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Volume 25
Issue 12
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Int. J. Mol. Sci., Volume 25, Issue 12 (June-2 2024) – 525 articles

Cover Story (view full-size image): Tau, glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL), as brain protein biomarkers, have the potential to improve diagnostic accuracy, disease monitoring, prognostic assessment and treatment efficacy. These biomarkers are released into the cerebrospinal fluid (CSF) and blood proportionally to the degree of neuron and astrocyte damage in different neurological disorders, including stroke, traumatic brain injury, multiple sclerosis, neurodegenerative dementia and Parkinson’s disease. Here, we review how Tau, GFAP and NfL biomarkers are detected in CSF and blood as crucial diagnostic tools, as well as the levels of these biomarkers used for differentiating a range of neurological diseases and monitoring disease progression. View this paper
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41 pages, 1975 KiB  
Review
Genetic and Biotechnological Approaches to Improve Fruit Bioactive Content: A Focus on Eggplant and Tomato Anthocyanins
by Maria Cammareri, Amy Frary, Anne Frary and Silvana Grandillo
Int. J. Mol. Sci. 2024, 25(12), 6811; https://doi.org/10.3390/ijms25126811 - 20 Jun 2024
Cited by 1 | Viewed by 1537
Abstract
Anthocyanins are a large group of water-soluble flavonoid pigments. These specialized metabolites are ubiquitous in the plant kingdom and play an essential role not only in plant reproduction and dispersal but also in responses to biotic and abiotic stresses. Anthocyanins are recognized as [...] Read more.
Anthocyanins are a large group of water-soluble flavonoid pigments. These specialized metabolites are ubiquitous in the plant kingdom and play an essential role not only in plant reproduction and dispersal but also in responses to biotic and abiotic stresses. Anthocyanins are recognized as important health-promoting and chronic-disease-preventing components in the human diet. Therefore, interest in developing food crops with improved levels and compositions of these important nutraceuticals is growing. This review focuses on work conducted to elucidate the genetic control of the anthocyanin pathway and modulate anthocyanin content in eggplant (Solanum melongena L.) and tomato (Solanum lycopersicum L.), two solanaceous fruit vegetables of worldwide relevance. While anthocyanin levels in eggplant fruit have always been an important quality trait, anthocyanin-based, purple-fruited tomato cultivars are currently a novelty. As detailed in this review, this difference in the anthocyanin content of the cultivated germplasm has largely influenced genetic studies as well as breeding and transgenic approaches to improve the anthocyanin content/profile of these two important solanaceous crops. The information provided should be of help to researchers and breeders in devising strategies to address the increasing consumer demand for nutraceutical foods. Full article
(This article belongs to the Special Issue Advances in Genetics, Epigenetics and Postharvest Biology of Fruits)
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19 pages, 10685 KiB  
Article
Evaluation of Microvascular Density in Glioblastomas in Relation to p53 and Ki67 Immunoexpression
by Tamás-Csaba Sipos, Attila Kövecsi, Lóránd Kocsis, Monica Nagy-Bota and Zsuzsánna Pap
Int. J. Mol. Sci. 2024, 25(12), 6810; https://doi.org/10.3390/ijms25126810 - 20 Jun 2024
Viewed by 956
Abstract
Glioblastoma is the most aggressive tumor in the central nervous system, with a survival rate of less than 15 months despite multimodal therapy. Tumor recurrence frequently occurs after removal. Tumoral angiogenesis, the formation of neovessels, has a positive impact on tumor progression and [...] Read more.
Glioblastoma is the most aggressive tumor in the central nervous system, with a survival rate of less than 15 months despite multimodal therapy. Tumor recurrence frequently occurs after removal. Tumoral angiogenesis, the formation of neovessels, has a positive impact on tumor progression and invasion, although there are controversial results in the specialized literature regarding its impact on survival. This study aims to correlate the immunoexpression of angiogenesis markers (CD34, CD105) with the proliferation index Ki67 and p53 in primary and secondary glioblastomas. This retrospective study included 54 patients diagnosed with glioblastoma at the Pathology Department of County Emergency Clinical Hospital Târgu Mureș. Microvascular density was determined using CD34 and CD105 antibodies, and the results were correlated with the immunoexpression of p53, IDH1, ATRX and Ki67. The number of neoformed blood vessels varied among cases, characterized by different shapes and calibers, with endothelial cells showing modified morphology and moderate to marked pleomorphism. Neovessels with a glomeruloid aspect, associated with intense positivity for CD34 or CD105 in endothelial cells, were observed, characteristic of glioblastomas. Mean microvascular density values were higher for the CD34 marker in all cases, though there were no statistically significant differences compared to CD105. Mutant IDH1 and ATRX glioblastomas, wild-type p53 glioblastomas, and those with a Ki67 index above 20% showed a more abundant microvascular density, with statistical correlations not reaching significance. This study highlighted a variety of percentage intervals of microvascular density in primary and secondary glioblastomas using immunohistochemical markers CD34 and CD105, respectively, with no statistically significant correlation between evaluated microvascular density and p53 or Ki67. Full article
(This article belongs to the Special Issue Current Developments in Glioblastoma Research and Therapy)
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18 pages, 5986 KiB  
Article
Regulation and Response Mechanism of Acute Low-Salinity Stress during Larval Stages in Macrobrachium rosenbergii Based on Multi-Omics Analysis
by Xilian Li, Binpeng Xu, Peijing Shen, Haihua Cheng, Yunpeng Fan and Qiang Gao
Int. J. Mol. Sci. 2024, 25(12), 6809; https://doi.org/10.3390/ijms25126809 - 20 Jun 2024
Viewed by 861
Abstract
Macrobrachium rosenbergii is an essential species for freshwater economic aquaculture in China, but in the larval process, their salinity requirement is high, which leads to salinity stress in the water. In order to elucidate the mechanisms regulating the response of M. rosenbergii to [...] Read more.
Macrobrachium rosenbergii is an essential species for freshwater economic aquaculture in China, but in the larval process, their salinity requirement is high, which leads to salinity stress in the water. In order to elucidate the mechanisms regulating the response of M. rosenbergii to acute low-salinity exposure, we conducted a comprehensive study of the response of M. rosenbergii exposed to different salinities’ (0‰, 6‰, and 12‰) data for 120 h. The activities of catalase, superoxide dismutase, and glutathione peroxidase were found to be significantly inhibited in the hepatopancreas and muscle following low-salinity exposure, resulting in oxidative damage and immune deficits in M. rosenbergii. Differential gene enrichment in transcriptomics indicated that low-salinity stress induced metabolic differences and immune and inflammatory dysfunction in M. rosenbergii. The differential expressions of MIH, JHEH, and EcR genes indicated the inhibition of growth, development, and molting ability of M. rosenbergii. At the proteomic level, low salinity induced metabolic differences and affected biological and cellular regulation, as well as the immune response. Tyramine, trans-1,2-Cyclohexanediol, sorbitol, acetylcholine chloride, and chloroquine were screened by metabolomics as differential metabolic markers. In addition, combined multi-omics analysis revealed that metabolite chloroquine was highly correlated with low-salt stress. Full article
(This article belongs to the Section Molecular Biology)
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12 pages, 2051 KiB  
Article
Inhibition of Toll-like Receptors Alters Macrophage Cholesterol Efflux and Foam Cell Formation
by Jaemi Kim, Ji-Yun Kim, Hye-Eun Byeon, Ji-Won Kim, Hyoun-Ah Kim, Chang-Hee Suh, Sangdun Choi, MacRae F. Linton and Ju-Yang Jung
Int. J. Mol. Sci. 2024, 25(12), 6808; https://doi.org/10.3390/ijms25126808 - 20 Jun 2024
Cited by 1 | Viewed by 1286
Abstract
Arterial macrophage cholesterol accumulation and impaired cholesterol efflux lead to foam cell formation and the development of atherosclerosis. Modified lipoproteins interact with toll-like receptors (TLR), causing an increased inflammatory response and altered cholesterol homeostasis. We aimed to determine the effects of TLR antagonists [...] Read more.
Arterial macrophage cholesterol accumulation and impaired cholesterol efflux lead to foam cell formation and the development of atherosclerosis. Modified lipoproteins interact with toll-like receptors (TLR), causing an increased inflammatory response and altered cholesterol homeostasis. We aimed to determine the effects of TLR antagonists on cholesterol efflux and foam cell formation in human macrophages. Stimulated monocytes were treated with TLR antagonists (MIP2), and the cholesterol efflux transporter expression and foam cell formation were analyzed. The administration of MIP2 attenuated the foam cell formation induced by lipopolysaccharides (LPS) and oxidized low-density lipoproteins (ox-LDL) in stimulated THP-1 cells (p < 0.001). The expression of ATP-binding cassette transporters A (ABCA)-1, ABCG-1, scavenger receptor (SR)-B1, liver X receptor (LXR)-α, and peroxisome proliferator-activated receptor (PPAR)-γ mRNA and proteins were increased (p < 0.001) following MIP2 administration. A concentration-dependent decrease in the phosphorylation of p65, p38, and JNK was also observed following MIP2 administration. Moreover, an inhibition of p65 phosphorylation enhanced the expression of ABCA1, ABCG1, SR-B1, and LXR-α. TLR inhibition promoted the cholesterol efflux pathway by increasing the expression of ABCA-1, ABCG-1, and SR-B1, thereby reducing foam cell formation. Our results suggest a potential role of the p65/NF-kB/LXR-α/ABCA1 axis in TLR-mediated cholesterol homeostasis. Full article
(This article belongs to the Section Molecular Endocrinology and Metabolism)
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14 pages, 6730 KiB  
Article
Accelerated Electron Ionization-Induced Changes in the Myenteric Plexus of the Rat Stomach
by Raina Ardasheva, Veselin Popov, Viktor Yotov, Natalia Prissadova, Mina Pencheva, Iva Slavova, Valentin Turiyski and Athanas Krastev
Int. J. Mol. Sci. 2024, 25(12), 6807; https://doi.org/10.3390/ijms25126807 - 20 Jun 2024
Viewed by 794
Abstract
The influence of accelerated electrons on neuronal structures is scarcely explored compared to gamma and X-rays. This study aims to investigate the effects of accelerated electron radiation on some pivotal neurotransmitter circuits (cholinergic and serotonergic) of rats’ myenteric plexus. Male Wistar rats were [...] Read more.
The influence of accelerated electrons on neuronal structures is scarcely explored compared to gamma and X-rays. This study aims to investigate the effects of accelerated electron radiation on some pivotal neurotransmitter circuits (cholinergic and serotonergic) of rats’ myenteric plexus. Male Wistar rats were irradiated with an electron beam (9 MeV, 5 Gy) generated by a multimodality linear accelerator. The contractile activity of isolated smooth muscle samples from the gastric corpus was measured. Furthermore, an electrical stimulation (200 μs, 20 Hz, 50 s, 60 V) was performed on the samples and an assessment of the cholinergic and serotonergic circuits was made. Five days after irradiation, the recorded mechanical responses were biphasic—contraction/relaxation in controls and contraction/contraction in irradiated samples. The nature of the contractile phase of control samples was cholinergic with serotonin involvement. The relaxation phase involved ACh-induced nitric oxide release from gastric neurons. There was a significant increase in serotonergic involvement during the first and second contractile phases of the irradiated samples, along with a diminished role of acetylcholine in the first phase. This study demonstrates an increased involvement of serotonergic neurotransmitter circuits in the gastric myenteric plexus caused by radiation with accelerated electrons. Full article
(This article belongs to the Special Issue Interactions between the Nervous System and Gastrointestinal Motility)
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14 pages, 17441 KiB  
Article
The Extract of Gloiopeltis tenax Enhances Myogenesis and Alleviates Dexamethasone-Induced Muscle Atrophy
by Si-Hyung Kim, Young-Eun Leem, Hye Eun Park, Hae-In Jeong, Jihye Lee and Jong-Sun Kang
Int. J. Mol. Sci. 2024, 25(12), 6806; https://doi.org/10.3390/ijms25126806 - 20 Jun 2024
Viewed by 1379
Abstract
The decline in the function and mass of skeletal muscle during aging or other pathological conditions increases the incidence of aging-related secondary diseases, ultimately contributing to a decreased lifespan and quality of life. Much effort has been made to surmise the molecular mechanisms [...] Read more.
The decline in the function and mass of skeletal muscle during aging or other pathological conditions increases the incidence of aging-related secondary diseases, ultimately contributing to a decreased lifespan and quality of life. Much effort has been made to surmise the molecular mechanisms underlying muscle atrophy and develop tools for improving muscle function. Enhancing mitochondrial function is considered critical for increasing muscle function and health. This study is aimed at evaluating the effect of an aqueous extract of Gloiopeltis tenax (GTAE) on myogenesis and muscle atrophy caused by dexamethasone (DEX). The GTAE promoted myogenic differentiation, accompanied by an increase in peroxisome proliferator-activated receptor γ coactivator α (PGC-1α) expression and mitochondrial content in myoblast cell culture. In addition, the GTAE alleviated the DEX-mediated myotube atrophy that is attributable to the Akt-mediated inhibition of the Atrogin/MuRF1 pathway. Furthermore, an in vivo study using a DEX-induced muscle atrophy mouse model demonstrated the efficacy of GTAE in protecting muscles from atrophy and enhancing mitochondrial biogenesis and function, even under conditions of atrophy. Taken together, this study suggests that the GTAE shows propitious potential as a nutraceutical for enhancing muscle function and preventing muscle wasting. Full article
(This article belongs to the Section Molecular Microbiology)
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44 pages, 2047 KiB  
Review
Role of Adipose-Derived Mesenchymal Stem Cells in Bone Regeneration
by Chau Sang Lau, So Yeon Park, Lalith Prabha Ethiraj, Priti Singh, Grace Raj, Jolene Quek, Somasundaram Prasadh, Yen Choo and Bee Tin Goh
Int. J. Mol. Sci. 2024, 25(12), 6805; https://doi.org/10.3390/ijms25126805 - 20 Jun 2024
Viewed by 1405
Abstract
Bone regeneration involves multiple factors such as tissue interactions, an inflammatory response, and vessel formation. In the event of diseases, old age, lifestyle, or trauma, bone regeneration can be impaired which could result in a prolonged healing duration or requiring an external intervention [...] Read more.
Bone regeneration involves multiple factors such as tissue interactions, an inflammatory response, and vessel formation. In the event of diseases, old age, lifestyle, or trauma, bone regeneration can be impaired which could result in a prolonged healing duration or requiring an external intervention for repair. Currently, bone grafts hold the golden standard for bone regeneration. However, several limitations hinder its clinical applications, e.g., donor site morbidity, an insufficient tissue volume, and uncertain post-operative outcomes. Bone tissue engineering, involving stem cells seeded onto scaffolds, has thus been a promising treatment alternative for bone regeneration. Adipose-derived mesenchymal stem cells (AD-MSCs) are known to hold therapeutic value for the treatment of various clinical conditions and have displayed feasibility and significant effectiveness due to their ease of isolation, non-invasive, abundance in quantity, and osteogenic capacity. Notably, in vitro studies showed AD-MSCs holding a high proliferation capacity, multi-differentiation potential through the release of a variety of factors, and extracellular vesicles, allowing them to repair damaged tissues. In vivo and clinical studies showed AD-MSCs favoring better vascularization and the integration of the scaffolds, while the presence of scaffolds has enhanced the osteogenesis potential of AD-MSCs, thus yielding optimal bone formation outcomes. Effective bone regeneration requires the interplay of both AD-MSCs and scaffolds (material, pore size) to improve the osteogenic and vasculogenic capacity. This review presents the advances and applications of AD-MSCs for bone regeneration and bone tissue engineering, focusing on the in vitro, in vivo, and clinical studies involving AD-MSCs for bone tissue engineering. Full article
(This article belongs to the Special Issue Bone Development and Regeneration 3.0)
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18 pages, 1456 KiB  
Review
(R)-(-)-Ketamine: The Promise of a Novel Treatment for Psychiatric and Neurological Disorders
by Hana Shafique, Julie C. Demers, Julia Biesiada, Lalit K. Golani, Rok Cerne, Jodi L. Smith, Marta Szostak and Jeffrey M. Witkin
Int. J. Mol. Sci. 2024, 25(12), 6804; https://doi.org/10.3390/ijms25126804 - 20 Jun 2024
Cited by 6 | Viewed by 1679
Abstract
NMDA receptor antagonists have potential for therapeutics in neurological and psychiatric diseases, including neurodegenerative diseases, epilepsy, traumatic brain injury, substance abuse disorder (SUD), and major depressive disorder (MDD). (S)-ketamine was the first of a novel class of antidepressants, rapid-acting antidepressants, to [...] Read more.
NMDA receptor antagonists have potential for therapeutics in neurological and psychiatric diseases, including neurodegenerative diseases, epilepsy, traumatic brain injury, substance abuse disorder (SUD), and major depressive disorder (MDD). (S)-ketamine was the first of a novel class of antidepressants, rapid-acting antidepressants, to be approved for medical use. The stereoisomer, (R)-ketamine (arketamine), is currently under development for treatment-resistant depression (TRD). The compound has demonstrated efficacy in multiple animal models. Two clinical studies disclosed efficacy in TRD and bipolar depression. A study by the drug sponsor recently failed to reach a priori clinical endpoints but post hoc analysis revealed efficacy. The clinical value of (R)-ketamine is supported by experimental data in humans and rodents, showing that it is less sedating, does not produce marked psychotomimetic or dissociative effects, has less abuse potential than (S)-ketamine, and produces efficacy in animal models of a range of neurological and psychiatric disorders. The mechanisms of action of the antidepressant effects of (R)-ketamine are hypothesized to be due to NMDA receptor antagonism and/or non-NMDA receptor mechanisms. We suggest that further clinical experimentation with (R)-ketamine will create novel and improved medicines for some of the neurological and psychiatric disorders that are underserved by current medications. Full article
(This article belongs to the Special Issue Stress-Related Disorders and Depression: From Molecular Basis to Therapy (2nd Edition))
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22 pages, 5849 KiB  
Article
Synthesis, Molecular Electron Density Theory Study, Molecular Docking, and Pharmacological Evaluation of New Coumarin–Sulfonamide–Nitroindazolyl–Triazole Hybrids as Monoamine Oxidase Inhibitors
by Mohammed Eddahmi, Gabriella La Spada, Luis R. Domingo, Gérard Vergoten, Christian Bailly, Marco Catto and Latifa Bouissane
Int. J. Mol. Sci. 2024, 25(12), 6803; https://doi.org/10.3390/ijms25126803 - 20 Jun 2024
Viewed by 1147
Abstract
Inhibitors of monoamine oxidases (MAOs) are of interest for the treatment of neurodegenerative disorders and other human pathologies. In this frame, the present work describes different synthetic strategies to obtain MAO inhibitors via the coupling of the aminocoumarin core with arylsulfonyl chlorides followed [...] Read more.
Inhibitors of monoamine oxidases (MAOs) are of interest for the treatment of neurodegenerative disorders and other human pathologies. In this frame, the present work describes different synthetic strategies to obtain MAO inhibitors via the coupling of the aminocoumarin core with arylsulfonyl chlorides followed by copper azide-alkyne cycloaddition, leading to coumarin–sulfonamide–nitroindazolyl–triazole hybrids. The nitration position on the coumarin moiety was confirmed through nuclear magnetic resonance spectroscopy and molecular electron density theory in order to elucidate the molecular mechanism and selectivity of the electrophilic aromatic substitution reaction. The coumarin derivatives were evaluated for their inhibitory potency against monoamine oxidases and cholinesterases. Molecular docking calculations provided a rational binding mode of the best compounds in the series with MAO A and B. The work identified hybrids 14a–c as novel MAO inhibitors, with a selective action against isoform B, of potential interest to combat neurological diseases. Full article
(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms, 3rd Edition)
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17 pages, 10290 KiB  
Article
Exploring the Spatial Arrangement of Simple 18-Membered Hexaazatetraamine Macrocyclic Ligands in Their Metal Complexes
by Julio Corredoira-Vázquez, Cristina González-Barreira, Jesús Sanmartín-Matalobos, Ana M. García-Deibe and Matilde Fondo
Int. J. Mol. Sci. 2024, 25(12), 6802; https://doi.org/10.3390/ijms25126802 - 20 Jun 2024
Viewed by 701
Abstract
Hexaazamacrocyclic Schiff bases have been extensively combined with lanthanoid (Ln) ions to obtain complexes with a highly axial geometry. However, the use of flexible hexaazatetraamine macrocycles containing two pyridines and acyclic spacers is rather uncommon. Accordingly, we obtained [DyL(OAc)2]OAc·7H2O·EtOH [...] Read more.
Hexaazamacrocyclic Schiff bases have been extensively combined with lanthanoid (Ln) ions to obtain complexes with a highly axial geometry. However, the use of flexible hexaazatetraamine macrocycles containing two pyridines and acyclic spacers is rather uncommon. Accordingly, we obtained [DyL(OAc)2]OAc·7H2O·EtOH and [DyLMe2(Cl)2]Cl·2H2O, where L and LMe2 are the 18-membered macrocycles 3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane and 3,10-dimethyl-3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane, respectively, which contain ethylene and methylethylene spacers between their N3 moieties. [DyL(OAc)2]OAc·7H2O·EtOH represents the first crystallographically characterized lanthanoid complex of L, while [DyLMe2(Cl)2]Cl·2H2O contributes to increasing the scarce number of LnIII compounds containing LMe2. Furthermore, the crystal structure of L·12H2O was solved, and it was compared with those of other related macrocycles previously published. Likewise, the crystal structures of the DyIII complexes were compared with those of the lanthanoid and d-metal complexes of other 18-membered N6 donor macrocycles. This comparison showed some effect of the spacers employed, as well as the influence of the size of the ancillary ligands and the metal ion. Additionally, the distinct folding behaviors of these macrocycles influenced their coordination geometries. Moreover, the luminescent properties of [DyL(OAc)2]OAc·7H2O·EtOH and [DyLMe2(Cl)2]Cl·2H2O were also investigated, showing that both complexes are fluorescent, with the emission being sensitized by the ligands. Full article
(This article belongs to the Special Issue Metal-Organic Coordination Compounds: Synthesis, Structure, Spectra, Applications)
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13 pages, 5186 KiB  
Article
Siloxane Containing Polyether Groups—Synthesis and Use as an Anti-Biocorrosion Coating
by Joanna Karasiewicz, Rafał M. Olszyński, Paulina Nowicka-Krawczyk, Joanna Krawczyk and Łukasz Majchrzycki
Int. J. Mol. Sci. 2024, 25(12), 6801; https://doi.org/10.3390/ijms25126801 - 20 Jun 2024
Viewed by 1052
Abstract
In the presented study, the effectiveness of a siloxane polyether (HOL7) coating on glass against microbiological colonization was assessed using microalgae as a key component of widespread aerial biofilms. The siloxane polyether was successfully synthesized by a hydrosilylation reaction in the presence of [...] Read more.
In the presented study, the effectiveness of a siloxane polyether (HOL7) coating on glass against microbiological colonization was assessed using microalgae as a key component of widespread aerial biofilms. The siloxane polyether was successfully synthesized by a hydrosilylation reaction in the presence of Karstedt’s catalyst. The product structure was confirmed by NMR spectroscopy and GPC analysis. In addition, the thermal stability of HOL7 was studied by thermogravimetric measurement. Subsequently, the surfaces of glass plates were modified with the obtained organosilicon derivative. In the next step, a microalgal experiment was conducted. A mixture of four strains of algal taxa isolated from building materials was used for the experiment—Chlorodium saccharophilum PNK010, Klebsormidium flaccidum PNK013, Pseudostichococcus monallantoides PNK037, and Trebouxia aggregata PNK080. The choice of these algae followed from their wide occurrence in terrestrial environments. Application of an organofunctional siloxane compound on the glass reduced, more or less effectively, the photosynthetic activity of algal cells, depending on the concentration of the compound. Since the structure of the compound was not based on biocide-active agents, its effectiveness was associated with a reduction in water content in the cells. Full article
(This article belongs to the Special Issue Molecular Insight into Surfactants)
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20 pages, 3164 KiB  
Article
Metabolomics Reveals the Impact of Overexpression of Cytosolic Fructose-1,6-Bisphosphatase on Photosynthesis and Growth in Nannochloropsis gaditana
by Zhengying Zhang, Yanyan Li, Shuting Wen, Shu Yang, Hongmei Zhu and Hantao Zhou
Int. J. Mol. Sci. 2024, 25(12), 6800; https://doi.org/10.3390/ijms25126800 - 20 Jun 2024
Cited by 1 | Viewed by 1117
Abstract
Nannochloropsis gaditana, a microalga known for its photosynthetic efficiency, serves as a cell factory, producing valuable biomolecules such as proteins, lipids, and pigments. These components make it an ideal candidate for biofuel production and pharmaceutical applications. In this study, we genetically engineered [...] Read more.
Nannochloropsis gaditana, a microalga known for its photosynthetic efficiency, serves as a cell factory, producing valuable biomolecules such as proteins, lipids, and pigments. These components make it an ideal candidate for biofuel production and pharmaceutical applications. In this study, we genetically engineered N. gaditana to overexpress the enzyme fructose-1,6-bisphosphatase (cyFBPase) using the Hsp promoter, aiming to enhance sugar metabolism and biomass accumulation. The modified algal strain, termed NgFBP, exhibited a 1.34-fold increase in cyFBPase activity under photoautotrophic conditions. This modification led to a doubling of biomass production and an increase in eicosapentaenoic acid (EPA) content in fatty acids to 20.78–23.08%. Additionally, the genetic alteration activated the pathways related to glycine, protoporphyrin, thioglucosides, pantothenic acid, CoA, and glycerophospholipids. This shift in carbon allocation towards chloroplast development significantly enhanced photosynthesis and growth. The outcomes of this study not only improve our understanding of photosynthesis and carbon allocation in N. gaditana but also suggest new biotechnological methods to optimize biomass yield and compound production in microalgae. Full article
(This article belongs to the Special Issue Plant Genome Editing)
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20 pages, 1784 KiB  
Review
Melatonin: The Multifaceted Molecule in Plant Growth and Defense
by Murtaza Khan, Adil Hussain, Byung-Wook Yun and Bong-Gyu Mun
Int. J. Mol. Sci. 2024, 25(12), 6799; https://doi.org/10.3390/ijms25126799 - 20 Jun 2024
Cited by 1 | Viewed by 1402
Abstract
Melatonin (MEL), a hormone primarily known for its role in regulating sleep and circadian rhythms in animals, has emerged as a multifaceted molecule in plants. Recent research has shed light on its diverse functions in plant growth and defense mechanisms. This review explores [...] Read more.
Melatonin (MEL), a hormone primarily known for its role in regulating sleep and circadian rhythms in animals, has emerged as a multifaceted molecule in plants. Recent research has shed light on its diverse functions in plant growth and defense mechanisms. This review explores the intricate roles of MEL in plant growth and defense responses. MEL is involved in plant growth owing to its influence on hormone regulation. MEL promotes root elongation and lateral root formation and enhances photosynthesis, thereby promoting overall plant growth and productivity. Additionally, MEL is implicated in regulating the circadian rhythm of plants, affecting key physiological processes that influence plant growth patterns. MEL also exhibits antioxidant properties and scavenges reactive oxygen species, thereby mitigating oxidative stress. Furthermore, it activates defense pathways against various biotic stressors. MEL also enhances the production of secondary metabolites that contribute to plant resistance against environmental changes. MEL’s ability to modulate plant response to abiotic stresses has also been extensively studied. It regulates stomatal closure, conserves water, and enhances stress tolerance by activating stress-responsive genes and modulating signaling pathways. Moreover, MEL and nitric oxide cooperate in stress responses, antioxidant defense, and plant growth. Understanding the mechanisms underlying MEL’s actions in plants will provide new insights into the development of innovative strategies for enhancing crop productivity, improving stress tolerance, and combating plant diseases. Further research in this area will deepen our knowledge of MEL’s intricate functions and its potential applications in sustainable agriculture. Full article
(This article belongs to the Special Issue Melatonin in Plant: From Molecular Basis to Functional Application)
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60 pages, 4977 KiB  
Review
Challenges and Opportunities Arising from Host–Botrytis cinerea Interactions to Outline Novel and Sustainable Control Strategies: The Key Role of RNA Interference
by Maria Spada, Claudio Pugliesi, Marco Fambrini and Susanna Pecchia
Int. J. Mol. Sci. 2024, 25(12), 6798; https://doi.org/10.3390/ijms25126798 - 20 Jun 2024
Cited by 1 | Viewed by 1802
Abstract
The necrotrophic plant pathogenic fungus Botrytis cinerea (Pers., 1794), the causative agent of gray mold disease, causes significant losses in agricultural production. Control of this fungal pathogen is quite difficult due to its wide host range and environmental persistence. Currently, the management of [...] Read more.
The necrotrophic plant pathogenic fungus Botrytis cinerea (Pers., 1794), the causative agent of gray mold disease, causes significant losses in agricultural production. Control of this fungal pathogen is quite difficult due to its wide host range and environmental persistence. Currently, the management of the disease is still mainly based on chemicals, which can have harmful effects not only on the environment and on human health but also because they favor the development of strains resistant to fungicides. The flexibility and plasticity of B. cinerea in challenging plant defense mechanisms and its ability to evolve strategies to escape chemicals require the development of new control strategies for successful disease management. In this review, some aspects of the host-pathogen interactions from which novel and sustainable control strategies could be developed (e.g., signaling pathways, molecules involved in plant immune mechanisms, hormones, post-transcriptional gene silencing) were analyzed. New biotechnological tools based on the use of RNA interference (RNAi) are emerging in the crop protection scenario as versatile, sustainable, effective, and environmentally friendly alternatives to the use of chemicals. RNAi-based fungicides are expected to be approved soon, although they will face several challenges before reaching the market. Full article
(This article belongs to the Collection Feature Papers in “Molecular Biology”)
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18 pages, 3488 KiB  
Article
The Role of TPM3 in Protecting Cardiomyocyte from Hypoxia-Induced Injury via Cytoskeleton Stabilization
by Ke Huang, Weijia Yang, Mingxuan Shi, Shiqi Wang, Yi Li and Zhaoqing Xu
Int. J. Mol. Sci. 2024, 25(12), 6797; https://doi.org/10.3390/ijms25126797 - 20 Jun 2024
Cited by 2 | Viewed by 1028
Abstract
Ischemic heart disease (IHD) remains a major global health concern, with ischemia-reperfusion injury exacerbating myocardial damage despite therapeutic interventions. In this study, we investigated the role of tropomyosin 3 (TPM3) in protecting cardiomyocytes against hypoxia-induced injury and oxidative stress. Using the AC16 and [...] Read more.
Ischemic heart disease (IHD) remains a major global health concern, with ischemia-reperfusion injury exacerbating myocardial damage despite therapeutic interventions. In this study, we investigated the role of tropomyosin 3 (TPM3) in protecting cardiomyocytes against hypoxia-induced injury and oxidative stress. Using the AC16 and H9c2 cell lines, we established a chemical hypoxia model by treating cells with cobalt chloride (CoCl2) to simulate low-oxygen conditions. We found that CoCl2 treatment significantly upregulated the expression of hypoxia-inducible factor 1 alpha (HIF-1α) in cardiomyocytes, indicating the successful induction of hypoxia. Subsequent morphological and biochemical analyses revealed that hypoxia altered cardiomyocyte morphology disrupted the cytoskeleton, and caused cellular damage, accompanied by increased lactate dehydrogenase (LDH) release and malondialdehyde (MDA) levels, and decreased superoxide dismutase (SOD) activity, indicative of oxidative stress. Lentivirus-mediated TPM3 overexpression attenuated hypoxia-induced morphological changes, cellular damage, and oxidative stress imbalance, while TPM3 knockdown exacerbated these effects. Furthermore, treatment with the HDAC1 inhibitor MGCD0103 partially reversed the exacerbation of hypoxia-induced injury caused by TPM3 knockdown. Protein–protein interaction (PPI) network and functional enrichment analysis suggested that TPM3 may modulate cardiac muscle development, contraction, and adrenergic signaling pathways. In conclusion, our findings highlight the therapeutic potential of TPM3 modulation in mitigating hypoxia-associated cardiac injury, suggesting a promising avenue for the treatment of ischemic heart disease and other hypoxia-related cardiac pathologies. Full article
(This article belongs to the Special Issue Genes and Human Diseases 2.0)
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13 pages, 2206 KiB  
Article
Identification and Molecular Simulation of Genetic Variants in ABCA1 Gene Associated with Susceptibility to Dyslipidemia in Type 2 Diabetes
by Asifa Majeed, Zunaira Ali Baig and Amir Rashid
Int. J. Mol. Sci. 2024, 25(12), 6796; https://doi.org/10.3390/ijms25126796 - 20 Jun 2024
Cited by 1 | Viewed by 953
Abstract
Genetic insights help us to investigate disease pathogenesis and risk. The ABCA1 protein encoded by ABCA1 is involved in transporting cholesterol across the cell membrane. Genetic variations in the ABCA1 gene are well documented; however, their role in the development of diabetic dyslipidemia [...] Read more.
Genetic insights help us to investigate disease pathogenesis and risk. The ABCA1 protein encoded by ABCA1 is involved in transporting cholesterol across the cell membrane. Genetic variations in the ABCA1 gene are well documented; however, their role in the development of diabetic dyslipidemia still needs to be explored. This study aimed to identify the associations of rs757194699 (K1587Q) and rs2066714 (I883M) with dyslipidemia in type 2 diabetes and performed molecular simulations. In our case–control study, 330 individuals were divided equally into a diabetic dyslipidemia cases and a healthy controls. Allele-specific polymerase chain reaction and restriction fragment length polymorphism were performed to screen selected variants of the ABCA1 gene. Sanger sequencing was also performed to find genetic mutations in exon 5 of the ABCA1 gene. The C allele of rs757194699 was observed at a high frequency in cases compared to controls and followed the overdominant genetic model (p < 0.0001, OR:3.84; CI:1.67–8.82). The frequency of G allele of rs2066714 was significantly higher in cases compared to controls and followed the genetic model of codominant (p< 0.0001, OR: 39.61; CI:9.97–157.32), dominant (p < 0.0001,OR:59.59; CI:15.19–233.81), overdominant (p< 0.0001, OR:9.75; CI:3.16–30.11), and log-additive (p< 0.0001, OR:42.15; CI:11.08–160.40). In silico modeling and docking revealed that rs2066714 and rs757194699 produced deleterious conformational changes in the ABCA1 protein, resulting in alterations in the binding of the apoA1 protein. There were no genetic variations found in exon-5 in Sanger sequencing. The G allele of rs2066714 and C allele of rs757194699 in the ABCA1 gene were found to be risk alleles in the development of dyslipidemia in type 2 diabetes. These polymorphisms could alter the binding site of ABCA1 with apoA1 thus disturbs the reverse cholesterol transport. Full article
(This article belongs to the Section Molecular Endocrinology and Metabolism)
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17 pages, 118952 KiB  
Article
Genome-Wide Identification of NDPK Family Genes and Expression Analysis under Abiotic Stress in Brassica napus
by Long Wang, Zhi Zhao, Huaxin Li, Damei Pei, Zhen Huang, Hongyan Wang and Lu Xiao
Int. J. Mol. Sci. 2024, 25(12), 6795; https://doi.org/10.3390/ijms25126795 - 20 Jun 2024
Viewed by 981
Abstract
The NDPK gene family is an important group of genes in plants, playing a crucial role in regulating energy metabolism, growth, and differentiation, cell signal transduction, and response to abiotic stress. However, our understanding of the NDPK gene family in Brassica napus L. [...] Read more.
The NDPK gene family is an important group of genes in plants, playing a crucial role in regulating energy metabolism, growth, and differentiation, cell signal transduction, and response to abiotic stress. However, our understanding of the NDPK gene family in Brassica napus L. remains limited. This paper systematically analyzes the NDPK gene family in B. napus, particularly focusing on the evolutionary differences within the species. In this study, sixteen, nine, and eight NDPK genes were identified in B. napus and its diploid ancestors, respectively. These genes are not only homologous but also highly similar in their chromosomal locations. Phylogenetic analysis showed that the identified NDPK proteins were divided into four clades, each containing unique motif sequences, with most NDPKs experiencing a loss of introns/exons during evolution. Collinearity analysis revealed that the NDPK genes underwent whole-genome duplication (WGD) events, resulting in duplicate copies, and most of these duplicate genes were subjected to purifying selection. Cis-acting element analysis identified in the promoters of most NDPK genes elements related to a light response, methyl jasmonate response, and abscisic acid response, especially with an increased number of abscisic acid response elements in B. napus. RNA-Seq results indicated that NDPK genes in B. napus exhibited different expression patterns across various tissues. Further analysis through qRT-PCR revealed that BnNDPK genes responded significantly to stress conditions such as salt, drought, and methyl jasmonate. This study enhances our understanding of the NDPK gene family in B. napus, providing a preliminary theoretical basis for the functional study of NDPK genes and offering some references for further revealing the phenomenon of polyploidization in plants. Full article
(This article belongs to the Special Issue Advance in Plant Abiotic Stress)
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20 pages, 4032 KiB  
Article
Hell’s Gate Globin-I from Methylacidiphilum infernorum Displays a Unique Temperature-Independent pH Sensing Mechanism Utililized a Lipid-Induced Conformational Change
by Brandon J. Reeder, Dimitri A. Svistunenko and Michael T. Wilson
Int. J. Mol. Sci. 2024, 25(12), 6794; https://doi.org/10.3390/ijms25126794 - 20 Jun 2024
Viewed by 911
Abstract
Hell’s Gate globin-I (HGb-I) is a thermally stable globin from the aerobic methanotroph Methylacidiphilium infernorum. Here we report that HGb-I interacts with lipids stoichiometrically to induce structural changes in the heme pocket, changing the heme iron distal ligation coordination from hexacoordinate to [...] Read more.
Hell’s Gate globin-I (HGb-I) is a thermally stable globin from the aerobic methanotroph Methylacidiphilium infernorum. Here we report that HGb-I interacts with lipids stoichiometrically to induce structural changes in the heme pocket, changing the heme iron distal ligation coordination from hexacoordinate to pentacoordinate. Such changes in heme geometry have only been previously reported for cytochrome c and cytoglobin, linked to apoptosis regulation and enhanced lipid peroxidation activity, respectively. However, unlike cytoglobin and cytochrome c, the heme iron of HGb-I is altered by lipids in ferrous as well as ferric oxidation states. The apparent affinity for lipids in this thermally stable globin is highly pH-dependent but essentially temperature-independent within the range of 20–60 °C. We propose a mechanism to explain these observations, in which lipid binding and stability of the distal endogenous ligand are juxtaposed as a function of temperature. Additionally, we propose that these coupled equilibria may constitute a mechanism through which this acidophilic thermophile senses the pH of its environment. Full article
(This article belongs to the Special Issue Hemoglobins: Structural, Functional and Evolutionary Characterization)
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41 pages, 1364 KiB  
Review
Towards Healthy Longevity: Comprehensive Insights from Molecular Targets and Biomarkers to Biological Clocks
by Khalishah Yusri, Sanjay Kumar, Sheng Fong, Jan Gruber and Vincenzo Sorrentino
Int. J. Mol. Sci. 2024, 25(12), 6793; https://doi.org/10.3390/ijms25126793 - 20 Jun 2024
Viewed by 4436
Abstract
Aging is a complex and time-dependent decline in physiological function that affects most organisms, leading to increased risk of age-related diseases. Investigating the molecular underpinnings of aging is crucial to identify geroprotectors, precisely quantify biological age, and propose healthy longevity approaches. This review [...] Read more.
Aging is a complex and time-dependent decline in physiological function that affects most organisms, leading to increased risk of age-related diseases. Investigating the molecular underpinnings of aging is crucial to identify geroprotectors, precisely quantify biological age, and propose healthy longevity approaches. This review explores pathways that are currently being investigated as intervention targets and aging biomarkers spanning molecular, cellular, and systemic dimensions. Interventions that target these hallmarks may ameliorate the aging process, with some progressing to clinical trials. Biomarkers of these hallmarks are used to estimate biological aging and risk of aging-associated disease. Utilizing aging biomarkers, biological aging clocks can be constructed that predict a state of abnormal aging, age-related diseases, and increased mortality. Biological age estimation can therefore provide the basis for a fine-grained risk stratification by predicting all-cause mortality well ahead of the onset of specific diseases, thus offering a window for intervention. Yet, despite technological advancements, challenges persist due to individual variability and the dynamic nature of these biomarkers. Addressing this requires longitudinal studies for robust biomarker identification. Overall, utilizing the hallmarks of aging to discover new drug targets and develop new biomarkers opens new frontiers in medicine. Prospects involve multi-omics integration, machine learning, and personalized approaches for targeted interventions, promising a healthier aging population. Full article
(This article belongs to the Special Issue Biomarkers and Drug Targets for Longevity)
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28 pages, 14254 KiB  
Article
Identification and Validation of Tumor Microenvironment-Associated Signature in Clear-Cell Renal Cell Carcinoma through Integration of DNA Methylation and Gene Expression
by Zijian Ye, Jialiang Xu, Xin Zhang, Yifan Zhang, Deyana Ivanova, Weiyu Lu, Jianning Zhang, Fangfang Li, Xuemei Chen, Yingxiong Wang, Meijiao Wang and Biao Xie
Int. J. Mol. Sci. 2024, 25(12), 6792; https://doi.org/10.3390/ijms25126792 - 20 Jun 2024
Viewed by 1312
Abstract
The tumor microenvironment (TME) is crucial in tumor development, metastasis, and response to immunotherapy. DNA methylation can regulate the TME without altering the DNA sequence. However, research on the methylation-driven TME in clear-cell renal cell carcinoma (ccRCC) is still lacking. In this study, [...] Read more.
The tumor microenvironment (TME) is crucial in tumor development, metastasis, and response to immunotherapy. DNA methylation can regulate the TME without altering the DNA sequence. However, research on the methylation-driven TME in clear-cell renal cell carcinoma (ccRCC) is still lacking. In this study, integrated DNA methylation and RNA-seq data were used to explore methylation-driven genes (MDGs). Immune scores were calculated using the ESTIMATE, which was employed to identify TME-related genes. A new signature connected with methylation-regulated TME using univariate, multivariate Cox regression and LASSO regression analyses was developed. This signature consists of four TME-MDGs, including AJAP1, HOXB9, MYH14, and SLC6A19, which exhibit high methylation and low expression in tumors. Validation was performed using qRT-PCR which confirmed their downregulation in ccRCC clinical samples. Additionally, the signature demonstrated stable predictive performance in different subtypes of ccRCC. Risk scores are positively correlated with TMN stages, immune cell infiltration, tumor mutation burden, and adverse outcomes of immunotherapy. Interestingly, the expression of four TME-MDGs are highly correlated with the sensitivity of first-line drugs in ccRCC treatment, especially pazopanib. Molecular docking indicates a high affinity binding between the proteins and pazopanib. In summary, our study elucidates the comprehensive role of methylation-driven TME in ccRCC, aiding in identifying patients sensitive to immunotherapy and targeted therapy, and providing new therapeutic targets for ccRCC treatment. Full article
(This article belongs to the Special Issue Male Genitourinary Tumors: Molecular Mechanisms and Potential Therapeutic Targets)
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20 pages, 5039 KiB  
Article
Knockdown of microRNA390 Enhances Maize Brace Root Growth
by Juan Meng, Weiya Li, Feiyan Qi, Tianxiao Yang, Na Li, Jiong Wan, Xiaoqi Li, Yajuan Jiang, Chenhui Wang, Meilian Huang, Yuanyuan Zhang, Yongqiang Chen, Sachin Teotia, Guiliang Tang, Zhanhui Zhang and Jihua Tang
Int. J. Mol. Sci. 2024, 25(12), 6791; https://doi.org/10.3390/ijms25126791 - 20 Jun 2024
Viewed by 3913
Abstract
Brace root architecture is a critical determinant of maize’s stalk anchorage and nutrition uptake, influencing root lodging resistance, stress tolerance, and plant growth. To identify the key microRNAs (miRNAs) in control of maize brace root growth, we performed small RNA sequencing using brace [...] Read more.
Brace root architecture is a critical determinant of maize’s stalk anchorage and nutrition uptake, influencing root lodging resistance, stress tolerance, and plant growth. To identify the key microRNAs (miRNAs) in control of maize brace root growth, we performed small RNA sequencing using brace root samples at emergence and growth stages. We focused on the genetic modulation of brace root development in maize through manipulation of miR390 and its downstream regulated auxin response factors (ARFs). In the present study, miR167, miR166, miR172, and miR390 were identified to be involved in maize brace root growth in inbred line B73. Utilizing short tandem target mimic (STTM) technology, we further developed maize lines with reduced miR390 expression and analyzed their root architecture compared to wild-type controls. Our findings show that STTM390 maize lines exhibit enhanced brace root length and increased whorl numbers. Gene expression analyses revealed that the suppression of miR390 leads to upregulation of its downstream regulated ARF genes, specifically ZmARF11 and ZmARF26, which may significantly alter root architecture. Additionally, loss-of-function mutants for ZmARF11 and ZmARF26 were characterized to further confirm the role of these genes in brace root growth. These results demonstrate that miR390, ZmARF11, and ZmARF26 play crucial roles in regulating maize brace root growth; the involved complicated molecular mechanisms need to be further explored. This study provides a genetic basis for breeding maize varieties with improved lodging resistance and adaptability to diverse agricultural environments. Full article
(This article belongs to the Special Issue Cellular and Molecular Regulatory Signals in Root Growth and Development)
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16 pages, 3997 KiB  
Article
Triphenylphosphonium-Conjugated Palmitic Acid for Mitochondrial Targeting of Pancreatic Cancer Cells: Proteomic and Molecular Evidence
by Giuliana Siragusa, Jessica Brandi, Tristan Rawling, Michael Murray and Daniela Cecconi
Int. J. Mol. Sci. 2024, 25(12), 6790; https://doi.org/10.3390/ijms25126790 - 20 Jun 2024
Viewed by 1483
Abstract
Pancreatic ductal adenocarcinoma (PDAC)’s resistance to therapies is mainly attributed to pancreatic cancer stem cells (PCSCs). Mitochondria-impairing agents can be used to hamper PCSC propagation and reduce PDAC progression. Therefore, to develop an efficient vector for delivering drugs to the mitochondria, we synthesized [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC)’s resistance to therapies is mainly attributed to pancreatic cancer stem cells (PCSCs). Mitochondria-impairing agents can be used to hamper PCSC propagation and reduce PDAC progression. Therefore, to develop an efficient vector for delivering drugs to the mitochondria, we synthesized tris(3,5-dimethylphenyl)phosphonium-conjugated palmitic acid. Triphenylphosphonium (TPP) is a lipophilic cationic moiety that promotes the accumulation of conjugated agents in the mitochondrion. Palmitic acid (PA), the most common saturated fatty acid, has pro-apoptotic activity in different types of cancer cells. TPP-PA was prepared by the reaction of 16-bromopalmitic acid with TPP, and its structure was characterized by 1H and 13C NMR and HRMS. We compared the proteomes of TPP-PA-treated and untreated PDAC cells and PCSCs, identifying dysregulated proteins and pathways. Furthermore, assessments of mitochondrial membrane potential, intracellular ROS, cardiolipin content and lipid peroxidation, ER stress, and autophagy markers provided information on the mechanism of action of TPP-PA. The findings showed that TPP-PA reduces PDAC cell proliferation through mitochondrial disruption that leads to increased ROS, activation of ER stress, and autophagy. Hence, TPP-PA might offer a new approach for eliminating both the primary population of cancer cells and PCSCs, which highlights the promise of TPP-derived compounds as anticancer agents for PDAC. Full article
(This article belongs to the Special Issue New Players in the Research of Oxidative Stress and Cancer)
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49 pages, 2110 KiB  
Review
Reviewing the Structure–Function Paradigm in Polyglutamine Disorders: A Synergistic Perspective on Theoretical and Experimental Approaches
by Nastasia Sanda Moldovean-Cioroianu
Int. J. Mol. Sci. 2024, 25(12), 6789; https://doi.org/10.3390/ijms25126789 - 20 Jun 2024
Viewed by 1151
Abstract
Polyglutamine (polyQ) disorders are a group of neurodegenerative diseases characterized by the excessive expansion of CAG (cytosine, adenine, guanine) repeats within host proteins. The quest to unravel the complex diseases mechanism has led researchers to adopt both theoretical and experimental methods, each offering [...] Read more.
Polyglutamine (polyQ) disorders are a group of neurodegenerative diseases characterized by the excessive expansion of CAG (cytosine, adenine, guanine) repeats within host proteins. The quest to unravel the complex diseases mechanism has led researchers to adopt both theoretical and experimental methods, each offering unique insights into the underlying pathogenesis. This review emphasizes the significance of combining multiple approaches in the study of polyQ disorders, focusing on the structure–function correlations and the relevance of polyQ-related protein dynamics in neurodegeneration. By integrating computational/theoretical predictions with experimental observations, one can establish robust structure–function correlations, aiding in the identification of key molecular targets for therapeutic interventions. PolyQ proteins’ dynamics, influenced by their length and interactions with other molecular partners, play a pivotal role in the polyQ-related pathogenic cascade. Moreover, conformational dynamics of polyQ proteins can trigger aggregation, leading to toxic assembles that hinder proper cellular homeostasis. Understanding these intricacies offers new avenues for therapeutic strategies by fine-tuning polyQ kinetics, in order to prevent and control disease progression. Last but not least, this review highlights the importance of integrating multidisciplinary efforts to advancing research in this field, bringing us closer to the ultimate goal of finding effective treatments against polyQ disorders. Full article
(This article belongs to the Special Issue Latest Review Papers in Molecular Neurobiology 2024)
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24 pages, 2775 KiB  
Review
Beyond the Usual Suspects: Examining the Role of Understudied Histone Variants in Breast Cancer
by Hejer Dhahri, Wesley N. Saintilnord, Darrell Chandler and Yvonne N. Fondufe-Mittendorf
Int. J. Mol. Sci. 2024, 25(12), 6788; https://doi.org/10.3390/ijms25126788 - 20 Jun 2024
Viewed by 1532
Abstract
The incorporation of histone variants has structural ramifications on nucleosome dynamics and stability. Due to their unique sequences, histone variants can alter histone–histone or histone–DNA interactions, impacting the folding of DNA around the histone octamer and the overall higher-order structure of chromatin fibers. [...] Read more.
The incorporation of histone variants has structural ramifications on nucleosome dynamics and stability. Due to their unique sequences, histone variants can alter histone–histone or histone–DNA interactions, impacting the folding of DNA around the histone octamer and the overall higher-order structure of chromatin fibers. These structural modifications alter chromatin compaction and accessibility of DNA by transcription factors and other regulatory proteins to influence gene regulatory processes such as DNA damage and repair, as well as transcriptional activation or repression. Histone variants can also generate a unique interactome composed of histone chaperones and chromatin remodeling complexes. Any of these perturbations can contribute to cellular plasticity and the progression of human diseases. Here, we focus on a frequently overlooked group of histone variants lying within the four human histone gene clusters and their contribution to breast cancer. Full article
(This article belongs to the Special Issue Novel Insight into Epigenomic Studies of Human Disease)
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35 pages, 49743 KiB  
Article
Proteomics Analysis of Proteotoxic Stress Response in In-Vitro Human Neuronal Models
by Ayodele Alaiya, Bothina Mohammed Alharbi, Zakia Shinwari, Mamoon Rashid, Tahani H. Albinhassan, Abderrezak Bouchama, Mai B. Alwesmi, Sameer Mohammad and Shuja Shafi Malik
Int. J. Mol. Sci. 2024, 25(12), 6787; https://doi.org/10.3390/ijms25126787 - 20 Jun 2024
Viewed by 1342
Abstract
Heat stroke, a hazardous hyperthermia-related illness, is characterized by CNS injury, particularly long-lasting brain damage. A root cause for hyperthermic neurological damage is heat-induced proteotoxic stress through protein aggregation, a known causative agent of neurological disorders. Stress magnitude and enduring persistence are highly [...] Read more.
Heat stroke, a hazardous hyperthermia-related illness, is characterized by CNS injury, particularly long-lasting brain damage. A root cause for hyperthermic neurological damage is heat-induced proteotoxic stress through protein aggregation, a known causative agent of neurological disorders. Stress magnitude and enduring persistence are highly correlated with hyperthermia-associated neurological damage. We used an untargeted proteomic approach using liquid chromatography–tandem mass spectrometry (LC-MS/MS) to identify and characterize time-series proteome-wide changes in dose-responsive proteotoxic stress models in medulloblastoma [Daoy], neuroblastoma [SH-SY5Y], and differentiated SH-SY5Y neuron-like cells [SH(D)]. An integrated analysis of condition–time datasets identified global proteome-wide differentially expressed proteins (DEPs) as part of the heat-induced proteotoxic stress response. The condition-specific analysis detected higher DEPs and upregulated proteins in extreme heat stress with a relatively conservative and tight regulation in differentiated SH-SY5Y neuron-like cells. Functional network analysis using ingenuity pathway analysis (IPA) identified common intercellular pathways associated with the biological processes of protein, RNA, and amino acid metabolism and cellular response to stress and membrane trafficking. The condition-wise temporal pathway analysis in the differentiated neuron-like cells detects a significant pathway, functional, and disease association of DEPs with processes like protein folding and protein synthesis, Nervous System Development and Function, and Neurological Disease. An elaborate dose-dependent stress-specific and neuroprotective cellular signaling cascade is also significantly activated. Thus, our study provides a comprehensive map of the heat-induced proteotoxic stress response associating proteome-wide changes with altered biological processes. This helps to expand our understanding of the molecular basis of the heat-induced proteotoxic stress response with potential translational connotations. Full article
(This article belongs to the Special Issue Neurometabolic Disorders in the Adults)
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15 pages, 4755 KiB  
Article
Chloroplast Genomes Evolution and Phylogenetic Relationships of Caragana species
by Xingyong Cui, Kangjia Liu, Enze Li, Zhixiang Zhang and Wenpan Dong
Int. J. Mol. Sci. 2024, 25(12), 6786; https://doi.org/10.3390/ijms25126786 - 20 Jun 2024
Viewed by 840
Abstract
Caragana sensu lato (s.l.) includes approximately 100 species that are mainly distributed in arid and semi-arid regions. Caragana species are ecologically valuable for their roles in windbreaking and sand fixation. However, the taxonomy and phylogenetic relationships of the genus Caragana are [...] Read more.
Caragana sensu lato (s.l.) includes approximately 100 species that are mainly distributed in arid and semi-arid regions. Caragana species are ecologically valuable for their roles in windbreaking and sand fixation. However, the taxonomy and phylogenetic relationships of the genus Caragana are still unclear. In this study, we sequenced and assembled the chloroplast genomes of representative species of Caragana and reconstructed robust phylogenetic relationships at the section level. The Caragana chloroplast genome has lost the inverted repeat region and wascategorized in the inverted repeat loss clade (IRLC). The chloroplast genomes of the eight species ranged from 128,458 bp to 135,401 bp and contained 110 unique genes. All the Caragana chloroplast genomes have a highly conserved structure and gene order. The number of long repeats and simple sequence repeats (SSRs) showed significant variation among the eight species, indicating heterogeneous evolution in Caragana. Selective pressure analysis of the genes revealed that most of the protein-coding genes evolved under purifying selection. The phylogenetic analyses indicated that each section forms a clade, except the section Spinosae, which was divided into two clades. This study elucidated the evolution of the chloroplast genome within the widely distributed genus Caragana. The detailed information obtained from this study can serve as a valuable resource for understanding the molecular dynamics and phylogenetic relationships within Caragana. Full article
(This article belongs to the Special Issue Plant Phylogenomics and Genetic Diversity (2nd Edition))
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18 pages, 1344 KiB  
Article
Key Regulators of Angiogenesis and Inflammation Are Dysregulated in Patients with Varicose Veins
by Daniel Zalewski, Paulina Chmiel, Przemysław Kołodziej, Marcin Kocki, Marcin Feldo, Janusz Kocki and Anna Bogucka-Kocka
Int. J. Mol. Sci. 2024, 25(12), 6785; https://doi.org/10.3390/ijms25126785 - 20 Jun 2024
Viewed by 1227
Abstract
Varicose veins (VVs) are the most common manifestation of chronic venous disease (CVD) and appear as abnormally enlarged and tortuous superficial veins. VVs result from functional abnormalities in the venous circulation of the lower extremities, such as venous hypertension, venous valve incompetence, and [...] Read more.
Varicose veins (VVs) are the most common manifestation of chronic venous disease (CVD) and appear as abnormally enlarged and tortuous superficial veins. VVs result from functional abnormalities in the venous circulation of the lower extremities, such as venous hypertension, venous valve incompetence, and venous reflux. Previous studies indicate that enhanced angiogenesis and inflammation contribute to the progression and onset of VVs; however, dysregulations in signaling pathways associated with these processes in VVs patients are poorly understood. Therefore, in our study, we aimed to identify key regulators of angiogenesis and inflammation that are dysregulated in patients with VVs. Expression levels of 18 genes were analyzed in peripheral blood mononuclear cells (PBMC) using real-time PCR, as well as plasma levels of 6 proteins were investigated using ELISA. Higher levels of CCL5, PDGFA, VEGFC, TGF-alpha, TGF-beta 1, and VEGF-A, as well as lower levels of VEGFB and VEGF-C, were found to be statistically significant in the VV group compared to the control subjects without VVs. None of the analyzed factors was associated with the venous localization of the varicosities. The presented study identified dysregulations in key angiogenesis- and inflammation-related factors in PBMC and plasma from VVs patients, providing new insight into molecular mechanisms that could contribute to the development of VVs and point out promising candidates for circulatory biomarkers of this disease. Full article
(This article belongs to the Special Issue Advances in Molecular and Translational Medicine: 2nd Edition)
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14 pages, 1526 KiB  
Article
Inflamma-miRs Profile in Myelodysplastic Syndrome Patients
by Paola Montes, Iryna Rusanova, Elena Cornejo, Paloma García, Ana Guerra-Librero, Mª del Señor López, Tomás de Haro, Germaine Escames and Darío Acuña-Castroviejo
Int. J. Mol. Sci. 2024, 25(12), 6784; https://doi.org/10.3390/ijms25126784 - 20 Jun 2024
Viewed by 1131
Abstract
Etiological factors involved in myelodysplastic syndrome (MDS) include immunologic, oxidative stress and inflammatory factors, among others, and these are targets for microRNAs (miRNs). Here, we evaluated whether some miRNs may affect tumor development comparing untreated and 5-azacitidine (5-AZA) MDS-treated patients. Peripheral blood samples [...] Read more.
Etiological factors involved in myelodysplastic syndrome (MDS) include immunologic, oxidative stress and inflammatory factors, among others, and these are targets for microRNAs (miRNs). Here, we evaluated whether some miRNs may affect tumor development comparing untreated and 5-azacitidine (5-AZA) MDS-treated patients. Peripheral blood samples were collected from 20 controls and 24 MDS patients, and selected miRNs related to redox balance and inflammation (inflamma-miRs), including miR-18a, miR-21, miR-34a and miR-146a, were isolated and measured by quantitative real-time polymerase chain reaction (qRTPCR). A differential expression profile of miRNs was detected in untreated MDS patients and the 5-AZA group. Inflammation increases miRNs and, specifically, miR-18a, miR-21 and miR-34a were significantly overexpressed in untreated MDS, compared to controls. However, we did not observe any miRN profile alteration during the progression of the disease. On the other hand, 5-AZA treatment tends to restore miRN expression levels. Relating to prognostic risk factors, high-risk MDS groups (high Revised International Prognostic Scoring System (IPSS-R), high cytogenetic risk, high molecular risk (HMR) mutations) tended to be related with higher expression levels of miR-18a and miR-34a. Higher miRN expression is correlated with lower glutathione peroxidase activity, while they are related with a higher profile of pro-inflammatory cytokines (IL-2, IL-6, IL-8, TNF-α). Although our study was limited by the low number of MDS patients included, we identified miRN deregulation involved in MDS development that could regulate redox sensors and inflammatory responses. Finally, 5-AZA treatment is related with lower miRN expression levels in MDS patients. Full article
(This article belongs to the Special Issue The Role of Inflammasomes in Human Disease)
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12 pages, 2131 KiB  
Article
Pilot Study by Liquid Biopsy in Gastrointestinal Stromal Tumors: Analysis of PDGFRA D842V Mutation and Hypermethylation of SEPT9 Presence by Digital Droplet PCR
by Rocío Olivera-Salazar, Gabriel Salcedo Cabañas, Luz Vega-Clemente, David Alonso-Martín, Víctor Manuel Castellano Megías, Peter Volward, Damián García-Olmo and Mariano García-Arranz
Int. J. Mol. Sci. 2024, 25(12), 6783; https://doi.org/10.3390/ijms25126783 - 20 Jun 2024
Viewed by 977
Abstract
Tissue biopsy remains the standard for diagnosing gastrointestinal stromal tumors (GISTs), although liquid biopsy is emerging as a promising alternative in oncology. In this pilot study, we advocate for droplet digital PCR (ddPCR) to diagnose GIST in tissue samples and explore its potential [...] Read more.
Tissue biopsy remains the standard for diagnosing gastrointestinal stromal tumors (GISTs), although liquid biopsy is emerging as a promising alternative in oncology. In this pilot study, we advocate for droplet digital PCR (ddPCR) to diagnose GIST in tissue samples and explore its potential for early diagnosis via liquid biopsy, focusing on the PDGFRA D842V mutation and SEPT9 hypermethylated gene. We utilized ddPCR to analyze the predominant PDGFRA mutation (D842V) in surgical tissue samples from 15 GIST patients, correlating with pathologists’ diagnoses. We expanded our analysis to plasma samples to compare DNA alterations between tumor tissue and plasma, also investigating SEPT9 gene hypermethylation. We successfully detected the PDGFRA D842V mutation in GIST tissues by ddPCR. Despite various protocols to enhance mutation detection in early-stage disease, it remained challenging, likely due to the low concentration of DNA in plasma samples. Additionally, the results of Area Under the Curve (AUC) for the hypermethylated SEPT9 gene, analyzing concentration, ratio, and abundance were 0.74 (95% Confidence Interval (CI): 0.52 to 0.97), 0.77 (95% CI: 0.56 to 0.98), and 0.79 (95% CI: 0.59 to 0.99), respectively. As a rare disease, the early detection of GIST through such biomarkers is particularly crucial, offering significant potential to improve patient outcomes. Full article
(This article belongs to the Special Issue New Sights: Genetic Advances and Challenges in Rare Diseases)
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21 pages, 3175 KiB  
Article
The First In Vivo Study Shows That Gyrophoric Acid Changes Behavior of Healthy Laboratory Rats
by Patrik Simko, Andrea Leskanicova, Maria Suvakova-Nunhart, Jan Koval, Nela Zidekova, Martina Karasova, Petra Majerova, Ludmila Verboova, Alzbeta Blicharova, Martin Kertys, Ivan Barvik, Andrej Kovac and Terezia Kiskova
Int. J. Mol. Sci. 2024, 25(12), 6782; https://doi.org/10.3390/ijms25126782 - 20 Jun 2024
Cited by 1 | Viewed by 865
Abstract
Gyrophoric acid (GA), a lichen secondary metabolite, has attracted more attention during the last years because of its potential biological effects. Until now, its effect in vivo has not yet been demonstrated. The aim of our study was to evaluate the basic physicochemical [...] Read more.
Gyrophoric acid (GA), a lichen secondary metabolite, has attracted more attention during the last years because of its potential biological effects. Until now, its effect in vivo has not yet been demonstrated. The aim of our study was to evaluate the basic physicochemical and pharmacokinetic properties of GA, which are directly associated with its biological activities. The stability of the GA in various pH was assessed by conducting repeated UV-VIS spectral measurements. Microsomal stability in rat liver microsomes was performed using Ultra-Performance LC/MS. Binding to human serum albumin (HSA) was assessed using synchronous fluorescence spectra, and molecular docking analysis was used to reveal the binding site of GA to HSA. In the in vivo experiment, 24 Sprague-Dawley rats (Velaz, Únetice, Czech Republic) were used. The animals were divided as follows. The first group (n = 6) included healthy males as control intact rats (♂INT), and the second group (n = 6) included healthy females as controls (♀INT). Groups three and four (♂GA/n = 6 and ♀GA/n = 6) consisted of animals with daily administered GA (10 mg/kg body weight) in an ethanol-water solution per os for a one-month period. We found that GA remained stable under various pH and temperature conditions. It bonded to human serum albumin with the binding constant 1.788 × 106 dm3mol−1 to reach the target tissue via this mechanism. In vivo, GA did not influence body mass gain, food, or fluid intake during the experiment. No liver toxicity was observed. However, GA increased the rearing frequency in behavioral tests (p < 0.01) and center crossings in the elevated plus-maze (p < 0.01 and p < 0.001, respectively). In addition, the time spent in the open arm was prolonged (p < 0.01 and p < 0.001, respectively). Notably, GA was able to pass through the blood–brain barrier, indicating its ability to permeate into the brain and to stimulate neurogenesis in the hilus and subgranular zone of the hippocampus. These observations highlight the potential role of GA in influencing brain function and neurogenesis. Full article
(This article belongs to the Special Issue Bioactive Compounds in Human Brain Structures and Diseases: 2nd Edition)
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