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Int. J. Mol. Sci., Volume 23, Issue 8 (April-2 2022) – 401 articles

Cover Story (view full-size image): Current cancer treatment drugs damage both tumor cells and healthy cells, and are usually poorly soluble. The development of effective gene delivery systems is thus the key to achieving successful gene therapy. Transporting drugs or genes in nanoliposomes may resolve such issues; since these agents can be released specifically in the affected cells, this approach improves their solubility, bioavailability and efficacy, reducing their adverse effects. These enhancements can improve current treatments and offer the possibility of administering certain antitumor drugs orally. For these purposes, functionalized liposome delivery systems are being developed, such as surface-PEGylated liposomes and responsive liposomes that trigger a release under specific environment conditions. View this paper 
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22 pages, 4078 KiB  
Article
Dendrobium nobile Lindley Administration Attenuates Atopic Dermatitis-like Lesions by Modulating Immune Cells
Int. J. Mol. Sci. 2022, 23(8), 4470; https://doi.org/10.3390/ijms23084470 - 18 Apr 2022
Cited by 12 | Viewed by 2769
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease that can significantly affect daily life by causing sleep disturbance due to extreme itching. In addition, if the symptoms of AD are severe, it can cause mental disorders such as ADHD and suicidal ideation. [...] Read more.
Atopic dermatitis (AD) is a chronic inflammatory skin disease that can significantly affect daily life by causing sleep disturbance due to extreme itching. In addition, if the symptoms of AD are severe, it can cause mental disorders such as ADHD and suicidal ideation. Corticosteroid preparations used for general treatment have good effects, but their use is limited due to side effects. Therefore, it is essential to minimize the side effects and study effective treatment methods. Dendrobium nobile Lindley (DNL) has been widely used for various diseases, but to the best of our knowledge, its effect on AD has not yet been proven. In this study, the inhibitory effect of DNL on AD was confirmed in a DNCB-induced Balb/c mouse. In addition, the inhibitory efficacy of inflammatory cytokines in TNF-α/IFN-γ-induced HaCaT cells and PMACI-induced HMC-1 cells was confirmed. The results demonstrated that DNL decreased IgE, IL-6, IL-4, scratching behavior, SCORAD index, infiltration of mast cells and eosinophils and decreased the thickness of the skin. Additionally, DNL inhibited the expression of cytokines and inhibited the MAPK and NF-κB signaling pathways. This suggests that DNL inhibits cytokine expression, protein signaling pathway, and immune cells, thereby improving AD symptoms in mice. Full article
(This article belongs to the Special Issue Biological Interactions of Bioactive Natural Products)
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16 pages, 3912 KiB  
Article
Coinfection of Porcine Circovirus 2 and Pseudorabies Virus Enhances Immunosuppression and Inflammation through NF-κB, JAK/STAT, MAPK, and NLRP3 Pathways
Int. J. Mol. Sci. 2022, 23(8), 4469; https://doi.org/10.3390/ijms23084469 - 18 Apr 2022
Cited by 17 | Viewed by 2791
Abstract
Porcine circovirus 2 (PCV2) and pseudorabies virus (PRV) are economically important pathogens in swine. PCV2 and PRV coinfection can cause more severe neurological and respiratory symptoms and higher mortality of piglets. However, the exact mechanism involved in the coinfection of PRV and PCV2 [...] Read more.
Porcine circovirus 2 (PCV2) and pseudorabies virus (PRV) are economically important pathogens in swine. PCV2 and PRV coinfection can cause more severe neurological and respiratory symptoms and higher mortality of piglets. However, the exact mechanism involved in the coinfection of PRV and PCV2 and its pathogenesis remain unknown. Here, porcine kidney cells (PK-15) were infected with PCV2 and/or PRV, and then the activation of immune and inflammatory pathways was evaluated to clarify the influence of the coinfection on immune and inflammatory responses. We found that the coinfection of PCV2 and PRV can promote the activation of nuclear factor-κB (NF-κB), c-Jun N-terminal protein kinases (JNK), p38, and nod-like receptor protein 3 (NLRP3) pathways, thus enhancing the expression of interferon-γ (IFN-γ), interferon-λ1 (IFN-λ1), interferon-stimulated gene (ISG15), interleukin 6 (IL6), and interleukin 1β (IL1β). Meanwhile, PCV2 and PRV also inhibit the expression and signal transduction of IFN-β, tumor necrosis factor α (TNFα), and the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway. In addition, PCV2 and PRV infection can also weaken extracellular-signal-regulated kinase (ERK) activity. These results indicate that the regulations of cellular antiviral immune responses and inflammatory responses mediated by NF-κB, JAK/STAT, mitogen-activated protein kinase (MAPK), and NLRP3 pathways, contribute to immune escape of PCV2 and PRV and host antiviral responses. Full article
(This article belongs to the Special Issue The Interaction between Cell and Virus)
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15 pages, 3815 KiB  
Article
The Discovery of Potent SHP2 Inhibitors with Anti-Proliferative Activity in Breast Cancer Cell Lines
Int. J. Mol. Sci. 2022, 23(8), 4468; https://doi.org/10.3390/ijms23084468 - 18 Apr 2022
Cited by 1 | Viewed by 3589
Abstract
Despite available treatments, breast cancer is the leading cause of cancer-related death. Knowing that the tyrosine phosphatase SHP2 is a regulator in tumorigenesis, developing inhibitors of SHP2 in breast cells is crucial. Our study investigated the effects of new compounds, purchased from NSC, [...] Read more.
Despite available treatments, breast cancer is the leading cause of cancer-related death. Knowing that the tyrosine phosphatase SHP2 is a regulator in tumorigenesis, developing inhibitors of SHP2 in breast cells is crucial. Our study investigated the effects of new compounds, purchased from NSC, on the phosphatase activity of SHP2 and the modulation of breast cancer cell lines’ proliferation and viability. A combined ligand-based and structure-based virtual screening protocol was validated, then performed, against SHP2 active site. Top ranked compounds were tested via SHP2 enzymatic assay, followed by measuring IC50 values. Subsequently, hits were tested for their anti-breast cancer viability and proliferative activity. Our experiments identified three compounds 13030, 24198, and 57774 as SHP2 inhibitors, with IC50 values in micromolar levels and considerable selectivity over the analogous enzyme SHP1. Long MD simulations of 500 ns showed a very promising binding mode in the SHP2 catalytic pocket. Furthermore, these compounds significantly reduced MCF-7 breast cancer cells’ proliferation and viability. Interestingly, two of our hits can have acridine or phenoxazine cyclic system known to intercalate in ds DNA. Therefore, our novel approach led to the discovery of SHP2 inhibitors, which could act as a starting point in the future for clinically useful anticancer agents. Full article
(This article belongs to the Special Issue Computational Studies of Drugs and Biomolecules)
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17 pages, 793 KiB  
Review
Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease
Int. J. Mol. Sci. 2022, 23(8), 4467; https://doi.org/10.3390/ijms23084467 - 18 Apr 2022
Cited by 16 | Viewed by 5967
Abstract
Globally, cardiovascular disease remains the leading cause of death. Most concerning is the rise in cardiovascular risk factors including obesity, diabetes and hypertension among youth, which increases the likelihood of the development of earlier and more severe cardiovascular disease. While lifestyle factors are [...] Read more.
Globally, cardiovascular disease remains the leading cause of death. Most concerning is the rise in cardiovascular risk factors including obesity, diabetes and hypertension among youth, which increases the likelihood of the development of earlier and more severe cardiovascular disease. While lifestyle factors are involved in these trends, an increasing body of evidence implicates environmental exposures in early life on health outcomes in adulthood. Maternal obesity and diabetes during pregnancy, which have increased dramatically in recent years, also have profound effects on fetal growth and development. Mounting evidence is emerging that maternal obesity and diabetes during pregnancy have lifelong effects on cardiovascular risk factors and heart disease development. However, the mechanisms responsible for these observations are unknown. In this review, we summarize the findings of recent experimental studies, showing that maternal obesity and diabetes during pregnancy affect energy metabolism and heart disease development in the offspring, with a focus on the mechanisms involved. We also evaluate early proof-of-concept studies for interventions that could mitigate maternal obesity and gestational diabetes-induced cardiovascular disease risk in the offspring. Full article
(This article belongs to the Special Issue Risk Factors and Molecular Mechanisms of Gestational Diabetes III)
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11 pages, 2822 KiB  
Article
AcidoCEST-UTE MRI Reveals an Acidic Microenvironment in Knee Osteoarthritis
Int. J. Mol. Sci. 2022, 23(8), 4466; https://doi.org/10.3390/ijms23084466 - 18 Apr 2022
Cited by 10 | Viewed by 4073 | Correction
Abstract
A relationship between an acidic pH in the joints, osteoarthritis (OA), and pain has been previously demonstrated. Acidosis Chemical Exchange Saturation Transfer (acidoCEST) indirectly measures the extracellular pH through the assessment of the exchange of protons between amide groups on iodinated contrast agents [...] Read more.
A relationship between an acidic pH in the joints, osteoarthritis (OA), and pain has been previously demonstrated. Acidosis Chemical Exchange Saturation Transfer (acidoCEST) indirectly measures the extracellular pH through the assessment of the exchange of protons between amide groups on iodinated contrast agents and bulk water. It is possible to estimate the extracellular pH in the osteoarthritic joint using acidoCEST MRI. However, conventional MR sequences cannot image deep layers of cartilage, meniscus, ligaments, and other musculoskeletal tissues that present with short echo time and fast signal decay. Ultrashort echo time (UTE) MRI, on the other hand, has been used successfully to image those joint tissues. Here, our goal is to compare the pH measured in the knee joints of volunteers without OA and patients with severe OA using acidoCEST-UTE MRI. Patients without knee OA and patients with severe OA were examined using acidoCEST-UTE MRI and the mean pH of cartilage, meniscus, and fluid was calculated. Additionally, the relationship between the pH measurements and the Knee Injury and Osteoarthritis Outcome Score (KOOS) was investigated. AcidoCEST-UTE MRI can detect significant differences in the pH of knee cartilage, meniscus, and fluid between joints without and with OA, with OA showing lower pH values. In addition, symptoms and knee-joint function become worse at lower pH measurements. Full article
(This article belongs to the Special Issue New Advances in Osteoarthritis)
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27 pages, 4740 KiB  
Article
Functional Characterization of Cardiac Actin Mutants Causing Hypertrophic (p.A295S) and Dilated Cardiomyopathy (p.R312H and p.E361G)
Int. J. Mol. Sci. 2022, 23(8), 4465; https://doi.org/10.3390/ijms23084465 - 18 Apr 2022
Cited by 3 | Viewed by 2111
Abstract
Human wild type (wt) cardiac α-actin and its mutants p.A295S or p.R312H and p.E361G correlated with hypertrophic or dilated cardiomyopathy, respectively, were expressed by using the baculovirus/Sf21 insect cell system. The c-actin variants inhibited DNase I, indicating maintenance of their native state. Electron [...] Read more.
Human wild type (wt) cardiac α-actin and its mutants p.A295S or p.R312H and p.E361G correlated with hypertrophic or dilated cardiomyopathy, respectively, were expressed by using the baculovirus/Sf21 insect cell system. The c-actin variants inhibited DNase I, indicating maintenance of their native state. Electron microscopy showed the formation of normal appearing actin filaments though they showed mutant specific differences in length and straightness correlating with their polymerization rates. TRITC-phalloidin staining showed that p.A295S and p.R312H exhibited reduced and the p.E361G mutant increased lengths of their formed filaments. Decoration of c-actins with cardiac tropomyosin (cTm) and troponin (cTn) conveyed Ca2+-sensitivity of the myosin-S1 ATPase stimulation, which was higher for the HCM p.A295S mutant and lower for the DCM p.R312H and p.E361G mutants than for wt c-actin. The lower Ca2+-sensitivity of myosin-S1 stimulation by both DCM actin mutants was corrected by the addition of levosimendan. Ca2+-dependency of the movement of pyrene-labeled cTm along polymerized c-actin variants decorated with cTn corresponded to the relations observed for the myosin-S1 ATPase stimulation though shifted to lower Ca2+-concentrations. The N-terminal C0C2 domain of cardiac myosin-binding protein-C increased the Ca2+-sensitivity of the pyrene-cTM movement of bovine, recombinant wt, p.A295S, and p.E361G c-actins, but not of the p.R312H mutant, suggesting decreased affinity to cTm. Full article
(This article belongs to the Section Molecular Biology)
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19 pages, 3521 KiB  
Article
Chaperone Hsp70 (HSPA1) Is Involved in the Molecular Mechanisms of Sleep Cycle Integration
Int. J. Mol. Sci. 2022, 23(8), 4464; https://doi.org/10.3390/ijms23084464 - 18 Apr 2022
Cited by 3 | Viewed by 1932
Abstract
The molecular mechanisms of sleep cycle integration at the beginning and the end of the inactive period are not clear. Sleep cycles with a predominance of deep slow-wave sleep (SWS) seem to be associated with accelerated protein synthesis in the brain. The inducible [...] Read more.
The molecular mechanisms of sleep cycle integration at the beginning and the end of the inactive period are not clear. Sleep cycles with a predominance of deep slow-wave sleep (SWS) seem to be associated with accelerated protein synthesis in the brain. The inducible Hsp70 chaperone corrects protein conformational changes and has protective properties. This research explores (1) whether the Hspa1 gene encoding Hsp70 protein activates during the daily rapid-eye-movement sleep (REMS) maximum, and (2) whether a lower daily deep SWS maximum affects the Hspa1 expression level during the subsequent REMS. Combining polysomnography in male Wistar rats, RT-qPCR, and Western blotting, we reveal a three-fold Hspa1 upregulation in the nucleus reticularis pontis oralis, which regulates REMS. Hspa1 expression increases during the daily REMS maximum, 5–7 h after the natural peak of deep SWS. Using short-term selective REMS deprivation, we demonstrate that REMS rebound after deprivation exceeds the natural daily maximum, but it is not accompanied by Hspa1 upregulation. The results suggest that a high proportion of deep SWS, usually observed after sleep onset, is a necessary condition for Hspa1 upregulation during subsequent REMS. The data obtained can inform the understanding of the molecular mechanisms integrating SWS and REMS and key biological function(s) of sleep. Full article
(This article belongs to the Collection State-of-the-Art Molecular Neurobiology in Russia)
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13 pages, 1149 KiB  
Review
MAPK Cascades and Transcriptional Factors: Regulation of Heavy Metal Tolerance in Plants
Int. J. Mol. Sci. 2022, 23(8), 4463; https://doi.org/10.3390/ijms23084463 - 18 Apr 2022
Cited by 26 | Viewed by 3354
Abstract
In nature, heavy metal (HM) stress is one of the most destructive abiotic stresses for plants. Heavy metals produce toxicity by targeting key molecules and important processes in plant cells. The mitogen-activated protein kinase (MAPK) cascade transfers the signals perceived by cell membrane [...] Read more.
In nature, heavy metal (HM) stress is one of the most destructive abiotic stresses for plants. Heavy metals produce toxicity by targeting key molecules and important processes in plant cells. The mitogen-activated protein kinase (MAPK) cascade transfers the signals perceived by cell membrane surface receptors to cells through phosphorylation and dephosphorylation and targets various effector proteins or transcriptional factors so as to result in the stress response. Signal molecules such as plant hormones, reactive oxygen species (ROS), and nitric oxide (NO) can activate the MAPK cascade through differentially expressed genes, the activation of the antioxidant system and synergistic crosstalk between different signal molecules in order to regulate plant responses to HMs. Transcriptional factors, located downstream of MAPK, are key factors in regulating plant responses to heavy metals and improving plant heavy metal tolerance and accumulation. Thus, understanding how HMs activate the expression of the genes related to the MAPK cascade pathway and then phosphorylate those transcriptional factors may allow us to develop a regulation network to increase our knowledge of HMs tolerance and accumulation. This review highlighted MAPK pathway activation and responses under HMs and mainly focused on the specificity of MAPK activation mediated by ROS, NO and plant hormones. Here, we also described the signaling pathways and their interactions under heavy metal stresses. Moreover, the process of MAPK phosphorylation and the response of downstream transcriptional factors exhibited the importance of regulating targets. It was conducive to analyzing the molecular mechanisms underlying heavy metal accumulation and tolerance. Full article
(This article belongs to the Special Issue Heavy Metals Accumulation, Toxicity and Detoxification in Plants 2.0)
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30 pages, 1201 KiB  
Review
Bone Marrow Niches of Hematopoietic Stem and Progenitor Cells
Int. J. Mol. Sci. 2022, 23(8), 4462; https://doi.org/10.3390/ijms23084462 - 18 Apr 2022
Cited by 17 | Viewed by 5486
Abstract
The mammalian hematopoietic system is remarkably efficient in meeting an organism’s vital needs, yet is highly sensitive and exquisitely regulated. Much of the organismal control over hematopoiesis comes from the regulation of hematopoietic stem cells (HSCs) by specific microenvironments called niches in bone [...] Read more.
The mammalian hematopoietic system is remarkably efficient in meeting an organism’s vital needs, yet is highly sensitive and exquisitely regulated. Much of the organismal control over hematopoiesis comes from the regulation of hematopoietic stem cells (HSCs) by specific microenvironments called niches in bone marrow (BM), where HSCs reside. The experimental studies of the last two decades using the most sophisticated and advanced techniques have provided important data on the identity of the niche cells controlling HSCs functions and some mechanisms underlying niche-HSC interactions. In this review we discuss various aspects of organization and functioning of the HSC cell niche in bone marrow. In particular, we review the anatomy of BM niches, various cell types composing the niche, niches for more differentiated cells, metabolism of HSCs in relation to the niche, niche aging, leukemic transformation of the niche, and the current state of HSC niche modeling in vitro. Full article
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19 pages, 2377 KiB  
Review
Serrated Colorectal Lesions: An Up-to-Date Review from Histological Pattern to Molecular Pathogenesis
Int. J. Mol. Sci. 2022, 23(8), 4461; https://doi.org/10.3390/ijms23084461 - 18 Apr 2022
Cited by 8 | Viewed by 6616
Abstract
Until 2010, colorectal serrated lesions were generally considered as harmless lesions and reported as hyperplastic polyps (HPs) by pathologists and gastroenterologists. However, recent evidence showed that they may bear the potential to develop into colorectal carcinoma (CRC). Therefore, the World Health Organization (WHO) [...] Read more.
Until 2010, colorectal serrated lesions were generally considered as harmless lesions and reported as hyperplastic polyps (HPs) by pathologists and gastroenterologists. However, recent evidence showed that they may bear the potential to develop into colorectal carcinoma (CRC). Therefore, the World Health Organization (WHO) classification has identified four categories of serrated lesions: hyperplastic polyps (HPs), sessile serrated lesions (SSLs), traditional serrated adenoma (TSAs) and unclassified serrated adenomas. SSLs with dysplasia and TSAs are the most common precursors of CRC. CRCs arising from serrated lesions originate via two different molecular pathways, namely sporadic microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP), the latter being considered as the major mechanism that drives the serrated pathway towards CRC. Unlike CRCs arising through the adenoma–carcinoma pathway, APC-inactivating mutations are rarely shown in the serrated neoplasia pathway. Full article
(This article belongs to the Special Issue 23rd Anniversary of IJMS: Advances in Biochemistry)
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14 pages, 8625 KiB  
Review
The Structural and the Functional Aspects of Intercellular Communication in iPSC-Cardiomyocytes
Int. J. Mol. Sci. 2022, 23(8), 4460; https://doi.org/10.3390/ijms23084460 - 18 Apr 2022
Cited by 3 | Viewed by 2465
Abstract
Recent advances in the technology of producing novel cardiomyocytes from induced pluripotent stem cells (iPSC-cardiomyocytes) fuel new hope for future clinical applications. The use of iPSC-cardiomyocytes is particularly promising for the therapy of cardiac diseases such as myocardial infarction, where these cells could [...] Read more.
Recent advances in the technology of producing novel cardiomyocytes from induced pluripotent stem cells (iPSC-cardiomyocytes) fuel new hope for future clinical applications. The use of iPSC-cardiomyocytes is particularly promising for the therapy of cardiac diseases such as myocardial infarction, where these cells could replace scar tissue and restore the functionality of the heart. Despite successful cardiogenic differentiation, medical applications of iPSC-cardiomyocytes are currently limited by their pronounced immature structural and functional phenotype. This review focuses on gap junction function in iPSC-cardiomyocytes and portrays our current understanding around the structural and the functional limitations of intercellular coupling and viable cardiac graft formation involving these novel cardiac muscle cells. We further highlight the role of the gap junction protein connexin 43 as a potential target for improving cell–cell communication and electrical signal propagation across cardiac tissue engineered from iPSC-cardiomyocytes. Better insight into the mechanisms that promote functional intercellular coupling is the foundation that will allow the development of novel strategies to combat the immaturity of iPSC-cardiomyocytes and pave the way toward cardiac tissue regeneration. Full article
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19 pages, 1861 KiB  
Article
Metabolic Alteration Analysis of Steroid Hormones in Niemann–Pick Disease Type C Model Cell Using Liquid Chromatography/Tandem Mass Spectrometry
Int. J. Mol. Sci. 2022, 23(8), 4459; https://doi.org/10.3390/ijms23084459 - 18 Apr 2022
Cited by 4 | Viewed by 2335
Abstract
Niemann–Pick disease type C (NPC) is an autosomal recessive disease caused by a functional deficiency of cholesterol-transporting proteins in lysosomes, and exhibits various clinical symptoms. Since mitochondrial dysfunction in NPC has recently been reported, cholesterol catabolism to steroid hormones may consequently be impaired. [...] Read more.
Niemann–Pick disease type C (NPC) is an autosomal recessive disease caused by a functional deficiency of cholesterol-transporting proteins in lysosomes, and exhibits various clinical symptoms. Since mitochondrial dysfunction in NPC has recently been reported, cholesterol catabolism to steroid hormones may consequently be impaired. In this study, we developed a comprehensive steroid hormone analysis method using liquid chromatography/tandem mass spectrometry (LC–MS/MS) and applied it to analyze changes in steroid hormone concentrations in NPC model cells. We investigated the analytical conditions for simultaneous LC–MS/MS analysis, which could be readily separated from each other and showed good reproducibility. The NPC phenotype was verified as an NPC model with mitochondrial abnormalities using filipin staining and organelle morphology observations. Steroid hormones in the cell suspension and cell culture medium were also analyzed. Steroid hormone analysis indicated that the levels of six steroid hormones were significantly decreased in the NPC model cell and culture medium compared to those in the wild-type cell and culture medium. These results indicate that some steroid hormones change during NPC pathophysiology and this change is accompanied by mitochondrial abnormalities. Full article
(This article belongs to the Special Issue Mass Spectrometry Techniques for Biomarker Discovery)
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19 pages, 2118 KiB  
Review
Applications of Metal-Organic Frameworks as Drug Delivery Systems
Int. J. Mol. Sci. 2022, 23(8), 4458; https://doi.org/10.3390/ijms23084458 - 18 Apr 2022
Cited by 59 | Viewed by 5091
Abstract
In the last decade, metal organic frameworks (MOFs) have shown great prospective as new drug delivery systems (DDSs) due to their unique properties: these materials exhibit fascinating architectures, surfaces, composition, and a rich chemistry of these compounds. The DSSs allow the release of [...] Read more.
In the last decade, metal organic frameworks (MOFs) have shown great prospective as new drug delivery systems (DDSs) due to their unique properties: these materials exhibit fascinating architectures, surfaces, composition, and a rich chemistry of these compounds. The DSSs allow the release of the active pharmaceutical ingredient to accomplish a desired therapeutic response. Over the past few decades, there has been exponential growth of many new classes of coordination polymers, and MOFs have gained popularity over other identified systems due to their higher biocompatibility and versatile loading capabilities. This review presents and assesses the most recent research, findings, and challenges associated with the use of MOFs as DDSs. Among the most commonly used MOFs for investigated-purpose MOFs, coordination polymers and metal complexes based on synthetic and natural polymers, are well known. Specific attention is given to the stimuli- and multistimuli-responsive MOFs-based DDSs. Of great interest in the COVID-19 pandemic is the use of MOFs for combination therapy and multimodal systems. Full article
(This article belongs to the Section Molecular Pharmacology)
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15 pages, 1005 KiB  
Review
Psoriasis and Systemic Inflammatory Disorders
Int. J. Mol. Sci. 2022, 23(8), 4457; https://doi.org/10.3390/ijms23084457 - 18 Apr 2022
Cited by 26 | Viewed by 4304
Abstract
Psoriasis is a representative inflammatory skin disease occupied by large surface involvement. As inflammatory cells and cytokines can systemically circulate in various organs, it has been speculated that psoriatic skin inflammation influences the systemic dysfunction of various organs. Recent updates of clinical studies [...] Read more.
Psoriasis is a representative inflammatory skin disease occupied by large surface involvement. As inflammatory cells and cytokines can systemically circulate in various organs, it has been speculated that psoriatic skin inflammation influences the systemic dysfunction of various organs. Recent updates of clinical studies and experimental studies showed the important interaction of psoriasis to systemic inflammatory diseases. Furthermore, the importance of systemic therapy in severe psoriasis is also highlighted to prevent the development of systemic inflammatory diseases. In this review, we introduced representative systemic inflammatory diseases associated with psoriasis and the detailed molecular mechanisms. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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6 pages, 218 KiB  
Editorial
Microgravity and Space Medicine 2.0
Int. J. Mol. Sci. 2022, 23(8), 4456; https://doi.org/10.3390/ijms23084456 - 18 Apr 2022
Viewed by 2223
Abstract
This Special Issue (SI), “Microgravity and Space Medicine 2 [...] Full article
(This article belongs to the Special Issue Microgravity and Space Medicine 2.0)
20 pages, 6030 KiB  
Article
Transcriptomic Data Meta-Analysis Sheds Light on High Light Response in Arabidopsis thaliana L.
Int. J. Mol. Sci. 2022, 23(8), 4455; https://doi.org/10.3390/ijms23084455 - 18 Apr 2022
Cited by 5 | Viewed by 2596
Abstract
The availability and intensity of sunlight are among the major factors of growth, development and metabolism in plants. However, excessive illumination disrupts the electronic balance of photosystems and leads to the accumulation of reactive oxygen species in chloroplasts, further mediating several regulatory mechanisms [...] Read more.
The availability and intensity of sunlight are among the major factors of growth, development and metabolism in plants. However, excessive illumination disrupts the electronic balance of photosystems and leads to the accumulation of reactive oxygen species in chloroplasts, further mediating several regulatory mechanisms at the subcellular, genetic, and molecular levels. We carried out a comprehensive bioinformatic analysis that aimed to identify genetic systems and candidate transcription factors involved in the response to high light stress in Arabidopsis thaliana L. using resources GEO NCBI, string-db, ShinyGO, STREME, and Tomtom, as well as programs metaRE, CisCross, and Cytoscape. Through the meta-analysis of five transcriptomic experiments, we selected a set of 1151 differentially expressed genes, including 453 genes that compose the gene network. Ten significantly enriched regulatory motifs for TFs families ZF-HD, HB, C2H2, NAC, BZR, and ARID were found in the promoter regions of differentially expressed genes. In addition, we predicted families of transcription factors associated with the duration of exposure (RAV, HSF), intensity of high light treatment (MYB, REM), and the direction of gene expression change (HSF, S1Fa-like). We predicted genetic components systems involved in a high light response and their expression changes, potential transcriptional regulators, and associated processes. Full article
(This article belongs to the Special Issue Plant Biology and Biotechnology: Focus on Genomics and Bioinformatics)
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27 pages, 3449 KiB  
Review
CRISPR-Based Genome Editing: Advancements and Opportunities for Rice Improvement
Int. J. Mol. Sci. 2022, 23(8), 4454; https://doi.org/10.3390/ijms23084454 - 18 Apr 2022
Cited by 11 | Viewed by 4016
Abstract
To increase the potentiality of crop production for future food security, new technologies for plant breeding are required, including genome editing technology—being one of the most promising. Genome editing with the CRISPR/Cas system has attracted researchers in the last decade as a safer [...] Read more.
To increase the potentiality of crop production for future food security, new technologies for plant breeding are required, including genome editing technology—being one of the most promising. Genome editing with the CRISPR/Cas system has attracted researchers in the last decade as a safer and easier tool for genome editing in a variety of living organisms including rice. Genome editing has transformed agriculture by reducing biotic and abiotic stresses and increasing yield. Recently, genome editing technologies have been developed quickly in order to avoid the challenges that genetically modified crops face. Developing transgenic-free edited plants without introducing foreign DNA has received regulatory approval in a number of countries. Several ongoing efforts from various countries are rapidly expanding to adopt the innovations. This review covers the mechanisms of CRISPR/Cas9, comparisons of CRISPR/Cas9 with other gene-editing technologies—including newly emerged Cas variants—and focuses on CRISPR/Cas9-targeted genes for rice crop improvement. We have further highlighted CRISPR/Cas9 vector construction model design and different bioinformatics tools for target site selection. Full article
(This article belongs to the Section Molecular Plant Sciences)
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13 pages, 1486 KiB  
Review
Revisiting the Role of Astrocytic MAOB in Parkinson’s Disease
Int. J. Mol. Sci. 2022, 23(8), 4453; https://doi.org/10.3390/ijms23084453 - 18 Apr 2022
Cited by 10 | Viewed by 4468
Abstract
Monoamine oxidase-B (MAOB) has been believed to mediate the degradation of monoamine neurotransmitters such as dopamine. However, this traditional belief has been challenged by demonstrating that it is not MAOB but MAOA which mediates dopamine degradation. Instead, MAOB mediates the aberrant synthesis of [...] Read more.
Monoamine oxidase-B (MAOB) has been believed to mediate the degradation of monoamine neurotransmitters such as dopamine. However, this traditional belief has been challenged by demonstrating that it is not MAOB but MAOA which mediates dopamine degradation. Instead, MAOB mediates the aberrant synthesis of GABA and hydrogen peroxide (H2O2) in reactive astrocytes of Parkinson’s disease (PD). Astrocytic GABA tonically suppresses the dopaminergic neuronal activity, whereas H2O2 aggravates astrocytic reactivity and dopaminergic neuronal death. Recently discovered reversible MAOB inhibitors reduce reactive astrogliosis and restore dopaminergic neuronal activity to alleviate PD symptoms in rodents. In this perspective, we redefine the role of MAOB for the aberrant suppression and deterioration of dopaminergic neurons through excessive GABA and H2O2 synthesis of reactive astrocytes in PD. Full article
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23 pages, 1954 KiB  
Review
Bio-Synthesized Nanoparticles in Developing Plant Abiotic Stress Resilience: A New Boon for Sustainable Approach
Int. J. Mol. Sci. 2022, 23(8), 4452; https://doi.org/10.3390/ijms23084452 - 18 Apr 2022
Cited by 23 | Viewed by 3661
Abstract
Agriculture crop development and production may be hampered in the modern era because of the increasing prevalence of ecological problems around the world. In the last few centuries, plant and agrarian scientific experts have shown significant progress in promoting efficient and eco-friendly approaches [...] Read more.
Agriculture crop development and production may be hampered in the modern era because of the increasing prevalence of ecological problems around the world. In the last few centuries, plant and agrarian scientific experts have shown significant progress in promoting efficient and eco-friendly approaches for the green synthesis of nanoparticles (NPs), which are noteworthy due to their unique physio-biochemical features as well as their possible role and applications. They are thought to be powerful sensing molecules that regulate a wide range of significant physiological and biochemical processes in plants, from germination to senescence, as well as unique strategies for coping with changing environmental circumstances. This review highlights current knowledge on the plant extract-mediated synthesis of NPs, as well as their significance in reprogramming plant traits and ameliorating abiotic stresses. Nano particles-mediated modulation of phytohormone content in response to abiotic stress is also displayed. Additionally, the applications and limitations of green synthesized NPs in various scientific regimes have also been highlighted. Full article
(This article belongs to the Special Issue Nanoparticles: From Synthesis to Applications)
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22 pages, 8971 KiB  
Article
E2F1 Expression and Apoptosis Initiation in Crayfish and Rat Peripheral Neurons and Glial Cells after Axonal Injury
Int. J. Mol. Sci. 2022, 23(8), 4451; https://doi.org/10.3390/ijms23084451 - 18 Apr 2022
Cited by 5 | Viewed by 2109
Abstract
Neurotrauma is among the main causes of human disability and mortality. The transcription factor E2F1 is one of the key proteins that determine the fate of cells. The involvement of E2F1 in the regulation of survival and death of peripheral nerve cells after [...] Read more.
Neurotrauma is among the main causes of human disability and mortality. The transcription factor E2F1 is one of the key proteins that determine the fate of cells. The involvement of E2F1 in the regulation of survival and death of peripheral nerve cells after axotomy has not been previously studied. We, for the first time, studied axotomy-induced changes in the expression and localization of E2F1 following axonal injury in rats and crayfish. Immunoblotting and immunofluorescence microscopy were used for the analysis of the expression and intracellular localization of E2F1 and its changes after axotomy. To evaluate whether this transcription factor promotes cell apoptosis, we examined the effect of pharmacological inhibition of E2F activity in axotomized rat models. In this work, axotomy caused increased expression of E2F1 as early as 4 h and even 1 h after axotomy of mechanoreceptor neurons and ganglia of crayfish ventral nerve cord (VNC), as well as rat dorsal root ganglia (DRG). The level of E2F1 expression increased both in the cytoplasm and the nuclei of neurons. Pharmacological inhibition of E2F demonstrated a pronounced neuroprotective activity against axotomized DRGs. E2F1 and downstream targets could be considered promising molecular targets for the development of potential neuroprotective agents. Full article
(This article belongs to the Special Issue Cell Apoptosis)
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16 pages, 2380 KiB  
Article
Arabidopsis KCS5 and KCS6 Play Redundant Roles in Wax Synthesis
Int. J. Mol. Sci. 2022, 23(8), 4450; https://doi.org/10.3390/ijms23084450 - 18 Apr 2022
Cited by 21 | Viewed by 2771
Abstract
3-ketoacyl-CoA synthases (KCSs), as components of a fatty acid elongase (FAE) complex, play key roles in determining the chain length of very-long-chain fatty acids (VLCFAs). KCS6, taking a predominate role during the elongation from C26 to C28, is well known to play an [...] Read more.
3-ketoacyl-CoA synthases (KCSs), as components of a fatty acid elongase (FAE) complex, play key roles in determining the chain length of very-long-chain fatty acids (VLCFAs). KCS6, taking a predominate role during the elongation from C26 to C28, is well known to play an important role in wax synthesis. KCS5 is one paralog of KCS6 and its role in wax synthesis remains unknown. Wax phenotype analysis showed that in kcs5 mutants, the total amounts of wax components derived from carbon 32 (C32) and C34 were apparently decreased in leaves, and those of C26 to C32 derivatives were obviously decreased in flowers. Heterologous yeast expression analysis showed that KCS5 alone displayed specificity towards C24 to C28 acids, and its coordination with CER2 and CER26 catalyzed the elongation of acids exceeding C28, especially displaying higher activity towards C28 acids than KCS6. BiLC experiments identified that KCS5 physically interacts with CER2 and CER26. Wax phenotype analysis of different organs in kcs5 and kcs6 single or double mutants showed that KCS6 mutation causes greater effects on the wax synthesis than KCS5 mutation in the tested organs, and simultaneous repression of both protein activities caused additive effects, suggesting that during the wax biosynthesis process, KCS5 and KCS6 play redundant roles, among which KCS6 plays a major role. In addition, simultaneous mutations of two genes nearly block drought-induced wax production, indicating that the reactions catalyzed by KCS5 and KCS6 play a critical role in the wax biosynthesis in response to drought. Full article
(This article belongs to the Collection Feature Papers in Molecular Plant Sciences)
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18 pages, 4623 KiB  
Article
The Ameliorative Effect of Dexamethasone on the Development of Autoimmune Lung Injury and Mediastinal Fat-Associated Lymphoid Clusters in an Autoimmune Disease Mouse Model
Int. J. Mol. Sci. 2022, 23(8), 4449; https://doi.org/10.3390/ijms23084449 - 18 Apr 2022
Cited by 2 | Viewed by 1836
Abstract
In our previous study, we revealed the ameliorative therapeutic effect of dexamethasone (Dex) for Lupus nephritis lesions in the MRL/MpJ-Fas lpr/lpr (Lpr) mouse model. The female Lpr mice developed a greater number of mediastinal fat-associated lymphoid clusters (MFALCs) and inflammatory lung lesions [...] Read more.
In our previous study, we revealed the ameliorative therapeutic effect of dexamethasone (Dex) for Lupus nephritis lesions in the MRL/MpJ-Fas lpr/lpr (Lpr) mouse model. The female Lpr mice developed a greater number of mediastinal fat-associated lymphoid clusters (MFALCs) and inflammatory lung lesions compared to the male mice. However, the effect of Dex, an immunosuppressive drug, on both lung lesions and the development of MFALCs in Lpr mice has not been identified yet. Therefore, in this study, we compared the development of lung lesions and MFALCs in female Lpr mice that received either saline (saline group “SG”) or dexamethasone (dexamethasone group “DG”) in drinking water as a daily dose along with weekly intraperitoneal injections for 10 weeks. Compared to the SG group, the DG group showed a significant reduction in the levels of serum anti-dsDNA antibodies, the size of MFALCs, the degree of lung injury, the area of high endothelial venules (HEVs), and the number of proliferating and immune cells in both MFALCs and the lungs. A significant positive correlation was observed between the size of MFALCs and the cellular aggregation in the lungs of Lpr mice. Therefore, this study confirmed the ameliorative effect of Dex on the development of lung injury and MFALCs via their regressive effect on both immune cells’ proliferative activity and the development of HEVs. Furthermore, the reprogramming of MFALCs by targeting immune cells and HEVs may provide a therapeutic strategy for autoimmune-disease-associated lung injury. Full article
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14 pages, 1450 KiB  
Perspective
Small RNAs beyond Model Organisms: Have We Only Scratched the Surface?
Int. J. Mol. Sci. 2022, 23(8), 4448; https://doi.org/10.3390/ijms23084448 - 18 Apr 2022
Cited by 4 | Viewed by 2171
Abstract
Small RNAs (sRNAs) are essential regulators in the adaptation of bacteria to environmental changes and act by binding targeted mRNAs through base complementarity. Approximately 550 distinct families of sRNAs have been identified since their initial characterization in the 1980s, accelerated by the emergence [...] Read more.
Small RNAs (sRNAs) are essential regulators in the adaptation of bacteria to environmental changes and act by binding targeted mRNAs through base complementarity. Approximately 550 distinct families of sRNAs have been identified since their initial characterization in the 1980s, accelerated by the emergence of RNA-sequencing. Small RNAs are found in a wide range of bacterial phyla, but they are more prominent in highly researched model organisms compared to the rest of the sequenced bacteria. Indeed, Escherichia coli and Salmonella enterica contain the highest number of sRNAs, with 98 and 118, respectively, with Enterobacteriaceae encoding 145 distinct sRNAs, while other bacteria families have only seven sRNAs on average. Although the past years brought major advances in research on sRNAs, we have perhaps only scratched the surface, even more so considering RNA annotations trail behind gene annotations. A distinctive trend can be observed for genes, whereby their number increases with genome size, but this is not observable for RNAs, although they would be expected to follow the same trend. In this perspective, we aimed at establishing a more accurate representation of the occurrence of sRNAs in bacteria, emphasizing the potential for novel sRNA discoveries. Full article
(This article belongs to the Special Issue Bacterial Non-coding RNA)
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12 pages, 2345 KiB  
Article
Thrombin Preconditioning Improves the Therapeutic Efficacy of Mesenchymal Stem Cells in Severe Intraventricular Hemorrhage Induced Neonatal Rats
Int. J. Mol. Sci. 2022, 23(8), 4447; https://doi.org/10.3390/ijms23084447 - 18 Apr 2022
Cited by 11 | Viewed by 2062
Abstract
Severe intraventricular hemorrhage (IVH) remains a major cause of high mortality and morbidity in extremely preterm infants. Mesenchymal stem cell (MSC) transplantation is a possible therapeutic option, and development of therapeutics with enhanced efficacy is necessary. This study investigated whether thrombin preconditioning improves [...] Read more.
Severe intraventricular hemorrhage (IVH) remains a major cause of high mortality and morbidity in extremely preterm infants. Mesenchymal stem cell (MSC) transplantation is a possible therapeutic option, and development of therapeutics with enhanced efficacy is necessary. This study investigated whether thrombin preconditioning improves the therapeutic efficacy of human Wharton’s jelly-derived MSC transplantation for severe neonatal IVH, using a rat model. Severe neonatal IVH was induced by injecting 150 μL blood into each lateral ventricle on postnatal day (P) 4 in Sprague-Dawley rats. After 2 days (P6), naïve MSCs or thrombin-preconditioned MSCs (1 × 105/10 μL) were transplanted intraventricularly. After behavioral tests, brain tissues and cerebrospinal fluid of P35 rats were obtained for histological and biochemical analyses, respectively. Thrombin-preconditioned MSC transplantation significantly reduced IVH-induced ventricular dilatation on in vivo magnetic resonance imaging, which was coincident with attenuations of reactive gliosis, cell death, and the number of activated microglia and levels of inflammatory cytokines after IVH induction, compared to naïve MSC transplantation. In the behavioral tests, the sensorimotor and memory functions significantly improved after transplantation of thrombin-preconditioned MSCs, compared to naïve MSCs. Overall, thrombin preconditioning significantly improves the therapeutic potential and more effectively attenuates brain injury, including progressive ventricular dilatation, gliosis, cell death, inflammation, and neurobehavioral functional impairment, in newborn rats with induced severe IVH than does naïve MSC transplantation. Full article
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13 pages, 6982 KiB  
Article
Leaf Mutant 7 Encoding Heat Shock Protein OsHSP40 Regulates Leaf Size in Rice
Int. J. Mol. Sci. 2022, 23(8), 4446; https://doi.org/10.3390/ijms23084446 - 18 Apr 2022
Cited by 6 | Viewed by 2010
Abstract
Leaf size is an important agronomic trait directly affecting yield in rice, and thus understanding the genes determining leaf size is important in breeding. In this study, one Leaf Mutant 7 (lm7) with small leaf size was isolated using ethyl methane [...] Read more.
Leaf size is an important agronomic trait directly affecting yield in rice, and thus understanding the genes determining leaf size is important in breeding. In this study, one Leaf Mutant 7 (lm7) with small leaf size was isolated using ethyl methane sulphonate (EMS) mutagenesis from the japonica Zhenggeng 1925. MutMap by whole genome resequencing of phenotypic bulks revealed that LM7 is likely located in the 133 kb region on chromosome 7 using F2 population from a cross between lm7 and wild-type (WT) Zhenggeng 1925. The candidate gene encoding heat shock protein OsHSP40 for LM7 was functionally validated. Disruption of this gene in Oshsp40 mutants significantly reduced the leaf size compared with that of WT in rice. Microscopic examination showed that OsHSP40 modulated leaf size via regulating the veins formation and cell size/cell number. Nucleotide diversity analysis indicated that a single nucleotide polymorphism (SNP) variation of C to T in the coding region of OsHSP40 may cause small leaves among rice accessions. Therefore, the natural variation of OsHSP40 contributing to leaf size might be useful for rice breeding. Full article
(This article belongs to the Section Molecular Plant Sciences)
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4 pages, 222 KiB  
Comment
Comment on Tremmel et al. In Vitro Metabolism of Six C-Glycosidic Flavonoids from Passiflora incarnata L. Int. J. Mol. Sci. 2021, 22, 6566
Int. J. Mol. Sci. 2022, 23(8), 4445; https://doi.org/10.3390/ijms23084445 - 18 Apr 2022
Viewed by 2079
Abstract
In recent years, growing attention has been paid to the chemical composition of aerial parts extracts and the bioavailability of active compounds from different species of Passiflora genus [...] Full article
(This article belongs to the Section Molecular Plant Sciences)
17 pages, 3595 KiB  
Article
HPR1 Is Required for High Light Intensity Induced Photorespiration in Arabidopsis thaliana
Int. J. Mol. Sci. 2022, 23(8), 4444; https://doi.org/10.3390/ijms23084444 - 18 Apr 2022
Cited by 7 | Viewed by 1957
Abstract
High light intensity as one of the stresses could lead to generation of large amounts of reactive oxygen species (ROS) in plants, resulting in severe plant growth retardation. The photorespiration metabolism plays an important role in producing and removing a variety of ROS, [...] Read more.
High light intensity as one of the stresses could lead to generation of large amounts of reactive oxygen species (ROS) in plants, resulting in severe plant growth retardation. The photorespiration metabolism plays an important role in producing and removing a variety of ROS, maintaining the dynamic balance of the redox reaction, and preventing photoinhibition. Arabidopsis hydroxypyruvate reductase 1 (HPR1) is a primary metabolic enzyme in the photorespiration cycle. However, the role of HPR1 in plants response to high light is not clear. Here, we found that the expression of HPR1 could be induced by high light intensity. The growth and photosynthetic capacity of hpr1 mutants are seriously affected under high light intensity. The absence of HPR1 suppresses the rates of photorepair of Photosystem II (PSII), aggravates the production of ROS, and accelerates photorespiration rates. Moreover, the activity of ROS scavenging enzymes in the hpr1 mutants is significantly higher. These results indicate that HPR1 is involved in plant response to high light intensity and is essential for maintaining the dynamic balance of ROS and photorespiration. Full article
(This article belongs to the Special Issue Light Reactions and Oxidative Stress in Photosynthesis)
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15 pages, 2841 KiB  
Article
A Non-Hazardous Deparaffinization Protocol Enables Quantitative Proteomics of Core Needle Biopsy-Sized Formalin-Fixed and Paraffin-Embedded (FFPE) Tissue Specimens
Int. J. Mol. Sci. 2022, 23(8), 4443; https://doi.org/10.3390/ijms23084443 - 18 Apr 2022
Cited by 6 | Viewed by 4995
Abstract
Most human tumor tissues that are obtained for pathology and diagnostic purposes are formalin-fixed and paraffin-embedded (FFPE). To perform quantitative proteomics of FFPE samples, paraffin has to be removed and formalin-induced crosslinks have to be reversed prior to proteolytic digestion. A central component [...] Read more.
Most human tumor tissues that are obtained for pathology and diagnostic purposes are formalin-fixed and paraffin-embedded (FFPE). To perform quantitative proteomics of FFPE samples, paraffin has to be removed and formalin-induced crosslinks have to be reversed prior to proteolytic digestion. A central component of almost all deparaffinization protocols is xylene, a toxic and highly flammable solvent that has been reported to negatively affect protein extraction and quantitative proteome analysis. Here, we present a ‘green’ xylene-free protocol for accelerated sample preparation of FFPE tissues based on paraffin-removal with hot water. Combined with tissue homogenization using disposable micropestles and a modified protein aggregation capture (PAC) digestion protocol, our workflow enables streamlined and reproducible quantitative proteomic profiling of FFPE tissue. Label-free quantitation of FFPE cores from human ductal breast carcinoma in situ (DCIS) xenografts with a volume of only 0.79 mm3 showed a high correlation between replicates (r2 = 0.992) with a median %CV of 16.9%. Importantly, this small volume is already compatible with tissue micro array (TMA) cores and core needle biopsies, while our results and its ease-of-use indicate that further downsizing is feasible. Finally, our FFPE workflow does not require costly equipment and can be established in every standard clinical laboratory. Full article
(This article belongs to the Special Issue New Insights on Mass Spectometry Applied to Bioscience)
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22 pages, 1378 KiB  
Review
Linear and Circular Long Non-Coding RNAs in Acute Lymphoblastic Leukemia: From Pathogenesis to Classification and Treatment
Int. J. Mol. Sci. 2022, 23(8), 4442; https://doi.org/10.3390/ijms23084442 - 18 Apr 2022
Cited by 6 | Viewed by 2927
Abstract
The coding regions account for only a small part of the human genome, and the remaining vast majority of the regions generate large amounts of non-coding RNAs. Although non-coding RNAs do not code for any protein, they are suggested to work as either [...] Read more.
The coding regions account for only a small part of the human genome, and the remaining vast majority of the regions generate large amounts of non-coding RNAs. Although non-coding RNAs do not code for any protein, they are suggested to work as either tumor suppressers or oncogenes through modulating the expression of genes and functions of proteins at transcriptional, posttranscriptional and post-translational levels. Acute Lymphoblastic Leukemia (ALL) originates from malignant transformed B/T-precursor-stage lymphoid progenitors in the bone marrow (BM). The pathogenesis of ALL is closely associated with aberrant genetic alterations that block lymphoid differentiation and drive abnormal cell proliferation as well as survival. While treatment of pediatric ALL represents a major success story in chemotherapy-based elimination of a malignancy, adult ALL remains a devastating disease with relatively poor prognosis. Thus, novel aspects in the pathogenesis and progression of ALL, especially in the adult population, need to be further explored. Accumulating evidence indicated that genetic changes alone are rarely sufficient for development of ALL. Recent advances in cytogenic and sequencing technologies revealed epigenetic alterations including that of non-coding RNAs as cooperating events in ALL etiology and progression. While the role of micro RNAs in ALL has been extensively reviewed, less attention, relatively, has been paid to other non-coding RNAs. Herein, we review the involvement of linear and circular long non-coding RNAs in the etiology, maintenance, and progression of ALL, highlighting the contribution of these non-coding RNAs in ALL classification and diagnosis, risk stratification as well as treatment. Full article
(This article belongs to the Special Issue Molecular Research on Acute Lymphoblastic Leukemia 2.0)
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25 pages, 2347 KiB  
Review
Circulating Tumor DNA in Precision Oncology and Its Applications in Colorectal Cancer
Int. J. Mol. Sci. 2022, 23(8), 4441; https://doi.org/10.3390/ijms23084441 - 18 Apr 2022
Cited by 27 | Viewed by 7138
Abstract
Circulating tumor DNA (ctDNA) is a component of cell-free DNA (cfDNA) that is shed by malignant tumors into the bloodstream and other bodily fluids. ctDNA can comprise up to 10% of a patient’s cfDNA depending on their tumor type and burden. The short [...] Read more.
Circulating tumor DNA (ctDNA) is a component of cell-free DNA (cfDNA) that is shed by malignant tumors into the bloodstream and other bodily fluids. ctDNA can comprise up to 10% of a patient’s cfDNA depending on their tumor type and burden. The short half-life of ctDNA ensures that its detection captures tumor burden in real-time and offers a non-invasive method of repeatedly evaluating the genomic profile of a patient’s tumor. A challenge in ctDNA detection includes clonal hematopoiesis of indeterminate potential (CHIP), which can be distinguished from tumor variants using a paired whole-blood control. Most assays for ctDNA quantification rely on measurements of somatic variant allele frequency (VAF), which is a mutation-dependent method. Patients with certain types of solid tumors, including colorectal cancer (CRC), can have levels of cfDNA 50 times higher than healthy patients. ctDNA undergoes a precipitous drop shortly after tumor resection and therapy, and rising levels can foreshadow radiologic recurrence on the order of months. The amount of tumor bulk required for ctDNA detection is lower than that for computed tomography (CT) scan detection, with ctDNA detection preceding radiologic recurrence in many cases. cfDNA/ctDNA can be used for tumor molecular profiling to identify resistance mutations when tumor biopsy is not available, to detect minimal residual disease (MRD), to monitor therapy response, and for the detection of tumor relapse. Although ctDNA is not yet implemented in clinical practice, studies are ongoing to define the appropriate way to use it as a tool in the clinic. In this review article, we examine the general aspects of ctDNA, its status as a biomarker, and its role in the management of early (II–III) and late (IV; mCRC) stage colorectal cancer (CRC). Full article
(This article belongs to the Special Issue Liquid Biopsies in Oncology)
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