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Int. J. Mol. Sci., Volume 25, Issue 7 (April-1 2024) – 571 articles

Cover Story (view full-size image): Glycosylation plays a crucial role in the maintenance of homeostasis in the body and at the onset of diseases such as inflammation, neurodegeneration, infection, diabetes, and cancer. It is also involved in bone metabolism. N- and O-glycans have been shown to regulate osteoblast and osteoclast differentiation. We recently demonstrated that ganglio-series and globo-series glycosphingolipids were essential for regulating the proliferation and differentiation of osteoblasts and osteoclasts in glycosyltransferase-knockout mice. Herein, we reviewed the importance of the regulation of bone metabolism by glycoconjugates, such as glycolipids and glycoproteins, including our recent results. View this paper
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20 pages, 23188 KiB  
Article
Boosting Clear Cell Renal Carcinoma-Specific Drug Discovery Using a Deep Learning Algorithm and Single-Cell Analysis
by Yishu Wang, Xiaomin Chen, Ningjun Tang, Mengyao Guo and Dongmei Ai
Int. J. Mol. Sci. 2024, 25(7), 4134; https://doi.org/10.3390/ijms25074134 - 8 Apr 2024
Viewed by 1003
Abstract
Clear cell renal carcinoma (ccRCC), the most common subtype of renal cell carcinoma, has the high heterogeneity of a highly complex tumor microenvironment. Existing clinical intervention strategies, such as target therapy and immunotherapy, have failed to achieve good therapeutic effects. In this article, [...] Read more.
Clear cell renal carcinoma (ccRCC), the most common subtype of renal cell carcinoma, has the high heterogeneity of a highly complex tumor microenvironment. Existing clinical intervention strategies, such as target therapy and immunotherapy, have failed to achieve good therapeutic effects. In this article, single-cell transcriptome sequencing (scRNA-seq) data from six patients downloaded from the GEO database were adopted to describe the tumor microenvironment (TME) of ccRCC, including its T cells, tumor-associated macrophages (TAMs), endothelial cells (ECs), and cancer-associated fibroblasts (CAFs). Based on the differential typing of the TME, we identified tumor cell-specific regulatory programs that are mediated by three key transcription factors (TFs), whilst the TF EPAS1/HIF-2α was identified via drug virtual screening through our analysis of ccRCC’s protein structure. Then, a combined deep graph neural network and machine learning algorithm were used to select anti-ccRCC compounds from bioactive compound libraries, including the FDA-approved drug library, natural product library, and human endogenous metabolite compound library. Finally, five compounds were obtained, including two FDA-approved drugs (flufenamic acid and fludarabine), one endogenous metabolite, one immunology/inflammation-related compound, and one inhibitor of DNA methyltransferase (N4-methylcytidine, a cytosine nucleoside analogue that, like zebularine, has the mechanism of inhibiting DNA methyltransferase). Based on the tumor microenvironment characteristics of ccRCC, five ccRCC-specific compounds were identified, which would give direction of the clinical treatment for ccRCC patients. Full article
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3 pages, 177 KiB  
Editorial
Molecular Research on Plasmodium Infection and Immunity
by Jean-Paul Coutelier and Sylviane Pied
Int. J. Mol. Sci. 2024, 25(7), 4133; https://doi.org/10.3390/ijms25074133 - 8 Apr 2024
Viewed by 637
Abstract
The WHO’s global strategy for malaria targets a reduction of at least 90% of both incidence and mortality rates for 2030 [...] Full article
(This article belongs to the Special Issue Molecular Research on Plasmodium Infection and Immunity)
17 pages, 3081 KiB  
Article
Inhibition of the Sodium–Calcium Exchanger Reverse Mode Activity Reduces Alcohol Consumption in Rats
by Gleice Kelli Silva-Cardoso and Prosper N’Gouemo
Int. J. Mol. Sci. 2024, 25(7), 4132; https://doi.org/10.3390/ijms25074132 - 8 Apr 2024
Viewed by 585
Abstract
Excessive and uncontrolled consumption of alcohol can cause alcohol use disorder (AUD), but its pharmacological mechanisms are not fully understood. Inhibiting the reverse mode activity of the sodium–calcium exchanger (NCX) can reduce the risk of alcohol withdrawal seizures, suggesting that NCX could play [...] Read more.
Excessive and uncontrolled consumption of alcohol can cause alcohol use disorder (AUD), but its pharmacological mechanisms are not fully understood. Inhibiting the reverse mode activity of the sodium–calcium exchanger (NCX) can reduce the risk of alcohol withdrawal seizures, suggesting that NCX could play a role in controlling alcohol consumption. Here, we investigated how two potent inhibitors of NCX reverse mode activity, SN-6 (NCX1) and KB-R7943 (NCX3), affect voluntary alcohol consumption in adult male and female rats using the intermittent alcohol access two-bottle choice paradigm. Initially, animals were trained to drink 7.5% ethanol and water for four weeks before administering SN-6 and KB-R7934. Afterward, their alcohol intake, preference, and water intake were recorded 2 and 24 h after exposure to water and 7.5% ethanol. SN-6 significantly reduced alcohol consumption by 48% in male and 36% in female rats without affecting their water intake. Additionally, SN-6 significantly reduced alcohol preference in females by 27%. However, KB-R7943 reduced alcohol consumption by 42% in female rats and did not affect alcohol preference or water intake. These findings suggest that alcohol exposure increased NCX reverse activity, and targeting NCX1 could be an effective strategy for reducing alcohol consumption in subjects susceptible to withdrawal seizures. Full article
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12 pages, 2293 KiB  
Communication
A Pilot Analysis of Whole Transcriptome of Human Cryopreserved Sperm
by Sara Stigliani, Adriana Amaro, Francesco Reggiani, Elena Maccarini, Claudia Massarotti, Matteo Lambertini, Paola Anserini and Paola Scaruffi
Int. J. Mol. Sci. 2024, 25(7), 4131; https://doi.org/10.3390/ijms25074131 - 8 Apr 2024
Viewed by 769
Abstract
Sperm cryopreservation is a procedure widely used to store gametes for later use, to preserve fertility in patients prior to gonadotoxic treatments or surgery, and for sperm donation programs. The purpose of the study was to assess the impact of cryopreservation on human [...] Read more.
Sperm cryopreservation is a procedure widely used to store gametes for later use, to preserve fertility in patients prior to gonadotoxic treatments or surgery, and for sperm donation programs. The purpose of the study was to assess the impact of cryopreservation on human sperm transcriptome. Semen samples were collected from 13 normospermic men. Each sample was divided into two aliquots. The total RNA was immediately extracted from one aliquot. The second aliquot was frozen and total RNA was extracted after a week of storage in liquid nitrogen. The RNA samples were randomized in four pools, each of six donors, and analyzed by microarrays. The paired Significance Analysis of Microarray was performed. We found 219 lower abundant transcripts and 28 higher abundant transcripts in cryopreserved sperm than fresh sperm. The gene ontology analysis disclosed that cryopreservation alters transcripts of pathways important for fertility (i.e., spermatogenesis, sperm motility, mitochondria function, fertilization, calcium homeostasis, cell differentiation, and early embryo development), although the increase of some transcripts involved in immune response can compensate for the harmful effects of freezing. Full article
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20 pages, 6036 KiB  
Article
Estrogen α and β Receptor Expression in the Various Regions of Resected Glioblastoma Multiforme Tumors and in an In Vitro Model
by Donata Simińska, Klaudyna Kojder, Dariusz Jeżewski, Maciej Tarnowski, Patrycja Tomasiak, Katarzyna Piotrowska, Agnieszka Kolasa, Kapczuk Patrycja, Dariusz Chlubek and Irena Baranowska-Bosiacka
Int. J. Mol. Sci. 2024, 25(7), 4130; https://doi.org/10.3390/ijms25074130 - 8 Apr 2024
Viewed by 782
Abstract
Glioblastoma multiforme (GBM) is a malignant tumor with a higher prevalence in men and a higher survival rate in transmenopausal women. It exhibits distinct areas influenced by changing environmental conditions. This study examines how these areas differ in the levels of estrogen receptors [...] Read more.
Glioblastoma multiforme (GBM) is a malignant tumor with a higher prevalence in men and a higher survival rate in transmenopausal women. It exhibits distinct areas influenced by changing environmental conditions. This study examines how these areas differ in the levels of estrogen receptors (ERs) which play an important role in the development and progression of many cancers, and whose expression levels are often correlated with patient survival. This study utilized two research models: an in vitro model employing the U87 cell line and a second model involving tumors resected from patients (including tumor core, enhancing tumor region, and peritumoral area). ER expression was assessed at both gene and protein levels, with the results validated using confocal microscopy and immunohistochemistry. Under hypoxic conditions, the U87 line displayed a decrease in ERβ mRNA expression and an increase in ERα mRNA expression. In patient samples, ERβ mRNA expression was lower in the tumor core compared to the enhancing tumor region (only in males when the study group was divided by sex). In addition, ERβ protein expression was lower in the tumor core than in the peritumoral area (only in women when the study group was divided by sex). Immunohistochemical analysis indicated the highest ERβ protein expression in the enhancing tumor area, followed by the peritumoral area, and the lowest in the tumor core. The findings suggest that ER expression may significantly influence the development of GBM, exhibiting variability under the influence of conditions present in different tumor areas. Full article
(This article belongs to the Section Molecular Oncology)
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18 pages, 5135 KiB  
Article
Kaempferol as an Alternative Cryosupplement for Bovine Spermatozoa: Cytoprotective and Membrane-Stabilizing Effects
by Štefan Baňas, Eva Tvrdá, Filip Benko, Michal Ďuračka, Natália Čmiková, Norbert Lukáč and Miroslava Kačániová
Int. J. Mol. Sci. 2024, 25(7), 4129; https://doi.org/10.3390/ijms25074129 - 8 Apr 2024
Viewed by 751
Abstract
Kaempferol (KAE) is a natural flavonoid with powerful reactive oxygen species (ROS) scavenging properties and beneficial effects on ex vivo sperm functionality. In this paper, we studied the ability of KAE to prevent or ameliorate structural, functional or oxidative damage to frozen–thawed bovine [...] Read more.
Kaempferol (KAE) is a natural flavonoid with powerful reactive oxygen species (ROS) scavenging properties and beneficial effects on ex vivo sperm functionality. In this paper, we studied the ability of KAE to prevent or ameliorate structural, functional or oxidative damage to frozen–thawed bovine spermatozoa. The analysis focused on conventional sperm quality characteristics prior to or following thermoresistance tests, namely the oxidative profile of semen alongside sperm capacitation patterns, and the levels of key proteins involved in capacitation signaling. Semen samples obtained from 30 stud bulls were frozen in the presence of 12.5, 25 or 50 μM KAE and compared to native ejaculates (negative control—CtrlN) as well as semen samples cryopreserved in the absence of KAE (positive control—CtrlC). A significant post-thermoresistance test maintenance of the sperm motility (p < 0.001), membrane (p < 0.001) and acrosome integrity (p < 0.001), mitochondrial activity (p < 0.001) and DNA integrity (p < 0.001) was observed following supplementation with all KAE doses in comparison to CtrlC. Experimental groups supplemented with all KAE doses presented a significantly lower proportion of prematurely capacitated spermatozoa (p < 0.001) when compared with CtrlC. A significant decrease in the levels of the superoxide radical was recorded following administration of 12.5 (p < 0.05) and 25 μM KAE (p < 0.01). At the same time, supplementation with 25 μM KAE in the cryopreservation medium led to a significant stabilization of the activity of Mg2+-ATPase (p < 0.05) and Na+/K+-ATPase (p < 0.0001) in comparison to CtrlC. Western blot analysis revealed that supplementation with 25 μM KAE in the cryopreservation medium prevented the loss of the protein kinase A (PKA) and protein kinase C (PKC), which are intricately involved in the process of sperm activation. In conclusion, we may speculate that KAE is particularly efficient in the protection of sperm metabolism during the cryopreservation process through its ability to promote energy synthesis while quenching excessive ROS and to protect enzymes involved in the process of sperm capacitation and hyperactivation. These properties may provide supplementary protection to spermatozoa undergoing the freeze–thaw process. Full article
(This article belongs to the Special Issue A Molecular Perspective on Reproductive Health)
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18 pages, 4024 KiB  
Review
Insights on Platelet-Derived Growth Factor Receptor α-Positive Interstitial Cells in the Male Reproductive Tract
by Tasuku Hiroshige, Kei-Ichiro Uemura, Kei-Ichiro Nakamura and Tsukasa Igawa
Int. J. Mol. Sci. 2024, 25(7), 4128; https://doi.org/10.3390/ijms25074128 - 8 Apr 2024
Viewed by 564
Abstract
Male infertility is a significant factor in approximately half of all infertility cases and is marked by a decreased sperm count and motility. A decreased sperm count is caused by not only a decreased production of sperm but also decreased numbers successfully passing [...] Read more.
Male infertility is a significant factor in approximately half of all infertility cases and is marked by a decreased sperm count and motility. A decreased sperm count is caused by not only a decreased production of sperm but also decreased numbers successfully passing through the male reproductive tract. Smooth muscle movement may play an important role in sperm transport in the male reproductive tract; thus, understanding the mechanism of this movement is necessary to elucidate the cause of sperm transport disorder. Recent studies have highlighted the presence of platelet-derived growth factor receptor α (PDGFRα)-positive interstitial cells (PICs) in various smooth muscle organs. Although research is ongoing, PICs in the male reproductive tract may be involved in the regulation of smooth muscle movement, as they are in other smooth muscle organs. This review summarizes the findings to date on PICs in male reproductive organs. Further exploration of the structural, functional, and molecular characteristics of PICs could provide valuable insights into the pathogenesis of male infertility and potentially lead to new therapeutic approaches. Full article
(This article belongs to the Section Molecular Biology)
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24 pages, 3809 KiB  
Review
Biomolecular Condensates Decipher Molecular Codes of Cell Fate: From Biophysical Fundamentals to Therapeutic Practices
by Xing Sun, Yangyang Zhou, Zhiyan Wang, Menglan Peng, Xianhua Wei, Yifang Xie, Chengcai Wen, Jing Liu and Mao Ye
Int. J. Mol. Sci. 2024, 25(7), 4127; https://doi.org/10.3390/ijms25074127 - 8 Apr 2024
Viewed by 735
Abstract
Cell fate is precisely modulated by complex but well-tuned molecular signaling networks, whose spatial and temporal dysregulation commonly leads to hazardous diseases. Biomolecular condensates (BCs), as a newly emerging type of biophysical assemblies, decipher the molecular codes bridging molecular behaviors, signaling axes, and [...] Read more.
Cell fate is precisely modulated by complex but well-tuned molecular signaling networks, whose spatial and temporal dysregulation commonly leads to hazardous diseases. Biomolecular condensates (BCs), as a newly emerging type of biophysical assemblies, decipher the molecular codes bridging molecular behaviors, signaling axes, and clinical prognosis. Particularly, physical traits of BCs play an important role; however, a panoramic view from this perspective toward clinical practices remains lacking. In this review, we describe the most typical five physical traits of BCs, and comprehensively summarize their roles in molecular signaling axes and corresponding major determinants. Moreover, establishing the recent observed contribution of condensate physics on clinical therapeutics, we illustrate next-generation medical strategies by targeting condensate physics. Finally, the challenges and opportunities for future medical development along with the rapid scientific and technological advances are highlighted. Full article
(This article belongs to the Section Molecular Biophysics)
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15 pages, 2965 KiB  
Article
Soluble NKG2DLs Are Elevated in Breast Cancer Patients and Associate with Disease Outcome
by Anna Seller, Christian M. Tegeler, Jonas Mauermann, Tatjana Schreiber, Ilona Hagelstein, Kai Liebel, André Koch, Jonas S. Heitmann, Sarah M. Greiner, Clara Hayn, Dominik Dannehl, Tobias Engler, Andreas D. Hartkopf, Markus Hahn, Sara Y. Brucker, Helmut R. Salih and Melanie Märklin
Int. J. Mol. Sci. 2024, 25(7), 4126; https://doi.org/10.3390/ijms25074126 - 8 Apr 2024
Viewed by 829
Abstract
Ligands of the natural killer group 2D (NKG2DL) family are expressed on malignant cells and are usually absent from healthy tissues. Recognition of NKG2DLs such as MICA/B and ULBP1-3 by the activating immunoreceptor NKG2D, expressed by NK and cytotoxic T cells, stimulates anti-tumor [...] Read more.
Ligands of the natural killer group 2D (NKG2DL) family are expressed on malignant cells and are usually absent from healthy tissues. Recognition of NKG2DLs such as MICA/B and ULBP1-3 by the activating immunoreceptor NKG2D, expressed by NK and cytotoxic T cells, stimulates anti-tumor immunity in breast cancer. Upregulation of membrane-bound NKG2DLs in breast cancer has been demonstrated by immunohistochemistry. Tumor cells release NKG2DLs via proteolytic cleavage as soluble (s)NKG2DLs, which allows for effective immune escape and is associated with poor prognosis. In this study, we collected serum from 140 breast cancer (BC) and 20 ductal carcinoma in situ (DCIS) patients at the time of initial diagnosis and 20 healthy volunteers (HVs). Serum levels of sNKG2DLs were quantified through the use of ELISA and correlated with clinical data. The analyzed sNKG2DLs were low to absent in HVs and significantly higher in BC patients. For some of the ligands analyzed, higher sNKG2DLs serum levels were associated with the classification of malignant tumor (TNM) stage and grading. Low sMICA serum levels were associated with significantly longer progression-free (PFS) and overall survival (OS). In conclusion, we provide the first insights into sNKG2DLs in BC patients and suggest their potential role in tumor immune escape in breast cancer. Furthermore, our observations suggest that serum sMICA levels may serve as a prognostic parameter in the patients analyzed in this study. Full article
(This article belongs to the Special Issue Molecular Research in Breast Cancer: Pathophysiology and Treatment)
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19 pages, 4195 KiB  
Article
Energy Transfer and Radical-Pair Dynamics in Photosystem I with Different Red Chlorophyll a Pigments
by Ivo H. M. van Stokkum, Marc G. Müller and Alfred R. Holzwarth
Int. J. Mol. Sci. 2024, 25(7), 4125; https://doi.org/10.3390/ijms25074125 - 8 Apr 2024
Viewed by 591
Abstract
We establish a general kinetic scheme for the energy transfer and radical-pair dynamics in photosystem I (PSI) of Chlamydomonas reinhardtii, Synechocystis PCC6803, Thermosynechococcus elongatus and Spirulina platensis grown under white-light conditions. With the help of simultaneous target analysis of transient-absorption data sets [...] Read more.
We establish a general kinetic scheme for the energy transfer and radical-pair dynamics in photosystem I (PSI) of Chlamydomonas reinhardtii, Synechocystis PCC6803, Thermosynechococcus elongatus and Spirulina platensis grown under white-light conditions. With the help of simultaneous target analysis of transient-absorption data sets measured with two selective excitations, we resolved the spectral and kinetic properties of the different species present in PSI. WL-PSI can be described as a Bulk Chl a in equilibrium with a higher-energy Chl a, one or two Red Chl a and a reaction-center compartment (WL-RC). Three radical pairs (RPs) have been resolved with very similar properties in the four model organisms. The charge separation is virtually irreversible with a rate of ≈900 ns−1. The second rate, of RP1 → RP2, ranges from 70–90 ns−1 and the third rate, of RP2 → RP3, is ≈30 ns−1. Since RP1 and the Red Chl a are simultaneously present, resolving the RP1 properties is challenging. In Chlamydomonas reinhardtii, the excited WL-RC and Bulk Chl a compartments equilibrate with a lifetime of ≈0.28 ps, whereas the Red and the Bulk Chl a compartments equilibrate with a lifetime of ≈2.65 ps. We present a description of the thermodynamic properties of the model organisms at room temperature. Full article
(This article belongs to the Special Issue New Insights into Photosystem I)
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18 pages, 7405 KiB  
Article
Effect of Addition of Tannin Extract from Underutilized Resources on Allergenic Proteins, Color and Textural Properties of Egg White Gels
by Yoko Tsurunaga, Mika Ishigaki, Tetsuya Takahashi, Shiori Arima, Sae Kumagai, Yoshimasa Tsujii and Shota Koyama
Int. J. Mol. Sci. 2024, 25(7), 4124; https://doi.org/10.3390/ijms25074124 - 8 Apr 2024
Viewed by 667
Abstract
Tannins, present in numerous plants, exhibit a binding affinity for proteins. In this study, we aimed to exploit this property to reduce the concentration of allergenic egg white proteins. Tannins were extracted, using hot water, from the lyophilized powder of underutilized resources, such [...] Read more.
Tannins, present in numerous plants, exhibit a binding affinity for proteins. In this study, we aimed to exploit this property to reduce the concentration of allergenic egg white proteins. Tannins were extracted, using hot water, from the lyophilized powder of underutilized resources, such as chestnut inner skin (CIS), young persimmon fruit (YPF), and bayberry leaves (BBLs). These extracts were then incorporated into an egg white solution (EWS) to generate an egg white gel (EWG). Allergen reduction efficacy was assessed using electrophoresis and ELISA. Our findings revealed a substantial reduction in allergenic proteins across all EWGs containing a 50% tannin extract. Notably, CIS and BBL exhibited exceptional efficacy in reducing low allergen levels. The addition of tannin extract resulted in an increase in the total polyphenol content of the EWG, with the order of effectiveness being CIS > YPF > BBL. Minimal color alteration was observed in the BBL-infused EWG compared to the other sources. Additionally, the introduction of tannin extract heightened the hardness stress, with BBL demonstrating the most significant effect, followed by CIS and YPF. In conclusion, incorporating tannin extract during EWG preparation was found to decrease the concentration of allergenic proteins while enhancing antioxidant properties and hardness stress, with BBL being particularly effective in preventing color changes in EWG. Full article
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16 pages, 4642 KiB  
Article
Usefulness and Limitations of PFGE Diagnosis and Nucleotide Sequencing Method in the Analysis of Food Poisoning Pathogens Found in Cooking Employees
by Mi-Na Park, Sang-Gu Yeo, Junhyuk Park, Yoomi Jung and Se-Min Hwang
Int. J. Mol. Sci. 2024, 25(7), 4123; https://doi.org/10.3390/ijms25074123 - 8 Apr 2024
Viewed by 566
Abstract
In the case of a food poisoning outbreak, it is essential to understand the relationship between cooking workers and food poisoning. Many biological diagnostic methods have recently been developed to detect food poisoning pathogens. Among these diagnostic tools, this study presents PCR-based pulsed-field [...] Read more.
In the case of a food poisoning outbreak, it is essential to understand the relationship between cooking workers and food poisoning. Many biological diagnostic methods have recently been developed to detect food poisoning pathogens. Among these diagnostic tools, this study presents PCR-based pulsed-field gel electrophoresis and nucleotide sequencing diagnostic analysis results for diagnosing food poisoning outbreaks associated with cooking employees in Chungcheongnam-do, Republic of Korea. Pulsed-field gel electrophoresis was useful in identifying the food poisoning outbreaks caused by Staphylococcus aureus and Enteropathogenic Escherichia coli. In the case of Norovirus, nucleotide sequencing was used to identify the relationship between cooking workers and the food poisoning outbreak. However, it is difficult to determine whether cooking employees directly caused the food poisoning outbreaks based on these molecular biological diagnostic results alone. A system is needed to integrate epidemiological and diagnostic information to identify a direct correlation between the food poisoning outbreak and cooking employees. Full article
(This article belongs to the Special Issue New Breakthroughs in Molecular Diagnostic Tools for Human Diseases)
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16 pages, 4108 KiB  
Article
The Anti-Microbial Peptide Citrocin Controls Pseudomonas aeruginosa Biofilms by Breaking Down Extracellular Polysaccharide
by Liyao Wang, Jiaqi Zheng, Wenchao Hou, Chaowen Zhang, Jie Zhang, Xuanbo Fan, Hongliang Zhang and Yuzhu Han
Int. J. Mol. Sci. 2024, 25(7), 4122; https://doi.org/10.3390/ijms25074122 - 8 Apr 2024
Viewed by 628
Abstract
Citrocin is an anti-microbial peptide that holds great potential in animal feed. This study evaluates the anti-microbial and anti-biofilm properties of Citrocin and explores the mechanism of action of Citrocin on the biofilm of P. aeruginosa. The results showed that Citrocin had [...] Read more.
Citrocin is an anti-microbial peptide that holds great potential in animal feed. This study evaluates the anti-microbial and anti-biofilm properties of Citrocin and explores the mechanism of action of Citrocin on the biofilm of P. aeruginosa. The results showed that Citrocin had a significant inhibitory effect on the growth of P. aeruginosa with a minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of 0.3 mg/mL. All five concentrations (1/4MIC, 1/2MIC, MIC, 2MIC, and 4MIC) of Citrocin inhibited P. aeruginosa biofilm formation. Citrocin at the MIC, 2MIC and 4MIC removed 42.7%, 76.0% and 83.2% of mature biofilms, respectively, and suppressed the swarming motility, biofilm metabolic activity and extracellular polysaccharide production of P. aeruginosa. Metabolomics analysis indicated that 0.3 mg/mL of Citrocin up- regulated 26 and down-regulated 83 metabolites, mainly comprising amino acids, fatty acids, organic acids and sugars. Glucose and amino acid metabolic pathways, including starch and sucrose metabolism as well as arginine and proline metabolism, were highly enriched by Citrocin. In summary, our research reveals the anti-biofilm mechanism of Citrocin at the metabolic level, which provides theoretical support for the development of novel anti-biofilm strategies for combatting P. aeruginosa. Full article
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18 pages, 1958 KiB  
Article
Elucidating the Role of OXPHOS Variants in Asthenozoospermia: Insights from Whole Genome Sequencing and an In Silico Analysis
by Maria-Anna Kyrgiafini, Themistoklis Giannoulis, Alexia Chatziparasidou and Zissis Mamuris
Int. J. Mol. Sci. 2024, 25(7), 4121; https://doi.org/10.3390/ijms25074121 - 8 Apr 2024
Viewed by 533
Abstract
Infertility is a global health challenge that affects an estimated 72.4 million people worldwide. Between 30 and 50% of these cases involve male factors, showcasing the complex nature of male infertility, which can be attributed to both environmental and genetic determinants. Asthenozoospermia, a [...] Read more.
Infertility is a global health challenge that affects an estimated 72.4 million people worldwide. Between 30 and 50% of these cases involve male factors, showcasing the complex nature of male infertility, which can be attributed to both environmental and genetic determinants. Asthenozoospermia, a condition characterized by reduced sperm motility, stands out as a significant contributor to male infertility. This study explores the involvement of the mitochondrial oxidative phosphorylation (OXPHOS) system, crucial for ATP production and sperm motility, in asthenozoospermia. Through whole-genome sequencing and in silico analysis, our aim was to identify and characterize OXPHOS gene variants specific to individuals with asthenozoospermia. Our analysis identified 680,099 unique variants, with 309 located within OXPHOS genes. Nine of these variants were prioritized due to their significant implications, such as potential associations with diseases, effects on gene expression, protein function, etc. Interestingly, none of these variants had been previously associated with male infertility, opening up new avenues for research. Thus, through our comprehensive approach, we provide valuable insights into the genetic factors that influence sperm motility, laying the foundation for future research in the field of male infertility. Full article
(This article belongs to the Special Issue Mitochondrial DNA and RNA 2.0)
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15 pages, 1102 KiB  
Review
The Golgi Apparatus: A Key Player in Innate Immunity
by Ion Mărunţelu, Alexandra-Elena Constantinescu, Razvan-Adrian Covache-Busuioc and Ileana Constantinescu
Int. J. Mol. Sci. 2024, 25(7), 4120; https://doi.org/10.3390/ijms25074120 - 8 Apr 2024
Viewed by 890
Abstract
The Golgi apparatus, long recognized for its roles in protein processing and vesicular trafficking, has recently been identified as a crucial contributor to innate immune signaling pathways. This review discusses our expanding understanding of the Golgi apparatus’s involvement in initiating and activating these [...] Read more.
The Golgi apparatus, long recognized for its roles in protein processing and vesicular trafficking, has recently been identified as a crucial contributor to innate immune signaling pathways. This review discusses our expanding understanding of the Golgi apparatus’s involvement in initiating and activating these pathways. It highlights the significance of membrane connections between the Golgi and other organelles, such as the endoplasmic reticulum, mitochondria, endosomes, and autophagosomes. These connections are vital for the efficient transmission of innate immune signals and the activation of effector responses. Furthermore, the article delves into the Golgi apparatus’s roles in key immune pathways, including the inflammasome-mediated activation of caspase-1, the cGAS-STING pathway, and TLR/RLR signaling. Overall, this review aims to provide insights into the multifunctional nature of the Golgi apparatus and its impact on innate immunity. Full article
(This article belongs to the Special Issue Latest Review Papers in Molecular Immunology 2024)
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20 pages, 28759 KiB  
Article
The Effect of Composition on the Properties and Application of CuO-NiO Nanocomposites Synthesized Using a Saponin-Green/Microwave-Assisted Hydrothermal Method
by Amnah Al-Yunus, Wafa Al-Arjan, Hassan Traboulsi and Manal Hessien
Int. J. Mol. Sci. 2024, 25(7), 4119; https://doi.org/10.3390/ijms25074119 - 8 Apr 2024
Viewed by 514
Abstract
In this study, we explored the formation of CuO nanoparticles, NiO nanoflakes, and CuO-NiO nanocomposites using saponin extract and a microwave-assisted hydrothermal method. Five green synthetic samples were prepared using aqueous saponin extract and a microwave-assisted hydrothermal procedure at 200 °C for 30 [...] Read more.
In this study, we explored the formation of CuO nanoparticles, NiO nanoflakes, and CuO-NiO nanocomposites using saponin extract and a microwave-assisted hydrothermal method. Five green synthetic samples were prepared using aqueous saponin extract and a microwave-assisted hydrothermal procedure at 200 °C for 30 min. The samples were pristine copper oxide (100C), 75% copper oxide–25% nickel oxide (75C25N), 50% copper oxide–50% nickel oxide (50C50N), 25% copper oxide–75% nickel oxide (25C75N), and pristine nickel oxide (100N). The samples were characterized using FT-IR, XRD, XPS, SEM, and TEM. The XRD results showed that copper oxide and nickel oxide formed monoclinic and cubic phases, respectively. The morphology of the samples was useful and consisted of copper oxide nanoparticles and nickel oxide nanoflakes. XPS confirmed the +2 oxidation state of both the copper and nickel ions. Moreover, the optical bandgaps of copper oxide and nickel oxide were determined to be in the range of 1.29–1.6 eV and 3.36–3.63 eV, respectively, and the magnetic property studies showed that the synthesized samples exhibited ferromagnetic and superparamagnetic properties. In addition, the catalytic activity was tested against para-nitrophenol, demonstrating that the catalyst efficiency gradually improved in the presence of CuO. The highest rate constants were obtained for the 100C and 75C25N samples, with catalytic efficiencies of 98.7% and 78.2%, respectively, after 45 min. Full article
(This article belongs to the Special Issue Advanced Catalytic Materials)
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18 pages, 5801 KiB  
Article
Extracellular Vesicles as Surrogates for the Regulation of the Drug Transporters ABCC2 (MRP2) and ABCG2 (BCRP)
by Juan Pablo Rigalli, Anna Gagliardi, Klara Diester, Gzona Bajraktari-Sylejmani, Antje Blank, Jürgen Burhenne, Alexander Lenard, Lars Werntz, Andrea Huppertz, Lena Münch, Janica Margrit Wendt, Max Sauter, Walter Emil Haefeli and Johanna Weiss
Int. J. Mol. Sci. 2024, 25(7), 4118; https://doi.org/10.3390/ijms25074118 - 8 Apr 2024
Viewed by 751
Abstract
Drug efflux transporters of the ATP-binding-cassette superfamily play a major role in the availability and concentration of drugs at their site of action. ABCC2 (MRP2) and ABCG2 (BCRP) are among the most important drug transporters that determine the pharmacokinetics of many drugs and [...] Read more.
Drug efflux transporters of the ATP-binding-cassette superfamily play a major role in the availability and concentration of drugs at their site of action. ABCC2 (MRP2) and ABCG2 (BCRP) are among the most important drug transporters that determine the pharmacokinetics of many drugs and whose overexpression is associated with cancer chemoresistance. ABCC2 and ABCG2 expression is frequently altered during treatment, thus influencing efficacy and toxicity. Currently, there are no routine approaches available to closely monitor transporter expression. Here, we developed and validated a UPLC-MS/MS method to quantify ABCC2 and ABCG2 in extracellular vesicles (EVs) from cell culture and plasma. In this way, an association between ABCC2 protein levels and transporter activity in HepG2 cells treated with rifampicin and hypericin and their derived EVs was observed. Although ABCG2 was detected in MCF7 cell-derived EVs, the transporter levels in the vesicles did not reflect the expression in the cells. An analysis of plasma EVs from healthy volunteers confirmed, for the first time at the protein level, the presence of both transporters in more than half of the samples. Our findings support the potential of analyzing ABC transporters, and especially ABCC2, in EVs to estimate the transporter expression in HepG2 cells. Full article
(This article belongs to the Section Biochemistry)
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17 pages, 2357 KiB  
Article
Tumor and Peritoneum-Associated Macrophage Gene Signature as a Novel Molecular Biomarker in Gastric Cancer
by Kevin M. Sullivan, Haiqing Li, Annie Yang, Zhifang Zhang, Ruben R. Munoz, Kelly M. Mahuron, Yate-Ching Yuan, Isaac Benjamin Paz, Daniel Von Hoff, Haiyong Han, Yuman Fong and Yanghee Woo
Int. J. Mol. Sci. 2024, 25(7), 4117; https://doi.org/10.3390/ijms25074117 - 8 Apr 2024
Cited by 1 | Viewed by 1090
Abstract
A spectrum of immune states resulting from tumor resident macrophages and T-lymphocytes in the solid tumor microenvironment correlates with patient outcomes. We hypothesized that in gastric cancer (GC), macrophages in a polarized immunosuppressive transcriptional state would be prognostic of poor survival. We derived [...] Read more.
A spectrum of immune states resulting from tumor resident macrophages and T-lymphocytes in the solid tumor microenvironment correlates with patient outcomes. We hypothesized that in gastric cancer (GC), macrophages in a polarized immunosuppressive transcriptional state would be prognostic of poor survival. We derived transcriptomic signatures for M2 (M2TS, MRC1; MS4A4A; CD36; CCL13; CCL18; CCL23; SLC38A6; FGL2; FN1; MAF) and M1 (M1TS, CCR7; IL2RA; CXCL11; CCL19; CXCL10; PLA1A; PTX3) macrophages, and cytolytic T-lymphocytes (CTLTS, GZMA; GZMB; GZMH; GZMM; PRF1). Primary GC in a TCGA stomach cancer dataset was evaluated for signature expressions, and a log-rank test determined overall survival (OS) and the disease-free interval (DFI). In 341 TCGA GC entries, high M2TS expression was associated with histological types and later stages. Low M2TS expression was associated with significantly better 5-year OS and DFI. We validated M2TS in prospectively collected peritoneal fluid of a GC patient cohort (n = 28). Single-cell RNA sequencing was used for signature expression in CD68+CD163+ cells and the log-rank test compared OS. GC patients with high M2TS in CD68+CD163+ cells in their peritoneal fluid had significantly worse OS than those with low expression. Multivariate analyses confirmed M2TS was significantly and independently associated with survival. As an independent predictor of poor survival, M2TS may be prognostic in primary tumors and peritoneal fluid of GC patients. Full article
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17 pages, 4643 KiB  
Article
Genome-Wide Identification and Analysis of the EIN3/EIL Transcription Factor Gene Family in Doubled Haploid (DH) Poplar
by Caixia Liu, Erqin Fan, Yuhang Liu, Meng Wang, Qiuyu Wang, Sui Wang, Su Chen, Chuanping Yang, Xiangling You and Guanzheng Qu
Int. J. Mol. Sci. 2024, 25(7), 4116; https://doi.org/10.3390/ijms25074116 - 8 Apr 2024
Viewed by 607
Abstract
Ethylene (ET) is an important phytohormone that regulates plant growth, development and stress responses. The ethylene-insensitive3/ethylene-insensitive3-like (EIN3/EIL) transcription factor family, as a key regulator of the ET signal transduction pathway, plays an important role in regulating the expression of ET-responsive genes. Although studies [...] Read more.
Ethylene (ET) is an important phytohormone that regulates plant growth, development and stress responses. The ethylene-insensitive3/ethylene-insensitive3-like (EIN3/EIL) transcription factor family, as a key regulator of the ET signal transduction pathway, plays an important role in regulating the expression of ET-responsive genes. Although studies of EIN3/EIL family members have been completed in many species, their role in doubled haploid (DH) poplar derived from another culture of diploid Populus simonii × P. nigra (donor tree, DT) remains ambiguous. In this study, a total of seven EIN3/EIL gene family members in the DH poplar genome were identified. Basic physical and chemical property analyses of these genes were performed, and these proteins were predicted to be localized to the nucleus. According to the phylogenetic relationship, EIN3/EIL genes were divided into two groups, and the genes in the same group had a similar gene structure and conserved motifs. The expression patterns of EIN3/EIL genes in the apical buds of different DH poplar plants were analyzed based on transcriptome data. At the same time, the expression patterns of PsnEIL1, PsnEIN3, PsnEIL4 and PsnEIL5 genes in different tissues of different DH plants were detected via RT-qPCR, including the apical buds, young leaves, functional leaves, xylem, cambium and roots. The findings presented above indicate notable variations in the expression levels of PsnEIL genes across various tissues of distinct DH plants. Finally, the PsnEIL1 gene was overexpressed in DT, and the transgenic plants showed a dwarf phenotype, indicating that the PsnEIL1 gene was involved in regulating the growth and development of poplar. In this study, the EIN3/EIL gene family of DH poplar was analyzed and functionally characterized, which provides a theoretical basis for the future exploration of the EIN3/EIL gene function. Full article
(This article belongs to the Special Issue Latest Research on Plant Genomics and Genome Editing)
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8 pages, 1369 KiB  
Brief Report
The Oligomeric State of Vasorin in the Plasma Membrane Measured Non-Invasively by Quantitative Fluorescence Fluctuation Spectroscopy
by Junyi Liang and Adam W. Smith
Int. J. Mol. Sci. 2024, 25(7), 4115; https://doi.org/10.3390/ijms25074115 - 8 Apr 2024
Viewed by 450
Abstract
Vasorin (VASN), a transmembrane protein heavily expressed in endothelial cells, has garnered recent interest due to its key role in vascular development and pathology. The oligomeric state of VASN is a crucial piece of knowledge given that receptor clustering is a frequent regulatory [...] Read more.
Vasorin (VASN), a transmembrane protein heavily expressed in endothelial cells, has garnered recent interest due to its key role in vascular development and pathology. The oligomeric state of VASN is a crucial piece of knowledge given that receptor clustering is a frequent regulatory mechanism in downstream signaling activation and amplification. However, documentation of VASN oligomerization is currently absent. In this brief report, we describe the measurement of VASN oligomerization in its native membranous environment, leveraging a class of fluorescence fluctuation spectroscopy. Our investigation revealed that the majority of VASN resides in a monomeric state, while a minority of VASN forms homodimers in the cellular membrane. This result raises the intriguing possibility that ligand-independent clustering of VASN may play a role in transforming growth factor signaling. Full article
(This article belongs to the Section Biochemistry)
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17 pages, 1172 KiB  
Review
Research Progress of Small Plant Peptides on the Regulation of Plant Growth, Development, and Abiotic Stress
by Guocheng Ren, Yanling Zhang, Zengting Chen, Xin Xue and Hai Fan
Int. J. Mol. Sci. 2024, 25(7), 4114; https://doi.org/10.3390/ijms25074114 - 8 Apr 2024
Viewed by 757
Abstract
Small peptides in plants are typically characterized as being shorter than 120 amino acids, with their biologically active variants comprising fewer than 20 amino acids. These peptides are instrumental in regulating plant growth, development, and physiological processes, even at minimal concentrations. They play [...] Read more.
Small peptides in plants are typically characterized as being shorter than 120 amino acids, with their biologically active variants comprising fewer than 20 amino acids. These peptides are instrumental in regulating plant growth, development, and physiological processes, even at minimal concentrations. They play a critical role in long-distance signal transduction within plants and act as primary responders to a range of stress conditions, including salinity, alkalinity, drought, high temperatures, and cold. This review highlights the crucial roles of various small peptides in plant growth and development, plant resistance to abiotic stress, and their involvement in long-distance transport. Furthermore, it elaborates their roles in the regulation of plant hormone biosynthesis. Special emphasis is given to the functions and mechanisms of small peptides in plants responding to abiotic stress conditions, aiming to provide valuable insights for researchers working on the comprehensive study and practical application of small peptides. Full article
(This article belongs to the Special Issue Advance in Plant Abiotic Stress)
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29 pages, 2019 KiB  
Review
Biological Basis of Breast Cancer-Related Disparities in Precision Oncology Era
by Anca-Narcisa Neagu, Pathea Bruno, Kaya R. Johnson, Gabriella Ballestas and Costel C. Darie
Int. J. Mol. Sci. 2024, 25(7), 4113; https://doi.org/10.3390/ijms25074113 - 8 Apr 2024
Viewed by 3216
Abstract
Precision oncology is based on deep knowledge of the molecular profile of tumors, allowing for more accurate and personalized therapy for specific groups of patients who are different in disease susceptibility as well as treatment response. Thus, onco-breastomics is able to discover novel [...] Read more.
Precision oncology is based on deep knowledge of the molecular profile of tumors, allowing for more accurate and personalized therapy for specific groups of patients who are different in disease susceptibility as well as treatment response. Thus, onco-breastomics is able to discover novel biomarkers that have been found to have racial and ethnic differences, among other types of disparities such as chronological or biological age-, sex/gender- or environmental-related ones. Usually, evidence suggests that breast cancer (BC) disparities are due to ethnicity, aging rate, socioeconomic position, environmental or chemical exposures, psycho-social stressors, comorbidities, Western lifestyle, poverty and rurality, or organizational and health care system factors or access. The aim of this review was to deepen the understanding of BC-related disparities, mainly from a biomedical perspective, which includes genomic-based differences, disparities in breast tumor biology and developmental biology, differences in breast tumors’ immune and metabolic landscapes, ecological factors involved in these disparities as well as microbiomics- and metagenomics-based disparities in BC. We can conclude that onco-breastomics, in principle, based on genomics, proteomics, epigenomics, hormonomics, metabolomics and exposomics data, is able to characterize the multiple biological processes and molecular pathways involved in BC disparities, clarifying the differences in incidence, mortality and treatment response for different groups of BC patients. Full article
(This article belongs to the Special Issue Cancer Genomics and Precision Oncology)
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11 pages, 4324 KiB  
Article
Interaction of Nipah Virus F and G with the Cellular Protein Cortactin Discovered by a Proximity Interactome Assay
by Chunmei Cui, Pengfei Hao, Chaozhi Jin, Wang Xu, Yuchen Liu, Letian Li, Shouwen Du, Limin Shang, Xin Jin, Ningyi Jin, Jian Wang and Chang Li
Int. J. Mol. Sci. 2024, 25(7), 4112; https://doi.org/10.3390/ijms25074112 - 8 Apr 2024
Viewed by 662
Abstract
Nipah virus (NiV) is a highly lethal zoonotic virus with a potential large-scale outbreak, which poses a great threat to world health and security. In order to explore more potential factors associated with NiV, a proximity labeling method was applied to investigate the [...] Read more.
Nipah virus (NiV) is a highly lethal zoonotic virus with a potential large-scale outbreak, which poses a great threat to world health and security. In order to explore more potential factors associated with NiV, a proximity labeling method was applied to investigate the F, G, and host protein interactions systematically. We screened 1996 and 1524 high-confidence host proteins that interacted with the NiV fusion (F) glycoprotein and attachment (G) glycoprotein in HEK293T cells by proximity labeling technology, and 863 of them interacted with both F and G. The results of GO and KEGG enrichment analysis showed that most of these host proteins were involved in cellular processes, molecular binding, endocytosis, tight junction, and other functions. Cytoscape software (v3.9.1) was used for visual analysis, and the results showed that Cortactin (CTTN), Serpine mRNA binding protein 1 (SERBP1), and stathmin 1 (STMN1) were the top 20 proteins and interacted with F and G, and were selected for further validation. We observed colocalization of F-CTTN, F-SERBP1, F-STMN1, G-CTTN, G-SERBP1, and G-STMN1 using confocal fluorescence microscopy, and the results showed that CTTN, SERBP1, and STMN1 overlapped with NiV F and NiV G in HEK293T cells. Further studies found that CTTN can significantly inhibit the infection of the Nipah pseudovirus (NiVpv) into host cells, while SERBP1 and STMN1 had no significant effect on pseudovirus infection. In addition, CTTN can also inhibit the infection of the Hendra pseudovirus (HeVpv) in 293T cells. In summary, this study revealed that the potential host proteins interacted with NiV F and G and demonstrated that CTTN could inhibit NiVpv and HeVpv infection, providing new evidence and targets for the study of drugs against these diseases. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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15 pages, 10118 KiB  
Article
Overexpression of AtMYB2 Promotes Tolerance to Salt Stress and Accumulations of Tanshinones and Phenolic Acid in Salvia miltiorrhiza
by Tianyu Li, Shuangshuang Zhang, Yidan Li, Lipeng Zhang, Wenqin Song and Chengbin Chen
Int. J. Mol. Sci. 2024, 25(7), 4111; https://doi.org/10.3390/ijms25074111 - 8 Apr 2024
Viewed by 617
Abstract
Salvia miltiorrhiza is a prized traditional Chinese medicinal plant species. Its red storage roots are primarily used for the treatment of cardiovascular and cerebrovascular diseases. In this study, a transcription factor gene AtMYB2 was cloned and introduced into Salvia miltiorrhiza for ectopic expression. [...] Read more.
Salvia miltiorrhiza is a prized traditional Chinese medicinal plant species. Its red storage roots are primarily used for the treatment of cardiovascular and cerebrovascular diseases. In this study, a transcription factor gene AtMYB2 was cloned and introduced into Salvia miltiorrhiza for ectopic expression. Overexpression of AtMYB2 enhanced salt stress resistance in S. miltiorrhiza, leading to a more resilient phenotype in transgenic plants exposed to high-salinity conditions. Physiological experiments have revealed that overexpression of AtMYB2 can decrease the accumulation of reactive oxygen species (ROS) during salt stress, boost the activity of antioxidant enzymes, and mitigate oxidative damage to cell membranes. In addition, overexpression of AtMYB2 promotes the synthesis of tanshinones and phenolic acids by upregulating the expression of biosynthetic pathway genes, resulting in increased levels of these secondary metabolites. In summary, our findings demonstrate that AtMYB2 not only enhances plant tolerance to salt stress, but also increases the accumulation of secondary metabolites in S. miltiorrhiza. Our study lays a solid foundation for uncovering the molecular mechanisms governed by AtMYB2 and holds significant implications for the molecular breeding of high-quality S. miltiorrhiza varieties. Full article
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30 pages, 18286 KiB  
Review
X-Linked Epilepsies: A Narrative Review
by Pia Bernardo, Claudia Cuccurullo, Marica Rubino, Gabriella De Vita, Gaetano Terrone, Leonilda Bilo and Antonietta Coppola
Int. J. Mol. Sci. 2024, 25(7), 4110; https://doi.org/10.3390/ijms25074110 - 8 Apr 2024
Viewed by 967
Abstract
X-linked epilepsies are a heterogeneous group of epileptic conditions, which often overlap with X-linked intellectual disability. To date, various X-linked genes responsible for epilepsy syndromes and/or developmental and epileptic encephalopathies have been recognized. The electro-clinical phenotype is well described for some genes in [...] Read more.
X-linked epilepsies are a heterogeneous group of epileptic conditions, which often overlap with X-linked intellectual disability. To date, various X-linked genes responsible for epilepsy syndromes and/or developmental and epileptic encephalopathies have been recognized. The electro-clinical phenotype is well described for some genes in which epilepsy represents the core symptom, while less phenotypic details have been reported for other recently identified genes. In this review, we comprehensively describe the main features of both X-linked epileptic syndromes thoroughly characterized to date (PCDH19-related DEE, CDKL5-related DEE, MECP2-related disorders), forms of epilepsy related to X-linked neuronal migration disorders (e.g., ARX, DCX, FLNA) and DEEs associated with recently recognized genes (e.g., SLC9A6, SLC35A2, SYN1, ARHGEF9, ATP6AP2, IQSEC2, NEXMIF, PIGA, ALG13, FGF13, GRIA3, SMC1A). It is often difficult to suspect an X-linked mode of transmission in an epilepsy syndrome. Indeed, different models of X-linked inheritance and modifying factors, including epigenetic regulation and X-chromosome inactivation in females, may further complicate genotype–phenotype correlations. The purpose of this work is to provide an extensive and updated narrative review of X-linked epilepsies. This review could support clinicians in the genetic diagnosis and treatment of patients with epilepsy featuring X-linked inheritance. Full article
(This article belongs to the Special Issue Molecular Advances in Epilepsy and Seizures)
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18 pages, 4447 KiB  
Article
Characterization of Biomarkers of Thrombo-Inflammation in Patients with First-Diagnosed Atrial Fibrillation
by Julian Friebel, Max Wegner, Leon Blöbaum, Philipp-Alexander Schencke, Kai Jakobs, Marianna Puccini, Emily Ghanbari, Stella Lammel, Tharusan Thevathasan, Verena Moos, Marco Witkowski, Ulf Landmesser and Ursula Rauch-Kröhnert
Int. J. Mol. Sci. 2024, 25(7), 4109; https://doi.org/10.3390/ijms25074109 - 8 Apr 2024
Viewed by 628
Abstract
Patients with first-diagnosed atrial fibrillation (FDAF) exhibit major adverse cardiovascular events (MACEs) during follow-up. Preclinical models have demonstrated that thrombo-inflammation mediates adverse cardiac remodeling and atherothrombotic events. We have hypothesized that thrombin activity (FIIa) links coagulation with inflammation and cardiac fibrosis/dysfunction. Surrogate markers [...] Read more.
Patients with first-diagnosed atrial fibrillation (FDAF) exhibit major adverse cardiovascular events (MACEs) during follow-up. Preclinical models have demonstrated that thrombo-inflammation mediates adverse cardiac remodeling and atherothrombotic events. We have hypothesized that thrombin activity (FIIa) links coagulation with inflammation and cardiac fibrosis/dysfunction. Surrogate markers of the thrombo-inflammatory response in plasma have not been characterized in FDAF. In this prospective longitudinal study, patients presenting with FDAF (n = 80), and 20 matched controls, were included. FIIa generation and activity in plasma were increased in the patients with early AF compared to the patients with chronic cardiovascular disease without AF (controls; p < 0.0001). This increase was accompanied by elevated biomarkers (ELISA) of platelet and endothelial activation in plasma. Pro-inflammatory peripheral immune cells (TNF-α+ or IL-6+) that expressed FIIa-activated protease-activated receptor 1 (PAR1) (flow cytometry) circulated more frequently in patients with FDAF compared to the controls (p < 0.0001). FIIa activity correlated with cardiac fibrosis (collagen turnover) and cardiac dysfunction (NT-pro ANP/NT-pro BNP) surrogate markers. FIIa activity in plasma was higher in patients with FDAF who experienced MACE. Signaling via FIIa might be a presumed link between the coagulation system (tissue factor-FXa/FIIa-PAR1 axis), inflammation, and pro-fibrotic pathways (thrombo-inflammation) in FDAF. Full article
(This article belongs to the Special Issue New Advances in Thrombosis 2.0)
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8 pages, 1441 KiB  
Article
Effect of Empagliflozin with or without the Addition of Evolocumab on HDL Subspecies in Individuals with Type 2 Diabetes Mellitus: A Post Hoc Analysis of the EXCEED-BHS3 Trial
by Isabella Bonilha, Érica Ivana Lázaro Gomes, Helison R. P. Carmo, Ikaro Breder, Joaquim Barreto, Jessica Breder, Daniel B. Munhoz, Luiz Sergio F. Carvalho, Thiago Quinaglia, Sheila T. Kimura-Medorima, Camila Moreira Gossi, Francesca Zimetti, Wilson Nadruz, Ilaria Zanotti and Andrei C. Sposito
Int. J. Mol. Sci. 2024, 25(7), 4108; https://doi.org/10.3390/ijms25074108 - 8 Apr 2024
Viewed by 607
Abstract
Evolocumab and empagliflozin yield a modest rise in plasma high-density lipoprotein cholesterol (HDL-C) through unknown mechanisms. This study aims to assess the effect of evolocumab plus empagliflozin vs. empagliflozin alone on HDL subspecies isolated from individuals with type 2 diabetes mellitus (T2D). This [...] Read more.
Evolocumab and empagliflozin yield a modest rise in plasma high-density lipoprotein cholesterol (HDL-C) through unknown mechanisms. This study aims to assess the effect of evolocumab plus empagliflozin vs. empagliflozin alone on HDL subspecies isolated from individuals with type 2 diabetes mellitus (T2D). This post hoc prespecified analysis of the EXCEED-BHS3 trial compared the effects of a 16-week therapy with empagliflozin (E) alone or in combination with evolocumab (EE) on the lipid profile and cholesterol content in HDL subspecies in individuals with T2D divided equally into two groups of 55 patients. Both treatments modestly increased HDL-C. The cholesterol content in HDL subspecies 2a (7.3%), 3a (7.2%) and 3c (15%) increased from baseline in the E group, while the EE group presented an increase from baseline in 3a (9.3%), 3b (16%) and 3c (25%). The increase in HDL 3b and 3c was higher in the EE group when compared to the E group (p < 0.05). No significant interactive association was observed between changes in hematocrit and HDL-C levels after treatment. Over a 16-week period, empagliflozin with or without the addition of evolocumab led to a modest but significant increase in HDL-C. The rise in smaller-sized HDL particles was heterogeneous amongst the treatment combinations. Full article
(This article belongs to the Special Issue Apolipoproteins and Lipoproteins in Health and Disease 2.0)
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14 pages, 3030 KiB  
Article
The Catalytic Activity of Human REV1 on Undamaged and Damaged DNA
by Anastasia D. Stolyarenko, Anna A. Novikova, Evgeniy S. Shilkin, Valentin A. Poltorachenko and Alena V. Makarova
Int. J. Mol. Sci. 2024, 25(7), 4107; https://doi.org/10.3390/ijms25074107 - 8 Apr 2024
Viewed by 602
Abstract
Eukaryotic REV1 serves as a scaffold protein for the coordination of DNA polymerases during DNA translesion synthesis. Besides this structural role, REV1 is a Y-family DNA polymerase with its own distributive deoxycytidyl transferase activity. However, data about the accuracy and efficiency of DNA [...] Read more.
Eukaryotic REV1 serves as a scaffold protein for the coordination of DNA polymerases during DNA translesion synthesis. Besides this structural role, REV1 is a Y-family DNA polymerase with its own distributive deoxycytidyl transferase activity. However, data about the accuracy and efficiency of DNA synthesis by REV1 in the literature are contrasting. Here, we expressed and purified the full-length human REV1 from Saccharomyces cerevisiae and characterized its activity on undamaged DNA and a wide range of damaged DNA templates. We demonstrated that REV1 carried out accurate synthesis opposite 8-oxoG and O6-meG with moderate efficiency. It also replicated thymine glycol surprisingly well in an error-prone manner, but was blocked by the intrastrand 1,2-GG cisplatin crosslink. By using the 1,N6-ethenoadenine and 7-deaza-adenine lesions, we have provided biochemical evidence of the importance for REV1 functioning of the Hoogsteen face of template A, the second preferable template after G. Full article
(This article belongs to the Section Biochemistry)
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14 pages, 1019 KiB  
Review
Iron Supplementation of Pregnant Sows to Prevent Iron Deficiency Anemia in Piglets: A Procedure of Questionable Effectiveness
by Rafał Mazgaj, Paweł Lipiński and Rafał R. Starzyński
Int. J. Mol. Sci. 2024, 25(7), 4106; https://doi.org/10.3390/ijms25074106 - 8 Apr 2024
Viewed by 929
Abstract
In pigs, iron deficiency anemia (IDA) is a common disorder that occurs during the early postnatal period, leading to the stunted growth and increased mortality of piglets. The main cause of IDA is low iron stores in the liver of newborn piglets; these [...] Read more.
In pigs, iron deficiency anemia (IDA) is a common disorder that occurs during the early postnatal period, leading to the stunted growth and increased mortality of piglets. The main cause of IDA is low iron stores in the liver of newborn piglets; these stores constitute the main source of iron needed to satisfy the erythropoietic requirements of the piglets in their first weeks of life. Insufficient iron stores in piglets are usually due to the inadequate placental iron transfer from the sow to the fetuses. Therefore, iron supplementation in pregnant sows has been implemented to enhance placental iron transfer and increase iron accumulation in the liver of the fetuses. Over the years, several oral and parenteral approaches have been attempted to supplement sows with various iron preparations, and consequently, to improve piglets’ red blood cell indices. However, there is debate with regard to the effectiveness of iron supplementation in pregnant sows for preventing IDA in newborn piglets. Importantly, this procedure should be carried out with caution to avoid iron over-supplementation, which can lead to iron toxicity. This article aims to critically review and evaluate the use of iron supplementation in pregnant sows as a procedure for preventing IDA in piglets. Full article
(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Iron Homeostasis)
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13 pages, 2313 KiB  
Article
Lentivirus-Mediated BCL-XL Overexpression Inhibits Stem Cell Apoptosis during Ex Vivo Expansion and Provides Competitive Advantage Following Xenotransplantation
by Patricia M. A. Zehnle, Ying Wu, Naile Koleci, Sheila Bohler and Miriam Erlacher
Int. J. Mol. Sci. 2024, 25(7), 4105; https://doi.org/10.3390/ijms25074105 - 7 Apr 2024
Viewed by 699
Abstract
Hematopoietic reconstitution after hematopoietic stem cell transplantation (HSCT) is influenced by the number of transplanted cells. However, under certain conditions donor cell counts are limited and impair clinical outcome. Hematopoietic stem and progenitor cell (HSPC) expansion prior to HSCT is a widely used [...] Read more.
Hematopoietic reconstitution after hematopoietic stem cell transplantation (HSCT) is influenced by the number of transplanted cells. However, under certain conditions donor cell counts are limited and impair clinical outcome. Hematopoietic stem and progenitor cell (HSPC) expansion prior to HSCT is a widely used method to achieve higher donor cell counts and minimize transplantation-related risks such as graft failure or delayed engraftment. Still, expansion in a non-physiological environment can trigger cell death mechanisms and hence counteract the desired effect. We have shown earlier that during HSCT a relevant amount of HSPCs were lost due to apoptosis and that cell death inhibition in donor HSPCs improved engraftment in xenotransplantation experiments. Here, we assessed the effect of combined ex vivo expansion and cell death inhibition on HSPC yield and their reconstitution potential in vivo. During expansion with cytokines and the small molecule inhibitor StemRegenin 1, concomitant lentiviral overexpression of antiapoptotic BCL-XL resulted in an increased yield of transduced HSPCs. Importantly, BCL-XL overexpression enhanced the reconstitution potential of HSPCs in xenotransplantation experiments in vivo. In contrast, treatment with caspase and necroptosis inhibitors had no favorable effects on HSPC yields nor on cell viability. We postulate that overexpression of antiapoptotic BCL-XL, both during ex vivo expansion and transplantation, is a promising approach to improve the outcome of HSCT in situations with limited donor cell numbers. However, such apoptosis inhibition needs to be transient to avoid long-term sequelae like leukemia. Full article
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