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Int. J. Mol. Sci., Volume 20, Issue 9 (May-1 2019)

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Cover Story (view full-size image) Seed storage proteins must be hydrolyzed by proteases to facilitate the delivery of amino acids [...] Read more.
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Open AccessArticle
Hepatoprotective Effect of Kombucha Tea in Rodent Model of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis
Int. J. Mol. Sci. 2019, 20(9), 2369; https://doi.org/10.3390/ijms20092369
Received: 1 April 2019 / Revised: 3 May 2019 / Accepted: 8 May 2019 / Published: 13 May 2019
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Abstract
Kombucha tea (KT) has emerged as a substance that protects the liver from damage; however, its mechanisms of action on the fatty liver remain unclear. Therefore, we investigated the potential role of KT and its underlying mechanisms on nonalcoholic fatty liver disease (NAFLD). [...] Read more.
Kombucha tea (KT) has emerged as a substance that protects the liver from damage; however, its mechanisms of action on the fatty liver remain unclear. Therefore, we investigated the potential role of KT and its underlying mechanisms on nonalcoholic fatty liver disease (NAFLD). db/db mice that were fed methionine/choline-deficient (MCD) diets for seven weeks were treated for vehicle (M + V) or KT (M + K) and fed with MCD for four additional weeks. Histomorphological injury and increased levels of liver enzymes and lipids were evident in the M + V group, whereas these symptoms were ameliorated in the M + K group. The M + K group had more proliferating and less apoptotic hepatocytic cells than the M + V group. Lipid uptake and lipogenesis significantly decreased, and free fatty acid (FFA) oxidation increased in the M + K, when compared with the M + V group. With the reduction of hedgehog signaling, inflammation and fibrosis also declined in the M + K group. Palmitate (PA) treatment increased the accumulation of lipid droplets and decreased the viability of primary hepatocytes, whereas KT suppressed PA-induced damage in these cells by enhancing intracellular lipid disposal. These results suggest that KT protects hepatocytes from lipid toxicity by influencing the lipid metabolism, and it attenuates inflammation and fibrosis, which contributes to liver restoration in mice with NAFLD. Full article
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Open AccessArticle
A Robust Model for Circadian Redox Oscillations
Int. J. Mol. Sci. 2019, 20(9), 2368; https://doi.org/10.3390/ijms20092368
Received: 26 March 2019 / Revised: 8 May 2019 / Accepted: 8 May 2019 / Published: 13 May 2019
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Abstract
The circadian clock is an endogenous oscillator that controls daily rhythms in metabolism, physiology, and behavior. Although the timekeeping components differ among species, a common design principle is a transcription-translation negative feedback loop. However, it is becoming clear that other mechanisms can contribute [...] Read more.
The circadian clock is an endogenous oscillator that controls daily rhythms in metabolism, physiology, and behavior. Although the timekeeping components differ among species, a common design principle is a transcription-translation negative feedback loop. However, it is becoming clear that other mechanisms can contribute to the generation of 24 h rhythms. Peroxiredoxins (Prxs) exhibit 24 h rhythms in their redox state in all kingdoms of life. In mammalian adrenal gland, heart and brown adipose tissue, such rhythms are generated as a result of an inactivating hyperoxidation reaction that is reduced by coordinated import of sulfiredoxin (Srx) into the mitochondria. However, a quantitative description of the Prx/Srx oscillating system is still missing. We investigate the basic principles that generate mitochondrial Prx/Srx rhythms using computational modeling. We observe that the previously described delay in mitochondrial Srx import, in combination with an appropriate separation of fast and slow reactions, is sufficient to generate robust self-sustained relaxation-like oscillations. We find that our conceptual model can be regarded as a series of three consecutive phases and two temporal switches, highlighting the importance of delayed negative feedback and switches in the generation of oscillations. Full article
(This article belongs to the Special Issue Circadian Rhythms: Molecular and Physiological Mechanisms)
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Open AccessArticle
25-Hydroxyvitamin D Inhibits Hepatitis C Virus Production in Hepatocellular Carcinoma Cell Line by a Vitamin D Receptor-Independent Mechanism
Int. J. Mol. Sci. 2019, 20(9), 2367; https://doi.org/10.3390/ijms20092367
Received: 20 March 2019 / Revised: 7 May 2019 / Accepted: 10 May 2019 / Published: 13 May 2019
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Abstract
Previously, we have reported that the active vitamin D metabolite, calcitriol and vitamin D3 (cholecalciferol), both remarkably inhibit hepatitis C virus production. The mechanism by which vitamin D3 exerts its effect is puzzling due to the low levels of calcitriol produced [...] Read more.
Previously, we have reported that the active vitamin D metabolite, calcitriol and vitamin D3 (cholecalciferol), both remarkably inhibit hepatitis C virus production. The mechanism by which vitamin D3 exerts its effect is puzzling due to the low levels of calcitriol produced in vitamin D3-treated Huh7.5 cells. In this study, we aimed to explore the mechanism of vitamin D3 anti-hepatitis C virus effect. We show that vitamin D3 activity is not mediated by its metabolic conversion to calcitriol, but may be due to its primary metabolic product 25(OH)D3. This is inferred from the findings that 25(OH)D3 could inhibit hepatitis C virus production in our system, and that adequate concentrations needed to exert this effect are produced in Huh7.5 cells treated with vitamin D3. Using the CRISPR-Cas9 editing technology to knockout the vitamin D receptor, we found that the antiviral activity of vitamin D3 and 25(OH)D3 was not impaired in the vitamin D receptor knockout cells. This result indicates that 25(OH)D3 anti-hepatitis C virus effect is exerted by a vitamin D receptor-independent mode of action. The possibility that vitamin D3 and 25(OH)D3, being 3β-hydroxysteroids, affect hepatitis C virus production by direct inhibition of the Hedgehog pathway in a vitamin D receptor-independent manner was ruled out. Taken together, this study proposes a novel mode of action for the anti-hepatitis C virus activity of vitamin D3 that is mediated by 25(OH)D3 in a vitamin D receptor-independent mechanism. Full article
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Open AccessReview
Glycation of Plant Proteins: Regulatory Roles and Interplay with Sugar Signalling?
Int. J. Mol. Sci. 2019, 20(9), 2366; https://doi.org/10.3390/ijms20092366
Received: 14 April 2019 / Revised: 8 May 2019 / Accepted: 9 May 2019 / Published: 13 May 2019
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Abstract
Glycation can be defined as an array of non-enzymatic post-translational modifications of proteins formed by their interaction with reducing carbohydrates and carbonyl products of their degradation. Initial steps of this process rely on reducing sugars and result in the formation of early glycation [...] Read more.
Glycation can be defined as an array of non-enzymatic post-translational modifications of proteins formed by their interaction with reducing carbohydrates and carbonyl products of their degradation. Initial steps of this process rely on reducing sugars and result in the formation of early glycation products—Amadori and Heyns compounds via Schiff base intermediates, whereas their oxidative degradation or reactions of proteins with α-dicarbonyl compounds yield a heterogeneous group of advanced glycation end products (AGEs). These compounds accompany thermal processing of protein-containing foods and are known to impact on ageing, pathogenesis of diabetes mellitus and Alzheimer’s disease in mammals. Surprisingly, despite high tissue carbohydrate contents, glycation of plant proteins was addressed only recently and its physiological role in plants is still not understood. Therefore, here we summarize and critically discuss the first steps done in the field of plant protein glycation during the last decade. We consider the main features of plant glycated proteome and discuss them in the context of characteristic metabolic background. Further, we address the possible role of protein glycation in plants and consider its probable contribution to protein degradation, methylglyoxal and sugar signalling, as well as interplay with antioxidant defense. Full article
(This article belongs to the Special Issue Signaling: From Past to Future)
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Open AccessArticle
Niemann-Pick Type A Disease: Behavior of Neutral Sphingomyelinase and Vitamin D Receptor
Int. J. Mol. Sci. 2019, 20(9), 2365; https://doi.org/10.3390/ijms20092365
Received: 22 March 2019 / Revised: 3 May 2019 / Accepted: 7 May 2019 / Published: 13 May 2019
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Abstract
Sphingomyelinase (SMase) is responsible for the breakdown of sphingomyelin (SM) with production of ceramide. The absence of acid sphingomyelinase (aSMase) causes abnormal synapse formation in Niemann-Pick type A (NPA) disease. Because high levels of ceramide in the NPA brain were demonstrated, the involvement [...] Read more.
Sphingomyelinase (SMase) is responsible for the breakdown of sphingomyelin (SM) with production of ceramide. The absence of acid sphingomyelinase (aSMase) causes abnormal synapse formation in Niemann-Pick type A (NPA) disease. Because high levels of ceramide in the NPA brain were demonstrated, the involvement of other SMases were supposed. In the present study we focused the attention on the neurogenic niches in the hippocampal gyrus dentatus (GD), a brain structure essential for forming cohesive memory. We demonstrated for the first time the increase of (Sex determining region Y)-box 2 (SOX2), and the down-regulation of glial fibrillary acidic protein (GFAP) NPA mice GD. Moreover, we found that the expression of Toll like receptors (TLRs), was increased in NPA mice, particularly TLR2, TLR7, TLR8 and TLR9 members. Although no significant change in neutral sphingomyelinase (nSMase) gene expression was detected in the NPA mice hippocampus of, protein levels were enhanced, probably because of the slower protein degradation rate in this area. Many studies demonstrated that vitamin D receptor (VDR) is expressed in the hippocampus GD. Unexpectedly, we showed that NPA mice exhibited VDR gene and protein expression up-regulation. In summary, our study suggests a relation between hippocampal cell differentiation defect, nSMase and VDR increase in NPA mice. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2019)
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Open AccessReview
Calcium-Binding Proteins in the Nervous System during Hibernation: Neuroprotective Strategies in Hypometabolic Conditions?
Int. J. Mol. Sci. 2019, 20(9), 2364; https://doi.org/10.3390/ijms20092364
Received: 14 April 2019 / Revised: 6 May 2019 / Accepted: 11 May 2019 / Published: 13 May 2019
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Abstract
Calcium-binding proteins (CBPs) can influence and react to Ca2+ transients and modulate the activity of proteins involved in both maintaining homeostatic conditions and protecting cells in harsh environmental conditions. Hibernation is a strategy that evolved in vertebrate and invertebrate species to survive [...] Read more.
Calcium-binding proteins (CBPs) can influence and react to Ca2+ transients and modulate the activity of proteins involved in both maintaining homeostatic conditions and protecting cells in harsh environmental conditions. Hibernation is a strategy that evolved in vertebrate and invertebrate species to survive in cold environments; it relies on molecular, cellular, and behavioral adaptations guided by the neuroendocrine system that together ensure unmatched tolerance to hypothermia, hypometabolism, and hypoxia. Therefore, hibernation is a useful model to study molecular neuroprotective adaptations to extreme conditions, and can reveal useful applications to human pathological conditions. In this review, we describe the known changes in Ca2+-signaling and the detection and activity of CBPs in the nervous system of vertebrate and invertebrate models during hibernation, focusing on cytosolic Ca2+ buffers and calmodulin. Then, we discuss these findings in the context of the neuroprotective and neural plasticity mechanisms in the central nervous system: in particular, those associated with cytoskeletal proteins. Finally, we compare the expression of CBPs in the hibernating nervous system with two different conditions of neurodegeneration, i.e., platinum-induced neurotoxicity and Alzheimer’s disease, to highlight the similarities and differences and demonstrate the potential of hibernation to shed light into part of the molecular mechanisms behind neurodegenerative diseases. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling)
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Open AccessReview
A Symphony of Signals: Intercellular and Intracellular Signaling Mechanisms Underlying Circadian Timekeeping in Mice and Flies
Int. J. Mol. Sci. 2019, 20(9), 2363; https://doi.org/10.3390/ijms20092363
Received: 1 April 2019 / Revised: 10 May 2019 / Accepted: 10 May 2019 / Published: 13 May 2019
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Abstract
The central pacemakers of circadian timekeeping systems are highly robust yet adaptable, providing the temporal coordination of rhythms in behavior and physiological processes in accordance with the demands imposed by environmental cycles. These features of the central pacemaker are achieved by a multi-oscillator [...] Read more.
The central pacemakers of circadian timekeeping systems are highly robust yet adaptable, providing the temporal coordination of rhythms in behavior and physiological processes in accordance with the demands imposed by environmental cycles. These features of the central pacemaker are achieved by a multi-oscillator network in which individual cellular oscillators are tightly coupled to the environmental day-night cycle, and to one another via intercellular coupling. In this review, we will summarize the roles of various neurotransmitters and neuropeptides in the regulation of circadian entrainment and synchrony within the mammalian and Drosophila central pacemakers. We will also describe the diverse functions of protein kinases in the relay of input signals to the core oscillator or the direct regulation of the molecular clock machinery. Full article
(This article belongs to the Special Issue Circadian Rhythms: Molecular and Physiological Mechanisms)
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Open AccessReview
PD-L1 Expression in Mastocytosis
Int. J. Mol. Sci. 2019, 20(9), 2362; https://doi.org/10.3390/ijms20092362
Received: 8 April 2019 / Revised: 1 May 2019 / Accepted: 4 May 2019 / Published: 13 May 2019
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Abstract
Programmed death 1 (PD-1), when activated by its ligands PD-L1 and PD-L2, suppresses active immune cells in normal immune regulation to limit autoimmunity and, in tumors, as a mechanism of immune evasion. PD-L1 expression has been described as both a prognostic and predictive [...] Read more.
Programmed death 1 (PD-1), when activated by its ligands PD-L1 and PD-L2, suppresses active immune cells in normal immune regulation to limit autoimmunity and, in tumors, as a mechanism of immune evasion. PD-L1 expression has been described as both a prognostic and predictive marker in many solid and hematologic neoplasms, as targeted therapies against the PD-1/PD-L1 interaction have gained clinical importance. PD-L1 expression has been assessed in a few studies on mastocytosis. We review this literature and the need for further investigation of the tumor-immune interaction in mastocytosis. Full article
(This article belongs to the Special Issue Mast Cells in Health and Disease)
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Open AccessArticle
P-element Somatic Inhibitor Protein Binding a Target Sequence in dsx Pre-mRNA Conserved in Bombyx mori and Spodoptera litura
Int. J. Mol. Sci. 2019, 20(9), 2361; https://doi.org/10.3390/ijms20092361
Received: 15 April 2019 / Revised: 10 May 2019 / Accepted: 10 May 2019 / Published: 13 May 2019
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Abstract
Bombyx mori doublesex (Bmdsx) functions as a double-switch gene in the final step of the sex-determination cascade in the silkworm Bombyx mori. The P-element somatic inhibitor (PSI) protein in B. mori interacts with Bmdsx pre-mRNA in CE1 as an exonic [...] Read more.
Bombyx mori doublesex (Bmdsx) functions as a double-switch gene in the final step of the sex-determination cascade in the silkworm Bombyx mori. The P-element somatic inhibitor (PSI) protein in B. mori interacts with Bmdsx pre-mRNA in CE1 as an exonic splicing silencer to promote male-specific splicing of Bmdsx. However, the character of the interaction between BmPSI and Bmdsx pre-mRNA remains unclear. Electrophoretic mobility shift assay (EMSA) results showed that the four KH_1 motifs in BmPSI are all essential for the binding, especially the former two KH_1 motifs. Three active sites (I116, L127, and IGGI) in the KH_1 motif were found to be necessary for the binding through EMSA, circular dichroism (CD) spectroscopy, and isothermal titration calorimetry (ITC). The PSI homologous protein in S. litura (SlPSI) was purified and the binding of SlPSI and CE1 was verified. Compared with BmPSI, the mutant SlPSI proteins of I116 and IGGI lost their ability to bind to CE1. In conclusion, the binding of PSI and dsx pre-mRNA are generally conserved in both B. mori and S. litura. These findings provide clues for sex determination in Lepidoptera. Full article
(This article belongs to the Special Issue Molecular Ecology, Physiology and Biochemistry of Insects)
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Open AccessArticle
OsbZIP81, A Homologue of Arabidopsis VIP1, May Positively Regulate JA Levels by Directly Targetting the Genes in JA Signaling and Metabolism Pathway in Rice
Int. J. Mol. Sci. 2019, 20(9), 2360; https://doi.org/10.3390/ijms20092360
Received: 12 April 2019 / Revised: 7 May 2019 / Accepted: 8 May 2019 / Published: 13 May 2019
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Abstract
Rice (Oryza sativa L.) is one of the most important food crops in the world. In plants, jasmonic acid (JA) plays essential roles in response to biotic and abiotic stresses. As one of the largest transcription factors (TFs), basic region/leucine zipper motif [...] Read more.
Rice (Oryza sativa L.) is one of the most important food crops in the world. In plants, jasmonic acid (JA) plays essential roles in response to biotic and abiotic stresses. As one of the largest transcription factors (TFs), basic region/leucine zipper motif (bZIP) TFs play pivotal roles through the whole life of plant growth. However, the relationship between JA and bZIP TFs were rarely reported, especially in rice. In this study, we found two rice homologues of Arabidopsis VIP1 (VirE2-interacting protein 1), OsbZIP81, and OsbZIP84. OsbZIP81 has at least two alternative transcripts, OsbZIP81.1 and OsbZIP81.2. OsbZIP81.1 and OsbZIP84 are typical bZIP TFs, while OsbZIP81.2 is not. OsbZIP81.1 can directly bind OsPIOX and activate its expression. In OsbZIP81.1 overexpression transgenic rice plant, JA (Jasmonic Acid) and SA (Salicylic acid) were up-regulated, while ABA (Abscisic acid) was down-regulated. Moreover, Agrobacterium, Methyl Jasmonic Acid (MeJA), and PEG6000 can largely induce OsbZIP81. Based on ChIP-Seq and Random DNA Binding Selection Assay (RDSA), we identified a novel cis-element OVRE (Oryza VIP1 response element). Combining ChIP-Seq and RNA-Seq, we obtained 1332 targeted genes that were categorized in biotic and abiotic responses, including α-linolenic acid metabolism and fatty acid degradation. Together, these results suggest that OsbZIP81 may positively regulate JA levels by directly targeting the genes in JA signaling and metabolism pathway in rice. Full article
(This article belongs to the collection Feature Papers in Molecular Plant Sciences)
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Open AccessArticle
A Natural mtDNA Polymorphism in Complex III Is a Modifier of Healthspan in Mice
Int. J. Mol. Sci. 2019, 20(9), 2359; https://doi.org/10.3390/ijms20092359
Received: 18 February 2019 / Revised: 3 May 2019 / Accepted: 9 May 2019 / Published: 13 May 2019
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Abstract
In this study, we provide experimental evidence that a maternally inherited polymorphism in the mitochondrial cytochrome b gene (mt-Cytb; m.15124A>G, Ile-Val) in mitochondrial complex III resulted in middle-aged obesity and higher susceptibility to diet-induced obesity, as well as age-related inflammatory disease, [...] Read more.
In this study, we provide experimental evidence that a maternally inherited polymorphism in the mitochondrial cytochrome b gene (mt-Cytb; m.15124A>G, Ile-Val) in mitochondrial complex III resulted in middle-aged obesity and higher susceptibility to diet-induced obesity, as well as age-related inflammatory disease, e.g., ulcerative dermatitis, in mice. As a consequence of the gene variation, we observed alterations in body composition, metabolism and mitochondrial functions, i.e., increased mitochondrial oxygen consumption rate and higher levels of reactive oxygen species, as well as in the commensal bacterial composition in the gut, with higher abundance of Proteobacteria in mice carrying the variant. These observations are in line with the previously described links of the mitochondrial complex III gene with obesity and metabolic diseases in humans. Given that these functional changes by the G variant at m.15124 in the mt-Cytb are already present in young mice that were kept under normal condition, it is plausible that the m.15124A>G variant is a disease susceptibility modifier to the diseases induced by additional stressors, i.e., dietary and/or aging stress, and that the variant results in the higher incidence of clinical diseases presentation in C57BL/6J-mt129S1/SvlmJ than C57BL/6J mice. Thus, mtDNA variants could be potential biomarkers to evaluate the healthspan. Full article
(This article belongs to the Special Issue mtDNA and Mitochondrial Stress Signaling in Human Diseases)
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Open AccessReview
Adipose Tissue Dysfunction as Determinant of Obesity-Associated Metabolic Complications
Int. J. Mol. Sci. 2019, 20(9), 2358; https://doi.org/10.3390/ijms20092358
Received: 30 April 2019 / Revised: 9 May 2019 / Accepted: 10 May 2019 / Published: 13 May 2019
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Abstract
Obesity is a critical risk factor for the development of type 2 diabetes (T2D), and its prevalence is rising worldwide. White adipose tissue (WAT) has a crucial role in regulating systemic energy homeostasis. Adipose tissue expands by a combination of an increase in [...] Read more.
Obesity is a critical risk factor for the development of type 2 diabetes (T2D), and its prevalence is rising worldwide. White adipose tissue (WAT) has a crucial role in regulating systemic energy homeostasis. Adipose tissue expands by a combination of an increase in adipocyte size (hypertrophy) and number (hyperplasia). The recruitment and differentiation of adipose precursor cells in the subcutaneous adipose tissue (SAT), rather than merely inflating the cells, would be protective from the obesity-associated metabolic complications. In metabolically unhealthy obesity, the storage capacity of SAT, the largest WAT depot, is limited, and further caloric overload leads to the fat accumulation in ectopic tissues (e.g., liver, skeletal muscle, and heart) and in the visceral adipose depots, an event commonly defined as “lipotoxicity.” Excessive ectopic lipid accumulation leads to local inflammation and insulin resistance (IR). Indeed, overnutrition triggers uncontrolled inflammatory responses in WAT, leading to chronic low-grade inflammation, therefore fostering the progression of IR. This review summarizes the current knowledge on WAT dysfunction in obesity and its associated metabolic abnormalities, such as IR. A better understanding of the mechanisms regulating adipose tissue expansion in obesity is required for the development of future therapeutic approaches in obesity-associated metabolic complications. Full article
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Open AccessReview
Plasticity and Potency of Mammary Stem Cell Subsets During Mammary Gland Development
Int. J. Mol. Sci. 2019, 20(9), 2357; https://doi.org/10.3390/ijms20092357
Received: 18 April 2019 / Revised: 4 May 2019 / Accepted: 11 May 2019 / Published: 13 May 2019
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Abstract
It is now widely believed that mammary epithelial cell plasticity, an important physiological process during the stages of mammary gland development, is exploited by the malignant cells for their successful disease progression. Normal mammary epithelial cells are heterogeneous and organized in hierarchical fashion, [...] Read more.
It is now widely believed that mammary epithelial cell plasticity, an important physiological process during the stages of mammary gland development, is exploited by the malignant cells for their successful disease progression. Normal mammary epithelial cells are heterogeneous and organized in hierarchical fashion, in which the mammary stem cells (MaSC) lie at the apex with regenerative capacity as well as plasticity. Despite the fact that the majority of studies supported the existence of multipotent MaSCs giving rise to both basal and luminal lineages, others proposed lineage restricted unipotent MaSCs. Consistent with the notion, the latest research has suggested that although normal MaSC subsets mainly stay in a quiescent state, they differ in their reconstituting ability, spatial localization, and molecular and epigenetic signatures in response to physiological stimuli within the respective microenvironment during the stages of mammary gland development. In this review, we will focus on current research on the biology of normal mammary stem cells with an emphasis on properties of cellular plasticity, self-renewal and quiescence, as well as the role of the microenvironment in regulating these processes. This will include a discussion of normal breast stem cell heterogeneity, stem cell markers, and lineage tracing studies. Full article
(This article belongs to the Section Molecular Endocrinology and Metabolism)
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Open AccessArticle
Transcriptomic Analysis Reveals a Comprehensive Calcium- and Phytohormone-Dominated Signaling Response in Leymus chinensis Self-Incompatibility
Int. J. Mol. Sci. 2019, 20(9), 2356; https://doi.org/10.3390/ijms20092356
Received: 21 April 2019 / Revised: 9 May 2019 / Accepted: 9 May 2019 / Published: 13 May 2019
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Abstract
Sheepgrass (Leymus chinensis (Trin.) Tzvel.) is an economically and ecologically important forage in the grass family. Self-incompatibility (SI) limits its seed production due to the low seed-setting rate after self-pollination. However, investigations into the molecular mechanisms of sheepgrass SI are lacking. Therefore, [...] Read more.
Sheepgrass (Leymus chinensis (Trin.) Tzvel.) is an economically and ecologically important forage in the grass family. Self-incompatibility (SI) limits its seed production due to the low seed-setting rate after self-pollination. However, investigations into the molecular mechanisms of sheepgrass SI are lacking. Therefore, microscopic observation of pollen germination and pollen tube growth, as well as transcriptomic analyses of pistils after self- and cross-pollination, were performed. The results indicated that pollen tube growth was rapidly inhibited from 10 to 30 min after self-pollination and subsequently stopped but preceded normally after cross-pollination. Time course comparative transcriptomics revealed different transcriptome dynamics between self- and cross-pollination. A pool of SI-related signaling genes and pathways was generated, including genes related to calcium (Ca2+) signaling, protein phosphorylation, plant hormone, reactive oxygen species (ROS), nitric oxide (NO), cytoskeleton, and programmed cell death (PCD). A putative SI response molecular model in sheepgrass was presented. The model shows that SI may trigger a comprehensive calcium- and phytohormone-dominated signaling cascade and activate PCD, which may explain the rapid inhibition of self-pollen tube growth as observed by cytological analyses. These results provided new insight into the molecular mechanisms of sheepgrass (grass family) SI. Full article
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Open AccessArticle
A Kriging Surrogate Model for Uncertainty Analysis of Graphene Based on a Finite Element Method
Int. J. Mol. Sci. 2019, 20(9), 2355; https://doi.org/10.3390/ijms20092355
Received: 18 April 2019 / Revised: 30 April 2019 / Accepted: 8 May 2019 / Published: 13 May 2019
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Abstract
Due to the inevitable presence of random defects, unpredictable grain boundaries in macroscopic samples, stress concentration at clamping points, and unknown load distribution in the investigation of graphene sheets, uncertainties are crucial and challenging issues that require more exploration. The application of the [...] Read more.
Due to the inevitable presence of random defects, unpredictable grain boundaries in macroscopic samples, stress concentration at clamping points, and unknown load distribution in the investigation of graphene sheets, uncertainties are crucial and challenging issues that require more exploration. The application of the Kriging surrogate model in vibration analysis of graphene sheets is proposed in this study. The Latin hypercube sampling method effectively propagates the uncertainties in geometrical and material properties of the finite element model. The accuracy and convergence of the Kriging surrogate model are confirmed by a comparison with the reported references. The uncertainty analysis for both Zigzag and Armchair graphene sheets are compared and discussed. Full article
(This article belongs to the Special Issue Nano-Materials and Methods)
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Open AccessArticle
Indole-Based Hydrazones Containing A Sulfonamide Moiety as Selective Inhibitors of Tumor-Associated Human Carbonic Anhydrase Isoforms IX and XII
Int. J. Mol. Sci. 2019, 20(9), 2354; https://doi.org/10.3390/ijms20092354
Received: 1 April 2019 / Revised: 23 April 2019 / Accepted: 10 May 2019 / Published: 12 May 2019
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Abstract
Novel sulfonamidoindole-based hydrazones with a 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide scaffold were synthesized and tested in enzyme inhibition assays against the tumor-associated carbonic anhydrase isoforms, hCA IX and XII, and the off-targets, hCA I and II. The compounds showed selectivity against hCA IX and XII [...] Read more.
Novel sulfonamidoindole-based hydrazones with a 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide scaffold were synthesized and tested in enzyme inhibition assays against the tumor-associated carbonic anhydrase isoforms, hCA IX and XII, and the off-targets, hCA I and II. The compounds showed selectivity against hCA IX and XII over hCA I and II. Six compounds showed KI values lower than 10 nM against hCA IX or XII. Molecular modeling studies were performed to suggest binding interactions between the ligand and the hCA active sites. Full article
(This article belongs to the Special Issue Protease and Carbonic Anhydrase Inhibitors, II)
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Open AccessReview
Role of Cyclin-Dependent Kinase Inhibitors in Endometrial Cancer
Int. J. Mol. Sci. 2019, 20(9), 2353; https://doi.org/10.3390/ijms20092353
Received: 28 February 2019 / Revised: 15 April 2019 / Accepted: 10 May 2019 / Published: 12 May 2019
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Abstract
Endometrial Cancer (EC) is an important cause of death in women worldwide. Despite early diagnosis and optimal treatment of localized disease, relapsed patients have few therapeutic options because after first line therapy, currently no standard of care exists. On the basis of endocrine [...] Read more.
Endometrial Cancer (EC) is an important cause of death in women worldwide. Despite early diagnosis and optimal treatment of localized disease, relapsed patients have few therapeutic options because after first line therapy, currently no standard of care exists. On the basis of endocrine positivity of most endometrioid ECs, Endocrine Therapy (ET) is a reasonable and widely accepted option. Better knowledge of molecular mechanisms involved in cancer highlighted the deregulated activity of Cyclin-Dependent Kinases (CDKs) in the cell cycle as a hallmark of carcinogenesis supporting the development of a new class of drugs: CDK inhibitors (CDKis). The aim of this review is to give an overview on CDKis preclinical, early clinical activity and future development in EC. Use of CDKis has a strong preclinical rationale but we have poor clinical data. Similar to breast cancer, most ongoing trials are investigating synergistic associations between CDKis and ET. These trials will probably help in defining the best clinical setting of CDKis in ECs, which are the best partner drugs, and how to manage CDKis toxicities with a focus on potential biomarkers of response. Full article
(This article belongs to the Special Issue Cyclin-dependent Kinases in Health and Diseases)
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Open AccessArticle
Interaction of Mycotoxin Alternariol with Serum Albumin
Int. J. Mol. Sci. 2019, 20(9), 2352; https://doi.org/10.3390/ijms20092352
Received: 19 April 2019 / Revised: 8 May 2019 / Accepted: 8 May 2019 / Published: 12 May 2019
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Abstract
Alternariol (AOH) is a mycotoxin produced by Alternaria species. In vitro studies suggest the genotoxic, mutagenic, and endocrine disruptor effects of AOH, and an increased incidence of esophageal cancer has been reported related to higher AOH exposure. Human serum albumin (HSA) is the [...] Read more.
Alternariol (AOH) is a mycotoxin produced by Alternaria species. In vitro studies suggest the genotoxic, mutagenic, and endocrine disruptor effects of AOH, and an increased incidence of esophageal cancer has been reported related to higher AOH exposure. Human serum albumin (HSA) is the most abundant plasma protein in the circulation, it is able to affect toxicokinetic properties of numerous xenobiotics. HSA forms stable complexes with several mycotoxins, however, the interaction of AOH with albumin has not been examined. In this study, the complex formation of AOH with HSA was tested, employing fluorescence spectroscopy, ultrafiltration, and molecular modeling. Each spectroscopic measurement shows the formation of stable AOH-HSA complexes (K = 4 × 105 L/mol). Investigations with site markers (in spectroscopic and ultrafiltration models) as well as modeling studies suggest that AOH occupies Sudlow’s site I as a high-affinity binding site in HSA. The binding affinity of AOH towards bovine, porcine, and rat albumins was also tested, suggesting that AOH binds to rat albumin with considerably higher affinity than other albumins tested. Our results demonstrate the strong interaction of AOH with serum albumins, suggesting the potential in vivo importance of these interactions. Full article
(This article belongs to the Section Bioactives and Nutraceuticals)
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Open AccessEditorial
mTOR in Human Diseases
Int. J. Mol. Sci. 2019, 20(9), 2351; https://doi.org/10.3390/ijms20092351
Received: 5 May 2019 / Accepted: 9 May 2019 / Published: 11 May 2019
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Abstract
The human body regenerates constantly in part under the control of signaling pathways that regulate cell growth [...] Full article
(This article belongs to the Special Issue mTOR in Human Diseases)
Open AccessArticle
Self-Assembled Benznidazole-Loaded Cationic Nanoparticles Containing Cholesterol/Sialic Acid: Physicochemical Properties, In Vitro Drug Release and In Vitro Anticancer Efficacy
Int. J. Mol. Sci. 2019, 20(9), 2350; https://doi.org/10.3390/ijms20092350
Received: 26 February 2019 / Revised: 8 April 2019 / Accepted: 10 April 2019 / Published: 11 May 2019
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Abstract
Cationic polymeric nanoparticles (NPs) have the ability to overcome biological membranes, leading to improved efficacy of anticancer drugs. The modulation of the particle-cell interaction is desired to control this effect and avoid toxicity to normal cells. In this study, we explored the surface [...] Read more.
Cationic polymeric nanoparticles (NPs) have the ability to overcome biological membranes, leading to improved efficacy of anticancer drugs. The modulation of the particle-cell interaction is desired to control this effect and avoid toxicity to normal cells. In this study, we explored the surface functionalization of cationic polymethylmethacrylate (PMMA) NPs with two natural compounds, sialic acid (SA) and cholesterol (Chol). The performance of benznidazole (BNZ) was assessed in vitro in the normal renal cell line (HEK-293) and three human cancer cell lines, as follows: human colorectal cancer (HT-29), human cervical carcinoma (HeLa), and human hepatocyte carcinoma (HepG2). The structural properties and feasibility of NPs were evaluated and the changes induced by SA and Chol were determined by using multiple analytical approaches. Small (<200 nm) spherical NPs, with a narrow size distribution and high drug-loading efficiency were prepared by using a simple and reproducible emulsification solvent evaporation method. The drug interactions in the different self-assembled NPs were assessed by using Fourier transform-infrared spectroscopy. All formulations exhibited a slow drug-release profile and physical stability for more than 6 weeks. Both SA and Chol changed the kinetic properties of NPs and the anticancer efficacy. The feasibility and potential of SA/Chol-functionalized NPs has been demonstrated in vitro in the HEK-293, HepG2, HeLa, and HT-29 cell lines as a promising system for the delivery of BNZ. Full article
(This article belongs to the Special Issue Surface-Functionalized Nanoparticles as Drug Carriers)
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Open AccessArticle
An Integrated Analysis of the Rice Transcriptome and Metabolome Reveals Differential Regulation of Carbon and Nitrogen Metabolism in Response to Nitrogen Availability
Int. J. Mol. Sci. 2019, 20(9), 2349; https://doi.org/10.3390/ijms20092349
Received: 17 April 2019 / Revised: 7 May 2019 / Accepted: 8 May 2019 / Published: 11 May 2019
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Abstract
Nitrogen (N) is an extremely important macronutrient for plant growth and development. It is the main limiting factor in most agricultural production. However, it is well known that the nitrogen use efficiency (NUE) of rice gradually decreases with the increase of the nitrogen [...] Read more.
Nitrogen (N) is an extremely important macronutrient for plant growth and development. It is the main limiting factor in most agricultural production. However, it is well known that the nitrogen use efficiency (NUE) of rice gradually decreases with the increase of the nitrogen application rate. In order to clarify the underlying metabolic and molecular mechanisms of this phenomenon, we performed an integrated analysis of the rice transcriptome and metabolome. Both differentially expressed genes (DEGs) and metabolite Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that carbon and nitrogen metabolism is significantly affected by nitrogen availability. Further analysis of carbon and nitrogen metabolism changes in rice under different nitrogen availability showed that high N inhibits nitrogen assimilation and aromatic metabolism pathways by regulating carbon metabolism pathways such as the tricarboxylic acid (TCA) cycle and the pentose phosphate pathway (PPP). Under low nitrogen, the TCA cycle is promoted to produce more energy and α-ketoglutarate, thereby enhancing nitrogen transport and assimilation. PPP is also inhibited by low N, which may be consistent with the lower NADPH demand under low nitrogen. Additionally, we performed a co-expression network analysis of genes and metabolites related to carbon and nitrogen metabolism. In total, 15 genes were identified as hub genes. In summary, this study reveals the influence of nitrogen levels on the regulation mechanisms for carbon and nitrogen metabolism in rice and provides new insights into coordinating carbon and nitrogen metabolism and improving nitrogen use efficiency in rice. Full article
(This article belongs to the Special Issue The Molecular Basis of Carbon and Nitrogen Metabolism in Plants)
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Open AccessArticle
Genetic Variation for Seed Metabolite Levels in Brachypodium distachyon
Int. J. Mol. Sci. 2019, 20(9), 2348; https://doi.org/10.3390/ijms20092348
Received: 27 March 2019 / Revised: 26 April 2019 / Accepted: 27 April 2019 / Published: 11 May 2019
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Abstract
Metabolite composition and concentrations in seed grains are important traits of cereals. To identify the variation in the seed metabolotypes of a model grass, namely Brachypodium distachyon, we applied a widely targeted metabolome analysis to forty inbred lines of B. distachyon and [...] Read more.
Metabolite composition and concentrations in seed grains are important traits of cereals. To identify the variation in the seed metabolotypes of a model grass, namely Brachypodium distachyon, we applied a widely targeted metabolome analysis to forty inbred lines of B. distachyon and examined the accumulation patterns of 183 compounds in the seeds. By comparing the metabolotypes with the population structure of these lines, we found signature metabolites that represent different accumulation patterns for each of the three B. distachyon subpopulations. Moreover, we found that thirty-seven metabolites exhibited significant differences in their accumulation between the lines Bd21 and Bd3-1. Using a recombinant inbred line (RIL) population from a cross between Bd3-1 and Bd21, we identified the quantitative trait loci (QTLs) linked with this variation in the accumulation of thirteen metabolites. Our metabolite QTL analysis illustrated that different genetic factors may presumably regulate the accumulation of 4-pyridoxate and pyridoxamine in vitamin B6 metabolism. Moreover, we found two QTLs on chromosomes 1 and 4 that affect the accumulation of an anthocyanin, chrysanthemin. These QTLs genetically interacted to regulate the accumulation of this compound. This study demonstrates the potential for metabolite QTL mapping in B. distachyon and provides new insights into the genetic dissection of metabolomic traits in temperate grasses. Full article
(This article belongs to the collection Feature Papers in Molecular Plant Sciences)
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Open AccessReview
Liver Zonation in Health and Disease: Hypoxia and Hypoxia-Inducible Transcription Factors as Concert Masters
Int. J. Mol. Sci. 2019, 20(9), 2347; https://doi.org/10.3390/ijms20092347
Received: 31 March 2019 / Revised: 6 May 2019 / Accepted: 8 May 2019 / Published: 11 May 2019
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Abstract
The liver and its zonation contribute to whole body homeostasis. Acute and chronic, not always liver, diseases impair proper metabolic zonation. Various underlying pathways, such as β-catenin, hedgehog signaling, and the Hippo pathway, along with the physiologically occurring oxygen gradient, appear to be [...] Read more.
The liver and its zonation contribute to whole body homeostasis. Acute and chronic, not always liver, diseases impair proper metabolic zonation. Various underlying pathways, such as β-catenin, hedgehog signaling, and the Hippo pathway, along with the physiologically occurring oxygen gradient, appear to be contributors. Interestingly, hypoxia and hypoxia-inducible transcription factors can orchestrate those pathways. In the current review, we connect novel findings of liver zonation in health and disease and provide a view about the dynamic interplay between these different pathways and cell-types to drive liver zonation and systemic homeostasis. Full article
(This article belongs to the Special Issue Liver Damage and Repair)
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Open AccessReview
The Cross-Talk Between the TNF-α and RASSF-Hippo Signalling Pathways
Int. J. Mol. Sci. 2019, 20(9), 2346; https://doi.org/10.3390/ijms20092346
Received: 27 March 2019 / Revised: 7 May 2019 / Accepted: 8 May 2019 / Published: 11 May 2019
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Abstract
The regulation of cell death through apoptosis is essential to a number of physiological processes. Defective apoptosis regulation is associated with many abnormalities including anomalies in organ development, altered immune response and the development of cancer. Several signalling pathways are known to regulate [...] Read more.
The regulation of cell death through apoptosis is essential to a number of physiological processes. Defective apoptosis regulation is associated with many abnormalities including anomalies in organ development, altered immune response and the development of cancer. Several signalling pathways are known to regulate apoptosis including the Tumour Necrosis Factor-α (TNF-α) and Hippo signalling pathways. In this paper we review the cross-talk between the TNF-α pathway and the Hippo signalling pathway. Several molecules that tightly regulate the Hippo pathway, such as members of the Ras-association domain family member (RASSF) family proteins, interact and modulate some key proteins within the TNF-α pathway. Meanwhile, TNF-α stimulation also affects the expression and activation of core components of the Hippo pathway. This implies the crucial role of signal integration between these two major pathways in regulating apoptosis. Full article
(This article belongs to the Special Issue Tumor Necrosis Factor (TNF))
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Open AccessReview
Divergent Approaches to Virulence in C. albicans and C. glabrata: Two Sides of the Same Coin
Int. J. Mol. Sci. 2019, 20(9), 2345; https://doi.org/10.3390/ijms20092345
Received: 10 April 2019 / Revised: 8 May 2019 / Accepted: 8 May 2019 / Published: 11 May 2019
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Abstract
Candida albicans and Candida glabrata are the two most prevalent etiologic agents of candidiasis worldwide. Although both are recognized as pathogenic, their choice of virulence traits is highly divergent. Indeed, it appears that these different approaches to fungal virulence may be equally successful [...] Read more.
Candida albicans and Candida glabrata are the two most prevalent etiologic agents of candidiasis worldwide. Although both are recognized as pathogenic, their choice of virulence traits is highly divergent. Indeed, it appears that these different approaches to fungal virulence may be equally successful in causing human candidiasis. In this review, the virulence mechanisms employed by C. albicans and C. glabrata are analyzed, with emphasis on the differences between the two systems. Pathogenesis features considered in this paper include dimorphic growth, secreted enzymes and signaling molecules, and stress resistance mechanisms. The consequences of these traits in tissue invasion, biofilm formation, immune system evasion, and macrophage escape, in a species dependent manner, are discussed. This review highlights the observation that C. albicans and C. glabrata follow different paths leading to a similar outcome. It also highlights the lack of knowledge on some of the specific mechanisms underlying C. glabrata pathogenesis, which deserve future scrutiny. Full article
(This article belongs to the Special Issue Microbial Virulence Factors)
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Open AccessCommunication
Predicting Apoptosis Protein Subcellular Locations based on the Protein Overlapping Property Matrix and Tri-Gram Encoding
Int. J. Mol. Sci. 2019, 20(9), 2344; https://doi.org/10.3390/ijms20092344
Received: 1 April 2019 / Revised: 25 April 2019 / Accepted: 8 May 2019 / Published: 11 May 2019
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Abstract
To reveal the working pattern of programmed cell death, knowledge of the subcellular location of apoptosis proteins is essential. Besides the costly and time-consuming method of experimental determination, research into computational locating schemes, focusing mainly on the innovation of representation techniques on protein [...] Read more.
To reveal the working pattern of programmed cell death, knowledge of the subcellular location of apoptosis proteins is essential. Besides the costly and time-consuming method of experimental determination, research into computational locating schemes, focusing mainly on the innovation of representation techniques on protein sequences and the selection of classification algorithms, has become popular in recent decades. In this study, a novel tri-gram encoding model is proposed, which is based on using the protein overlapping property matrix (POPM) for predicting apoptosis protein subcellular location. Next, a 1000-dimensional feature vector is built to represent a protein. Finally, with the help of support vector machine-recursive feature elimination (SVM-RFE), we select the optimal features and put them into a support vector machine (SVM) classifier for predictions. The results of jackknife tests on two benchmark datasets demonstrate that our proposed method can achieve satisfactory prediction performance level with less computing capacity required and could work as a promising tool to predict the subcellular locations of apoptosis proteins. Full article
(This article belongs to the Special Issue Artificial Intelligence and Computer Aided Drug Design)
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Open AccessArticle
Computational Aminoacyl-tRNA Synthetase Library Design for Photocaged Tyrosine
Int. J. Mol. Sci. 2019, 20(9), 2343; https://doi.org/10.3390/ijms20092343
Received: 16 April 2019 / Revised: 7 May 2019 / Accepted: 9 May 2019 / Published: 11 May 2019
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Abstract
Engineering aminoacyl-tRNA synthetases (aaRSs) provides access to the ribosomal incorporation of noncanonical amino acids via genetic code expansion. Conventional targeted mutagenesis libraries with 5–7 positions randomized cover only marginal fractions of the vast sequence space formed by up to 30 active site residues. [...] Read more.
Engineering aminoacyl-tRNA synthetases (aaRSs) provides access to the ribosomal incorporation of noncanonical amino acids via genetic code expansion. Conventional targeted mutagenesis libraries with 5–7 positions randomized cover only marginal fractions of the vast sequence space formed by up to 30 active site residues. This frequently results in selection of weakly active enzymes. To overcome this limitation, we use computational enzyme design to generate a focused library of aaRS variants. For aaRS enzyme redesign, photocaged ortho-nitrobenzyl tyrosine (ONBY) was chosen as substrate due to commercial availability and its diverse applications. Diversifying 17 first- and second-shell sites and performing conventional aaRS positive and negative selection resulted in a high-activity aaRS. This MjTyrRS variant carries ten mutations and outperforms previously reported ONBY-specific aaRS variants isolated from traditional libraries. In response to a single in-frame amber stop codon, it mediates the in vivo incorporation of ONBY with an efficiency matching that of the wild type MjTyrRS enzyme acylating cognate tyrosine. These results exemplify an improved general strategy for aaRS library design and engineering. Full article
(This article belongs to the Special Issue Expanding and Reprogramming the Genetic Code)
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Open AccessReview
Current Understanding of Autophagy in Pregnancy
Int. J. Mol. Sci. 2019, 20(9), 2342; https://doi.org/10.3390/ijms20092342
Received: 12 April 2019 / Revised: 9 May 2019 / Accepted: 10 May 2019 / Published: 11 May 2019
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Abstract
Autophagy is an evolutionarily conserved process in eukaryotes to maintain cellular homeostasis under environmental stress. Intracellular control is exerted to produce energy or maintain intracellular protein quality controls. Autophagy plays an important role in embryogenesis, implantation, and maintenance of pregnancy. This role includes [...] Read more.
Autophagy is an evolutionarily conserved process in eukaryotes to maintain cellular homeostasis under environmental stress. Intracellular control is exerted to produce energy or maintain intracellular protein quality controls. Autophagy plays an important role in embryogenesis, implantation, and maintenance of pregnancy. This role includes supporting extravillous trophoblasts (EVTs) that invade the decidua (endometrium) until the first third of uterine myometrium and migrate along the lumina of spiral arterioles under hypoxic and low-nutrient conditions in early pregnancy. In addition, autophagy inhibition has been linked to poor placentation—a feature of preeclamptic placentas—in a placenta-specific autophagy knockout mouse model. Studies of autophagy in human placentas have revealed controversial results, especially with regard to preeclampsia and gestational diabetes mellitus (GDM). Without precise estimation of autophagy flux, wrong interpretation would lead to fixed tissues. This paper presents a review of the role of autophagy in pregnancy and elaborates on the interpretation of autophagy in human placental tissues. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Preeclampsia)
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Open AccessArticle
Electrical Stimulation of the Mesencephalic Locomotor Region Attenuates Neuronal Loss and Cytokine Expression in the Perifocal Region of Photothrombotic Stroke in Rats
Int. J. Mol. Sci. 2019, 20(9), 2341; https://doi.org/10.3390/ijms20092341
Received: 9 April 2019 / Revised: 6 May 2019 / Accepted: 9 May 2019 / Published: 11 May 2019
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Abstract
Deep brain stimulation of the mesencephalic locomotor region (MLR) improves the motor symptoms in Parkinson’s disease and experimental stroke by intervening in the motor cerebral network. Whether high-frequency stimulation (HFS) of the MLR is involved in non-motor processes, such as neuroprotection and inflammation [...] Read more.
Deep brain stimulation of the mesencephalic locomotor region (MLR) improves the motor symptoms in Parkinson’s disease and experimental stroke by intervening in the motor cerebral network. Whether high-frequency stimulation (HFS) of the MLR is involved in non-motor processes, such as neuroprotection and inflammation in the area surrounding the photothrombotic lesion, has not been elucidated. This study evaluates whether MLR-HFS exerts an anti-apoptotic and anti-inflammatory effect on the border zone of cerebral photothrombotic stroke. Rats underwent photothrombotic stroke of the right sensorimotor cortex and the implantation of a microelectrode into the ipsilesional MLR. After intervention, either HFS or sham stimulation of the MLR was applied for 24 h. The infarct volumes were calculated from consecutive brain sections. Neuronal apoptosis was analyzed by TUNEL staining. Flow cytometry and immunohistochemistry determined the perilesional inflammatory response. Neuronal apoptosis was significantly reduced in the ischemic penumbra after MLR-HFS, whereas the infarct volumes did not differ between the groups. MLR-HFS significantly reduced the release of cytokines and chemokines within the ischemic penumbra. MLR-HFS is neuroprotective and it reduces pro-inflammatory mediators in the area that surrounds the photothrombotic stroke without changing the number of immune cells, which indicates that MLR-HFS enables the function of inflammatory cells to be altered on a molecular level. Full article
(This article belongs to the Special Issue Neuroinflammation and Cell Death)
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Open AccessReview
Emerging Roles of C-Myc in Cancer Stem Cell-Related Signaling and Resistance to Cancer Chemotherapy: A Potential Therapeutic Target Against Colorectal Cancer
Int. J. Mol. Sci. 2019, 20(9), 2340; https://doi.org/10.3390/ijms20092340
Received: 19 April 2019 / Revised: 29 April 2019 / Accepted: 9 May 2019 / Published: 11 May 2019
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Abstract
Myc is a nuclear transcription factor that mainly regulates cell growth, cell cycle, metabolism, and survival. Myc family proteins contain c-Myc, n-Myc, and l-Myc. Among them, c-Myc can become a promising therapeutic target molecule in cancer. Cancer stem cells (CSCs) are known to [...] Read more.
Myc is a nuclear transcription factor that mainly regulates cell growth, cell cycle, metabolism, and survival. Myc family proteins contain c-Myc, n-Myc, and l-Myc. Among them, c-Myc can become a promising therapeutic target molecule in cancer. Cancer stem cells (CSCs) are known to be responsible for the therapeutic resistance. In the previous study, we demonstrated that c-Myc mediates drug resistance of colorectal CSCs using a patient-derived primary three-dimensional (3D) organoid culture. In this review, we mainly focus on the roles of c-Myc-related signaling in the regulation of CSCs, chemotherapy resistance, and colorectal cancer organoids. Finally, we introduce the various types of c-Myc inhibitors and propose the possibility of c-Myc as a therapeutic target against colorectal cancer. Full article
(This article belongs to the Special Issue Myc Function and Regulation)
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