history of oral MA is sufficient to induce some signs of anxiety-like behavior and cognitive dysfunction during early withdrawal that reflect, at least in part, MA-induced changes in the corticolimbic expression of certain glutamate receptor subtypes of potential relevance to treating symptoms of MA use disorder. Full article
(This article belongs to the Special Issue Biochemical and Molecular Changes in the Brain Caused by Drug Abuse: Implications for Therapeutic Intervention)
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12 pages, 3039 KiB  
Article
Adhesion States Greatly Affect Cellular Susceptibility to Graphene Oxide: Therapeutic Implications for Cancer Metastasis
by Keiko Morotomi-Yano, Shinya Hayami and Ken-ichi Yano
Int. J. Mol. Sci. 2024, 25(3), 1927; https://doi.org/10.3390/ijms25031927 - 5 Feb 2024
Cited by 1 | Viewed by 1230
Abstract
Graphene oxide (GO) has received increasing attention in the life sciences because of its potential for various applications. Although GO is generally considered biocompatible, it can negatively impact cell physiology under some circumstances. Here, we demonstrate that the cytotoxicity of GO greatly varies [...] Read more.
Graphene oxide (GO) has received increasing attention in the life sciences because of its potential for various applications. Although GO is generally considered biocompatible, it can negatively impact cell physiology under some circumstances. Here, we demonstrate that the cytotoxicity of GO greatly varies depending on the cell adhesion states. Human HCT-116 cells in a non-adhered state were more susceptible to GO than those in an adherent state. Apoptosis was partially induced by GO in both adhered and non-adhered cells to a similar extent, suggesting that apoptosis induction does not account for the selective effects of GO on non-adhered cells. GO treatment rapidly decreased intracellular ATP levels in non-adhered cells but not in adhered ones, suggesting ATP depletion as the primary cause of GO-induced cell death. Concurrently, autophagy induction, a cellular response for energy homeostasis, was more evident in non-adhered cells than in adhered cells. Collectively, our observations provide novel insights into GO’s action with regard to cell adhesion states. Because the elimination of non-adhered cells is important in preventing cancer metastasis, the selective detrimental effects of GO on non-adhered cells suggest its therapeutic potential for use in cancer metastasis. Full article
(This article belongs to the Special Issue Carbon–Multidisciplinary Investigations and Innovative Solutions)
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33 pages, 11443 KiB  
Review
Zebrafish Insights into Nanomaterial Toxicity: A Focused Exploration on Metallic, Metal Oxide, Semiconductor, and Mixed-Metal Nanoparticles
by Chinmaya Mutalik, Nivedita, Chandrasekaran Sneka, Dyah Ika Krisnawati, Sibidou Yougbaré, Chuan-Chih Hsu and Tsung-Rong Kuo
Int. J. Mol. Sci. 2024, 25(3), 1926; https://doi.org/10.3390/ijms25031926 - 5 Feb 2024
Cited by 3 | Viewed by 2398
Abstract
Nanomaterials are widely used in various fields, and ongoing research is focused on developing safe and sustainable nanomaterials. Using zebrafish as a model organism for studying the potentially toxic effects of nanomaterials highlights the importance of developing safe and sustainable nanomaterials. Studies conducted [...] Read more.
Nanomaterials are widely used in various fields, and ongoing research is focused on developing safe and sustainable nanomaterials. Using zebrafish as a model organism for studying the potentially toxic effects of nanomaterials highlights the importance of developing safe and sustainable nanomaterials. Studies conducted on nanomaterials and their toxicity and potential risks to human and environmental health are vital in biomedical sciences. In the present review, we discuss the potential toxicity of nanomaterials (inorganic and organic) and exposure risks based on size, shape, and concentration. The review further explores various types of nanomaterials and their impacts on zebrafish at different levels, indicating that exposure to nanomaterials can lead to developmental defects, changes in gene expressions, and various toxicities. The review also covers the importance of considering natural organic matter and chorion membranes in standardized nanotoxicity testing. While some nanomaterials are biologically compatible, metal and semiconductor nanomaterials that enter the water environment can increase toxicity to aquatic creatures and can potentially accumulate in the human body. Further investigations are necessary to assess the safety of nanomaterials and their impacts on the environment and human health. Full article
(This article belongs to the Special Issue Nanomaterials in Nanobiotechnology and Nanomedicine)
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19 pages, 15194 KiB  
Article
Nuclear Binding Protein 2/Nesfatin-1 Affects Trophoblast Cell Fusion during Placental Development via the EGFR-PLCG1-CAMK4 Pathway
by Qinyu Dang, Yandi Zhu, Yadi Zhang, Zhuo Hu, Yuchen Wei, Zhaoyang Chen, Xinyin Jiang, Xiaxia Cai and Huanling Yu
Int. J. Mol. Sci. 2024, 25(3), 1925; https://doi.org/10.3390/ijms25031925 - 5 Feb 2024
Cited by 1 | Viewed by 1344
Abstract
Previous studies have shown that nuclear binding protein 2 (NUCB2) is expressed in the human placenta and increases with an increase in the syncytialization of trophoblast cells. This study aimed to investigate the role of NUCB2 in the differentiation and fusion [...] Read more.
Previous studies have shown that nuclear binding protein 2 (NUCB2) is expressed in the human placenta and increases with an increase in the syncytialization of trophoblast cells. This study aimed to investigate the role of NUCB2 in the differentiation and fusion of trophectoderm cells. In this study, the expression levels of NUCB2 and E-cadherin in the placentas of rats at different gestation stages were investigated. The results showed that there was an opposite trend between the expression of placental NUCB2 and E-cadherin in rat placentas in different trimesters. When primary human trophoblast (PHT) and BeWo cells were treated with high concentrations of Nesfatin-1, the trophoblast cell syncytialization was significantly inhibited. The effects of NUCB2 knockdown in BeWo cells and Forskolin-induced syncytialization were investigated. These cells showed a significantly decreased cell fusion rate. The mechanism underlying NUCB2-regulated trophoblast cell syncytialization was explored using RNA-Seq and the results indicated that the epidermal growth factor receptor (EGFR)-phospholipase C gamma 1 (PLCG1)-calmodulin-dependent protein kinase IV (CAMK4) pathway might be involved. The results suggested that the placental expression of NUCB2 plays an important role in the fusion of trophoblasts during differentiation via the EGFR-PLCG1-CAMK4 pathway. Full article
(This article belongs to the Section Molecular Biology)
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17 pages, 4068 KiB  
Article
Exploring the Regulatory Dynamics of BrFLC-Associated lncRNA in Modulating the Flowering Response of Chinese Cabbage
by Yun Dai, Xinyu Gao, Shifan Zhang, Fei Li, Hui Zhang, Guoliang Li, Rifei Sun, Shujiang Zhang and Xilin Hou
Int. J. Mol. Sci. 2024, 25(3), 1924; https://doi.org/10.3390/ijms25031924 - 5 Feb 2024
Cited by 1 | Viewed by 1264
Abstract
Vernalization plays a crucial role in the flowering and yield of Chinese cabbage, a process intricately influenced by long non-coding RNAs (lncRNAs). Our research focused on lncFLC1, lncFLC2a, and lncFLC2b, which emerged as key players in this process. These lncRNAs [...] Read more.
Vernalization plays a crucial role in the flowering and yield of Chinese cabbage, a process intricately influenced by long non-coding RNAs (lncRNAs). Our research focused on lncFLC1, lncFLC2a, and lncFLC2b, which emerged as key players in this process. These lncRNAs exhibited an inverse expression pattern to the flowering repressor genes FLOWERING LOCUS C 1 (BrFLC1) and FLOWERING LOCUS C 2 (BrFLC2) during vernalization, suggesting a complex regulatory mechanism. Notably, their expression in the shoot apex and leaves was confirmed through in fluorescent in situ hybridization (FISH). Furthermore, when these lncRNAs were overexpressed in Arabidopsis, a noticeable acceleration in flowering was observed, unveiling functional similarities to Arabidopsis’s COLD ASSISTED INTRONIC NONCODING RNA (COOLAIR). This resemblance suggests a potentially conserved regulatory mechanism across species. This study not only enhances our understanding of lncRNAs in flowering regulation, but also opens up new possibilities for their application in agricultural practices. Full article
(This article belongs to the Special Issue Vegetable Genetics and Genomics 2.0)
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19 pages, 5015 KiB  
Article
Cholesterol Content Regulates the Interaction of αA-, αB-, and α-Crystallin with the Model of Human Lens-Lipid Membranes
by Raju Timsina, Preston Hazen, Geraline Trossi-Torres, Nawal K. Khadka, Navdeep Kalkat and Laxman Mainali
Int. J. Mol. Sci. 2024, 25(3), 1923; https://doi.org/10.3390/ijms25031923 - 5 Feb 2024
Cited by 3 | Viewed by 1189
Abstract
α-Crystallin (αABc) is a major protein comprised of αA-crystallin (αAc) and αB-crystallin (αBc) that is found in the human eye lens and works as a molecular chaperone by preventing the aggregation of proteins and providing tolerance to stress. However, with age and cataract [...] Read more.
α-Crystallin (αABc) is a major protein comprised of αA-crystallin (αAc) and αB-crystallin (αBc) that is found in the human eye lens and works as a molecular chaperone by preventing the aggregation of proteins and providing tolerance to stress. However, with age and cataract formation, the concentration of αABc in the eye lens cytoplasm decreases, with a corresponding increase in the membrane-bound αABc. This study uses the electron paramagnetic resonance (EPR) spin-labeling method to investigate the role of cholesterol (Chol) and Chol bilayer domains (CBDs) in the binding of αAc, αBc, and αABc to the Chol/model of human lens-lipid (Chol/MHLL) membranes. The maximum percentage of membrane surface occupied (MMSO) by αAc, αBc, and αABc to Chol/MHLL membranes at a mixing ratio of 0 followed the trends: MMSO (αAc) > MMSO (αBc) ≈ MMSO (αABc), indicating that a higher amount of αAc binds to these membranes compared to αBc and αABc. However, with an increase in the Chol concentration in the Chol/MHLL membranes, the MMSO by αAc, αBc, and αABc decreases until it is completely diminished at a mixing ratio of 1.5. The Ka of αAc, αBc, and αABc to Chol/MHLL membranes at a mixing ratio of 0 followed the trend: Ka (αBc) ≈ Ka (αABc) > Ka (αAc), but it was close to zero with the diminished binding at a Chol/MHLL mixing ratio of 1.5. The mobility near the membrane headgroup regions decreased with αAc, αBc, and αABc binding, and the Chol antagonized the capacity of the αAc, αBc, and αABc to decrease mobility near the headgroup regions. No significant change in membrane order near the headgroup regions was observed, with an increase in αAc, αBc, and αABc concentrations. Our results show that αAc, αBc, and αABc bind differently with Chol/MHLL membranes at mixing ratios of 0 and 0.5, decreasing the mobility and increasing hydrophobicity near the membrane headgroup region, likely forming the hydrophobic barrier for the passage of polar and ionic molecules, including antioxidants (glutathione), creating an oxidative environment inside the lens, leading to the development of cataracts. However, all binding was completely diminished at a mixing ratio of 1.5, indicating that high Chol and CBDs inhibit the binding of αAc, αBc, and αABc to membranes, preventing the formation of hydrophobic barriers and likely protecting against cataract formation. Full article
(This article belongs to the Special Issue Cellular and Molecular Insights into Ocular Changes Associated with Systemic Disorders and Conditions)
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15 pages, 2561 KiB  
Article
TRPV1 Channel in Human Eosinophils: Functional Expression and Inflammatory Modulation
by Tobias Weihrauch, Natalie Gray, Daniela Wiebe, Martin Schmelz, Maren M. Limberg and Ulrike Raap
Int. J. Mol. Sci. 2024, 25(3), 1922; https://doi.org/10.3390/ijms25031922 - 5 Feb 2024
Cited by 2 | Viewed by 2113
Abstract
The transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel expressed on sensory neurons and immune cells. We hypothesize that TRPV1 plays a role in human eosinophil function and is modulated by inflammatory conditions. TRPV1 expression on human eosinophils was examined [...] Read more.
The transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel expressed on sensory neurons and immune cells. We hypothesize that TRPV1 plays a role in human eosinophil function and is modulated by inflammatory conditions. TRPV1 expression on human eosinophils was examined by qPCR, flow cytometry, and immunohistochemistry, respectively. TRPV1 functionality was analyzed by investigating calcium flux, apoptosis, modulation by cytokines and acidic pH, and CD69 externalization using flow cytometry. Activation of TRPV1 induced calcium influx and prolonged survival. Although eosinophils were not directly activated by TRPV1 agonists, activation by IL-3 or GM-CSF was mainly restricted to TRPV1-positive eosinophils. TRPV1 surface content was increased by acidic pH, IL-3, IL-31, IL-33, TSLP, TNF-α, BDNF, and NGF-β. Interestingly, TRPV1 was also expressed by eosinophils located in proximity to peripheral nerves in atopic dermatitis (AD) skin. In conclusion, eosinophils express functional TRPV1 channels which are increased by extracellular acidification and AD-related cytokines. Since eosinophils also express TRPV1 in AD skin, our results indicate an important role of TRPV1 for neuroimmune interaction mechanisms in itchy, inflammatory skin diseases, like AD. Full article
(This article belongs to the Special Issue Inflammation in Skin and Joints)
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17 pages, 2078 KiB  
Article
Bis(Disulfide)-Bridged Somatostatin-14 Analogs and Their [111In]In-Radioligands: Synthesis and Preclinical Profile
by Aikaterini Tatsi, Theodosia Maina, Beatrice Waser, Eric P. Krenning, Marion de Jong, Jean Claude Reubi, Paul Cordopatis and Berthold A. Nock
Int. J. Mol. Sci. 2024, 25(3), 1921; https://doi.org/10.3390/ijms25031921 - 5 Feb 2024
Viewed by 1221
Abstract
The overexpression of one or more somatostatin receptors (SST1–5R) in human tumors has provided an opportunity for diagnosis and therapy with somatostatin-like radionuclide carriers. The application of “pansomatostatin” analogs is expected to broaden the clinical indications and upgrade the diagnostic/therapeutic efficacy [...] Read more.
The overexpression of one or more somatostatin receptors (SST1–5R) in human tumors has provided an opportunity for diagnosis and therapy with somatostatin-like radionuclide carriers. The application of “pansomatostatin” analogs is expected to broaden the clinical indications and upgrade the diagnostic/therapeutic efficacy of currently applied SST2R-prefering radioligands. In pursuit of this goal, we now introduce two bicyclic somatostatin-14 (SS14) analogs, AT5S (DOTA-Ala1-Gly2-c[Cys3-Lys4-Asn5-c[Cys6-Phe7-DTrp8-Lys9-Thr10-Cys11]-Thr12-Ser13-Cys14]) and AT6S (DOTA-Ala1-Gly2-c[Cys3-Lys4-c[Cys5-Phe6-Phe7-DTrp8-Lys9-Thr10-Phe11-Cys12]-Ser13-Cys14]), suitable for labeling with trivalent radiometals and designed to sustain in vivo degradation. Both AT5S and AT6S and the respective [111In]In-AT5S and [111In]In-AT6S were evaluated in a series of in vitro assays, while radioligand stability and biodistribution were studied in mice. The 8/12-mer bicyclic AT6S showed expanded affinity for all SST1–5R and agonistic properties at the SST2R, whereas AT5S lost all affinity to SST1–5R. Both [111In]In-AT5S and [111In]In-AT6S remained stable in the peripheral blood of mice, while [111In]In-AT6S displayed low, but specific uptake in AR4-2J tumors and higher uptake in HEK293-SST3R tumors in mice. In summary, high radioligand stability was acquired by the two disulfide bridges introduced into the SS14 motif, but only the 8/12-mer ring AT6S retained a pansomatostatin profile. In consequence, [111In]In-AT6S targeted SST2R-/SST3R-positive xenografts in mice. These results call for further research on pansomatostatin-like radioligands for cancer theranostics. Full article
(This article belongs to the Special Issue Bioactive Peptides in Human Health and Disease 2.0)
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15 pages, 7563 KiB  
Article
HSP70 Is a Critical Regulator of HSP90 Inhibitor’s Effectiveness in Preventing HCl-Induced Chronic Lung Injury and Pulmonary Fibrosis
by Ruben M. L. Colunga Biancatelli, Pavel A. Solopov, Tierney Day, Betsy Gregory, Michael Osei-nkansah, Christiana Dimitropoulou and John D. Catravas
Int. J. Mol. Sci. 2024, 25(3), 1920; https://doi.org/10.3390/ijms25031920 - 5 Feb 2024
Cited by 2 | Viewed by 1379
Abstract
Exposure to hydrochloric acid (HCl) can provoke acute and chronic lung injury. Because of its extensive production for industrial use, frequent accidental exposures occur, making HCl one of the top five chemicals causing inhalation injuries. There are no Food and Drug Administration (FDA)-approved [...] Read more.
Exposure to hydrochloric acid (HCl) can provoke acute and chronic lung injury. Because of its extensive production for industrial use, frequent accidental exposures occur, making HCl one of the top five chemicals causing inhalation injuries. There are no Food and Drug Administration (FDA)-approved treatments for HCl exposure. Heat shock protein 90 (HSP90) inhibitors modulate transforming growth factor-β (TGF-β) signaling and the development of chemical-induced pulmonary fibrosis. However, little is known on the role of Heat Shock Protein 70 (HSP70) during injury and treatment with HSP90 inhibitors. We hypothesized that administration of geranylgeranyl-acetone (GGA), an HSP70 inducer, or gefitinib (GFT), an HSP70 suppressant, alone or in combination with the HSP90 inhibitor, TAS-116, would improve or worsen, respectively, HCl-induced chronic lung injury in vivo and endothelial barrier dysfunction in vitro. GGA, alone, improved HCl-induced human lung microvascular endothelial cells (HLMVEC) barrier dysfunction and, in combination with TAS-116, improved the protective effect of TAS-116. In mice, GGA reduced HCl toxicity and while TAS-116 alone blocked HCl-induced chronic lung injury, co-administration with GGA, resulted in further improvement. Conversely, GFT potentiated HCl-induced barrier dysfunction and impaired the antidotal effects of TAS-116. We conclude that combined treatments with HSP90 inhibitors and HSP70 inducers may represent a novel therapeutic approach to manage HCl-induced chronic lung injury and pulmonary fibrosis. Full article
(This article belongs to the Special Issue Novel Insight into Pulmonary Vascular Disease)
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18 pages, 8512 KiB  
Article
Stratification of Colorectal Patients Based on Survival Analysis Shows the Value of Consensus Molecular Subtypes and Reveals the CBLL1 Gene as a Biomarker of CMS2 Tumours
by Gloria Alfonsín, Alberto Berral-González, Andrea Rodríguez-Alonso, Macarena Quiroga, Javier De Las Rivas and Angélica Figueroa
Int. J. Mol. Sci. 2024, 25(3), 1919; https://doi.org/10.3390/ijms25031919 - 5 Feb 2024
Viewed by 1821
Abstract
The consensus molecular subtypes (CMSs) classification of colorectal cancer (CRC) is a system for patient stratification that can be potentially applied to therapeutic decisions. Hakai (CBLL1) is an E3 ubiquitin–ligase that induces the ubiquitination and degradation of E-cadherin, inducing epithelial-to-mesenchymal transition (EMT), tumour [...] Read more.
The consensus molecular subtypes (CMSs) classification of colorectal cancer (CRC) is a system for patient stratification that can be potentially applied to therapeutic decisions. Hakai (CBLL1) is an E3 ubiquitin–ligase that induces the ubiquitination and degradation of E-cadherin, inducing epithelial-to-mesenchymal transition (EMT), tumour progression and metastasis. Using bioinformatic methods, we have analysed CBLL1 expression on a large integrated cohort of primary tumour samples from CRC patients. The cohort included survival data and was divided into consensus molecular subtypes. Colon cancer tumourspheres were used to analyse the expression of stem cancer cells markers via RT-PCR and Western blotting. We show that CBLL1 gene expression is specifically associated with canonical subtype CMS2. WNT target genes LGR5 and c-MYC show a similar association with CMS2 as CBLL1. These mRNA levels are highly upregulated in cancer tumourspheres, while CBLL1 silencing shows a clear reduction in tumoursphere size and in stem cell biomarkers. Importantly, CMS2 patients with high CBLL1 expression displayed worse overall survival (OS), which is similar to that associated with CMS4 tumours. Our findings reveal CBLL1 as a specific biomarker for CMS2 and the potential of using CMS2 with high CBLL1 expression to stratify patients with poor OS. Full article
(This article belongs to the Special Issue Cancer Genomics)
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27 pages, 3039 KiB  
Review
Advancements and Prospects of Genome-Wide Association Studies (GWAS) in Maize
by Javed Hussain Sahito, Hao Zhang, Zeeshan Ghulam Nabi Gishkori, Chenhui Ma, Zhihao Wang, Dong Ding, Xuehai Zhang and Jihua Tang
Int. J. Mol. Sci. 2024, 25(3), 1918; https://doi.org/10.3390/ijms25031918 - 5 Feb 2024
Cited by 10 | Viewed by 6577
Abstract
Genome-wide association studies (GWAS) have emerged as a powerful tool for unraveling intricate genotype–phenotype association across various species. Maize (Zea mays L.), renowned for its extensive genetic diversity and rapid linkage disequilibrium (LD), stands as an exemplary candidate for GWAS. In maize, [...] Read more.
Genome-wide association studies (GWAS) have emerged as a powerful tool for unraveling intricate genotype–phenotype association across various species. Maize (Zea mays L.), renowned for its extensive genetic diversity and rapid linkage disequilibrium (LD), stands as an exemplary candidate for GWAS. In maize, GWAS has made significant advancements by pinpointing numerous genetic loci and potential genes associated with complex traits, including responses to both abiotic and biotic stress. These discoveries hold the promise of enhancing adaptability and yield through effective breeding strategies. Nevertheless, the impact of environmental stress on crop growth and yield is evident in various agronomic traits. Therefore, understanding the complex genetic basis of these traits becomes paramount. This review delves into current and future prospectives aimed at yield, quality, and environmental stress resilience in maize and also addresses the challenges encountered during genomic selection and molecular breeding, all facilitated by the utilization of GWAS. Furthermore, the integration of omics, including genomics, transcriptomics, proteomics, metabolomics, epigenomics, and phenomics has enriched our understanding of intricate traits in maize, thereby enhancing environmental stress tolerance and boosting maize production. Collectively, these insights not only advance our understanding of the genetic mechanism regulating complex traits but also propel the utilization of marker-assisted selection in maize molecular breeding programs, where GWAS plays a pivotal role. Therefore, GWAS provides robust support for delving into the genetic mechanism underlying complex traits in maize and enhancing breeding strategies. Full article
(This article belongs to the Section Molecular Plant Sciences)
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13 pages, 6821 KiB  
Article
Isolation and Functional Characterization of a Constitutive Promoter in Upland Cotton (Gossypium hirsutum L.)
by Yang Yang, Xiaorong Li, Chenyu Li, Hui Zhang, Zumuremu Tuerxun, Fengjiao Hui, Juan Li, Zhigang Liu, Guo Chen, Darun Cai, Xunji Chen and Bo Li
Int. J. Mol. Sci. 2024, 25(3), 1917; https://doi.org/10.3390/ijms25031917 - 5 Feb 2024
Viewed by 1766
Abstract
Multiple cis-acting elements are present in promoter sequences that play critical regulatory roles in gene transcription and expression. In this study, we isolated the cotton FDH (Fiddlehead) gene promoter (pGhFDH) using a real-time reverse transcription-PCR (qRT-PCR) expression analysis and performed a cis-acting elements [...] Read more.
Multiple cis-acting elements are present in promoter sequences that play critical regulatory roles in gene transcription and expression. In this study, we isolated the cotton FDH (Fiddlehead) gene promoter (pGhFDH) using a real-time reverse transcription-PCR (qRT-PCR) expression analysis and performed a cis-acting elements prediction analysis. The plant expression vector pGhFDH::GUS was constructed using the Gateway approach and was used for the genetic transformation of Arabidopsis and upland cotton plants to obtain transgenic lines. Histochemical staining and a β-glucuronidase (GUS) activity assay showed that the GUS protein was detected in the roots, stems, leaves, inflorescences, and pods of transgenic Arabidopsis thaliana lines. Notably, high GUS activity was observed in different tissues. In the transgenic lines, high GUS activity was detected in different tissues such as leaves, stalks, buds, petals, androecium, endosperm, and fibers, where the pGhFDH-driven GUS expression levels were 3–10-fold higher compared to those under the CaMV 35S promoter at 10–30 days post-anthesis (DPA) during fiber development. The results indicate that pGhFDH can be used as an endogenous constitutive promoter to drive the expression of target genes in various cotton tissues to facilitate functional genomic studies and accelerate cotton molecular breeding. Full article
(This article belongs to the Section Molecular Plant Sciences)
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18 pages, 4014 KiB  
Article
A Novel Cre Recombinase Mouse Strain for Cell-Specific Deletion of Floxed Genes in Ribbon Synapse-Forming Retinal Neurons
by Shweta Suiwal, Philipp Wartenberg, Ulrich Boehm, Frank Schmitz and Karin Schwarz
Int. J. Mol. Sci. 2024, 25(3), 1916; https://doi.org/10.3390/ijms25031916 - 5 Feb 2024
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Abstract
We generated a novel Cre mouse strain for cell-specific deletion of floxed genes in ribbon synapse-forming retinal neurons. Previous studies have shown that the RIBEYE promotor targets the expression of recombinant proteins such as fluorescently tagged RIBEYE to photoreceptors and retinal bipolar cells [...] Read more.
We generated a novel Cre mouse strain for cell-specific deletion of floxed genes in ribbon synapse-forming retinal neurons. Previous studies have shown that the RIBEYE promotor targets the expression of recombinant proteins such as fluorescently tagged RIBEYE to photoreceptors and retinal bipolar cells and generates fluorescent synaptic ribbons in situ in these neurons. Here, we used the same promotor to generate a novel transgenic mouse strain in which the RIBEYE promotor controls the expression of a Cre-ER(T2) recombinase (RIBEYE-Cre). To visualize Cre expression, the RIBEYE-Cre animals were crossed with ROSA26 tau-GFP (R26-τGFP) reporter mice. In the resulting RIBEYE-Cre/R26 τGFP animals, Cre-mediated removal of a transcriptional STOP cassette results in the expression of green fluorescent tau protein (tau-GFP) that binds to cellular microtubules. We detected robust tau-GFP expression in retinal bipolar cells. Surprisingly, we did not find fluorescent tau-GFP expression in mouse photoreceptors. The lack of tau-GFP reporter protein in these cells could be based on the previously reported absence of tau protein in mouse photoreceptors which could lead to the degradation of the recombinant tau protein. Consistent with this, we detected Cre and tau-GFP mRNA in mouse photoreceptor slices by RT-PCR. The transgenic RIBEYE-Cre mouse strain provides a new tool to study the deletion of floxed genes in ribbon synapse-forming neurons of the retina and will also allow for analyzing gene deletions that are lethal if globally deleted in neurons. Full article
(This article belongs to the Special Issue Ribbon Synapses: Molecular Mechanisms of Synaptic Signaling and Involvement in Diseases 2.0)
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