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Int. J. Mol. Sci., Volume 22, Issue 20 (October-2 2021) – 402 articles

Cover Story (view full-size image): This review focuses on the clinical translation of preclinical studies, especially those that have used stem cells in the treatment of glaucoma, with an emphasis on optic nerve regeneration. The studies referred to in the review aim to treat optic nerve atrophy, while cell therapies targeting other sites in the eye, such as the trabecular meshwork, have not been addressed. By analyzing the facts associated with failure, important lessons are to be learned: the type of stem cells used, the route of administration, the selection of patients eligible for these treatments, additional therapies that support stem cell transplantation and their mode of action, and methods for avoiding the host’s immune response.View this paper
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Article
Effects of Variation in Al Content on the Emission of Eu Doped CaAlSiN3 Red Phosphor Synthesized by Combustion Synthesis Method for White LEDs
Int. J. Mol. Sci. 2021, 22(20), 11301; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011301 - 19 Oct 2021
Viewed by 566
Abstract
Effects of Al content on the formation and the photoluminescence properties of CaAlSiN3:Eu2+ phosphor (CASIN) were investigated by a combustion synthesis method. XRD (X-ray diffraction), combined with PL (photoluminescence), TEM-EDS (transmission electron microscope equipped with an energy-dispersive X-ray spectroscope), and [...] Read more.
Effects of Al content on the formation and the photoluminescence properties of CaAlSiN3:Eu2+ phosphor (CASIN) were investigated by a combustion synthesis method. XRD (X-ray diffraction), combined with PL (photoluminescence), TEM-EDS (transmission electron microscope equipped with an energy-dispersive X-ray spectroscope), and SAED (selected area electron diffraction) measurements, show that the bar-like CASIN gives a stronger emission than the plate-like and agglomerated fine particles. The emission intensity increases as the Al content increased from Al = 0.2 to Al = 0.8, which resulted from the extent of formation of CASIN increases. Then, the emission intensity decreases as the Al content is increased from Al = 0.8 to Al = 1.5, which resulted from the transformation of morphology of CASIN and a large amount formation of AlN. In addition, the extent of formation of CASIN increases with increasing Al from Al = 0.2 to Al = 1.2 and begins to decrease as Al is further increased to 1.5, and thus the peak emission wavelength increases from 647 nm to 658 nm as the Al molar ratio is increased from 0.2 to 1.2 and begins to decrease when further increasing the Al molar ratio to 1.5, which resulted from the large amount of AlN formed. Full article
(This article belongs to the Special Issue Dual Fluorescence Effects)
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Review
Stimulus-Responsive Smart Nanoparticles-Based CRISPR-Cas Delivery for Therapeutic Genome Editing
Int. J. Mol. Sci. 2021, 22(20), 11300; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011300 - 19 Oct 2021
Viewed by 783
Abstract
The innovative research in genome editing domains such as CRISPR-Cas technology has enabled genetic engineers to manipulate the genomes of living organisms effectively in order to develop the next generation of therapeutic tools. This technique has started the new era of “genome surgery”. [...] Read more.
The innovative research in genome editing domains such as CRISPR-Cas technology has enabled genetic engineers to manipulate the genomes of living organisms effectively in order to develop the next generation of therapeutic tools. This technique has started the new era of “genome surgery”. Despite these advances, the barriers of CRISPR-Cas9 techniques in clinical applications include efficient delivery of CRISPR/Cas9 and risk of off-target effects. Various types of viral and non-viral vectors are designed to deliver the CRISPR/Cas9 machinery into the desired cell. These methods still suffer difficulties such as immune response, lack of specificity, and efficiency. The extracellular and intracellular environments of cells and tissues differ in pH, redox species, enzyme activity, and light sensitivity. Recently, smart nanoparticles have been synthesized for CRISPR/Cas9 delivery to cells based on endogenous (pH, enzyme, redox specie, ATP) and exogenous (magnetic, ultrasound, temperature, light) stimulus signals. These methodologies can leverage genome editing through biological signals found within disease cells with less off-target effects. Here, we review the recent advances in stimulus-based smart nanoparticles to deliver the CRISPR/Cas9 machinery into the desired cell. This review article will provide extensive information to cautiously utilize smart nanoparticles for basic biomedical applications and therapeutic genome editing. Full article
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Article
Design, Synthesis, Antibacterial, Antifungal and Anticancer Evaluations of Novel β-Pinene Quaternary Ammonium Salts
Int. J. Mol. Sci. 2021, 22(20), 11299; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011299 - 19 Oct 2021
Cited by 1 | Viewed by 467
Abstract
β-pinene is a monoterpene isolated from turpentine oil and numerous other plants’ essential oils, which has a broad spectrum of biological activities. In the current work, six novel β-pinene quaternary ammonium (β-PQA) salts were synthesized and evaluated in vitro [...] Read more.
β-pinene is a monoterpene isolated from turpentine oil and numerous other plants’ essential oils, which has a broad spectrum of biological activities. In the current work, six novel β-pinene quaternary ammonium (β-PQA) salts were synthesized and evaluated in vitro for their antifungal, antibacterial and anticancer activities. The in vitro assay results revealed that compounds 4a and 4b presented remarkable antimicrobial activity against the tested fungi and bacteria. In particular, compound 4a showed excellent activities against F. oxysporum f.sp. niveum, P. nicotianae var.nicotianae, R. solani, D. pinea and Fusicoccumaesculi, with EC50 values of 4.50, 10.92, 9.45, 10.82 and 6.34 μg/mL, respectively. Moreover, compound 4a showed the best antibacterial action against E. coli, P. aeruginosa, S. aureus and B. subtilis, with MIC at 2.5, 0.625, 1.25 and 1.25 μg/mL, respectively. The anticancer activity results demonstrated that compounds 4a, 4b, 4c and 4f exhibited remarkable activity against HCT-116 and MCF-7 cell lines, with IC50 values ranged from 1.10 to 25.54 μM. Notably, the compound 4c displayed the strongest cytotoxicity against HCT-116 and MCF-7 cell lines, with the IC50 values of 1.10 and 2.46 μM, respectively. Furthermore, preliminary antimicrobial mechanistic studies revealed that compound 4a might cause mycelium abnormalities of microbial, cell membrane permeability changes and inhibition of the activity of ATP. Altogether, these findings open interesting perspectives to the application of β-PQA salts as a novel leading structure for the development of effective antimicrobial and anticancer agents. Full article
(This article belongs to the Section Biochemistry)
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Article
Smart Vitamin Micelles as Cancer Nanomedicines for Enhanced Intracellular Delivery of Doxorubicin
Int. J. Mol. Sci. 2021, 22(20), 11298; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011298 - 19 Oct 2021
Viewed by 526
Abstract
Chemotherapy is one of the most effective treatments for cancer. However, intracellular delivery of many anticancer drugs is hindered by their hydrophobicity and low molecular weight. Here, we describe highly biocompatible and biodegradable amphiphilic vitamin conjugates comprising hydrophobic vitamin E and hydrophilic vitamin [...] Read more.
Chemotherapy is one of the most effective treatments for cancer. However, intracellular delivery of many anticancer drugs is hindered by their hydrophobicity and low molecular weight. Here, we describe highly biocompatible and biodegradable amphiphilic vitamin conjugates comprising hydrophobic vitamin E and hydrophilic vitamin B labeled with dual pH and glutathione-responsive degradable linkages. Vitamin-based micelles (vitamicelles), formed by self-assembly in aqueous solutions, were optimized based on their stability after encapsulation of doxorubicin (DOX). The resulting vitamicelles have great potential as vehicles for anticancer drugs because they show excellent biocompatibility (>94% after 48 h of incubation) and rapid biodegradability (>90% after 2.5 h). Compared with free DOX, DOX-loaded vitamicelles showed a markedly enhanced anticancer effect as they released the drug rapidly and inhibited drug efflux out of cells efficiently. By exploiting these advantages, this study not only provides a promising strategy for circumventing existing challenges regarding the delivery of anticancer drugs but also extends the utility of current DOX-induced chemotherapy. Full article
(This article belongs to the Special Issue Nano-Materials and Methods 3.0)
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Article
Full Length Transcriptome Highlights the Coordination of Plastid Transcript Processing
Int. J. Mol. Sci. 2021, 22(20), 11297; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011297 - 19 Oct 2021
Viewed by 542
Abstract
Plastid gene expression involves many post-transcriptional maturation steps resulting in a complex transcriptome composed of multiple isoforms. Although short-read RNA-Seq has considerably improved our understanding of the molecular mechanisms controlling these processes, it is unable to sequence full-length transcripts. This information is crucial, [...] Read more.
Plastid gene expression involves many post-transcriptional maturation steps resulting in a complex transcriptome composed of multiple isoforms. Although short-read RNA-Seq has considerably improved our understanding of the molecular mechanisms controlling these processes, it is unable to sequence full-length transcripts. This information is crucial, however, when it comes to understanding the interplay between the various steps of plastid gene expression. Here, we describe a protocol to study the plastid transcriptome using nanopore sequencing. In the leaf of Arabidopsis thaliana, with about 1.5 million strand-specific reads mapped to the chloroplast genome, we could recapitulate most of the complexity of the plastid transcriptome (polygenic transcripts, multiple isoforms associated with post-transcriptional processing) using virtual Northern blots. Even if the transcripts longer than about 2500 nucleotides were missing, the study of the co-occurrence of editing and splicing events identified 42 pairs of events that were not occurring independently. This study also highlighted a preferential chronology of maturation events with splicing happening after most sites were edited. Full article
(This article belongs to the Special Issue Post-transcriptional Regulation in Plant Organelles)
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Article
Biological Control of Leaf Blight Disease Caused by Pestalotiopsis maculans and Growth Promotion of Quercus acutissima Carruth Container Seedlings Using Bacillus velezensis CE 100
Int. J. Mol. Sci. 2021, 22(20), 11296; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011296 - 19 Oct 2021
Viewed by 435
Abstract
Leaf blight disease caused by Pestalotiopsismaculans lead to deleterious losses in the quality of forest container seedlings. The use of plant growth-promoting bacteria provides a promising strategy to simultaneously control diseases and enhance forest seedling production. This study investigated the biocontrol of [...] Read more.
Leaf blight disease caused by Pestalotiopsismaculans lead to deleterious losses in the quality of forest container seedlings. The use of plant growth-promoting bacteria provides a promising strategy to simultaneously control diseases and enhance forest seedling production. This study investigated the biocontrol of leaf blight disease and growth promotion potential of Bacillus velezensis CE 100 in Quercus acutissima Carruth seedlings. B. velezensis CE 100 produced cell wall degrading enzymes, such as chitinase, β-l,3-glucanase, and protease, which caused cell wall lysis and hyphae deformation of P. maculans, leading to mycelial growth inhibition by 54.94%. Inoculation of B. velezensis CE 100 suppressed P. maculans infection and increased seedling survival rate by 1.6-fold and 1.3-fold compared to chemical fertilizer and control, respectively. In addition, B. velezensis CE 100 produced indole-3-acetic acid, which improved root development and nutrient uptake compared to chemical fertilizer and control. Especially, inoculation with B. velezensis CE 100 increased the total nitrogen content of Q. acutissima seedlings, improved the chlorophyll index in the leaves, and increased seedling biomass by 1.3-fold and 2.2-fold compared to chemical fertilizer and control, respectively. Thus, B. velezensis CE 100 could be applied in the eco-friendly production of high-quality forest seedlings. Full article
(This article belongs to the Special Issue Synthetic and Natural Antifungals—Desirable and Hazardous Effects)
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Review
The Genetics of Diabetes: What We Can Learn from Drosophila
Int. J. Mol. Sci. 2021, 22(20), 11295; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011295 - 19 Oct 2021
Viewed by 617
Abstract
Diabetes mellitus is a heterogeneous disease characterized by hyperglycemia due to impaired insulin secretion and/or action. All diabetes types have a strong genetic component. The most frequent forms, type 1 diabetes (T1D), type 2 diabetes (T2D) and gestational diabetes mellitus (GDM), are multifactorial [...] Read more.
Diabetes mellitus is a heterogeneous disease characterized by hyperglycemia due to impaired insulin secretion and/or action. All diabetes types have a strong genetic component. The most frequent forms, type 1 diabetes (T1D), type 2 diabetes (T2D) and gestational diabetes mellitus (GDM), are multifactorial syndromes associated with several genes’ effects together with environmental factors. Conversely, rare forms, neonatal diabetes mellitus (NDM) and maturity onset diabetes of the young (MODY), are caused by mutations in single genes. Large scale genome screenings led to the identification of hundreds of putative causative genes for multigenic diabetes, but all the loci identified so far explain only a small proportion of heritability. Nevertheless, several recent studies allowed not only the identification of some genes as causative, but also as putative targets of new drugs. Although monogenic forms of diabetes are the most suited to perform a precision approach and allow an accurate diagnosis, at least 80% of all monogenic cases remain still undiagnosed. The knowledge acquired so far addresses the future work towards a study more focused on the identification of diabetes causal variants; this aim will be reached only by combining expertise from different areas. In this perspective, model organism research is crucial. This review traces an overview of the genetics of diabetes and mainly focuses on Drosophila as a model system, describing how flies can contribute to diabetes knowledge advancement. Full article
(This article belongs to the Special Issue New Advance in Diabetes Genetics)
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Article
Light Tailoring: Impact of UV-C Irradiation on Biosynthesis, Physiognomies, and Clinical Activities of Morus macroura-Mediated Monometallic (Ag and ZnO) and Bimetallic (Ag–ZnO) Nanoparticles
Int. J. Mol. Sci. 2021, 22(20), 11294; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011294 - 19 Oct 2021
Viewed by 463
Abstract
A nano-revolution based on the green synthesis of nanomaterials could affect all areas of human life, and nanotechnology represents a propitious platform for various biomedical applications. During the synthesis of nanoparticles, various factors can control their physiognomies and clinical activities. Light is one [...] Read more.
A nano-revolution based on the green synthesis of nanomaterials could affect all areas of human life, and nanotechnology represents a propitious platform for various biomedical applications. During the synthesis of nanoparticles, various factors can control their physiognomies and clinical activities. Light is one of the major physical factors that can play an important role in tuning/refining the properties of nanoparticles. In this study, biocompatible monometallic (AgNPs and ZnONPs) and bimetallic Ag–ZnONPs (0.1/0.1 and 0.1/0.5) were synthesized under UV-C light irradiation from the leaf extract of Morus macroura, which possesses enriched TPC (4.238 ± 0.26 mg GAE/g DW) and TFC (1.073 ± 0.18 mg QE/g DW), as well as strong FRSA (82.39%). These green synthesized NPs were evaluated for their anti-diabetic, anti-glycation, and biocompatibility activities. Furthermore, their anti-cancerous activity against HepG2 cell lines was assessed in terms of cell viability, production of reactive oxygen/nitrogen species, mitochondrial membrane potential, and apoptotic caspase-3/7 expression and activity. Synthesized NPs were characterized by techniques including ultraviolet-visible spectroscopy, SEM, EDX, FTIR, and XRD. UV-C mediated monometallic and bimetallic NPs showed well-defined characteristic shapes with a more disperse particle distribution, definite crystalline structures, and reduced sizes as compared to their respective controls. In the case of clinical activities, the highest anti-diabetic activity (67.77 ± 3.29% against α-amylase and 35.83 ± 2.40% against α-glucosidase) and anti-glycation activity (37.68 ± 3.34% against pentosidine-like AGEs and 67.87 ± 2.99% against vesperlysine-like AGEs) was shown by UV-C mediated AgNPs. The highest biocompatibility (IC50 = 14.23 ± 1.68 µg/mL against brine shrimp and 2.48 ± 0.32% hemolysis of human red blood cells) was shown by UV-C mediated ZnONPs. In the case of anti-cancerous activities, the lowest viability (23.45 ± 1.40%) with enhanced ROS/NOS production led to a significant disruption of mitochondrial membrane potential and greater caspase-3/7 gene expression and activity by UV-C mediated bimetallic Ag–ZnONPs (0.1/0.5). The present work highlights the positive effects of UV-C light on physico-chemical physiognomies as well as the clinical activities of NPs. Full article
(This article belongs to the Special Issue Advances in Nanoparticles-Biomolecules Interactions)
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Article
ELTD1 Activation Induces an Endothelial-EMT Transition to a Myofibroblast Phenotype
Int. J. Mol. Sci. 2021, 22(20), 11293; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011293 - 19 Oct 2021
Viewed by 651
Abstract
ELTD1 is expressed in endothelial and vascular smooth muscle cells and has a role in angiogenesis. It has been classified as an adhesion GPCR, but as yet, no ligand has been identified and its function remains unknown. To establish its role, ELTD1 was [...] Read more.
ELTD1 is expressed in endothelial and vascular smooth muscle cells and has a role in angiogenesis. It has been classified as an adhesion GPCR, but as yet, no ligand has been identified and its function remains unknown. To establish its role, ELTD1 was overexpressed in endothelial cells. Expression and consequently ligand independent activation of ELTD1 results in endothelial-mesenchymal transistion (EndMT) with a loss of cell-cell contact, formation of stress fibres and mature focal adhesions and an increased expression of smooth muscle actin. The effect was pro-angiogenic, increasing Matrigel network formation and endothelial sprouting. RNA-Seq analysis after the cells had undergone EndMT revealed large increases in chemokines and cytokines involved in regulating immune response. Gene set enrichment analysis of the data identified a number of pathways involved in myofibroblast biology suggesting that the endothelial cells had undergone a type II EMT. This type of EMT is involved in wound repair and is closely associated with inflammation implicating ELTD1 in these processes. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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Review
EHMT2/G9a as an Epigenetic Target in Pediatric and Adult Brain Tumors
Int. J. Mol. Sci. 2021, 22(20), 11292; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011292 - 19 Oct 2021
Viewed by 569
Abstract
Epigenetic mechanisms, including post-translational modifications of DNA and histones that influence chromatin structure, regulate gene expression during normal development and are also involved in carcinogenesis and cancer progression. The histone methyltransferase G9a (euchromatic histone lysine methyltransferase 2, EHMT2), which mostly mediates mono- and [...] Read more.
Epigenetic mechanisms, including post-translational modifications of DNA and histones that influence chromatin structure, regulate gene expression during normal development and are also involved in carcinogenesis and cancer progression. The histone methyltransferase G9a (euchromatic histone lysine methyltransferase 2, EHMT2), which mostly mediates mono- and dimethylation by histone H3 lysine 9 (H3K9), influences gene expression involved in embryonic development and tissue differentiation. Overexpression of G9a has been observed in several cancer types, and different classes of G9a inhibitors have been developed as potential anticancer agents. Here, we review the emerging evidence suggesting the involvement of changes in G9a activity in brain tumors, namely glioblastoma (GBM), the main type of primary malignant brain cancer in adults, and medulloblastoma (MB), the most common type of malignant brain cancer in children. We also discuss the role of G9a in neuroblastoma (NB) and the drug development of G9a inhibitors. Full article
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Article
Genome-Wide Identification and Expression Analysis of R2R3-MYB Family Genes Associated with Petal Pigment Synthesis in Liriodendron
Int. J. Mol. Sci. 2021, 22(20), 11291; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011291 - 19 Oct 2021
Viewed by 503
Abstract
The MYB transcription factor family is one of the largest families in plants, and its members have various biological functions. R2R3-MYB genes are involved in the synthesis of pigments that yield petal colors. Liriodendron plants are widely cultivated as ornamental trees owing to [...] Read more.
The MYB transcription factor family is one of the largest families in plants, and its members have various biological functions. R2R3-MYB genes are involved in the synthesis of pigments that yield petal colors. Liriodendron plants are widely cultivated as ornamental trees owing to their peculiar leaves, tulip-like flowers, and colorful petals. However, the mechanism underlying petal coloring in this species is unknown, and minimal information about MYB genes in Liriodendron is available. Herein, this study aimed to discern gene(s) involved in petal coloration in Liriodendron via genome-wide identification, HPLC, and RT-qPCR assays. In total, 204 LcMYB superfamily genes were identified in the Liriodendron chinense genome, and 85 R2R3-MYB genes were mapped onto 19 chromosomes. Chromosome 4 contained the most (10) R2R3-MYB genes, and chromosomes 14 and 16 contained the fewest (only one). MEME analysis showed that R2R3-MYB proteins in L. chinense were highly conserved and that their exon-intron structures varied. The HPLC results showed that three major carotenoids were uniformly distributed in the petals of L. chinense, while lycopene and β-carotene were concentrated in the orange band region in the petals of Liriodendron tulipifera. Furthermore, the expression profiles via RT-qPCR assays revealed that four R2R3-MYB genes were expressed at the highest levels at the S3P/S4P stage in L. tulipifera. This result combined with the HPLC results showed that these four R2R3-MYB genes might participate in carotenoid synthesis in the petals of L. tulipifera. This work laid a cornerstone for further functional characterization of R2R3-MYB genes in Liriodendron plants. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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Review
Probiotic Supplements: Their Strategies in the Therapeutic and Prophylactic of Human Life-Threatening Diseases
Int. J. Mol. Sci. 2021, 22(20), 11290; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011290 - 19 Oct 2021
Viewed by 682
Abstract
Chronic diseases and viral infections have threatened human life over the ages and constitute the main reason for increasing death globally. The rising burden of these diseases extends to negatively affecting the economy and trading globally, as well as daily life, which requires [...] Read more.
Chronic diseases and viral infections have threatened human life over the ages and constitute the main reason for increasing death globally. The rising burden of these diseases extends to negatively affecting the economy and trading globally, as well as daily life, which requires inexpensive, novel, and safe therapeutics. Therefore, scientists have paid close attention to probiotics as safe remedies to combat these morbidities owing to their health benefits and biotherapeutic effects. Probiotics have been broadly adopted as functional foods, nutraceuticals, and food supplements to improve human health and prevent some morbidity. Intriguingly, recent research indicates that probiotics are a promising solution for treating and prophylactic against certain dangerous diseases. Probiotics could also be associated with their essential role in animating the immune system to fight COVID-19 infection. This comprehensive review concentrates on the newest literature on probiotics and their metabolism in treating life-threatening diseases, including immune disorders, pathogens, inflammatory and allergic diseases, cancer, cardiovascular disease, gastrointestinal dysfunctions, and COVID-19 infection. The recent information in this report will particularly furnish a platform for emerging novel probiotics-based therapeutics as cheap and safe, encouraging researchers and stakeholders to develop innovative treatments based on probiotics to prevent and treat chronic and viral diseases. Full article
(This article belongs to the Special Issue Probiotics in Human Health and Diseases)
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Review
The Role of Emerin in Cancer Progression and Metastasis
Int. J. Mol. Sci. 2021, 22(20), 11289; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011289 - 19 Oct 2021
Viewed by 406
Abstract
It is commonly recognized in the field that cancer cells exhibit changes in the size and shape of their nuclei. These features often serve as important biomarkers in the diagnosis and prognosis of cancer patients. Nuclear size can significantly impact cell migration due [...] Read more.
It is commonly recognized in the field that cancer cells exhibit changes in the size and shape of their nuclei. These features often serve as important biomarkers in the diagnosis and prognosis of cancer patients. Nuclear size can significantly impact cell migration due to its incredibly large size. Nuclear structural changes are predicted to regulate cancer cell migration. Nuclear abnormalities are common across a vast spectrum of cancer types, regardless of tissue source, mutational spectrum, and signaling dependencies. The pervasiveness of nuclear alterations suggests that changes in nuclear structure may be crucially linked to the transformation process. The factors driving these nuclear abnormalities, and the functional consequences, are not completely understood. Nuclear envelope proteins play an important role in regulating nuclear size and structure in cancer. Altered expression of nuclear lamina proteins, including emerin, is found in many cancers and this expression is correlated with better clinical outcomes. A model is emerging whereby emerin, as well as other nuclear lamina proteins, binding to the nucleoskeleton regulates the nuclear structure to impact metastasis. In this model, emerin and lamins play a central role in metastatic transformation, since decreased emerin expression during transformation causes the nuclear structural defects required for increased cell migration, intravasation, and extravasation. Herein, we discuss the cellular functions of nuclear lamina proteins, with a particular focus on emerin, and how these functions impact cancer progression and metastasis. Full article
(This article belongs to the Special Issue Nuclear Envelope Proteins 2.0)
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Article
Responses of Sphagneticola trilobata, Sphagneticola calendulacea and Their Hybrid to Drought Stress
Int. J. Mol. Sci. 2021, 22(20), 11288; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011288 - 19 Oct 2021
Viewed by 339
Abstract
Sphagneticola trilobata is an invasive plant in South China. A hybrid between S. trilobata and Sphagneticola calendulacea (a native related species) has also been found in South China. The drought resistance of S. calendulacea, S. trilobata and their hybrid [...] Read more.
Sphagneticola trilobata is an invasive plant in South China. A hybrid between S. trilobata and Sphagneticola calendulacea (a native related species) has also been found in South China. The drought resistance of S. calendulacea, S. trilobata and their hybrid was studied in this paper. Under drought stress, the leaves of S. trilobata synthesized more abscisic acid (ABA) than those of the other species to reduce stomatal opening and water loss. The activities of antioxidant enzymes were the highest in S. trilobata and the lowest in S. calendulacea. The leaves of S. calendulacea suffered the most serious damage, and their maximum photochemical efficiency was the lowest. RNA-sequencing ware used to analyze the expression levels of genes in ABA, antioxidant enzyme, sugar and proline synthesis and photosynthesis pathways. Further real-time PCR detection verified the RNA-sequence results, and the results were in accordance with the physiological data. The results showed that S. trilobata was the most drought tolerant, and the drought tolerance of the hybrid did not show heterosis but was higher than S. calendulacea. Therefore, compared with S. trilobata and the hybrid, the population number and distribution of S. calendulacea may be less in arid areas. Full article
(This article belongs to the Special Issue Drought-Stress Induced Physiological and Molecular Changes in Plants)
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Article
Peimine, an Anti-Inflammatory Compound from Chinese Herbal Extracts, Modulates Muscle-Type Nicotinic Receptors
Int. J. Mol. Sci. 2021, 22(20), 11287; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011287 - 19 Oct 2021
Viewed by 521
Abstract
Fritillaria bulbs are used in Traditional Chinese Medicine to treat several illnesses. Peimine (Pm), an anti-inflammatory compound from Fritillaria, is known to inhibit some voltage-dependent ion channels and muscarinic receptors, but its interaction with ligand-gated ion channels remains unexplored. We have studied [...] Read more.
Fritillaria bulbs are used in Traditional Chinese Medicine to treat several illnesses. Peimine (Pm), an anti-inflammatory compound from Fritillaria, is known to inhibit some voltage-dependent ion channels and muscarinic receptors, but its interaction with ligand-gated ion channels remains unexplored. We have studied if Pm affects nicotinic acetylcholine receptors (nAChRs), since they play broad functional roles, both in the nervous system and non-neuronal tissues. Muscle-type nAChRs were incorporated to Xenopus oocytes and the action of Pm on the membrane currents elicited by ACh (IAChs) was assessed. Functional studies were combined with virtual docking and molecular dynamics assays. Co-application of ACh and Pm reversibly blocked IACh, with an IC50 in the low micromolar range. Pm inhibited nAChR by: (i) open-channel blockade, evidenced by the voltage-dependent inhibition of IAch, (ii) enhancement of nAChR desensitization, revealed by both an accelerated IACh decay and a decelerated IACh deactivation, and (iii) resting-nAChR blockade, deduced from the IACh inhibition elicited by Pm when applied before ACh superfusion. In good concordance, virtual docking and molecular dynamics assays demonstrated that Pm binds to different sites at the nAChR, mostly at the transmembrane domain. Thus, Pm from Fritillaria bulbs, considered therapeutic herbs, targets nAChRs with high affinity, which might account for its anti-inflammatory actions. Full article
(This article belongs to the Special Issue Cholinergic Control of Inflammation)
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Review
The Pathogenesis, Molecular Mechanisms, and Therapeutic Potential of the Interferon Pathway in Systemic Lupus Erythematosus and Other Autoimmune Diseases
Int. J. Mol. Sci. 2021, 22(20), 11286; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011286 - 19 Oct 2021
Viewed by 760
Abstract
Therapeutic success in treating patients with systemic lupus erythematosus (SLE) is limited by the multivariate disease etiology, multi-organ presentation, systemic involvement, and complex immunopathogenesis. Agents targeting B-cell differentiation and survival are not efficacious for all patients, indicating a need to target other inflammatory [...] Read more.
Therapeutic success in treating patients with systemic lupus erythematosus (SLE) is limited by the multivariate disease etiology, multi-organ presentation, systemic involvement, and complex immunopathogenesis. Agents targeting B-cell differentiation and survival are not efficacious for all patients, indicating a need to target other inflammatory mediators. One such target is the type I interferon pathway. Type I interferons upregulate interferon gene signatures and mediate critical antiviral responses. Dysregulated type I interferon signaling is detectable in many patients with SLE and other autoimmune diseases, and the extent of this dysregulation is associated with disease severity, making type I interferons therapeutically tangible targets. The recent approval of the type I interferon-blocking antibody, anifrolumab, by the US Food and Drug Administration for the treatment of patients with SLE demonstrates the value of targeting this pathway. Nevertheless, the interferon pathway has pleiotropic biology, with multiple cellular targets and signaling components that are incompletely understood. Deconvoluting the complexity of the type I interferon pathway and its intersection with lupus disease pathology will be valuable for further development of targeted SLE therapeutics. This review summarizes the immune mediators of the interferon pathway, its association with disease pathogenesis, and therapeutic modalities targeting the dysregulated interferon pathway. Full article
(This article belongs to the Special Issue Interferons in Lupus)
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Article
Sodium Butyrate Enhances Curcuminoids Permeability through the Blood-Brain Barrier, Restores Wnt/β-Catenin Pathway Antagonists Gene Expression and Reduces the Viability of Glioblastoma Cells
Int. J. Mol. Sci. 2021, 22(20), 11285; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011285 - 19 Oct 2021
Viewed by 617
Abstract
Glioblastoma (GBM) is an extremely aggressive brain tumor awaiting novel, efficient, and minimally toxic treatment. Curcuminoids (CCM), polyphenols from Curcuma longa, and sodium butyrate (NaBu), a histone deacetylase inhibitor naturally occurring in the human body, await elucidation as potential anti-GBM agents. Thus, [...] Read more.
Glioblastoma (GBM) is an extremely aggressive brain tumor awaiting novel, efficient, and minimally toxic treatment. Curcuminoids (CCM), polyphenols from Curcuma longa, and sodium butyrate (NaBu), a histone deacetylase inhibitor naturally occurring in the human body, await elucidation as potential anti-GBM agents. Thus, the aim of this study was to analyze CCM and NaBu both separately and as a combination treatment using three GBM cell lines. MTT was used for cytotoxicity evaluation, and the combination index was calculated for synergism prediction. Cell cycle, apoptosis, and reactive oxygen species (ROS) generation were analyzed using flow cytometry. DNA methylation was verified by MS-HRM and mRNA expression by qPCR. The permeability through the blood-brain barrier (BBB) and through the nasal cavity was evaluated using PAMPA model. The results of this study indicate that CCM and NaBu synergistically reduce the viability of GBM cells inducing apoptosis and cell cycle arrest. These effects are mediated via ROS generation and changes in gene expression, including upregulation of Wnt/β-catenin pathway antagonists, SFRP1, and RUNX3, and downregulation of UHRF1, the key epigenetic regulator. Moreover, NaBu ameliorated CCM permeability through the BBB and the nasal cavity. We conclude that CCM and NaBu are promising agents with anti-GBM properties. Full article
(This article belongs to the Special Issue Curcumin in Health and Disease 3.0)
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Review
The Dopaminergic Control of Movement-Evolutionary Considerations
Int. J. Mol. Sci. 2021, 22(20), 11284; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011284 - 19 Oct 2021
Viewed by 592
Abstract
Dopamine is likely the most studied modulatory neurotransmitter, in great part due to characteristic motor deficits in Parkinson’s disease that arise after the degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNc). The SNc, together with the ventral tegmental area [...] Read more.
Dopamine is likely the most studied modulatory neurotransmitter, in great part due to characteristic motor deficits in Parkinson’s disease that arise after the degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNc). The SNc, together with the ventral tegmental area (VTA), play a key role modulating motor responses through the basal ganglia. In contrast to the large amount of existing literature addressing the mammalian dopaminergic system, comparatively little is known in other vertebrate groups. However, in the last several years, numerous studies have been carried out in basal vertebrates, allowing a better understanding of the evolution of the dopaminergic system, especially the SNc/VTA. We provide an overview of existing research in basal vertebrates, mainly focusing on lampreys, belonging to the oldest group of extant vertebrates. The lamprey dopaminergic system and its role in modulating motor responses have been characterized in significant detail, both anatomically and functionally, providing the basis for understanding the evolution of the SNc/VTA in vertebrates. When considered alongside results from other early vertebrates, data in lampreys show that the key role of the SNc/VTA dopaminergic neurons modulating motor responses through the basal ganglia was already well developed early in vertebrate evolution. Full article
(This article belongs to the Special Issue Development of Dopaminergic Neurons)
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Article
Synthesis and Inhibition Activity Study of Triazinyl-Substituted Amino(alkyl)-benzenesulfonamide Conjugates with Polar and Hydrophobic Amino Acids as Inhibitors of Human Carbonic Anhydrases I, II, IV, IX, and XII
Int. J. Mol. Sci. 2021, 22(20), 11283; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011283 - 19 Oct 2021
Viewed by 394
Abstract
Primary sulfonamide derivatives with various heterocycles represent the most widespread group of potential human carbonic anhydrase (hCA) inhibitors with high affinity and selectivity towards specific isozymes from the hCA family. In this work, new 4-aminomethyl- and aminoethyl-benzenesulfonamide derivatives with 1,3,5-triazine disubstituted with a [...] Read more.
Primary sulfonamide derivatives with various heterocycles represent the most widespread group of potential human carbonic anhydrase (hCA) inhibitors with high affinity and selectivity towards specific isozymes from the hCA family. In this work, new 4-aminomethyl- and aminoethyl-benzenesulfonamide derivatives with 1,3,5-triazine disubstituted with a pair of identical amino acids, possessing a polar (Ser, Thr, Asn, Gln) and non-polar (Ala, Tyr, Trp) side chain, have been synthesized. The optimized synthetic, purification, and isolation procedures provided several pronounced benefits such as a short reaction time (in sodium bicarbonate aqueous medium), satisfactory yields for the majority of new products (20.6–91.8%, average 60.4%), an effective, well defined semi-preparative RP-C18 liquid chromatography (LC) isolation of desired products with a high purity (>97%), as well as preservation of green chemistry principles. These newly synthesized conjugates, plus their 4-aminobenzenesulfonamide analogues prepared previously, have been investigated in in vitro inhibition studies towards hCA I, II, IV and tumor-associated isozymes IX and XII. The experimental results revealed the strongest inhibition of hCA XII with low nanomolar inhibitory constants (Kis) for the derivatives with amino acids possessing non-polar side chains (7.5–9.6 nM). Various derivatives were also promising for some other isozymes. Full article
(This article belongs to the Collection Carbonic Anhydrase and Carbonic Anhydrase Inhibitors)
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Article
Generation of a Soluble Form of Human Endoglin Fused to Green Fluorescent Protein
Int. J. Mol. Sci. 2021, 22(20), 11282; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011282 - 19 Oct 2021
Viewed by 479
Abstract
Endoglin (Eng, CD105) is a type I membrane glycoprotein that functions in endothelial cells as an auxiliary receptor for transforming growth factor β (TGF-β)/bone morphogenetic protein (BMP) family members and as an integrin ligand, modulating the vascular pathophysiology. Besides the membrane-bound [...] Read more.
Endoglin (Eng, CD105) is a type I membrane glycoprotein that functions in endothelial cells as an auxiliary receptor for transforming growth factor β (TGF-β)/bone morphogenetic protein (BMP) family members and as an integrin ligand, modulating the vascular pathophysiology. Besides the membrane-bound endoglin, there is a soluble form of endoglin (sEng) that can be generated by the action of the matrix metalloproteinase (MMP)-14 or -12 on the juxtamembrane region of its ectodomain. High levels of sEng have been reported in patients with preeclampsia, hypercholesterolemia, atherosclerosis and cancer. In addition, sEng is a marker of cardiovascular damage in patients with hypertension and diabetes, plays a pathogenic role in preeclampsia, and inhibits angiogenesis and tumor proliferation, migration, and invasion in cancer. However, the mechanisms of action of sEng have not yet been elucidated, and new tools and experimental approaches are necessary to advance in this field. To this end, we aimed to obtain a fluorescent form of sEng as a new tool for biological imaging. Thus, we cloned the extracellular domain of endoglin in the pEGFP-N1 plasmid to generate a fusion protein with green fluorescent protein (GFP), giving rise to pEGFP-N1/Eng.EC. The recombinant fusion protein was characterized by transient and stable transfections in CHO-K1 cells using fluorescence microscopy, SDS-PAGE, immunodetection, and ELISA techniques. Upon transfection with pEGFP-N1/Eng.EC, fluorescence was readily detected in cells, indicating that the GFP contained in the recombinant protein was properly folded into the cytosol. Furthermore, as evidenced by Western blot analysis, the secreted fusion protein yielded the expected molecular mass and displayed a specific fluorescent signal. The fusion protein was also able to bind to BMP9 and BMP10 in vitro. Therefore, the construct described here could be used as a tool for functional in vitro studies of the extracellular domain of endoglin. Full article
(This article belongs to the Special Issue Recombinant Proteins 2.0)
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Article
8-Hydroxyquinoline-Amino Acid Hybrids and Their Half-Sandwich Rh and Ru Complexes: Synthesis, Anticancer Activities, Solution Chemistry and Interaction with Biomolecules
Int. J. Mol. Sci. 2021, 22(20), 11281; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011281 - 19 Oct 2021
Viewed by 470
Abstract
Solution chemical properties of two novel 8-hydroxyquinoline-D-proline and homo-proline hybrids were investigated along with their complex formation with [Rh(η5-C5Me5)(H2O)3]2+ and [Ru(η6-p-cymene)(H2O)3]2+ ions by [...] Read more.
Solution chemical properties of two novel 8-hydroxyquinoline-D-proline and homo-proline hybrids were investigated along with their complex formation with [Rh(η5-C5Me5)(H2O)3]2+ and [Ru(η6-p-cymene)(H2O)3]2+ ions by pH-potentiometry, UV-visible spectrophotometry and 1H NMR spectroscopy. Due to the zwitterionic structure of the ligands, they possess excellent water solubility as well as their complexes. The complexes exhibit high solution stability in a wide pH range; no significant dissociation occurs at physiological pH. The hybrids and their Rh(η5-C5Me5) complexes displayed enhanced cytotoxicity in human colon adenocarcinoma cell lines and exhibited multidrug resistance selectivity. In addition, the Rh(η5-C5Me5) complexes showed increased selectivity to the chemosensitive cancer cells over the normal cells; meanwhile, the Ru(η6-p-cymene) complexes were inactive, most likely due to arene loss. Interaction of the complexes with human serum albumin (HSA) and calf-thymus DNA (ct-DNA) was investigated by capillary electrophoresis, fluorometry and circular dichroism. The complexes are able to bind strongly to HSA and ct-DNA, but DNA cleavage was not observed. Changing the five-membered proline ring to the six-membered homoproline resulted in increased lipophilicity and cytotoxicity of the Rh(η5-C5Me5) complexes while changing the configuration (L vs. D) rather has an impact on HSA or ct-DNA binding. Full article
(This article belongs to the Special Issue Synthesis and Transformations of Bioactive Hydroxyquinolines)
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Article
Investigating Pathogenetic Mechanisms of Alzheimer’s Disease by Systems Biology Approaches for Drug Discovery
Int. J. Mol. Sci. 2021, 22(20), 11280; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011280 - 19 Oct 2021
Viewed by 386
Abstract
Alzheimer’s disease (AD) is the most common cause of dementia, characterized by progressive cognitive decline and neurodegenerative disorder. Abnormal aggregations of intracellular neurofibrillary tangles (NFTs) and unusual accumulations of extracellular amyloid-β (Aβ) peptides are two important pathological features in AD brains. However, in [...] Read more.
Alzheimer’s disease (AD) is the most common cause of dementia, characterized by progressive cognitive decline and neurodegenerative disorder. Abnormal aggregations of intracellular neurofibrillary tangles (NFTs) and unusual accumulations of extracellular amyloid-β (Aβ) peptides are two important pathological features in AD brains. However, in spite of large-scale clinical studies and computational simulations, the molecular mechanisms of AD development and progression are still unclear. In this study, we divided all of the samples into two groups: early stage (Braak score I–III) and later stage (Braak score IV–VI). By big database mining, the candidate genetic and epigenetic networks (GEN) have been constructed. In order to find out the real GENs for two stages of AD, we performed systems identification and system order detection scheme to prune false positives with the help of corresponding microarray data. Applying the principal network projection (PNP) method, core GENs were extracted from real GENs based on the projection values. By the annotation of KEGG pathway, we could obtain core pathways from core GENs and investigate pathogenetic mechanisms for the early and later stage of AD, respectively. Consequently, according to pathogenetic mechanisms, several potential biomarkers are identified as drug targets for multiple-molecule drug design in the treatment of AD. Full article
(This article belongs to the Collection Feature Papers in Molecular Biophysics)
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Review
Alveolar Regeneration in COVID-19 Patients: A Network Perspective
Int. J. Mol. Sci. 2021, 22(20), 11279; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011279 - 19 Oct 2021
Viewed by 592
Abstract
A viral infection involves entry and replication of viral nucleic acid in a host organism, subsequently leading to biochemical and structural alterations in the host cell. In the case of SARS-CoV-2 viral infection, over-activation of the host immune system may lead to lung [...] Read more.
A viral infection involves entry and replication of viral nucleic acid in a host organism, subsequently leading to biochemical and structural alterations in the host cell. In the case of SARS-CoV-2 viral infection, over-activation of the host immune system may lead to lung damage. Albeit the regeneration and fibrotic repair processes being the two protective host responses, prolonged injury may lead to excessive fibrosis, a pathological state that can result in lung collapse. In this review, we discuss regeneration and fibrosis processes in response to SARS-CoV-2 and provide our viewpoint on the triggering of alveolar regeneration in coronavirus disease 2019 (COVID-19) patients. Full article
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Review
What Do We Know about Classical and Non-Classical Progesterone Receptors in the Human Female Reproductive Tract? A Review
Int. J. Mol. Sci. 2021, 22(20), 11278; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011278 - 19 Oct 2021
Viewed by 341
Abstract
The progesterone hormone regulates the human menstrual cycle, pregnancy, and parturition by its action via the different progesterone receptors and signaling pathways in the female reproductive tract. Progesterone actions can be exerted through classical and non-classical receptors, or even a combination of both. [...] Read more.
The progesterone hormone regulates the human menstrual cycle, pregnancy, and parturition by its action via the different progesterone receptors and signaling pathways in the female reproductive tract. Progesterone actions can be exerted through classical and non-classical receptors, or even a combination of both. The former are nuclear receptors whose activation leads to transcriptional activity regulation and thus in turn leads to slower but long-lasting responses. The latter are composed of progesterone receptors membrane components (PGRMC) and membrane progestin receptors (mPRs). These receptors rapidly activate the appropriate intracellular signal transduction pathways, and they can subsequently initiate specific cell responses or even modulate genomic cell responses. This review covers our current knowledge on the mechanisms of action and the relevance of classical and non-classical progesterone receptors in female reproductive tissues ranging from the ovary and uterus to the cervix, and it exposes their crucial role in female infertility. Full article
(This article belongs to the Special Issue Molecular Mechanism and Function of Progesterone Receptor)
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Article
Differential Membrane Lipid Profiles and Vibrational Spectra of Three Edaphic Algae and One Cyanobacterium
Int. J. Mol. Sci. 2021, 22(20), 11277; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011277 - 19 Oct 2021
Viewed by 320
Abstract
The membrane glycerolipids of four phototrophs that were isolated from an edaphic assemblage were determined by UPLC–MS after cultivation in a laboratory growth chamber. Identification was carried out by 18S and 16S rDNA sequencing. The algal species were Klebsormidium flaccidum (Charophyta), Oocystis sp. [...] Read more.
The membrane glycerolipids of four phototrophs that were isolated from an edaphic assemblage were determined by UPLC–MS after cultivation in a laboratory growth chamber. Identification was carried out by 18S and 16S rDNA sequencing. The algal species were Klebsormidium flaccidum (Charophyta), Oocystis sp. (Chlorophyta), and Haslea spicula (Bacillariophyta), and the cyanobacterium was Microcoleus vaginatus (Cyanobacteria). The glycerolipid profile of Oocystis sp. was dominated by monogalactosyldiacylglycerol (MGDG) species, with MGDG(18:3/16:4) accounting for 68.6%, whereas MGDG(18:3/16:3) was the most abundant glycerolipid in K. flaccidum (50.1%). A ratio of digalactosyldiacylglycerol (DGDG) species to MGDG species (DGDG/MGDG) was shown to be higher in K. flaccidum (0.26) than in Oocystis sp. (0.14). This ratio increased under high light (HL) as compared to low light (LL) in all the organisms, with its highest value being shown in cyanobacterium (0.38–0.58, LL−HL). High contents of eicosapentaenoic acid (EPA, C20:5) and hexadecenoic acid were observed in the glycerolipids of H. spicula. Similar Fourier transform infrared (FTIR) and Raman spectra were found for K. flaccidum and Oocystis sp. Specific bands at 1629.06 and 1582.78 cm−1 were shown by M. vaginatus in the Raman spectra. Conversely, specific bands in the FTIR spectrum were observed for H. spicula at 1143 and 1744 cm−1. The results of this study point out differences in the membrane lipid composition between species, which likely reflects their different morphology and evolutionary patterns. Full article
(This article belongs to the Section Biochemistry)
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Article
High Mobility Group Box 1 Protein in Cerebral Thromboemboli
Int. J. Mol. Sci. 2021, 22(20), 11276; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011276 - 19 Oct 2021
Viewed by 373
Abstract
High-mobility group box 1 protein (HMGB1) is a damage-associated molecular pattern (DAMP) involved in neutrophil extracellular trap (NET) formation and thrombosis. NETs are regularly found in cerebral thromboemboli. We here analyzed associated HMGB1 expression in human thromboemboli retrieved via mechanical thrombectomy from 37 [...] Read more.
High-mobility group box 1 protein (HMGB1) is a damage-associated molecular pattern (DAMP) involved in neutrophil extracellular trap (NET) formation and thrombosis. NETs are regularly found in cerebral thromboemboli. We here analyzed associated HMGB1 expression in human thromboemboli retrieved via mechanical thrombectomy from 37 stroke patients with large vessel occlusion. HMGB1 was detected in all thromboemboli, accounting for 1.7% (IQR 0.6–6.2%) of the total thromboemboli area and was found to be colocalized with neutrophils and NETs and in spatial proximity to platelets. Correlation analysis revealed that the detection of HMGB1 was strongly related to the number of neutrophils (r = 0.58, p = 0.0002) and platelets (r = 0.51, p = 0.001). Our results demonstrate that HMGB1 is a substantial constituent of thromboemboli causing large vessel occlusion stroke. Full article
(This article belongs to the Special Issue Cellular and Molecular Targets in Acute Ischemic Stroke)
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Review
Nuclear mRNA Quality Control and Cytoplasmic NMD Are Linked by the Guard Proteins Gbp2 and Hrb1
Int. J. Mol. Sci. 2021, 22(20), 11275; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011275 - 19 Oct 2021
Viewed by 421
Abstract
Pre-mRNA splicing is critical for cells, as defects in this process can lead to altered open reading frames and defective proteins, potentially causing neurodegenerative diseases and cancer. Introns are removed in the nucleus and splicing is documented by the addition of exon-junction-complexes (EJCs) [...] Read more.
Pre-mRNA splicing is critical for cells, as defects in this process can lead to altered open reading frames and defective proteins, potentially causing neurodegenerative diseases and cancer. Introns are removed in the nucleus and splicing is documented by the addition of exon-junction-complexes (EJCs) at exon-exon boundaries. This “memory” of splicing events is important for the ribosome, which translates the RNAs in the cytoplasm. In case a stop codon was detected before an EJC, translation is blocked and the RNA is eliminated by the nonsense-mediated decay (NMD). In the model organism Saccharomyces cerevisiae, two guard proteins, Gbp2 and Hrb1, have been identified as nuclear quality control factors for splicing. In their absence, intron-containing mRNAs leak into the cytoplasm. Their presence retains transcripts until the process is completed and they release the mRNAs by recruitment of the export factor Mex67. On transcripts that experience splicing problems, these guard proteins recruit the nuclear RNA degradation machinery. Interestingly, they continue their quality control function on exported transcripts. They support NMD by inhibiting translation and recruiting the cytoplasmic degradation factors. In this way, they link the nuclear and cytoplasmic quality control systems. These discoveries are also intriguing for humans, as homologues of these guard proteins are present also in multicellular organisms. Here, we provide an overview of the quality control mechanisms of pre-mRNA splicing, and present Gbp2 and Hrb1, as well as their human counterparts, as important players in these pathways. Full article
(This article belongs to the Special Issue Splicing Modulators Which Affect Gene Expression)
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Review
Functions of PPR Proteins in Plant Growth and Development
Int. J. Mol. Sci. 2021, 22(20), 11274; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011274 - 19 Oct 2021
Viewed by 442
Abstract
Pentatricopeptide repeat (PPR) proteins form a large protein family in land plants, with hundreds of different members in angiosperms. In the last decade, a number of studies have shown that PPR proteins are sequence-specific RNA-binding proteins involved in multiple aspects of plant organellar [...] Read more.
Pentatricopeptide repeat (PPR) proteins form a large protein family in land plants, with hundreds of different members in angiosperms. In the last decade, a number of studies have shown that PPR proteins are sequence-specific RNA-binding proteins involved in multiple aspects of plant organellar RNA processing, and perform numerous functions in plants throughout their life cycle. Recently, computational and structural studies have provided new insights into the working mechanisms of PPR proteins in RNA recognition and cytidine deamination. In this review, we summarized the research progress on the functions of PPR proteins in plant growth and development, with a particular focus on their effects on cytoplasmic male sterility, stress responses, and seed development. We also documented the molecular mechanisms of PPR proteins in mediating RNA processing in plant mitochondria and chloroplasts. Full article
(This article belongs to the Special Issue Research Progress in RNA-Binding Proteins)
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Article
Oleanolic Acid’s Semisynthetic Derivatives HIMOXOL and Br-HIMOLID Show Proautophagic Potential and Inhibit Migration of HER2-Positive Breast Cancer Cells In Vitro
Int. J. Mol. Sci. 2021, 22(20), 11273; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011273 - 19 Oct 2021
Viewed by 462
Abstract
Approximately 20–30% of the diagnosed breast cancers overexpress the human epidermal growth factor receptor 2 (HER2). This type of cancer is associated with a more aggressive phenotype; thus, there is a need for the discovery of new compounds that would improve the survival [...] Read more.
Approximately 20–30% of the diagnosed breast cancers overexpress the human epidermal growth factor receptor 2 (HER2). This type of cancer is associated with a more aggressive phenotype; thus, there is a need for the discovery of new compounds that would improve the survival in HER2-positive breast cancer patients. It seems that one of the most promising therapeutic cancer strategies could be based on the biological activity of pentacyclic triterpenes’ derivatives and the best-known representative of this group, oleanolic acid (OA). The biological activity of oleanolic acid and its two semisynthetic derivatives, methyl 3-hydroxyimino-11-oxoolean-12-en-28-oate (HIMOXOL) and 12α-bromo-3-hydroxyimonoolean-28→13-olide (Br-HIMOLID), was assessed in SK-BR-3 breast cancer cells (HER2-positive). Viability tests, cell cycle assessment, evaluation of apoptosis, autophagy, and adhesion/migration processes were performed using MTT, clonogenic, cytofluorometry, Western blot, and qPCR. Both derivatives revealed higher cytotoxicity in studied breast cancer cells than the maternal compound, OA. They also decreased cell viability, induced autophagy, and (when applied in sub-cytotoxic concentrations) decreased the migration of SK-BR-3 cells.This study is the first to report the cytostatic, proautophagic (mTOR/LC3/SQSTM/BECN1 pathway), and anti-migratory (integrin β1/FAK/paxillin pathway) activities of HIMOXOL and Br-HIMOLID in HER2-positive breast cancer cells. Full article
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Review
Advances in Nanotechnology towards Development of Silver Nanoparticle-Based Wound-Healing Agents
Int. J. Mol. Sci. 2021, 22(20), 11272; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011272 - 19 Oct 2021
Cited by 1 | Viewed by 441
Abstract
Since antiquity, silver-based therapies have been used in wound healing, wound care and management of infections to provide adequate healing. These therapies are associated with certain limitations, such as toxicity, skin discolouration and bacterial resistance, which have limited their use. As a result, [...] Read more.
Since antiquity, silver-based therapies have been used in wound healing, wound care and management of infections to provide adequate healing. These therapies are associated with certain limitations, such as toxicity, skin discolouration and bacterial resistance, which have limited their use. As a result, new and innovative wound therapies, or strategies to improve the existing therapies, are sought after. Silver nanoparticles (AgNPs) have shown the potential to circumvent the limitations associated with conventional silver-based therapies as described above. AgNPs are effective against a broad spectrum of microorganisms and are less toxic, effective at lower concentrations and produce no skin discolouration. Furthermore, AgNPs can be decorated or coupled with other healing-promoting materials to provide optimum healing. This review details the history and impact of silver-based therapies leading up to AgNPs and AgNP-based nanoformulations in wound healing. It also highlights the properties of AgNPs that aid in wound healing and that make them superior to conventional silver-based wound treatment therapies. Full article
(This article belongs to the Section Macromolecules)
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