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Volume 21
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Int. J. Mol. Sci., Volume 21, Issue 11 (June-1 2020) – 452 articles

Cover Story (view full-size image): Bone morphogenetic proteins (BMPs) are multifunctional secreted signaling molecules that act in a highly context-dependent fashion. Interaction of BMPs to their cognate receptors is tightly controlled by a diverse set of secreted BMP antagonists. Perturbations of BMP antagonist expression are implicated in a range of human diseases and disorders, including cancer. Here, we review how BMP antagonists are involved in cancer initiation and progression not only by affecting the cancer cells themselves, but also other crucial cell types in the tumor microenvironment. View this paper
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17 pages, 2724 KiB  
Article
RNA Binding Proteins as Drivers and Therapeutic Target Candidates in Pancreatic Ductal Adenocarcinoma
by Markus Glaß, Patrick Michl and Stefan Hüttelmaier
Int. J. Mol. Sci. 2020, 21(11), 4190; https://doi.org/10.3390/ijms21114190 - 11 Jun 2020
Cited by 18 | Viewed by 3668
Abstract
Pancreatic ductal adenocarcinomas (PDAC) belong to the most frequent and most deadly malignancies in the western world. Mutations in KRAS and TP53 along with some other frequent polymorphisms occur almost universally and are likely to be responsible for tumor initiation. However, these mutations [...] Read more.
Pancreatic ductal adenocarcinomas (PDAC) belong to the most frequent and most deadly malignancies in the western world. Mutations in KRAS and TP53 along with some other frequent polymorphisms occur almost universally and are likely to be responsible for tumor initiation. However, these mutations cannot explain the heterogeneity in therapeutic responses observed in PDAC patients, which limits efficiency of current therapeutic strategies. Instead, recent classifications of PDAC tumor samples are based on transcriptomics data and thus include information about epigenetic, transcriptomic, and post-transcriptomic deregulations. RNA binding proteins (RBPs) are important post-transcriptional regulators involved in every aspect of the RNA life cycle and thus considerably influence the transcriptome. In this study, we systematically investigated deregulated expression, prognostic value, and essentiality reported for RBPs in PDAC or PDAC cancer models using publicly available data. We identified 44 RBPs with suggested oncogenic potential. These include various proteins, e.g., IGF2 mRNA binding proteins (IGF2BPs), with reported tumor-promoting roles. We further characterized these RBPs and found common patterns regarding their expression, interaction, and regulation by microRNAs. These analyses suggest four prime candidate oncogenic RBPs with partially validated target potential: APOBEC1, IGF2BP1 and 3, and OASL. Full article
(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)
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15 pages, 1518 KiB  
Article
Relationship between IL-8 Circulating Levels and TLR2 Hepatic Expression in Women with Morbid Obesity and Nonalcoholic Steatohepatitis
by Teresa Auguet, Laia Bertran, Jessica Binetti, Carmen Aguilar, Salomé Martínez, Fàtima Sabench, Jesús Miguel Lopez-Dupla, José Antonio Porras, David Riesco, Daniel Del Castillo and Cristóbal Richart
Int. J. Mol. Sci. 2020, 21(11), 4189; https://doi.org/10.3390/ijms21114189 - 11 Jun 2020
Cited by 34 | Viewed by 4101
Abstract
The progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) is linked to systemic inflammation. Currently, two of the aspects that need further investigation are diagnosis and treatment of NASH. In this sense, the aim of this study was to assess [...] Read more.
The progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) is linked to systemic inflammation. Currently, two of the aspects that need further investigation are diagnosis and treatment of NASH. In this sense, the aim of this study was to assess the relationship between circulating levels of cytokines, hepatic expression of toll-like receptors (TLRs), and degrees of NAFLD, and to investigate whether these levels could serve as noninvasive biomarkers of NASH. The present study assessed plasma levels of cytokines in 29 normal-weight women and 82 women with morbid obesity (MO) (subclassified: normal liver (n = 29), simple steatosis (n = 32), and NASH (n = 21)). We used enzyme-linked immunosorbent assays (ELISAs) to quantify cytokine and TLR4 levels and RTqPCR to assess TLRs hepatic expression. IL-1β, IL-8, IL-10, TNF-α, tPAI-1, and MCP-1 levels were increased, and adiponectin levels were decreased in women with MO. IL-8 was significantly higher in MO with NASH than in NL. To sum up, high levels of IL-8 were associated with the diagnosis of NASH in a cohort of women with morbid obesity. Moreover, a positive correlation between TLR2 hepatic expression and IL-8 circulating levels was found. Full article
(This article belongs to the Special Issue Medicines for the Treatment of Obesity)
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22 pages, 9060 KiB  
Article
A Proline Derivative-Enriched Fraction from Sideroxylon obtusifolium Protects the Hippocampus from Intracerebroventricular Pilocarpine-Induced Injury Associated with Status Epilepticus in Mice
by Pedro Everson Alexandre de Aquino, Jéssica Rabelo Bezerra, Tyciane de Souza Nascimento, Juliete Tavares, Ítalo Rosal Lustosa, Adriano José Maia Chaves Filho, Melina Mottin, Danielle Macêdo Gaspar, Geanne Matos de Andrade, Kelly Rose Tavares Neves, Giuseppe Biagini, Edilberto Rocha Silveira and Glauce Socorro de Barros Viana
Int. J. Mol. Sci. 2020, 21(11), 4188; https://doi.org/10.3390/ijms21114188 - 11 Jun 2020
Cited by 7 | Viewed by 3772
Abstract
The N-methyl-(2S,4R)-trans-4-hydroxy-l-proline-enriched fraction (NMP) from Sideroxylon obtusifolium was evaluated as a neuroprotective agent in the intracerebroventricular (icv) pilocarpine (Pilo) model. To this aim, male mice were subdivided into sham (SO, vehicle), Pilo (300 µg/1 µL icv, followed by the vehicle [...] Read more.
The N-methyl-(2S,4R)-trans-4-hydroxy-l-proline-enriched fraction (NMP) from Sideroxylon obtusifolium was evaluated as a neuroprotective agent in the intracerebroventricular (icv) pilocarpine (Pilo) model. To this aim, male mice were subdivided into sham (SO, vehicle), Pilo (300 µg/1 µL icv, followed by the vehicle per os, po) and NMP-treated groups (Pilo 300 µg/1 µL icv, followed by 100 or 200 mg/kg po). The treatments started one day after the Pilo injection and continued for 15 days. The effects of NMP were assessed by characterizing the preservation of cognitive function in both the Y-maze and object recognition tests. The hippocampal cell viability was evaluated by Nissl staining. Additional markers of damage were studied—the glial fibrillary acidic protein (GFAP) and the ionized calcium-binding adaptor molecule 1 (Iba-1) expression using, respectively, immunofluorescence and western blot analyses. We also performed molecular docking experiments revealing that NMP binds to the γ-aminobutyric acid (GABA) transporter 1 (GAT1). GAT1 expression in the hippocampus was also characterized. Pilo induced cognitive deficits, cell damage, increased GFAP, Iba-1, and GAT1 expression in the hippocampus. These alterations were prevented, especially by the higher NMP dose. These data highlight NMP as a promising candidate for the protection of the hippocampus, as shown by the icv Pilo model. Full article
(This article belongs to the Special Issue Epilepsy: From Molecular Mechanisms to Targeted Therapies 2.0)
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21 pages, 3436 KiB  
Article
A Neuroprotective Dose of Isatin Causes Multilevel Changes Involving the Brain Proteome: Prospects for Further Research
by Alexei Medvedev, Arthur Kopylov, Olga Buneeva, Leonid Kurbatov, Olga Tikhonova, Alexis Ivanov and Victor Zgoda
Int. J. Mol. Sci. 2020, 21(11), 4187; https://doi.org/10.3390/ijms21114187 - 11 Jun 2020
Cited by 20 | Viewed by 3229
Abstract
Isatin (indole-2,3-dione) is an endogenous regulator, exhibiting a wide range of biological and pharmacological activities. At doses of 100 mg/kg and above, isatin is neuroprotective in different experimental models of neurodegeneration. Good evidence exists that its effects are realized via interaction with numerous [...] Read more.
Isatin (indole-2,3-dione) is an endogenous regulator, exhibiting a wide range of biological and pharmacological activities. At doses of 100 mg/kg and above, isatin is neuroprotective in different experimental models of neurodegeneration. Good evidence exists that its effects are realized via interaction with numerous isatin-binding proteins identified in the brain and peripheral tissues studied. In this study, we investigated the effect of a single dose administration of isatin to mice (100 mg/kg, 24 h) on differentially expressed proteins and a profile of the isatin-binding proteins in brain hemispheres. Isatin administration to mice caused downregulation of 31 proteins. However, these changes cannot be attributed to altered expression of corresponding genes. Although at this time point isatin influenced the expression of more than 850 genes in brain hemispheres (including 433 upregulated and 418 downregulated genes), none of them could account for the changes in the differentially expressed proteins. Comparative proteomic analysis of brain isatin-binding proteins of control and isatin-treated mice revealed representative groups of proteins sensitive to isatin administration. Control-specific proteins (n = 55) represent specific targets that interact directly with isatin. Appearance of brain isatin-binding proteins specific to isatin-treated mice (n = 94) may be attributed to the formation of new clusters of protein–protein interactions and/or novel binding sites induced by a high concentration of this regulator (ligand-induced binding sites). Thus, isatin administration produces multiple effects in the brain, which include changes in gene expression and also profiles of isatin-binding proteins and their interactomes. Further studies are needed for deeper insight into the mechanisms of the multilevel changes in the brain proteome induced by isatin. In the context of the neuroprotective action, these changes may be aimed at interruption of pathological links that begin to form after initiation of pathological processes. Full article
(This article belongs to the Special Issue Biological Activities and Biomedical Application of Isatin and Its Analogues)
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15 pages, 3100 KiB  
Article
CaCML13 Acts Positively in Pepper Immunity Against Ralstonia solanacearum Infection Forming Feedback Loop with CabZIP63
by Lei Shen, Sheng Yang, Deyi Guan and Shuilin He
Int. J. Mol. Sci. 2020, 21(11), 4186; https://doi.org/10.3390/ijms21114186 - 11 Jun 2020
Cited by 19 | Viewed by 3034
Abstract
Ca2+-signaling—which requires the presence of calcium sensors such as calmodulin (CaM) and calmodulin-like (CML) proteins—is crucial for the regulation of plant immunity against pathogen attack. However, the underlying mechanisms remain elusive, especially the roles of CMLs involved in plant immunity remains [...] Read more.
Ca2+-signaling—which requires the presence of calcium sensors such as calmodulin (CaM) and calmodulin-like (CML) proteins—is crucial for the regulation of plant immunity against pathogen attack. However, the underlying mechanisms remain elusive, especially the roles of CMLs involved in plant immunity remains largely uninvestigated. In the present study, CaCML13, a calmodulin-like protein of pepper that was originally found to be upregulated by Ralstonia solanacearum inoculation (RSI) in RNA-seq, was functionally characterized in immunity against RSI. CaCML13 was found to target the whole epidermal cell including plasma membrane, cytoplasm and nucleus. We also confirmed that CaCML13 was upregulated by RSI in pepper roots by quantitative real-time PCR (qRT-PCR). The silencing of CaCML13 significantly enhanced pepper plants’ susceptibility to RSI accompanied with downregulation of immunity-related CaPR1, CaNPR1, CaDEF1 and CabZIP63. In contrast, CaCML13 transient overexpression induced clear hypersensitivity-reaction (HR)-mimicked cell death and upregulation of the tested immunity-related genes. In addition, we also revealed that the G-box-containing CaCML13 promoter was bound by CabZIP63 and CaCML13 was positively regulated by CabZIP63 at transcriptional level. Our data collectively indicate that CaCML13 act as a positive regulator in pepper immunity against RSI forming a positive feedback loop with CabZIP63. Full article
(This article belongs to the Special Issue Plant Disease Resistance)
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20 pages, 6017 KiB  
Article
Targeted Delivery of Mesenchymal Stem Cell-Derived Nanovesicles for Spinal Cord Injury Treatment
by Ju-Ro Lee, Jae Won Kyung, Hemant Kumar, Sung Pil Kwon, Seuk Young Song, In-Bo Han and Byung-Soo Kim
Int. J. Mol. Sci. 2020, 21(11), 4185; https://doi.org/10.3390/ijms21114185 - 11 Jun 2020
Cited by 50 | Viewed by 6254
Abstract
Due to the safety issues and poor engraftment of mesenchymal stem cell (MSC) implantation, MSC-derived exosomes have been spotlighted as an alternative therapy for spinal cord injury (SCI). However, insufficient productivity of exosomes limits their therapeutic potential for clinical application. Moreover, low targeting [...] Read more.
Due to the safety issues and poor engraftment of mesenchymal stem cell (MSC) implantation, MSC-derived exosomes have been spotlighted as an alternative therapy for spinal cord injury (SCI). However, insufficient productivity of exosomes limits their therapeutic potential for clinical application. Moreover, low targeting ability of unmodified exosomes is a critical obstacle for their further applications as a therapeutic agent. In the present study, we fabricated macrophage membrane-fused exosome-mimetic nanovesicles (MF-NVs) from macrophage membrane-fused umbilical cord blood-derived MSCs (MF-MSCs) and confirmed their therapeutic potential in a clinically relevant mouse SCI model (controlled mechanical compression injury model). MF-NVs contained larger quantity of ischemic region-targeting molecules compared to normal MSC-derived nanovesicles (N-NVs). The targeting molecules in MF-NVs, which were derived from macrophage membranes, increased the accumulation of MF-NVs in the injured spinal cord after the in vivo systemic injection. Increased accumulation of MF-NVs attenuated apoptosis and inflammation, prevented axonal loss, enhanced blood vessel formation, decreased fibrosis, and consequently, improved spinal cord function. Synthetically, we developed targeting efficiency-potentiated exosome-mimetic nanovesicles and present their possibility of clinical application for SCI. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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22 pages, 1405 KiB  
Review
NLRP3 Inflammasome Activation in Adipose Tissues and Its Implications on Metabolic Diseases
by Kelvin Ka-Lok Wu, Samson Wing-Ming Cheung and Kenneth King-Yip Cheng
Int. J. Mol. Sci. 2020, 21(11), 4184; https://doi.org/10.3390/ijms21114184 - 11 Jun 2020
Cited by 52 | Viewed by 8053
Abstract
Adipose tissue is an active endocrine and immune organ that controls systemic immunometabolism via multiple pathways. Diverse immune cell populations reside in adipose tissue, and their composition and immune responses vary with nutritional and environmental conditions. Adipose tissue dysfunction, characterized by sterile low-grade [...] Read more.
Adipose tissue is an active endocrine and immune organ that controls systemic immunometabolism via multiple pathways. Diverse immune cell populations reside in adipose tissue, and their composition and immune responses vary with nutritional and environmental conditions. Adipose tissue dysfunction, characterized by sterile low-grade chronic inflammation and excessive immune cell infiltration, is a hallmark of obesity, as well as an important link to cardiometabolic diseases. Amongst the pro-inflammatory factors secreted by the dysfunctional adipose tissue, interleukin (IL)-1β, induced by the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, not only impairs peripheral insulin sensitivity, but it also interferes with the endocrine and immune functions of adipose tissue in a paracrine manner. Human studies indicated that NLRP3 activity in adipose tissues positively correlates with obesity and its metabolic complications, and treatment with the IL-1β antibody improves glycaemia control in type 2 diabetic patients. In mouse models, genetic or pharmacological inhibition of NLRP3 activation pathways or IL-1β prevents adipose tissue dysfunction, including inflammation, fibrosis, defective lipid handling and adipogenesis, which in turn alleviates obesity and its related metabolic disorders. In this review, we summarize both the negative and positive regulators of NLRP3 inflammasome activation, and its pathophysiological consequences on immunometabolism. We also discuss the potential therapeutic approaches to targeting adipose tissue inflammasome for the treatment of obesity and its related metabolic disorders. Full article
(This article belongs to the Special Issue Adipogenesis and Adipose Tissue Metabolism)
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31 pages, 7572 KiB  
Article
Genome Wild Analysis and Molecular Understanding of the Aquaporin Diversity in Olive Trees (Olea Europaea L.)
by Mohamed Faize, Boris Fumanal, Francisco Luque, Jorge A. Ramírez-Tejero, Zhi Zou, Xueying Qiao, Lydia Faize, Aurélie Gousset-Dupont, Patricia Roeckel-Drevet, Philippe Label and Jean-Stéphane Venisse
Int. J. Mol. Sci. 2020, 21(11), 4183; https://doi.org/10.3390/ijms21114183 - 11 Jun 2020
Cited by 18 | Viewed by 4377
Abstract
Cellular aquaporin water channels (AQPs) constitute a large family of transmembrane proteins present throughout all kingdoms of life, playing important roles in the uptake of water and many solutes across the membranes. In olive trees, AQP diversity, protein features and their biological functions [...] Read more.
Cellular aquaporin water channels (AQPs) constitute a large family of transmembrane proteins present throughout all kingdoms of life, playing important roles in the uptake of water and many solutes across the membranes. In olive trees, AQP diversity, protein features and their biological functions are still largely unknown. This study focuses on the structure and functional and evolution diversity of AQP subfamilies in two olive trees, the wild species Olea europaea var. sylvestris (OeuAQPs) and the domesticated species Olea europaea cv. Picual (OleurAQPs), and describes their involvement in different physiological processes of early plantlet development and in biotic and abiotic stress tolerance in the domesticated species. A scan of genomes from the wild and domesticated olive species revealed the presence of 52 and 79 genes encoding full-length AQP sequences, respectively. Cross-genera phylogenetic analysis with orthologous clustered OleaAQPs into five established subfamilies: PIP, TIP, NIP, SIP, and XIP. Subsequently, gene structures, protein motifs, substrate specificities and cellular localizations of the full length OleaAQPs were predicted. Functional prediction based on the NPA motif, ar/R selectivity filter, Froger’s and specificity-determining positions suggested differences in substrate specificities of Olea AQPs. Expression analysis of the OleurAQP genes indicates that some genes are tissue-specific, whereas few others show differential expressions at different developmental stages and in response to various biotic and abiotic stresses. The current study presents the first detailed genome-wide analysis of the AQP gene family in olive trees and it provides valuable information for further functional analysis to infer the role of AQP in the adaptation of olive trees in diverse environmental conditions in order to help the genetic improvement of domesticated olive trees. Full article
(This article belongs to the Collection Feature Papers in Molecular Plant Sciences)
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19 pages, 1475 KiB  
Review
Non-Coding RNAs as Potential Novel Biomarkers for Early Diagnosis of Hepatic Insulin Resistance
by Ariadna Pielok and Krzysztof Marycz
Int. J. Mol. Sci. 2020, 21(11), 4182; https://doi.org/10.3390/ijms21114182 - 11 Jun 2020
Cited by 23 | Viewed by 4435
Abstract
In the recent years, the prevalence of metabolic conditions such as type 2 Diabetes (T2D) and metabolic syndrome (MetS) raises. The impairment of liver metabolism resulting in hepatic insulin resistance is a common symptom and a critical step in the development of T2D [...] Read more.
In the recent years, the prevalence of metabolic conditions such as type 2 Diabetes (T2D) and metabolic syndrome (MetS) raises. The impairment of liver metabolism resulting in hepatic insulin resistance is a common symptom and a critical step in the development of T2D and MetS. The liver plays a crucial role in maintaining glucose homeostasis. Hepatic insulin resistance can often be identified before other symptoms arrive; therefore, establishing methods for its early diagnosis would allow for the implementation of proper treatment in patients before the disease develops. Non-coding RNAs such as miRNAs (micro-RNA) and lncRNAs (long-non-coding RNA) are being recognized as promising novel biomarkers and therapeutic targets—especially due to their regulatory function. The dysregulation of miRNA and lncRNA activity has been reported in the livers of insulin-resistant patients. Many of those transcripts are involved in the regulation of the hepatic insulin signaling cascade. Furthermore, for several miRNAs (miR-802, miR-499-5p, and miR-122) and lncRNAs (H19 imprinted maternally expressed transcript (H19), maternally expressed gene 3 (MEG3), and metastasis associated lung adenocarcinoma transcript 1 (MALAT1)), circulating levels were altered in patients with prediabetes, T2D, and MetS. In the course of this review, the role of the aforementioned ncRNAs in hepatic insulin signaling cascade, as well as their potential application in diagnostics, is discussed. Overall, circulating ncRNAs are precise indicators of hepatic insulin resistance in the development of metabolic diseases and could be applied as early diagnostic and/or therapeutic tools in conditions associated with insulin resistance. Full article
(This article belongs to the Collection Regulation by Non-coding RNAs)
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15 pages, 4016 KiB  
Review
Evolutionary Aspects of TRPMLs and TPCs
by Dawid Jaślan, Julia Böck, Einar Krogsaeter and Christian Grimm
Int. J. Mol. Sci. 2020, 21(11), 4181; https://doi.org/10.3390/ijms21114181 - 11 Jun 2020
Cited by 25 | Viewed by 4176
Abstract
Transient receptor potential (TRP) or transient receptor potential channels are a highly diverse family of mostly non-selective cation channels. In the mammalian genome, 28 members can be identified, most of them being expressed predominantly in the plasma membrane with the exception of the [...] Read more.
Transient receptor potential (TRP) or transient receptor potential channels are a highly diverse family of mostly non-selective cation channels. In the mammalian genome, 28 members can be identified, most of them being expressed predominantly in the plasma membrane with the exception of the mucolipins or TRPMLs which are expressed in the endo-lysosomal system. In mammalian organisms, TRPMLs have been associated with a number of critical endo-lysosomal functions such as autophagy, endo-lysosomal fusion/fission and trafficking, lysosomal exocytosis, pH regulation, or lysosomal motility and positioning. The related non-selective two-pore cation channels (TPCs), likewise expressed in endosomes and lysosomes, have also been found to be associated with endo-lysosomal trafficking, autophagy, pH regulation, or lysosomal exocytosis, raising the question why these two channel families have evolved independently. We followed TRP/TRPML channels and TPCs through evolution and describe here in which species TRP/TRPMLs and/or TPCs are found, which functions they have in different species, and how this compares to the functions of mammalian orthologs. Full article
(This article belongs to the Special Issue TRP Channels)
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16 pages, 3440 KiB  
Article
Characterization of CD4-Positive Lymphocytes in the Antiviral Response of Olive Flounder (Paralichthys oliveceus) to Nervous Necrosis Virus
by Jae Wook Jung, Jin Hong Chun, Jung Seok Lee, Si Won Kim, Ae Rin Lee, Jaesung Kim, Jassy Mary S. Lazarte, Young Rim Kim, Hyoung Jun Kim, Kim D. Thompson and Tae Sung Jung
Int. J. Mol. Sci. 2020, 21(11), 4180; https://doi.org/10.3390/ijms21114180 - 11 Jun 2020
Cited by 15 | Viewed by 3139
Abstract
The presence of CD4 T lymphocytes has been described for several teleost species, while many of the main T cell subsets have not been characterized at a cellular level, because of a lack of suitable tools for their identification, e.g., monoclonal antibodies (mAbs) [...] Read more.
The presence of CD4 T lymphocytes has been described for several teleost species, while many of the main T cell subsets have not been characterized at a cellular level, because of a lack of suitable tools for their identification, e.g., monoclonal antibodies (mAbs) against cell markers. We previously described the tissue distribution and immune response related to CD3ε and CD4-1 T cells in olive flounder (Paralichthys oliveceus) in response to a viral infection. In the present study, we successfully produce an mAb against CD4-2 T lymphocytes from olive flounder and confirmed its specificity using immuno-blotting, immunofluorescence staining, flow cytometry analysis and reverse transcription polymerase chain reaction (RT-PCR). Using these mAbs, we were able to demonstrate that the CD3ε T cell populations contain both types of CD4+ cells, with the majority of the CD4 T cell subpopulations being CD4-1+/CD4-2+ cells, determined using two-color flow cytometry analysis. We also examined the functional activity of the CD4-1 and CD4-2 cells in vivo in response to a viral infection, with the numbers of both types of CD4 T cells increasing significantly during the virus infection. Collectively, these findings suggest that the CD4 T lymphocytes in olive flounder are equivalent to the helper T cells in mammals in terms of their properties and function, and it is the CD4-2 T lymphocytes rather than the CD4-1 T cells that play an important role in the Th1 immune response against viral infections in olive flounder. Full article
(This article belongs to the Special Issue Fish Immunology)
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19 pages, 2972 KiB  
Article
Apelin Controls Angiogenesis-Dependent Glioblastoma Growth
by Anne Frisch, Stefanie Kälin, Raymond Monk, Josefine Radke, Frank L. Heppner and Roland E. Kälin
Int. J. Mol. Sci. 2020, 21(11), 4179; https://doi.org/10.3390/ijms21114179 - 11 Jun 2020
Cited by 26 | Viewed by 4201
Abstract
Glioblastoma (GBM) present with an abundant and aberrant tumor neo-vasculature. While rapid growth of solid tumors depends on the initiation of tumor angiogenesis, GBM also progress by infiltrative growth and vascular co-option. The angiogenic factor apelin (APLN) and its receptor ( [...] Read more.
Glioblastoma (GBM) present with an abundant and aberrant tumor neo-vasculature. While rapid growth of solid tumors depends on the initiation of tumor angiogenesis, GBM also progress by infiltrative growth and vascular co-option. The angiogenic factor apelin (APLN) and its receptor (APLNR) are upregulated in GBM patient samples as compared to normal brain tissue. Here, we studied the role of apelin/APLNR signaling in GBM angiogenesis and growth. By functional analysis of apelin in orthotopic GBM mouse models, we found that apelin/APLNR signaling is required for in vivo tumor angiogenesis. Knockdown of tumor cell-derived APLN massively reduced the tumor vasculature. Additional loss of the apelin signal in endothelial tip cells using the APLN-knockout (KO) mouse led to a further reduction of GBM angiogenesis. Direct infusion of the bioactive peptide apelin-13 rescued the vascular loss-of-function phenotype specifically. In addition, APLN depletion massively reduced angiogenesis-dependent tumor growth. Consequently, survival of GBM-bearing mice was significantly increased when APLN expression was missing in the brain tumor microenvironment. Thus, we suggest that targeting vascular apelin may serve as an alternative strategy for anti-angiogenesis in GBM. Full article
(This article belongs to the Special Issue Advances of Molecular Biology and Translational Aspects in CNS Tumors)
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19 pages, 4047 KiB  
Article
Innate Immune Response against Staphylococcus aureus Preincubated with Subinhibitory Concentration of trans-Anethole
by Paweł Kwiatkowski, Bartosz Wojciuk, Iwona Wojciechowska-Koszko, Łukasz Łopusiewicz, Bartłomiej Grygorcewicz, Agata Pruss, Monika Sienkiewicz, Karol Fijałkowski, Edward Kowalczyk and Barbara Dołęgowska
Int. J. Mol. Sci. 2020, 21(11), 4178; https://doi.org/10.3390/ijms21114178 - 11 Jun 2020
Cited by 18 | Viewed by 5009
Abstract
The study aimed to analyze morphological and functional changes of Staphylococcus aureus cells due to trans-anethole (a terpenoid and the major constituent of fennel, anise, or star anise essential oils) exposition, and their consequences for human neutrophils phagocytic activity as well as [...] Read more.
The study aimed to analyze morphological and functional changes of Staphylococcus aureus cells due to trans-anethole (a terpenoid and the major constituent of fennel, anise, or star anise essential oils) exposition, and their consequences for human neutrophils phagocytic activity as well as IL-8 production (recognized as the major chemoattractant). The investigation included the evaluation of changes occurring in S. aureus cultures, i.e., staphyloxanthin production, antioxidant activities, cell size distribution, and cells composition as a result of incubation with trans-anethole. It was found that the presence of trans-anethole in the culture medium reduced the level of staphyloxanthin production, as well as decreased antioxidant activities. Furthermore, trans-anethole-treated cells were characterized by larger size and a tendency to diffuse in comparison to the non-treated cells. Several cell components, such as phospholipids and peptidoglycan, were found remarkably elevated in the cultures treated with trans-anethole. As a result of the aforementioned cellular changes, the bacteria were phagocytized by neutrophils more efficiently (ingestion and parameters associated with killing activity were at a higher level as compared to the control system). Additionally, IL-8 production was at a higher level for trans-anethole modified bacteria. Our results suggest that trans-anethole represents a promising measure in combating severe staphylococcal infections, which has an important translational potential for clinical applications. Full article
(This article belongs to the Special Issue Terpenes and Essential Oils: Health Risks and Benefits)
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25 pages, 3058 KiB  
Review
Calcium Entry through TRPV1: A Potential Target for the Regulation of Proliferation and Apoptosis in Cancerous and Healthy Cells
by Kevin Zhai, Alena Liskova, Peter Kubatka and Dietrich Büsselberg
Int. J. Mol. Sci. 2020, 21(11), 4177; https://doi.org/10.3390/ijms21114177 - 11 Jun 2020
Cited by 78 | Viewed by 7128
Abstract
Intracellular calcium (Ca2+) concentration ([Ca2+]i) is a key determinant of cell fate and is implicated in carcinogenesis. Membrane ion channels are structures through which ions enter or exit the cell, depending on the driving forces. The opening [...] Read more.
Intracellular calcium (Ca2+) concentration ([Ca2+]i) is a key determinant of cell fate and is implicated in carcinogenesis. Membrane ion channels are structures through which ions enter or exit the cell, depending on the driving forces. The opening of transient receptor potential vanilloid 1 (TRPV1) ligand-gated ion channels facilitates transmembrane Ca2+ and Na+ entry, which modifies the delicate balance between apoptotic and proliferative signaling pathways. Proliferation is upregulated through two mechanisms: (1) ATP binding to the G-protein-coupled receptor P2Y2, commencing a kinase signaling cascade that activates the serine-threonine kinase Akt, and (2) the transactivation of the epidermal growth factor receptor (EGFR), leading to a series of protein signals that activate the extracellular signal-regulated kinases (ERK) 1/2. The TRPV1-apoptosis pathway involves Ca2+ influx and efflux between the cytosol, mitochondria, and endoplasmic reticulum (ER), the release of apoptosis-inducing factor (AIF) and cytochrome c from the mitochondria, caspase activation, and DNA fragmentation and condensation. While proliferative mechanisms are typically upregulated in cancerous tissues, shifting the balance to favor apoptosis could support anti-cancer therapies. TRPV1, through [Ca2+]i signaling, influences cancer cell fate; therefore, the modulation of the TRPV1-enforced proliferation–apoptosis balance is a promising avenue in developing anti-cancer therapies and overcoming cancer drug resistance. As such, this review characterizes and evaluates the role of TRPV1 in cell death and survival, in the interest of identifying mechanistic targets for drug discovery. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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12 pages, 4404 KiB  
Article
Bioshell Calcium Oxide (BiSCaO) Ointment for the Disinfection and Healing of Pseudomonas aeruginosa-Infected Wounds in Hairless Rats
by Tomohiro Takayama, Masayuki Ishihara, Shingo Nakamura, Yoko Sato, Sumiyo Hiruma, Koichi Fukuda, Kaoru Murakami and Hidetaka Yokoe
Int. J. Mol. Sci. 2020, 21(11), 4176; https://doi.org/10.3390/ijms21114176 - 11 Jun 2020
Cited by 8 | Viewed by 3703
Abstract
Bioshell calcium oxide (BiSCaO) possesses deodorizing properties and broad microbicidal activity. This study aimed to investigate the application of BiSCaO ointment for the prevention and treatment of infection in chronic wounds in healing-impaired patients, without delaying wound healing. The bactericidal activities of 0.04, [...] Read more.
Bioshell calcium oxide (BiSCaO) possesses deodorizing properties and broad microbicidal activity. This study aimed to investigate the application of BiSCaO ointment for the prevention and treatment of infection in chronic wounds in healing-impaired patients, without delaying wound healing. The bactericidal activities of 0.04, 0.2, 1, and 5 wt% BiSCaO ointment, 3 wt% povidone iodine ointment, and control (ointment only) were compared to evaluate the in vivo disinfection and healing of Pseudomonas aeruginosa-infected wounds in hairless rats. Treatment of the infected wounds with 0.2 wt% BiSCaO ointment daily for 3 days significantly enhanced wound healing and reduced the in vivo bacterial counts compared with povidone iodine ointment and control (no wound cleaning). Although 5 wt% BiSCaO ointment provided the lowest bacterial counts during 3 days’ treatment, it delayed wound healing. Histological examinations showed significantly advanced granulation tissue and capillary formation in wounds treated with 0.2 wt% BiSCaO ointment for 3 days compared to wounds treated with the other ointments. This study suggested that using 0.2 wt% BiSCaO ointment as a disinfectant for infected wounds and limiting disinfection to 3 days may be sufficient to avoid the negative effects of BiSCaO on wound repair. Full article
(This article belongs to the Special Issue Advanced Biomaterials for Wound Healing 2021)
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14 pages, 2959 KiB  
Article
The Effect of Substituted Benzene-Sulfonamides and Clinically Licensed Drugs on the Catalytic Activity of CynT2, a Carbonic Anhydrase Crucial for Escherichia coli Life Cycle
by Sonia Del Prete, Viviana De Luca, Silvia Bua, Alessio Nocentini, Vincenzo Carginale, Claudiu T. Supuran and Clemente Capasso
Int. J. Mol. Sci. 2020, 21(11), 4175; https://doi.org/10.3390/ijms21114175 - 11 Jun 2020
Cited by 21 | Viewed by 3395
Abstract
Proteins are relevant antimicrobial drug targets, and among them, enzymes represent a significant group, since most of them catalyze reactions essential for supporting the central metabolism, or are necessary for the pathogen vitality. Genomic exploration of pathogenic and non-pathogenic microorganisms has revealed genes [...] Read more.
Proteins are relevant antimicrobial drug targets, and among them, enzymes represent a significant group, since most of them catalyze reactions essential for supporting the central metabolism, or are necessary for the pathogen vitality. Genomic exploration of pathogenic and non-pathogenic microorganisms has revealed genes encoding for a superfamily of metalloenzymes, known as carbonic anhydrases (CAs, EC 4.2.1.1). CAs catalyze the physiologically crucial reversible reaction of the carbon dioxide hydration to bicarbonate and protons. Herein, we investigated the sulfonamide inhibition profile of the recombinant β-CA (CynT2) identified in the genome of the Gram-negative bacterium Escherichia coli. This biocatalyst is indispensable for the growth of the microbe at atmospheric pCO2. Surprisingly, this enzyme has not been investigated for its inhibition with any class of CA inhibitors. Here, we show that CynT2 was strongly inhibited by some substituted benzene-sulfonamides and the clinically used inhibitor sulpiride (KIs in the range of 82–97 nM). This study may be relevant for identifying novel CA inhibitors, as well as for another essential part of the drug discovery pipeline, such as the structure–activity relationship for this class of enzyme inhibitors. Full article
(This article belongs to the Special Issue Protease and Carbonic Anhydrase Inhibitors, II)
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17 pages, 2217 KiB  
Article
Serum Biomarkers of Cardiovascular Remodelling Reflect Extra-Valvular Cardiac Damage in Patients with Severe Aortic Stenosis
by Laura Bäz, Gudrun Dannberg, Katja Grün, Julian Westphal, Sven Möbius-Winkler, Christian Jung, Alexander Pfeil, P. Christian Schulze and Marcus Franz
Int. J. Mol. Sci. 2020, 21(11), 4174; https://doi.org/10.3390/ijms21114174 - 11 Jun 2020
Cited by 14 | Viewed by 3077
Abstract
In patients with aortic stenosis (AS), a novel staging classification of extra-valvular left and right heart damage with prognostic relevance was introduced in 2017. The aim of the study was to evaluate the biomarkers of cardiovascular tissue remodelling in relation to this novel [...] Read more.
In patients with aortic stenosis (AS), a novel staging classification of extra-valvular left and right heart damage with prognostic relevance was introduced in 2017. The aim of the study was to evaluate the biomarkers of cardiovascular tissue remodelling in relation to this novel staging classification. Patients were categorized according to the novel staging classification into stages 0 to 4. The levels of matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinases 1 (TIMP-1), B and C domain containing tenascin-C (B+ Tn-C, C+ Tn-C), the ED-A and ED-B domain containing fibronectin (ED-A+ Fn, ED-B+ Fn), endothelin 1 (ET-1) and neutrophil gelatinase-associated lipocalin (NGAL) were determined in serum by ELISA. There were significantly decreased serum levels of MMP-9 and increased levels of B+ Tn-C and C+ Tn-C when comparing stages 0 and 1 with stage 2, with no further dynamics in stages 3 and 4. In contrast, for TIMP-1, C+ Tn-C, ED-A+ Fn, ET-1 and NGAL, significantly increased serum levels could be detected in stages 3 and 4 compared to both stages 0 and 1 and stage 2. ED-A+ Fn and ET-1 could be identified as independent predictors of the presence of stage 3 and/or 4. To the best of our knowledge, this is the first study identifying novel serum biomarkers differentially reflecting the patterns of left and right heart extra-valvular damage in patients suffering from AS. Our findings might indicate a more precise initial diagnosis and risk stratification. Full article
(This article belongs to the Special Issue Extracellular Matrix in Heart Disease)
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16 pages, 4119 KiB  
Article
Graphene Oxide Scaffold Stimulates Differentiation and Proangiogenic Activities of Myogenic Progenitor Cells
by Mateusz Wierzbicki, Anna Hotowy, Marta Kutwin, Sławomir Jaworski, Jaśmina Bałaban, Malwina Sosnowska, Barbara Wójcik, Aleksandra Wędzińska, André Chwalibog and Ewa Sawosz
Int. J. Mol. Sci. 2020, 21(11), 4173; https://doi.org/10.3390/ijms21114173 - 11 Jun 2020
Cited by 19 | Viewed by 3689
Abstract
The physiological process of muscle regeneration is quite limited due to low satellite cell quantity and also the inability to regenerate and reconstruct niche tissue. The purpose of the study was to examine whether a graphene oxide scaffold is able to stimulate myogenic [...] Read more.
The physiological process of muscle regeneration is quite limited due to low satellite cell quantity and also the inability to regenerate and reconstruct niche tissue. The purpose of the study was to examine whether a graphene oxide scaffold is able to stimulate myogenic progenitor cell proliferation and the endocrine functions of differentiating cells, and therefore, their active participation in the construction of muscle tissue. Studies were carried out using mesenchymal cells taken from 6-day-old chicken embryos and human umbilical vein endothelial cells (HUVEC) were used to assess angiogenesis. The graphene scaffold was readily colonized by myogenic progenitor cells and the cells dissected from heart, brain, eye, and blood vessels did not avoid the scaffold. The scaffold strongly induced myogenic progenitor cell signaling pathways and simultaneously activated proangiogenic signaling pathways via exocrine vascular endothelial growth factor (VEGF) secretion. The present study revealed that the graphene oxide (GO) scaffold initiates the processes of muscle cell differentiation due to mechanical interaction with myogenic progenitor cell. Full article
(This article belongs to the Special Issue Graphene-Based Materials: Biological and Biomedical Applications)
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22 pages, 1482 KiB  
Review
Epigenetic Modulation of Chromatin States and Gene Expression by G-Quadruplex Structures
by Chiara Reina and Vincenzo Cavalieri
Int. J. Mol. Sci. 2020, 21(11), 4172; https://doi.org/10.3390/ijms21114172 - 11 Jun 2020
Cited by 28 | Viewed by 7319
Abstract
G-quadruplexes are four-stranded helical nucleic acid structures formed by guanine-rich sequences. A considerable number of studies have revealed that these noncanonical structural motifs are widespread throughout the genome and transcriptome of numerous organisms, including humans. In particular, G-quadruplexes occupy strategic locations in genomic [...] Read more.
G-quadruplexes are four-stranded helical nucleic acid structures formed by guanine-rich sequences. A considerable number of studies have revealed that these noncanonical structural motifs are widespread throughout the genome and transcriptome of numerous organisms, including humans. In particular, G-quadruplexes occupy strategic locations in genomic DNA and both coding and noncoding RNA molecules, being involved in many essential cellular and organismal functions. In this review, we first outline the fundamental structural features of G-quadruplexes and then focus on the concept that these DNA and RNA structures convey a distinctive layer of epigenetic information that is critical for the complex regulation, either positive or negative, of biological activities in different contexts. In this framework, we summarize and discuss the proposed mechanisms underlying the functions of G-quadruplexes and their interacting factors. Furthermore, we give special emphasis to the interplay between G-quadruplex formation/disruption and other epigenetic marks, including biochemical modifications of DNA bases and histones, nucleosome positioning, and three-dimensional organization of chromatin. Finally, epigenetic roles of RNA G-quadruplexes in post-transcriptional regulation of gene expression are also discussed. Undoubtedly, the issues addressed in this review take on particular importance in the field of comparative epigenetics, as well as in translational research. Full article
(This article belongs to the Special Issue The Polymorphic World of G-Quadruplexes: From Structural Insights to Functional Activity)
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37 pages, 1540 KiB  
Review
The Genetic and Endoplasmic Reticulum-Mediated Molecular Mechanisms of Primary Open-Angle Glaucoma
by Wioletta Rozpędek-Kamińska, Radosław Wojtczak, Jacek P. Szaflik, Jerzy Szaflik and Ireneusz Majsterek
Int. J. Mol. Sci. 2020, 21(11), 4171; https://doi.org/10.3390/ijms21114171 - 11 Jun 2020
Cited by 19 | Viewed by 7084
Abstract
Glaucoma is a heterogenous, chronic, progressive group of eye diseases, which results in irreversible loss of vision. There are several types of glaucoma, whereas the primary open-angle glaucoma (POAG) constitutes the most common type of glaucoma, accounting for three-quarters of all glaucoma cases. [...] Read more.
Glaucoma is a heterogenous, chronic, progressive group of eye diseases, which results in irreversible loss of vision. There are several types of glaucoma, whereas the primary open-angle glaucoma (POAG) constitutes the most common type of glaucoma, accounting for three-quarters of all glaucoma cases. The pathological mechanisms leading to POAG pathogenesis are multifactorial and still poorly understood, but it is commonly known that significantly elevated intraocular pressure (IOP) plays a crucial role in POAG pathogenesis. Besides, genetic predisposition and aggregation of abrogated proteins within the endoplasmic reticulum (ER) lumen and subsequent activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dependent unfolded protein response (UPR) signaling pathway may also constitute important factors for POAG pathogenesis at the molecular level. Glaucoma is commonly known as a ‘silent thief of sight’, as it remains asymptomatic until later stages, and thus its diagnosis is frequently delayed. Thereby, detailed knowledge about the glaucoma pathophysiology is necessary to develop both biochemical and genetic tests to improve its early diagnosis as well as develop a novel, ground-breaking treatment strategy, as currently used medical therapies against glaucoma are limited and may evoke numerous adverse side-effects in patients. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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15 pages, 1600 KiB  
Review
Regulatory Mechanisms of Somatostatin Expression
by Emmanuel Ampofo, Lisa Nalbach, Michael D. Menger and Matthias W. Laschke
Int. J. Mol. Sci. 2020, 21(11), 4170; https://doi.org/10.3390/ijms21114170 - 11 Jun 2020
Cited by 47 | Viewed by 8493
Abstract
Somatostatin is a peptide hormone, which most commonly is produced by endocrine cells and the central nervous system. In mammals, somatostatin originates from pre-prosomatostatin and is processed to a shorter form, i.e., somatostatin-14, and a longer form, i.e., somatostatin-28. The two peptides repress [...] Read more.
Somatostatin is a peptide hormone, which most commonly is produced by endocrine cells and the central nervous system. In mammals, somatostatin originates from pre-prosomatostatin and is processed to a shorter form, i.e., somatostatin-14, and a longer form, i.e., somatostatin-28. The two peptides repress growth hormone secretion and are involved in the regulation of glucagon and insulin synthesis in the pancreas. In recent years, the processing and secretion of somatostatin have been studied intensively. However, little attention has been paid to the regulatory mechanisms that control its expression. This review provides an up-to-date overview of these mechanisms. In particular, it focuses on the role of enhancers and silencers within the promoter region as well as on the binding of modulatory transcription factors to these elements. Moreover, it addresses extracellular factors, which trigger key signaling pathways, leading to an enhanced somatostatin expression in health and disease. Full article
(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation)
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19 pages, 5224 KiB  
Article
Comparative Analysis of Age-Related Changes in Lacrimal Glands and Meibomian Glands of a C57BL/6 Male Mouse Model
by Chang Ho Yoon, Jin Suk Ryu, Ho Sik Hwang and Mee Kum Kim
Int. J. Mol. Sci. 2020, 21(11), 4169; https://doi.org/10.3390/ijms21114169 - 11 Jun 2020
Cited by 32 | Viewed by 4190
Abstract
It is not known how biological changes in the lacrimal (LGs) and meibomian (MGs) glands contribute to dry eye disease (DED) in a time-dependent manner. In this study, we investigated time-sequenced changes in the inflammation, oxidative stress, and senescence of stem cells in [...] Read more.
It is not known how biological changes in the lacrimal (LGs) and meibomian (MGs) glands contribute to dry eye disease (DED) in a time-dependent manner. In this study, we investigated time-sequenced changes in the inflammation, oxidative stress, and senescence of stem cells in both glands of an aging-related DED mouse model. Eight-week (8W)-, one-year (1Y)-, and two-year (2Y)-old C57BL/6 male mice were used. MG areas of the upper and lower eyelids were analyzed by transillumination meibography imaging. The number of CD45+, 8-OHdG+, Ki-67+, and BrdU+ cells was compared in both glands. Increased corneal staining and decreased tear secretion were observed in aged mice. The MG dropout area increased with aging, and the age-adjusted MG area in lower lids was negatively correlated with the National Eye Institute (NEI) score. Increased CD4+ interferon (IFN)-γ+ cells in LGs were found in both aged mice. An increase in 8-OHdG+ cells in both glands was evident in 2Y-old mice. Reduced Ki-67+ cells, but no change in CD45+ cells, was observed in the MGs of 1Y-old mice. Increased BrdU+ cells were observed in the LGs of aged mice. This suggests that age-dependent DED in C57BL/6 mice is related to inflammation of the LGs, the development of MG atrophy, and oxidative stress in both glands. Full article
(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders 2.0)
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12 pages, 475 KiB  
Review
Prion Protein in Stem Cells: A Lipid Raft Component Involved in the Cellular Differentiation Process
by Stefano Martellucci, Costantino Santacroce, Francesca Santilli, Valeria Manganelli, Maurizio Sorice and Vincenzo Mattei
Int. J. Mol. Sci. 2020, 21(11), 4168; https://doi.org/10.3390/ijms21114168 - 11 Jun 2020
Cited by 16 | Viewed by 3882
Abstract
The prion protein (PrP) is an enigmatic molecule with a pleiotropic effect on different cell types; it is localized stably in lipid raft microdomains and it is able to recruit downstream signal transduction pathways by its interaction with various biochemical partners. Since its [...] Read more.
The prion protein (PrP) is an enigmatic molecule with a pleiotropic effect on different cell types; it is localized stably in lipid raft microdomains and it is able to recruit downstream signal transduction pathways by its interaction with various biochemical partners. Since its discovery, this lipid raft component has been involved in several functions, although most of the publications focused on the pathological role of the protein. Recent studies report a key role of cellular prion protein (PrPC) in physiological processes, including cellular differentiation. Indeed, the PrPC, whose expression is modulated according to the cell differentiation degree, appears to be part of the multimolecular signaling pathways of the neuronal differentiation process. In this review, we aim to summarize the main findings that report the link between PrPC and stem cells. Full article
(This article belongs to the Special Issue Prions and Prion Diseases)
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18 pages, 4436 KiB  
Article
Comparison of Metabolome and Transcriptome of Flavonoid Biosynthesis Pathway in a Purple-Leaf Tea Germplasm Jinmingzao and a Green-Leaf Tea Germplasm Huangdan reveals Their Relationship with Genetic Mechanisms of Color Formation
by Xuejin Chen, Pengjie Wang, Yucheng Zheng, Mengya Gu, Xinying Lin, Shuyan Wang, Shan Jin and Naixing Ye
Int. J. Mol. Sci. 2020, 21(11), 4167; https://doi.org/10.3390/ijms21114167 - 11 Jun 2020
Cited by 47 | Viewed by 5372
Abstract
Purple-leaf tea is a phenotype with unique color because of its high anthocyanin content. The special flavor of purple-leaf tea is highly different from that of green-leaf tea, and its main ingredient is also of economic value. To probe the genetic mechanism of [...] Read more.
Purple-leaf tea is a phenotype with unique color because of its high anthocyanin content. The special flavor of purple-leaf tea is highly different from that of green-leaf tea, and its main ingredient is also of economic value. To probe the genetic mechanism of the phenotypic characteristics of tea leaf color, we conducted widely targeted metabolic and transcriptomic profiling. The metabolites in the flavonoid biosynthetic pathway of purple- and green-leaf tea were compared, and results showed that phenolic compounds, including phenolic acids, flavonoids, and tannins, accumulated in purple-leaf tea. The high expression of genes related to flavonoid biosynthesis (e.g., PAL and LAR) exhibits the specific expression of biosynthesis and the accumulation of these metabolites. Our result also shows that two CsUFGTs were positively related to the accumulation of anthocyanin. Moreover, genes encoding transcription factors that regulate flavonoids were identified by coexpression analysis. These results may help to identify the metabolic factors that influence leaf color differentiation and provide reference for future research on leaf color biology and the genetic improvement of tea. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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15 pages, 12216 KiB  
Article
Ultrastructural Location and Interactions of the Immunoglobulin Receptor Binding Sequence within Fibrillar Type I Collagen
by Jie Zhu, Rama S. Madhurapantula, Aruna Kalyanasundaram, Tanya Sabharwal, Olga Antipova, Sandra W. Bishnoi and Joseph P. R. O. Orgel
Int. J. Mol. Sci. 2020, 21(11), 4166; https://doi.org/10.3390/ijms21114166 - 11 Jun 2020
Cited by 13 | Viewed by 5098
Abstract
Collagen type I is a major constituent of animal bodies. It is found in large quantities in tendon, bone, skin, cartilage, blood vessels, bronchi, and the lung interstitium. It is also produced and accumulates in large amounts in response to certain inflammations such [...] Read more.
Collagen type I is a major constituent of animal bodies. It is found in large quantities in tendon, bone, skin, cartilage, blood vessels, bronchi, and the lung interstitium. It is also produced and accumulates in large amounts in response to certain inflammations such as lung fibrosis. Our understanding of the molecular organization of fibrillar collagen and cellular interaction motifs, such as those involved with immune-associated molecules, continues to be refined. In this study, antibodies raised against type I collagen were used to label intact D-periodic type I collagen fibrils and observed with atomic force microscopy (AFM), and X-ray diffraction (XRD) and immunolabeling positions were observed with both methods. The antibodies bind close to the C-terminal telopeptide which verifies the location and accessibility of both the major histocompatibility complex (MHC) class I (MHCI) binding domain and C-terminal telopeptide on the outside of the collagen fibril. The close proximity of the C-telopeptide and the MHC1 domain of type I collagen to fibronectin, discoidin domain receptor (DDR), and collagenase cleavage domains likely facilitate the interaction of ligands and receptors related to cellular immunity and the collagen-based Extracellular Matrix. Full article
(This article belongs to the Special Issue Molecular Tissue Responses to Mechanical Loading)
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14 pages, 2007 KiB  
Article
Septoria Leaf Blotch and Reduced Nitrogen Availability Alter WRKY Transcription Factor Expression in a Codependent Manner
by Alistair A. Poll, Jack Lee, Roy A. Sanderson, Ed Byrne, John A. Gatehouse, Ari Sadanandom, Angharad M. R. Gatehouse and Martin G. Edwards
Int. J. Mol. Sci. 2020, 21(11), 4165; https://doi.org/10.3390/ijms21114165 - 11 Jun 2020
Cited by 6 | Viewed by 2946
Abstract
A major cause of yield loss in wheat worldwide is the fungal pathogen Zymoseptoria tritici, a hemibiotrophic fungus which causes Septoria leaf blotch, the most destructive wheat disease in Europe. Resistance in commercial wheat varieties is poor, however, a link between reduced [...] Read more.
A major cause of yield loss in wheat worldwide is the fungal pathogen Zymoseptoria tritici, a hemibiotrophic fungus which causes Septoria leaf blotch, the most destructive wheat disease in Europe. Resistance in commercial wheat varieties is poor, however, a link between reduced nitrogen availability and increased Septoria tolerance has been observed. We have shown that Septoria load is not affected by nitrogen, whilst the fungus is in its first, symptomless stage of growth. This suggests that a link between nitrogen and Septoria is only present during the necrotrophic phase of Septoria infection. Quantitative real-time PCR data demonstrated that WRKYs, a superfamily of plant-specific transcription factors, are differentially expressed in response to both reduced nitrogen and Septoria. WRKY39 was downregulated over 30-fold in response to necrotrophic stage Septoria, whilst changes in the expression of WRKY68a during the late biotrophic phase were dependent on the concentration of nitrogen under which wheat is grown. WRKY68a may therefore mediate a link between nitrogen and Septoria. The potential remains to identify key regulators in the link between nitrogen and Septoria, and as such, elucidate molecular markers for wheat breeding, or targets for molecular-based breeding approaches. Full article
(This article belongs to the Special Issue Wheat Breeding through Genetic and Physical Mapping)
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17 pages, 1385 KiB  
Review
Back to the Future: Genetically Encoded Fluorescent Proteins as Inert Tracers of the Intracellular Environment
by Francesco Cardarelli
Int. J. Mol. Sci. 2020, 21(11), 4164; https://doi.org/10.3390/ijms21114164 - 11 Jun 2020
Cited by 17 | Viewed by 4178
Abstract
Over the past decades, the discovery and development of genetically encoded fluorescent proteins (FPs) has brought a revolution into our ability to study biologic phenomena directly within living matter. First, FPs enabled fluorescence-labeling of a variety of molecules of interest to study their [...] Read more.
Over the past decades, the discovery and development of genetically encoded fluorescent proteins (FPs) has brought a revolution into our ability to study biologic phenomena directly within living matter. First, FPs enabled fluorescence-labeling of a variety of molecules of interest to study their localization, interactions and dynamic behavior at various scales—from cells to whole organisms/animals. Then, rationally engineered FP-based sensors facilitated the measurement of physicochemical parameters of living matter—especially at the intracellular level, such as ion concentration, temperature, viscosity, pressure, etc. In addition, FPs were exploited as inert tracers of the intracellular environment in which they are expressed. This oft-neglected role is made possible by two distinctive features of FPs: (i) the quite null, unspecific interactions of their characteristic β-barrel structure with the molecular components of the cellular environment; and (ii) their compatibility with the use of time-resolved fluorescence-based optical microscopy techniques. This review seeks to highlight the potential of such unique combinations of properties and report on the most significative and original applications (and related advancements of knowledge) produced to date. It is envisioned that the use of FPs as inert tracers of living matter structural organization holds a potential for several lines of further development in the next future, discussed in the last section of the review, which in turn can lead to new breakthroughs in bioimaging. Full article
(This article belongs to the Special Issue Bioluminescent and Fluorescent Proteins: Molecular Mechanisms and Modern Applications)
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17 pages, 5508 KiB  
Article
Ectopic Expression of OsPYL/RCAR7, an ABA Receptor Having Low Signaling Activity, Improves Drought Tolerance without Growth Defects in Rice
by Nikita Bhatnagar, Rigyeong Kim, Seungsu Han, Jaeeun Song, Gang Seob Lee, Sangho Lee, Myung Ki Min and Beom-Gi Kim
Int. J. Mol. Sci. 2020, 21(11), 4163; https://doi.org/10.3390/ijms21114163 - 11 Jun 2020
Cited by 17 | Viewed by 3469
Abstract
Overexpression of abscisic acid (ABA) receptors has been reported to enhance drought tolerance, but also to cause stunted growth and decreased crop yield. Here, we constructed transgenic rice for all monomeric ABA receptors and observed that only transgenic rice over-expressing OsPYL/RCAR7 showed similar [...] Read more.
Overexpression of abscisic acid (ABA) receptors has been reported to enhance drought tolerance, but also to cause stunted growth and decreased crop yield. Here, we constructed transgenic rice for all monomeric ABA receptors and observed that only transgenic rice over-expressing OsPYL/RCAR7 showed similar phenotype with wild type, without total yield loss when grown under normal growth condition in a paddy field. Even though transgenic rice over-expressing OsPYL/RCAR7 showed neither an ABA-sensitivity nor an osmotic stress tolerance in plate assay, it showed drought tolerance. We investigated the ABA-dependent interaction with OsPP2CAs and ABA signaling induction by OsPYL/RCAR7. In yeast two hybrid assay, OsPYL/RCAR7 required critically higher ABA concentrations to interact with OsPP2CAs than other ABA receptors, and co-immunoprecipitation assay showed strong interaction under ABA treatment. When ABA-responsive signaling activity was monitored using a transient expression system in rice protoplasts, OsPYL/RCAR7 had the lowest ABA-responsive signaling activity as compared with other ABA receptors. OsPYL/RCAR7 also showed weak suppression of phosphatase activity as compared with other ABA receptors in vitro. Transcriptome analysis of transgenic rice over-expressing OsPYL/RCAR7 suggested that only a few genes were induced similar to control under without exogenous ABA, but a large number of genes was induced under ABA treatment compared with control. We conclude that OsPYL/RCAR7 is a novel functional ABA receptor that has low ABA signaling activity and exhibits high ABA dependence. These results lay the foundation for a new strategy to improve drought stress tolerance without compromising crop growth. Full article
(This article belongs to the Section Molecular Biology)
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14 pages, 2064 KiB  
Article
Identification of circRNA-Associated-ceRNA Networks Involved in Milk Fat Metabolism under Heat Stress
by Dongyang Wang, Zujing Chen, Xiaona Zhuang, Junyi Luo, Ting Chen, Qianyun Xi, Yongliang Zhang and Jiajie Sun
Int. J. Mol. Sci. 2020, 21(11), 4162; https://doi.org/10.3390/ijms21114162 - 11 Jun 2020
Cited by 36 | Viewed by 3975
Abstract
Summer temperatures are generally high in Southern China, and cows are likely to suffer a heat stress reaction. Heat stress will have a negative impact on the performance of dairy cows; however, the mechanism by which high temperature affects lactation is not clear. [...] Read more.
Summer temperatures are generally high in Southern China, and cows are likely to suffer a heat stress reaction. Heat stress will have a negative impact on the performance of dairy cows; however, the mechanism by which high temperature affects lactation is not clear. CircRNA is a type of non-coding RNA discovered in recent years, which performs a crucial function in many biological activities. However, the effects of circRNA on lactation function of dairy cows under heat stress is unknown. The present study aimed to explore the expression levels of circRNA in the mammary gland tissue of cows under heat stress. Firstly, we collected blood and milk samples of summer and winter cows and evaluated lactation performance using serum indicators, milk production, and milk composition. Incorporating the calculation of the temperature and humidity index, we conformed the heat stress status of cows in summer. Heat stress increased the concentration of HSP70 and decreased the concentration of SOD and PRL. Heat stress not only reduced milk yield but also affected milk quality, with milk lactose and milk protein decreasing with increased temperature. The analysis of the fatty acid composition in summer milk found significantly reduced concentrations of unsaturated fatty acids, especially long-chain unsaturated fatty acids. Sequencing of the cow’s mammary gland transcriptome revealed that compared to the appropriate temperature (ST) group, the heat stress (HS) group had a total of 2204 upregulated and 3501 downregulated transcripts. GO enrichment and KEGG pathway analysis showed that these genes were mainly related to milk fat metabolism. In addition, 19 upregulated and 19 downregulated circRNA candidates were found in response to heat stress. We used Pearson’s test to establish the correlation of circRNA-mRNA and identified four pairs of circRNA-miRNA networks between four circRNAs, six miRNAs, and the CD36 gene. In this study, we revealed the possible role of circRNAs in lactation of dairy cows and identified that circRNA-miRNA-mRNA networks might exist in the cow’s mammary glands, providing valuable experience for dairy lactation and milk quality. Full article
(This article belongs to the Special Issue Crosstalk between MicroRNA and Oxidative Stress in Physiology and Pathology 2.0)
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4 pages, 167 KiB  
Editorial
Molecular Processes in Chondrocyte Biology
by Toshihisa Komori
Int. J. Mol. Sci. 2020, 21(11), 4161; https://doi.org/10.3390/ijms21114161 - 11 Jun 2020
Cited by 7 | Viewed by 3052
Abstract
Chondrocyte biology is a hot topic, because osteoarthritis (OA) is a serious problem in an aging society, but there are no fundamental therapeutic drugs [...] Full article
(This article belongs to the Special Issue Molecular Processes in Chondrocyte Biology)
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