International Journal of Molecular Sciences

18 pages, 2752 KiB

Open AccessArticle

CaWRKY30 Positively Regulates Pepper Immunity by Targeting CaWRKY40 against Ralstonia solanacearum Inoculation through Modulating Defense-Related Genes

by Ansar Hussain, Muhammad Ifnan Khan, Mohammed Albaqami, Shahzadi Mahpara, Ijaz Rasool Noorka, Mohamed A. A. Ahmed, Bandar S. Aljuaid, Ahmed M. El-Shehawi, Zhiqin Liu, Shahid Farooq and Ali Tan Kee Zuan

Int. J. Mol. Sci. 2021, 22(21), 12091; https://doi.org/10.3390/ijms222112091 - 08 Nov 2021

Cited by 10 | Viewed by 2798

Abstract

The WRKY transcription factors (TFs) network is composed of WRKY TFs’ subset, which performs a critical role in immunity regulation of plants. However, functions of WRKY TFs’ network remain unclear, particularly in non-model plants such as pepper (Capsicum annuum L.). This study [...] Read more.

The WRKY transcription factors (TFs) network is composed of WRKY TFs’ subset, which performs a critical role in immunity regulation of plants. However, functions of WRKY TFs’ network remain unclear, particularly in non-model plants such as pepper (Capsicum annuum L.). This study functionally characterized CaWRKY30—a member of group III Pepper WRKY protein—for immunity of pepper against Ralstonia solanacearum infection. The CaWRKY30 was detected in nucleus, and its transcriptional expression levels were significantly upregulated by R. solanacearum inoculation (RSI), and foliar application ethylene (ET), abscisic acid (ABA), and salicylic acid (SA). Virus induced gene silencing (VIGS) of CaWRKY30 amplified pepper’s vulnerability to RSI. Additionally, the silencing of CaWRKY30 by VIGS compromised HR-like cell death triggered by RSI and downregulated defense-associated marker genes, like CaPR1, CaNPR1, CaDEF1, CaABR1, CaHIR1, and CaWRKY40. Conversely, transient over-expression of CaWRKY30 in pepper leaves instigated HR-like cell death and upregulated defense-related maker genes. Furthermore, transient over-expression of CaWRKY30 upregulated transcriptional levels of CaWRKY6, CaWRKY22, CaWRKY27, and CaWRKY40. On the other hand, transient over-expression of CaWRKY6, CaWRKY22, CaWRKY27, and CaWRKY40 upregulated transcriptional expression levels of CaWRKY30. The results recommend that newly characterized CaWRKY30 positively regulates pepper’s immunity against Ralstonia attack, which is governed by synergistically mediated signaling by phytohormones like ET, ABA, and SA, and transcriptionally assimilating into WRKY TFs networks, consisting of CaWRKY6, CaWRKY22, CaWRKY27, and CaWRKY40. Collectively, our data will facilitate to explicate the underlying mechanism of crosstalk between pepper’s immunity and response to RSI. Full article

(This article belongs to the Special Issue Plant Disease Resistance 2.0)

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29 pages, 661 KiB

Open AccessArticle

Transcriptome Analysis of Pterygium and Pinguecula Reveals Evidence of Genomic Instability Associated with Chronic Inflammation

by María Fernanda Suarez, José Echenique, Juan Manuel López, Esteban Medina, Mariano Irós, Horacio M. Serra and M. Elizabeth Fini

Int. J. Mol. Sci. 2021, 22(21), 12090; https://doi.org/10.3390/ijms222112090 - 08 Nov 2021

Cited by 7 | Viewed by 4147

Abstract

Solar damage due to ultraviolet radiation (UVR) is implicated in the development of two proliferative lesions of the ocular surface: pterygium and pinguecula. Pterygium and pinguecula specimens were collected, along with adjacent healthy conjunctiva specimens. RNA was extracted and sequenced. Pairwise comparisons were [...] Read more.

Solar damage due to ultraviolet radiation (UVR) is implicated in the development of two proliferative lesions of the ocular surface: pterygium and pinguecula. Pterygium and pinguecula specimens were collected, along with adjacent healthy conjunctiva specimens. RNA was extracted and sequenced. Pairwise comparisons were made of differentially expressed genes (DEGs). Computational methods were used for analysis. Transcripts from 18,630 genes were identified. Comparison of two subgroups of pterygium specimens uncovered evidence of genomic instability associated with inflammation and the immune response; these changes were also observed in pinguecula, but to a lesser extent. Among the top DEGs were four genes encoding tumor suppressors that were downregulated in pterygium: C10orf90, RARRES1, DMBT1 and SCGB3A1; C10orf90 and RARRES1 were also downregulated in pinguecula. Ingenuity Pathway Analysis overwhelmingly linked DEGs to cancer for both lesions; however, both lesions are clearly still benign, as evidenced by the expression of other genes indicating their well-differentiated and non-invasive character. Pathways for epithelial cell proliferation were identified that distinguish the two lesions, as well as genes encoding specific pathway components. Upregulated DEGs common to both lesions, including KRT9 and TRPV3, provide a further insight into pathophysiology. Our findings suggest that pterygium and pinguecula, while benign lesions, are both on the pathological pathway towards neoplastic transformation. Full article

(This article belongs to the Special Issue Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches)

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21 pages, 3414 KiB

Open AccessReview

The Use of Inhibitors of Tyrosine Kinase in Paediatric Haemato-Oncology—When and Why?

by Agnieszka Kaczmarska, Patrycja Śliwa, Monika Lejman and Joanna Zawitkowska

Int. J. Mol. Sci. 2021, 22(21), 12089; https://doi.org/10.3390/ijms222112089 - 08 Nov 2021

Cited by 7 | Viewed by 2766

Abstract

The fundamental pathophysiology of malignancies is dysregulation of the signalling pathways. Protein tyrosine kinases (PTKs) are among the enzymes which, if mutated, play a critical role in carcinogenesis. The best-studied rearrangement, which enhances PTK activity and causes atypical proliferation, is BCR-ABL1. Abnormal [...] Read more.

The fundamental pathophysiology of malignancies is dysregulation of the signalling pathways. Protein tyrosine kinases (PTKs) are among the enzymes which, if mutated, play a critical role in carcinogenesis. The best-studied rearrangement, which enhances PTK activity and causes atypical proliferation, is BCR-ABL1. Abnormal expression of PTKs has proven to play a significant role in the development of various malignancies, such as chronic myelogenous leukaemia, brain tumours, neuroblastoma, and gastrointestinal stromal tumours. The use of tyrosine kinase inhibitors (TKIs) is an outstanding example of successful target therapy. TKIs have been effectively applied in the adult oncology setting, but there is a need to establish TKIs’ importance in paediatric patients. Many years of research have allowed a significant improvement in the outcome of childhood cancers. However, there are still groups of patients who have a poor prognosis, where the intensification of chemotherapy could even cause death. TKIs are designed to target specific PTKs, which lead to the limitation of severe adverse effects and increase overall survival. These advances will hopefully allow new therapeutic approaches in paediatric haemato-oncology to emerge. In this review, we present an analysis of the current data on tyrosine kinase inhibitors in childhood cancers. Full article

(This article belongs to the Special Issue Advances in Kinase Drug Discovery)

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21 pages, 8816 KiB

Open AccessArticle

Molecular and Functional Analysis of U-box E3 Ubiquitin Ligase Gene Family in Rice (Oryza sativa)

by Me-Sun Kim, Kwon-Kyoo Kang and Yong-Gu Cho

Int. J. Mol. Sci. 2021, 22(21), 12088; https://doi.org/10.3390/ijms222112088 - 08 Nov 2021

Cited by 11 | Viewed by 3124

Abstract

Proteins encoded by U-box type ubiquitin ligase (PUB) genes in rice are known to play an important role in plant responses to abiotic and biotic stresses. Functional analysis has revealed a detailed molecular mechanism involving PUB proteins in relation to abiotic and biotic [...] Read more.

Proteins encoded by U-box type ubiquitin ligase (PUB) genes in rice are known to play an important role in plant responses to abiotic and biotic stresses. Functional analysis has revealed a detailed molecular mechanism involving PUB proteins in relation to abiotic and biotic stresses. In this study, characteristics of 77 OsPUB genes in rice were identified. Systematic and comprehensive analyses of the OsPUB gene family were then performed, including analysis of conserved domains, phylogenetic relationships, gene structure, chromosome location, cis-acting elements, and expression patterns. Through transcriptome analysis, we confirmed that 16 OsPUB genes show similar expression patterns in drought stress and blast infection response pathways. Numerous cis-acting elements were found in promoter sequences of 16 OsPUB genes, indicating that the OsPUB genes might be involved in complex regulatory networks to control hormones, stress responses, and cellular development. We performed qRT-PCR on 16 OsPUB genes under drought stress and blast infection to further identify the reliability of transcriptome and cis-element analysis data. It was confirmed that the expression pattern was similar to RNA-sequencing analysis results. The transcription of OsPUB under various stress conditions indicates that the PUB gene might have various functions in the responses of rice to abiotic and biotic stresses. Taken together, these results indicate that the genome-wide analysis of OsPUB genes can provide a solid basis for the functional analysis of U-box E3 ubiquitin ligase genes. The molecular information of the U-box E3 ubiquitin ligase gene family in rice, including gene expression patterns and cis-acting regulatory elements, could be useful for future crop breeding programs by genome editing. Full article

(This article belongs to the Special Issue Crop Genome Editing)

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21 pages, 10836 KiB

Open AccessReview

Focus on the Small GTPase Rab1: A Key Player in the Pathogenesis of Parkinson’s Disease

by José Ángel Martínez-Menárguez, Emma Martínez-Alonso, Mireia Cara-Esteban and Mónica Tomás

Int. J. Mol. Sci. 2021, 22(21), 12087; https://doi.org/10.3390/ijms222112087 - 08 Nov 2021

Cited by 9 | Viewed by 3320

Abstract

Parkinson’s disease (PD) is the second most frequent neurodegenerative disease. It is characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of large aggregates in the survival neurons called Lewy bodies, which mainly contain α-synuclein (α-syn). The cause [...] Read more.

Parkinson’s disease (PD) is the second most frequent neurodegenerative disease. It is characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of large aggregates in the survival neurons called Lewy bodies, which mainly contain α-synuclein (α-syn). The cause of cell death is not known but could be due to mitochondrial dysfunction, protein homeostasis failure, and alterations in the secretory/endolysosomal/autophagic pathways. Survival nigral neurons overexpress the small GTPase Rab1. This protein is considered a housekeeping Rab that is necessary to support the secretory pathway, the maintenance of the Golgi complex structure, and the regulation of macroautophagy from yeast to humans. It is also involved in signaling, carcinogenesis, and infection for some pathogens. It has been shown that it is directly linked to the pathogenesis of PD and other neurodegenerative diseases. It has a protective effect against α–σψν toxicity and has recently been shown to be a substrate of LRRK2, which is the most common cause of familial PD and the risk of sporadic disease. In this review, we analyze the key aspects of Rab1 function in dopamine neurons and its implications in PD neurodegeneration/restauration. The results of the current and former research support the notion that this GTPase is a good candidate for therapeutic strategies. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: From Molecular Basis to Therapy)

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15 pages, 2642 KiB

Open AccessArticle

Dual Role of Thrombospondin-1 in Flow-Induced Remodeling

by Céline Grenier, Antoine Caillon, Mathilde Munier, Linda Grimaud, Tristan Champin, Bertrand Toutain, Céline Fassot, Olivier Blanc-Brude and Laurent Loufrani

Int. J. Mol. Sci. 2021, 22(21), 12086; https://doi.org/10.3390/ijms222112086 - 08 Nov 2021

Viewed by 2260

Abstract

(1) Background: Chronic increases in blood flow, as in cardiovascular diseases, induce outward arterial remodeling. Thrombospondin-1 (TSP-1) is known to interact with matrix proteins and immune cell-surface receptors, but its contribution to flow-mediated remodeling in the microcirculation remains unknown. (2) Methods: Mesenteric arteries [...] Read more.

(1) Background: Chronic increases in blood flow, as in cardiovascular diseases, induce outward arterial remodeling. Thrombospondin-1 (TSP-1) is known to interact with matrix proteins and immune cell-surface receptors, but its contribution to flow-mediated remodeling in the microcirculation remains unknown. (2) Methods: Mesenteric arteries were ligated in vivo to generate high- (HF) and normal-flow (NF) arteries in wild-type (WT) and TSP-1-deleted mice (TSP-1^−/−). After 7 days, arteries were isolated and studied ex vivo. (3) Results: Chronic increases in blood flow induced outward remodeling in WT mice (increasing diameter from 221 ± 10 to 280 ± 10 µm with 75 mmHg intraluminal pressure) without significant effect in TSP-1^−/− (296 ± 18 to 303 ± 14 µm), neutropenic or adoptive bone marrow transfer mice. Four days after ligature, pro inflammatory gene expression levels (CD68, Cox2, Gp91phox, p47phox and p22phox) increased in WT HF arteries but not in TSP-1^−/− mice. Perivascular neutrophil accumulation at day 4 was significantly lower in TSP-1^−/− than in WT mice. (4) Conclusions: TSP-1 origin is important; indeed, circulating TSP-1 participates in vasodilation, whereas both circulating and tissue TSP-1 are involved in arterial wall thickness and diameter expansion. Full article

(This article belongs to the Special Issue Molecular Vascular Physiology)

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18 pages, 4635 KiB

Open AccessArticle

Modulation of Cellular NAD⁺ Attenuates Cancer-Associated Hypercoagulability and Thrombosis via the Inhibition of Tissue Factor and Formation of Neutrophil Extracellular Traps

by Wa Cao, Meng-Yu Zhu, Seung-Hoon Lee, Su-Bin Lee, Hyung-Jin Kim, Byung-Ouk Park, Cheol-Hwan Yoon, Dipendra Khadka, Gi-Su Oh, Hyeok Shim, Tae-Hwan Kwak and Hong-Seob So

Int. J. Mol. Sci. 2021, 22(21), 12085; https://doi.org/10.3390/ijms222112085 - 08 Nov 2021

Cited by 8 | Viewed by 3216

Abstract

Cancer-associated thrombosis is the second-leading cause of mortality in patients with cancer and presents a poor prognosis, with a lack of effective treatment strategies. NAD(P)H quinone oxidoreductase 1 (NQO1) increases the cellular nicotinamide adenine dinucleotide (NAD⁺) levels by accelerating the oxidation [...] Read more.

Cancer-associated thrombosis is the second-leading cause of mortality in patients with cancer and presents a poor prognosis, with a lack of effective treatment strategies. NAD(P)H quinone oxidoreductase 1 (NQO1) increases the cellular nicotinamide adenine dinucleotide (NAD⁺) levels by accelerating the oxidation of NADH to NAD⁺, thus playing important roles in cellular homeostasis, energy metabolism, and inflammatory responses. Using a murine orthotopic 4T1 breast cancer model, in which multiple thrombi are generated in the lungs at the late stage of cancer development, we investigated the effects of regulating the cellular NAD⁺ levels on cancer-associated thrombosis. In this study, we show that dunnione (a strong substrate of NQO1) attenuates the prothrombotic state and lung thrombosis in tumor-bearing mice by inhibiting the expression of tissue factor and formation of neutrophil extracellular traps (NETs). Dunnione increases the cellular NAD⁺ levels in lung tissues of tumor-bearing mice to restore the declining sirtuin 1 (SIRT1) activity, thus deacetylating nuclear factor-kappa B (NF-κB) and preventing the overexpression of tissue factor in bronchial epithelial and vascular endothelial cells. In addition, we demonstrated that dunnione abolishes the ability of neutrophils to generate NETs by suppressing histone acetylation and NADPH oxidase (NOX) activity. Overall, our results reveal that the regulation of cellular NAD⁺ levels by pharmacological agents may inhibit pulmonary embolism in tumor-bearing mice, which may potentially be used as a viable therapeutic approach for the treatment of cancer-associated thrombosis. Full article

(This article belongs to the Special Issue Novel Biological Molecules for Cancer Treatments)

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19 pages, 3598 KiB

Open AccessArticle

Glycation of Host Proteins Increases Pathogenic Potential of Porphyromonas gingivalis

by Michał Śmiga, John W. Smalley, Paulina Ślęzak, Jason L. Brown, Klaudia Siemińska, Rosalind E. Jenkins, Edwin A. Yates and Teresa Olczak

Int. J. Mol. Sci. 2021, 22(21), 12084; https://doi.org/10.3390/ijms222112084 - 08 Nov 2021

Cited by 13 | Viewed by 2967

Abstract

The non-enzymatic addition of glucose (glycation) to circulatory and tissue proteins is a ubiquitous pathophysiological consequence of hyperglycemia in diabetes. Given the high incidence of periodontitis and diabetes and the emerging link between these conditions, it is of crucial importance to define the [...] Read more.

The non-enzymatic addition of glucose (glycation) to circulatory and tissue proteins is a ubiquitous pathophysiological consequence of hyperglycemia in diabetes. Given the high incidence of periodontitis and diabetes and the emerging link between these conditions, it is of crucial importance to define the basic virulence mechanisms employed by periodontopathogens such as Porphyromonas gingivalis in mediating the disease process. The aim of this study was to determine whether glycated proteins are more easily utilized by P. gingivalis to stimulate growth and promote the pathogenic potential of this bacterium. We analyzed the properties of three commonly encountered proteins in the periodontal environment that are known to become glycated and that may serve as either protein substrates or easily accessible heme sources. In vitro glycated proteins were characterized using colorimetric assays, mass spectrometry, far- and near-UV circular dichroism and UV–visible spectroscopic analyses and SDS-PAGE. The interaction of glycated hemoglobin, serum albumin and type one collagen with P. gingivalis cells or HmuY protein was examined using spectroscopic methods, SDS-PAGE and co-culturing P. gingivalis with human keratinocytes. We found that glycation increases the ability of P. gingivalis to acquire heme from hemoglobin, mostly due to heme sequestration by the HmuY hemophore-like protein. We also found an increase in biofilm formation on glycated collagen-coated abiotic surfaces. We conclude that glycation might promote the virulence of P. gingivalis by making heme more available from hemoglobin and facilitating bacterial biofilm formation, thus increasing P. gingivalis pathogenic potential in vivo. Full article

(This article belongs to the Special Issue Molecular Links between Periodontitis and Systemic Diseases)

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22 pages, 6245 KiB

Open AccessArticle

Translation Inhibitors Activate Autophagy Master Regulators TFEB and TFE3

by Thao Thi Dang and Sung Hoon Back

Int. J. Mol. Sci. 2021, 22(21), 12083; https://doi.org/10.3390/ijms222112083 - 08 Nov 2021

Cited by 12 | Viewed by 4801

Abstract

The autophagy-lysosome pathway is a major protein degradation pathway stimulated by multiple cellular stresses, including nutrient or growth factor deprivation, hypoxia, misfolded proteins, damaged organelles, and intracellular pathogens. Recent studies have revealed that transcription factor EB (TFEB) and transcription factor E3 (TFE3) play [...] Read more.

The autophagy-lysosome pathway is a major protein degradation pathway stimulated by multiple cellular stresses, including nutrient or growth factor deprivation, hypoxia, misfolded proteins, damaged organelles, and intracellular pathogens. Recent studies have revealed that transcription factor EB (TFEB) and transcription factor E3 (TFE3) play a pivotal role in the biogenesis and functions of autophagosome and lysosome. Here we report that three translation inhibitors (cycloheximide, lactimidomycin, and rocaglamide A) can facilitate the nuclear translocation of TFEB/TFE3 via dephosphorylation and 14-3-3 dissociation. In addition, the inhibitor-mediated TFEB/TFE3 nuclear translocation significantly increases the transcriptional expression of their downstream genes involved in the biogenesis and function of autophagosome and lysosome. Furthermore, we demonstrated that translation inhibition increased autophagosome biogenesis but impaired the degradative autolysosome formation because of lysosomal dysfunction. These results highlight the previously unrecognized function of the translation inhibitors as activators of TFEB/TFE3, suggesting a novel biological role of translation inhibition in autophagy regulation. Full article

(This article belongs to the Section Molecular Biology)

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24 pages, 1835 KiB

Open AccessReview

Memory Disorders Related to Hippocampal Function: The Interest of 5-HT₄Rs Targeting

by Candice M. Roux, Marianne Leger and Thomas Freret

Int. J. Mol. Sci. 2021, 22(21), 12082; https://doi.org/10.3390/ijms222112082 - 08 Nov 2021

Cited by 7 | Viewed by 5253

Abstract

The hippocampus has long been considered as a key structure for memory processes. Multilevel alterations of hippocampal function have been identified as a common denominator of memory impairments in a number of psychiatric and neurodegenerative diseases. For many years, the glutamatergic and cholinergic [...] Read more.

The hippocampus has long been considered as a key structure for memory processes. Multilevel alterations of hippocampal function have been identified as a common denominator of memory impairments in a number of psychiatric and neurodegenerative diseases. For many years, the glutamatergic and cholinergic systems have been the main targets of therapeutic treatments against these symptoms. However, the high rate of drug development failures has left memory impairments on the sideline of current therapeutic strategies. This underscores the urgent need to focus on new therapeutic targets for memory disorders, such as type 4 serotonin receptors (5-HT₄Rs). Ever since the discovery of their expression in the hippocampus, 5-HT₄Rs have gained growing interest for potential use in the treatment of learning and memory impairments. To date, much of the researched information gathered by scientists from both animal models and humans converge on pro-mnesic and anti-amnesic properties of 5-HT₄Rs activation, although the mechanisms at work require more work to be fully understood. This review addresses a fundamental, yet poorly understood set of evidence of the potential of 5-HT₄Rs to re-establish or limit hippocampal alterations related to neurological diseases. Most importantly, the potential of 5-HT₄Rs is translated by refining hypotheses regarding the benefits of their activation in memory disorders at the hippocampal level. Full article

(This article belongs to the Special Issue Pathophysiology of the Serotonin System in the Nervous System and Beyond)

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25 pages, 2791 KiB

Open AccessReview

Pathogenic Basis of Thromboinflammation and Endothelial Injury in COVID-19: Current Findings and Therapeutic Implications

by Yasutomi Higashikuni, Wenhao Liu, Takumi Obana and Masataka Sata

Int. J. Mol. Sci. 2021, 22(21), 12081; https://doi.org/10.3390/ijms222112081 - 08 Nov 2021

Cited by 20 | Viewed by 3687

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic with a great impact on social and economic activities, as well as public health. In most patients, the symptoms of COVID-19 are a high-grade fever [...] Read more.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic with a great impact on social and economic activities, as well as public health. In most patients, the symptoms of COVID-19 are a high-grade fever and a dry cough, and spontaneously resolve within ten days. However, in severe cases, COVID-19 leads to atypical bilateral interstitial pneumonia, acute respiratory distress syndrome, and systemic thromboembolism, resulting in multiple organ failure with high mortality and morbidity. SARS-CoV-2 has immune evasion mechanisms, including inhibition of interferon signaling and suppression of T cell and B cell responses. SARS-CoV-2 infection directly and indirectly causes dysregulated immune responses, platelet hyperactivation, and endothelial dysfunction, which interact with each other and are exacerbated by cardiovascular risk factors. In this review, we summarize current knowledge on the pathogenic basis of thromboinflammation and endothelial injury in COVID-19. We highlight the distinct contributions of dysregulated immune responses, platelet hyperactivation, and endothelial dysfunction to the pathogenesis of COVID-19. In addition, we discuss potential therapeutic strategies targeting these mechanisms. Full article

(This article belongs to the Special Issue Cardiovascular Injuries in Severe Respiratory Infectious Diseases 2.0)

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Graphical abstract

16 pages, 3781 KiB

Open AccessArticle

Prediction of Peptide Detectability Based on CapsNet and Convolutional Block Attention Module

by Minzhe Yu, Yushuai Duan, Zhong Li and Yang Zhang

Int. J. Mol. Sci. 2021, 22(21), 12080; https://doi.org/10.3390/ijms222112080 - 08 Nov 2021

Cited by 9 | Viewed by 2354

Abstract

According to proteomics technology, as impacted by the complexity of sampling in the experimental process, several problems remain with the reproducibility of mass spectrometry experiments, and the peptide identification and quantitative results continue to be random. Predicting the detectability exhibited by peptides can [...] Read more.

According to proteomics technology, as impacted by the complexity of sampling in the experimental process, several problems remain with the reproducibility of mass spectrometry experiments, and the peptide identification and quantitative results continue to be random. Predicting the detectability exhibited by peptides can optimize the mentioned results to be more accurate, so such a prediction is of high research significance. This study builds a novel method to predict the detectability of peptides by complying with the capsule network (CapsNet) and the convolutional block attention module (CBAM). First, the residue conical coordinate (RCC), the amino acid composition (AAC), the dipeptide composition (DPC), and the sequence embedding code (SEC) are extracted as the peptide chain features. Subsequently, these features are divided into the biological feature and sequence feature, and separately inputted into the neural network of CapsNet. Moreover, the attention module CBAM is added to the network to assign weights to channels and spaces, as an attempt to enhance the feature learning and improve the network training effect. To verify the effectiveness of the proposed method, it is compared with some other popular methods. As revealed from the experimentally achieved results, the proposed method outperforms those methods in most performance assessments. Full article

(This article belongs to the Section Molecular Biophysics)

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17 pages, 9827 KiB

Open AccessArticle

AMBRA1 Negatively Regulates the Function of ALDH1B1, a Cancer Stem Cell Marker, by Controlling Its Ubiquitination

by Seung-Heon Baek and Yeun-Kyu Jang

Int. J. Mol. Sci. 2021, 22(21), 12079; https://doi.org/10.3390/ijms222112079 - 08 Nov 2021

Cited by 5 | Viewed by 2604

Abstract

Activating molecule in Beclin-1-regulated autophagy (AMBRA1), a negative regulator of tumorigenesis, is a substrate receptor of the ubiquitin conjugation system. ALDH1B1, an aldehyde dehydrogenase, is a cancer stem cell (CSC) marker that is required for carcinogenesis via upregulation of the β-catenin pathway. Although [...] Read more.

Activating molecule in Beclin-1-regulated autophagy (AMBRA1), a negative regulator of tumorigenesis, is a substrate receptor of the ubiquitin conjugation system. ALDH1B1, an aldehyde dehydrogenase, is a cancer stem cell (CSC) marker that is required for carcinogenesis via upregulation of the β-catenin pathway. Although accumulating evidence suggests a role for ubiquitination in the regulation of CSC markers, the ubiquitination-mediated regulation of ALDH1B1 has not been unraveled. While proteome analysis has suggested that AMBRA1 and ALDH1B1 can interact, their interaction has not been validated. Here, we show that AMBRA1 is a negative regulator of ALDH1B1. The expression of ALDH1B1-regulated genes, including PTEN, CTNNB1 (β-catenin), and CSC-related β-catenin target genes, is inversely regulated by AMBRA1, suggesting a negative regulatory role of AMBRA1 in the expression of ALDH1B1-regulated genes. We found that the K27- and K33-linked ubiquitination of ALDH1B1 is mediated via the cooperation of AMBRA1 with other E3 ligases, such as TRAF6. Importantly, ubiquitination site mapping revealed that K506, K511, and K515 are important for the K27-linked ubiquitination of ALDH1B1, while K33-linked ubiquitination occurs at K506. A ubiquitination-defective mutant of ALDH1B1 increased the self-association ability of ALDH1B1, suggesting a negative correlation between the ubiquitination and self-association of ALDH1B1. Together, our findings indicate that ALDH1B1 is negatively regulated by AMBRA1-mediated noncanonical ubiquitination. Full article

(This article belongs to the Section Molecular Biology)

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15 pages, 1327 KiB

Open AccessReview

Senolytics: A Novel Strategy for Neuroprotection in ALS?

by Alexandra Maximova, Eryn L. Werry and Michael Kassiou

Int. J. Mol. Sci. 2021, 22(21), 12078; https://doi.org/10.3390/ijms222112078 - 08 Nov 2021

Cited by 6 | Viewed by 3322

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive motor neurodegenerative disease that currently has no cure and has few effective treatments. On a cellular level, ALS manifests through significant changes in the proper function of astrocytes, microglia, motor neurons, and other central nervous system [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a progressive motor neurodegenerative disease that currently has no cure and has few effective treatments. On a cellular level, ALS manifests through significant changes in the proper function of astrocytes, microglia, motor neurons, and other central nervous system (CNS) cells, leading to excess neuroinflammation and neurodegeneration. Damage to the upper and lower motor neurons results in neural and muscular dysfunction, leading to death most often due to respiratory paralysis. A new therapeutic strategy is targeting glial cells affected by senescence, which contribute to motor neuron degeneration. Whilst this new therapeutic approach holds much promise, it is yet to be trialled in ALS-relevant preclinical models and needs to be designed carefully to ensure selectivity. This review summarizes the pathways involved in ALS-related senescence, as well as known senolytic agents and their mechanisms of action, all of which may inform strategies for ALS-focused drug discovery efforts. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention 2.0)

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29 pages, 858 KiB

Open AccessReview

Role of Oxytocin and Vasopressin in Neuropsychiatric Disorders: Therapeutic Potential of Agonists and Antagonists

by Valeska Cid-Jofré, Macarena Moreno, Miguel Reyes-Parada and Georgina M. Renard

Int. J. Mol. Sci. 2021, 22(21), 12077; https://doi.org/10.3390/ijms222112077 - 08 Nov 2021

Cited by 13 | Viewed by 6450

Abstract

Oxytocin (OT) and vasopressin (AVP) are hypothalamic neuropeptides classically associated with their regulatory role in reproduction, water homeostasis, and social behaviors. Interestingly, this role has expanded in recent years and has positioned these neuropeptides as therapeutic targets for various neuropsychiatric diseases such as [...] Read more.

Oxytocin (OT) and vasopressin (AVP) are hypothalamic neuropeptides classically associated with their regulatory role in reproduction, water homeostasis, and social behaviors. Interestingly, this role has expanded in recent years and has positioned these neuropeptides as therapeutic targets for various neuropsychiatric diseases such as autism, addiction, schizophrenia, depression, and anxiety disorders. Due to the chemical-physical characteristics of these neuropeptides including short half-life, poor blood-brain barrier penetration, promiscuity for AVP and OT receptors (AVP-R, OT-R), novel ligands have been developed in recent decades. This review summarizes the role of OT and AVP in neuropsychiatric conditions, as well as the findings of different OT-R and AVP-R agonists and antagonists, used both at the preclinical and clinical level. Furthermore, we discuss their possible therapeutic potential for central nervous system (CNS) disorders. Full article

(This article belongs to the Special Issue Advances in Oxytocin)

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30 pages, 1930 KiB

Open AccessReview

Bioprospecting Antimicrobials from Lactiplantibacillus plantarum: Key Factors Underlying Its Probiotic Action

by Maria Teresa Rocchetti, Pasquale Russo, Vittorio Capozzi, Djamel Drider, Giuseppe Spano and Daniela Fiocco

Int. J. Mol. Sci. 2021, 22(21), 12076; https://doi.org/10.3390/ijms222112076 - 08 Nov 2021

Cited by 26 | Viewed by 5426

Abstract

Lactiplantibacillus plantarum (L. plantarum) is a well-studied and versatile species of lactobacilli. It is found in several niches, including human mucosal surfaces, and it is largely employed in the food industry and boasts a millenary tradition of safe use, sharing a [...] Read more.

Lactiplantibacillus plantarum (L. plantarum) is a well-studied and versatile species of lactobacilli. It is found in several niches, including human mucosal surfaces, and it is largely employed in the food industry and boasts a millenary tradition of safe use, sharing a long-lasting relationship with humans. L. plantarum is generally recognised as safe and exhibits a strong probiotic character, so that several strains are commercialised as health-promoting supplements and functional food products. For these reasons, L. plantarum represents a valuable model to gain insight into the nature and mechanisms of antimicrobials as key factors underlying the probiotic action of health-promoting microbes. Probiotic antimicrobials can inhibit the growth of pathogens in the gut ensuring the intestinal homeostasis and contributing to the host health. Furthermore, they may be attractive alternatives to conventional antibiotics, holding potential in several biomedical applications. The aim of this review is to investigate the most relevant papers published in the last ten years, bioprospecting the antimicrobial activity of characterised probiotic L. plantarum strains. Specifically, it focuses on the different chemical nature, the action spectra and the mechanisms underlying the bioactivity of their antibacterial and antiviral agents. Emerging trends in postbiotics, some in vivo applications of L. plantarum antimicrobials, including strengths and limitations of their therapeutic potential, are addressed and discussed. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms Underlying Probiotic Activity)

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11 pages, 2427 KiB

Open AccessArticle

Tubular Assembly Formation Induced by Leucine Alignment along the Hydrophobic Helix of Amphiphilic Polypeptides

by Mohammed A. Abosheasha, Toru Itagaki, Yoshihiro Ito and Motoki Ueda

Int. J. Mol. Sci. 2021, 22(21), 12075; https://doi.org/10.3390/ijms222112075 - 08 Nov 2021

Cited by 2 | Viewed by 2104

Abstract

The introduction of α-helical structure with a specific helix–helix interaction into an amphipathic molecule enables the determination of the molecular packing in the assembly and the morphological control of peptide assemblies. We previously reported that the amphiphilic polypeptide SL12 with a polysarcosine (PSar) [...] Read more.

The introduction of α-helical structure with a specific helix–helix interaction into an amphipathic molecule enables the determination of the molecular packing in the assembly and the morphological control of peptide assemblies. We previously reported that the amphiphilic polypeptide SL12 with a polysarcosine (PSar) hydrophilic chain and hydrophobic α-helix (l-Leu-Aib)₆ involving the LxxxLxxxL sequence, which induces homo-dimerization due to the concave–convex interaction, formed a nanotube with a uniform 80 nm diameter. In this study, we investigated the importance of the LxxxLxxxL sequence for tube formation by comparing amphiphilic polypeptide SL4A4L4 with hydrophobic α-helix (l-Leu-Aib)₂-(l-Ala-Aib)₂-(l-Leu-Aib)₂ and SL12. SL4A4L4 formed spherical vesicles and micelles. The effect of the LxxxLxxxL sequence elongation on tube formation was demonstrated by studying assemblies of PSar-b-(l-Ala-Aib)-(l-Leu-Aib)₆-(l-Ala-Aib) (SA2L12A2) and PSar-b-(l-Leu-Aib)₈ (SL16). SA2L12A2 formed nanotubes with a uniform 123 nm diameter, while SL16 assembled into vesicles. These results showed that LxxxLxxxL is a necessary and sufficient sequence for the self-assembly of nanotubes. Furthermore, we fabricated a double-layer nanotube by combining two kinds of nanotubes with 80 and 120 nm diameters—SL12 and SA2L12A2. When SA2L12A2 self-assembled in SL12 nanotube dispersion, SA2L12A2 initially formed a rolled sheet, the sheet then wrapped the SL12 nanotube, and a double-layer nanotube was obtained. Full article

(This article belongs to the Section Macromolecules)

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25 pages, 3489 KiB

Open AccessArticle

Human Recombinant DNase I (Pulmozyme^®) Inhibits Lung Metastases in Murine Metastatic B16 Melanoma Model That Correlates with Restoration of the DNase Activity and the Decrease SINE/LINE and c-Myc Fragments in Blood Cell-Free DNA

by Ludmila Alekseeva, Aleksandra Sen’kova, Innokenty Savin, Marina Zenkova and Nadezhda Mironova

Int. J. Mol. Sci. 2021, 22(21), 12074; https://doi.org/10.3390/ijms222112074 - 08 Nov 2021

Cited by 5 | Viewed by 3511

Abstract

Tumor-associated cell-free DNAs (cfDNA) play an important role in the promotion of metastases. Previous studies proved the high antimetastatic potential of bovine pancreatic DNase I and identified short interspersed nuclear elements (SINEs) and long interspersed nuclear elements (LINEs)and fragments of oncogenes in cfDNA [...] Read more.

Tumor-associated cell-free DNAs (cfDNA) play an important role in the promotion of metastases. Previous studies proved the high antimetastatic potential of bovine pancreatic DNase I and identified short interspersed nuclear elements (SINEs) and long interspersed nuclear elements (LINEs)and fragments of oncogenes in cfDNA as the main molecular targets of enzyme in the bloodstream. Here, recombinant human DNase I (commercial name Pulmozyme^®), which is used for the treatment of cystic fibrosis in humans, was repurposed for the inhibition of lung metastases in the B16 melanoma model in mice. We found that Pulmozyme^® strongly reduced migration and induced apoptosis of B16 cells in vitro and effectively inhibited metastases in lungs and liver in vivo. Pulmozyme^® was shown to be two times more effective when administered intranasally (i.n.) than bovine DNase I, but intramuscular (i.m.) administration forced it to exhibit as high an antimetastatic activity as bovine DNase I. Both DNases administered to mice either i.m. or i.n. enhanced the DNase activity of blood serum to the level of healthy animals, significantly decreased cfDNA concentrations, efficiently degraded SINE and LINE repeats and c-Myc fragments in the bloodstream and induced apoptosis and disintegration of neutrophil extracellular traps in metastatic foci; as a result, this manifested as the inhibition of metastases spread. Thus, Pulmozyme^®, which is already an approved drug, can be recommended for use in the treatment of lung metastases. Full article

(This article belongs to the Special Issue New Findings and Insights in Inflammation-Induced DNA Damage, Mutations and Cancer)

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2 pages, 176 KiB

Open AccessEditorial

Multifunctional Nanomaterials: Synthesis, Properties and Applications

by Raghvendra Singh Yadav

Int. J. Mol. Sci. 2021, 22(21), 12073; https://doi.org/10.3390/ijms222112073 - 08 Nov 2021

Cited by 5 | Viewed by 1692

Abstract

In this Special Issue “Multifunctional Nanomaterials: Synthesis, Properties and Applications”, we published three review papers and nine original research articles [...] Full article

(This article belongs to the Special Issue Multifunctional Nanomaterials: Synthesis, Properties and Applications)

26 pages, 8492 KiB

Open AccessReview

Photopharmacology of Ion Channels through the Light of the Computational Microscope

by Alba Nin-Hill, Nicolas Pierre Friedrich Mueller, Carla Molteni, Carme Rovira and Mercedes Alfonso-Prieto

Int. J. Mol. Sci. 2021, 22(21), 12072; https://doi.org/10.3390/ijms222112072 - 08 Nov 2021

Cited by 6 | Viewed by 3114

Abstract

The optical control and investigation of neuronal activity can be achieved and carried out with photoswitchable ligands. Such compounds are designed in a modular fashion, combining a known ligand of the target protein and a photochromic group, as well as an additional electrophilic [...] Read more.

The optical control and investigation of neuronal activity can be achieved and carried out with photoswitchable ligands. Such compounds are designed in a modular fashion, combining a known ligand of the target protein and a photochromic group, as well as an additional electrophilic group for tethered ligands. Such a design strategy can be optimized by including structural data. In addition to experimental structures, computational methods (such as homology modeling, molecular docking, molecular dynamics and enhanced sampling techniques) can provide structural insights to guide photoswitch design and to understand the observed light-regulated effects. This review discusses the application of such structure-based computational methods to photoswitchable ligands targeting voltage- and ligand-gated ion channels. Structural mapping may help identify residues near the ligand binding pocket amenable for mutagenesis and covalent attachment. Modeling of the target protein in a complex with the photoswitchable ligand can shed light on the different activities of the two photoswitch isomers and the effect of site-directed mutations on photoswitch binding, as well as ion channel subtype selectivity. The examples presented here show how the integration of computational modeling with experimental data can greatly facilitate photoswitchable ligand design and optimization. Recent advances in structural biology, both experimental and computational, are expected to further strengthen this rational photopharmacology approach. Full article

(This article belongs to the Special Issue Light-Controlled Modulation and Analysis of Neuronal Functions)

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16 pages, 2796 KiB

Open AccessArticle

Insights into Intra-Tumoral Heterogeneity: Transcriptional Profiling of Chemoresistant MPM Cell Subpopulations Reveals Involvement of NFkB and DNA Repair Pathways and Contributes a Prognostic Signature

by Mario Cioce, Andrea Sacconi, Harvey I. Pass, Claudia Canino, Sabrina Strano, Giovanni Blandino and Vito Michele Fazio

Int. J. Mol. Sci. 2021, 22(21), 12071; https://doi.org/10.3390/ijms222112071 - 08 Nov 2021

Cited by 8 | Viewed by 2182

Abstract

Chemoresistance is a hallmark of malignant pleural mesothelioma (MPM) management and the expression of ALDH1A3 is responsible for the survival and activity of MPM chemoresistant cell subpopulations (ALDH^bright cells). We enriched mesothelioma ALDH^bright cells to near homogeneity by FACS sorting and [...] Read more.

Chemoresistance is a hallmark of malignant pleural mesothelioma (MPM) management and the expression of ALDH1A3 is responsible for the survival and activity of MPM chemoresistant cell subpopulations (ALDH^bright cells). We enriched mesothelioma ALDH^bright cells to near homogeneity by FACS sorting and an Aldefluor assay and performed unbiased Affymetrix gene expression profiling. Viability and ELISA assays were used to rule out significant apoptosis in the sorted cell subpopulations and to assess target engagement by butein. Statistical analysis of the results, pathway enrichment and promoter enrichment were employed for the generation of the data. Q-RTPCR was used to validate a subset of the identified, modulated mRNAs In this work, we started from the observation that the mRNA levels of the ALDH1A3 isoform could prognostically stratify MPM patients. Thus, we purified MPM ALDH^bright cells from NCI-H2595 cells and interrogated their gene expression (GES) profile. We analyzed the GES of the purified cells at both a steady state and upon treatment with butein (a multifunctional tetrahydroxy-chalcone), which abates the ALDH^bright cell number, thereby exerting chemo-sensitizing effects in vitro and in vivo. We identified 924 genes modulated in a statistically significant manner as a function of ALDH status and of the response to the inhibitor. Pathway and promoter enrichment identified the molecular determinant of high ALDH status and how butein treatment altered the molecular portrait of those chemoresistant cell subpopulations. Further, we unraveled an eighteen-gene signature with high prognostic significance for MPM patients, and showed that most of the identified prognostic contributors escaped the analysis of unfractionated samples. This work proves that digging into the unexplored field of intra-tumor heterogeneity (ITH) by working at the cell subpopulation level may provide findings of prognostic relevance, in addition to mechanistic insights into tumor resistance to therapy. Full article

(This article belongs to the Special Issue Cancer Chemoresistance: Novel Mechanistic Insights and Emerging Therapeutic Strategies)

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13 pages, 289 KiB

Open AccessReview

The Significance of mRNA in the Biology of Multiple Myeloma and Its Clinical Implications

by Anna Puła, Paweł Robak, Damian Mikulski and Tadeusz Robak

Int. J. Mol. Sci. 2021, 22(21), 12070; https://doi.org/10.3390/ijms222112070 - 08 Nov 2021

Cited by 3 | Viewed by 2397

Abstract

Multiple myeloma (MM) is a genetically complex disease that results from a multistep transformation of normal to malignant plasma cells in the bone marrow. However, the molecular mechanisms responsible for the initiation and heterogeneous evolution of MM remain largely unknown. A fundamental step [...] Read more.

Multiple myeloma (MM) is a genetically complex disease that results from a multistep transformation of normal to malignant plasma cells in the bone marrow. However, the molecular mechanisms responsible for the initiation and heterogeneous evolution of MM remain largely unknown. A fundamental step needed to understand the oncogenesis of MM and its response to therapy is the identification of driver mutations. The introduction of gene expression profiling (GEP) in MM is an important step in elucidating the molecular heterogeneity of MM and its clinical relevance. Since some mutations in myeloma occur in non-coding regions, studies based on the analysis of mRNA provide more comprehensive information on the oncogenic pathways and mechanisms relevant to MM biology. In this review, we discuss the role of gene expression profiling in understanding the biology of multiple myeloma together with the clinical manifestation of the disease, as well as its impact on treatment decisions and future directions. Full article

(This article belongs to the Special Issue mRNAs in Biology)

21 pages, 3994 KiB

Open AccessArticle

Conditioned Media of Adipose-Derived Stem Cells Suppresses Sidestream Cigarette Smoke Extract Induced Cell Death and Epithelial-Mesenchymal Transition in Lung Epithelial Cells

by Tzu-Yin Chen, Chia-Hao Liu, Tsung-Hsien Chen, Mei-Ru Chen, Shan-Wen Liu, Pinpin Lin and Kurt Ming-Chao Lin

Int. J. Mol. Sci. 2021, 22(21), 12069; https://doi.org/10.3390/ijms222112069 - 08 Nov 2021

Cited by 5 | Viewed by 2494

Abstract

The role of the epithelial–mesenchymal transition (EMT) in lung epithelial cells is increasingly being recognized as a key stage in the development of COPD, fibrosis, and lung cancers, which are all highly associated with cigarette smoking and with exposure to second-hand smoke. Using [...] Read more.

The role of the epithelial–mesenchymal transition (EMT) in lung epithelial cells is increasingly being recognized as a key stage in the development of COPD, fibrosis, and lung cancers, which are all highly associated with cigarette smoking and with exposure to second-hand smoke. Using the exposure of human lung cancer epithelial A549 cells and non-cancerous Beas-2B cells to sidestream cigarette smoke extract (CSE) as a model, we studied the protective effects of adipose-derived stem cell-conditioned medium (ADSC-CM) against CSE-induced cell death and EMT. CSE dose-dependently induced cell death, decreased epithelial markers, and increased the expression of mesenchymal markers. Upstream regulator analysis of differentially expressed genes after CSE exposure revealed similar pathways as those observed in typical EMT induced by TGF-β1. CSE-induced cell death was clearly attenuated by ADSC-CM but not by other control media, such as a pass-through fraction of ADSC-CM or A549-CM. ADSC-CM effectively inhibited CSE-induced EMT and was able to reverse the gradual loss of epithelial marker expression associated with TGF-β1 treatment. CSE or TGF-β1 enhanced the speed of A549 migration by 2- to 3-fold, and ADSC-CM was effective in blocking the cell migration induced by either agent. Future work will build on the results of this in vitro study by defining the molecular mechanisms through which ADSC-CM protects lung epithelial cells from EMT induced by toxicants in second-hand smoke. Full article

(This article belongs to the Special Issue Mesenchymal Stem/Progenitor Cells and Their Derivates in Tissue Regeneration)

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18 pages, 2440 KiB

Open AccessReview

Hydrogen Sulfide in Plants: Crosstalk with Other Signal Molecules in Response to Abiotic Stresses

by Chunlei Wang, Yuzheng Deng, Zesheng Liu and Weibiao Liao

Int. J. Mol. Sci. 2021, 22(21), 12068; https://doi.org/10.3390/ijms222112068 - 08 Nov 2021

Cited by 34 | Viewed by 2885

Abstract

Hydrogen sulfide (H₂S) has recently been considered as a crucial gaseous transmitter occupying extensive roles in physiological and biochemical processes throughout the life of plant species. Furthermore, plenty of achievements have been announced regarding H₂S working in combination with [...] Read more.

Hydrogen sulfide (H₂S) has recently been considered as a crucial gaseous transmitter occupying extensive roles in physiological and biochemical processes throughout the life of plant species. Furthermore, plenty of achievements have been announced regarding H₂S working in combination with other signal molecules to mitigate environmental damage, such as nitric oxide (NO), abscisic acid (ABA), calcium ion (Ca²⁺), hydrogen peroxide (H₂O₂), salicylic acid (SA), ethylene (ETH), jasmonic acid (JA), proline (Pro), and melatonin (MT). This review summarizes the current knowledge within the mechanism of H₂S and the above signal compounds in response to abiotic stresses in plants, including maintaining cellular redox homeostasis, exchanging metal ion transport, regulating stomatal aperture, and altering gene expression and enzyme activities. The potential relationship between H₂S and other signal transmitters is also proposed and discussed. Full article

(This article belongs to the Special Issue Hydrogen Sulfide and Reactive Oxygen Species, Antioxidant Defense, Abiotic Stress Tolerance Mechanisms in Plants)

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11 pages, 1177 KiB

Open AccessCommunication

Cubic Octa-Carbon: Quantum-Chemical Design of Molecular Structure and Potential Way of Its Synthesis from Cubane

by Denis V. Chachkov and Oleg V. Mikhailov

Int. J. Mol. Sci. 2021, 22(21), 12067; https://doi.org/10.3390/ijms222112067 - 08 Nov 2021

Viewed by 2130

Abstract

Quantum-chemical calculation of most important parameters of molecular and electronic structures of octa-carbon C₈ having cubic form (bond lengths, bond and torsion angles) using CCSD(T)/QZVP and DFT B3PW91/QZVP methods, has been carried out. NBO analysis data and HOMO/LUMO images for this compound [...] Read more.

Quantum-chemical calculation of most important parameters of molecular and electronic structures of octa-carbon C₈ having cubic form (bond lengths, bond and torsion angles) using CCSD(T)/QZVP and DFT B3PW91/QZVP methods, has been carried out. NBO analysis data and HOMO/LUMO images for this compound are presented, too. Good agreement was found between the structural data obtained using the above two quantum-chemical methods and, also, with corresponding experimental data. Also, the standard thermodynamic parameters of formation of cubic C₈ considered here, and namely standard enthalpy Δ_fH⁰(298K), entropy S_f⁰(298K) and Gibbs’ energy Δ_fG⁰(298K) of formation for this compound were calculated. By using this data, a theoretically possible variant of the synthesis of this compound by dehydrogenation of cubane C₈H₈ is considered, and the thermodynamic characteristics of each of the four stages of this process have been calculated. It is noted that each of the four stages of this process is characterized by a very high (about 500 kJ/mol) enthalpy of activation, as a result of that, for their realization within a sufficiently short time, the use of appropriate catalysts is necessary. Full article

(This article belongs to the Special Issue Simple Substances of Non-metals: Molecular Structures Modeling with Using DFT and More Advanced Methods of Quantum Chemistry)

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18 pages, 5662 KiB

Open AccessArticle

Substrate Stiffness Drives Epithelial to Mesenchymal Transition and Proliferation through the NEAT1-Wnt/β-Catenin Pathway in Liver Cancer

by Xichao Xu, Yi Zhang, Xing Wang, Shun Li and Liling Tang

Int. J. Mol. Sci. 2021, 22(21), 12066; https://doi.org/10.3390/ijms222112066 - 08 Nov 2021

Cited by 24 | Viewed by 3165

Abstract

Background: Extracellular matrix (ECM)-derived mechanical stimuli regulate many cellular processes and phenotypes through mechanotransduction signaling pathways. Substrate stiffness changes cell phenotypes and promotes angiogenesis, epithelial to mesenchymal transition (EMT), and metastasis in tumors. Enhanced liver tissue matrix stiffness plays a crucial role in [...] Read more.

Background: Extracellular matrix (ECM)-derived mechanical stimuli regulate many cellular processes and phenotypes through mechanotransduction signaling pathways. Substrate stiffness changes cell phenotypes and promotes angiogenesis, epithelial to mesenchymal transition (EMT), and metastasis in tumors. Enhanced liver tissue matrix stiffness plays a crucial role in the tumorigenesis and malignant development of liver cancer and is associated with unfavorable survival outcomes. However, how liver cancer cells sense changes in ECM stiffness and the underlying molecular mechanisms are largely unknown. Methods: Seeding HepG2 cells on the micropillar gels, HepG2 cells were assessed for responsiveness to mechanotransduction using Western blot and immunofluorescence. Conclusions: We found that higher substrate stiffness dramatically enhanced malignant cell phenotypes and promoted G1/S transition in HepG2 cells. Furthermore, nuclear paraspeckle assembly transcript 1 (NEAT1) was identified as a matrix stiffness-responsive long non-coding RNA (lncRNA) regulating proliferation and EMT in response to increasing matrix stiffness during the progression of HepG2 cells towards liver cancer phenotypes. Higher matrix stiffness contributed to enhancing NEAT1 expression, which activated the WNT/β-catenin pathway. β-catenin translocates and enters the nucleus and the EMT transcription factor zinc finger E-box binding homeobox 1 (ZEB1) was upregulated to trigger EMT. Additionally, the proteins required for matrix stiffness-induced proliferation and resistance were strikingly upregulated in HepG2 cells. Therefore, our findings provide evidence that ECM-derived mechanical signals regulate cell proliferation and drive EMT through a NEAT1/WNT/β-catenin mechanotransduction pathway in the tumor microenvironment of liver cancer. Full article

(This article belongs to the Special Issue Non-coding RNA Biogenesis and Function 2021)

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15 pages, 4500 KiB

Open AccessArticle

Rhizosphere Microbiomes of Potato Cultivated under Bacillus subtilis Treatment Influence the Quality of Potato Tubers

by Jian Song, Zhi-Qiang Kong, Dan-Dan Zhang, Jie-Yin Chen, Xiao-Feng Dai and Ran Li

Int. J. Mol. Sci. 2021, 22(21), 12065; https://doi.org/10.3390/ijms222112065 - 08 Nov 2021

Cited by 12 | Viewed by 2885

Abstract

Plants serve as a niche for the growth and proliferation of a diversity of microorganisms. Soil microorganisms, which closely interact with plants, are increasingly being recognized as factors important to plant health. In this study, we explored the use of high-throughput DNA sequencing [...] Read more.

Plants serve as a niche for the growth and proliferation of a diversity of microorganisms. Soil microorganisms, which closely interact with plants, are increasingly being recognized as factors important to plant health. In this study, we explored the use of high-throughput DNA sequencing of the fungal ITS and bacterial 16S for characterization of the fungal and bacterial microbiomes following biocontrol treatment (DT) with Bacillus subtilis strain Bv17 relative to treatments without biocontrol (DC) during the potato growth cycle at three time points. A total of 5631 operational taxonomic units (OTUs) were identified from the 16S data, and 2236 OTUs were identified from the ITS data. The number of bacterial and fungal OTU in DT was higher than in DC and gradually increased during potato growth. In addition, indices such as Ace, Chao, Shannon, and Simpson were higher in DT than in DC, indicating greater richness and community diversity in soil following the biocontrol treatment. Additionally, the potato tuber yields improved without a measurable change in the bacterial communities following the B. subtilis strain Bv17 treatment. These results suggest that soil microbial communities in the rhizosphere are differentially affected by the biocontrol treatment while improving potato yield, providing a strong basis for biocontrol utilization in crop production. Full article

(This article belongs to the Collection Recent Advances in Plant Molecular Science in China 2021)

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19 pages, 5320 KiB

Open AccessArticle

Early Deconditioning of Human Skeletal Muscles and the Effects of a Thigh Cuff Countermeasure

by Théo Fovet, Corentin Guilhot, Laurence Stevens, Valérie Montel, Pierre Delobel, Rémi Roumanille, Michel-Yves Semporé, Damien Freyssenet, Guillaume Py, Thomas Brioche and Angèle Chopard

Int. J. Mol. Sci. 2021, 22(21), 12064; https://doi.org/10.3390/ijms222112064 - 08 Nov 2021

Cited by 6 | Viewed by 2446

Abstract

Muscle deconditioning is a major consequence of a wide range of conditions from spaceflight to a sedentary lifestyle, and occurs as a result of muscle inactivity, leading to a rapid decrease in muscle strength, mass, and oxidative capacity. The early changes that appear [...] Read more.

Muscle deconditioning is a major consequence of a wide range of conditions from spaceflight to a sedentary lifestyle, and occurs as a result of muscle inactivity, leading to a rapid decrease in muscle strength, mass, and oxidative capacity. The early changes that appear in the first days of inactivity must be studied to determine effective methods for the prevention of muscle deconditioning. To evaluate the mechanisms of muscle early changes and the vascular effect of a thigh cuff, a five-day dry immersion (DI) experiment was conducted by the French Space Agency at the MEDES Space Clinic (Rangueil, Toulouse). Eighteen healthy males were recruited and divided into a control group and a thigh cuff group, who wore a thigh cuff at 30 mmHg. All participants underwent five days of DI. Prior to and at the end of the DI, the lower limb maximal strength was measured and muscle biopsies were collected from the vastus lateralis muscle. Five days of DI resulted in muscle deconditioning in both groups. The maximal voluntary isometric contraction of knee extension decreased significantly. The muscle fiber cross-sectional area decreased significantly by 21.8%, and the protein balance seems to be impaired, as shown by the reduced activation of the mTOR pathway. Measurements of skinned muscle fibers supported these results and potential changes in oxidative capacity were highlighted by a decrease in PGC1-α levels. The use of the thigh cuff did not prevent muscle deconditioning or impact muscle function. These results suggest that the major effects of muscle deconditioning occur during the first few days of inactivity, and countermeasures against muscle deconditioning should target this time period. These results are also relevant for the understanding of muscle weakness induced by muscle diseases, aging, and patients in intensive care. Full article

(This article belongs to the Special Issue Skeletal Muscle Molecular Signalling in Various Models of Disuse and Unloading)

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21 pages, 12860 KiB

Open AccessArticle

Clioquinol Decreases Levels of Phosphorylated, Truncated, and Oligomerized Tau Protein

by Gaoping Lin, Feiyan Zhu, Nicholas M. Kanaan, Rei Asano, Norimichi Shirafuji, Hirohito Sasaki, Tomohisa Yamaguchi, Soichi Enomoto, Yoshinori Endo, Asako Ueno, Masamichi Ikawa, Kouji Hayashi, Osamu Yamamura, Shu-Hui Yen, Yasunari Nakamoto and Tadanori Hamano

Int. J. Mol. Sci. 2021, 22(21), 12063; https://doi.org/10.3390/ijms222112063 - 08 Nov 2021

Cited by 10 | Viewed by 2537

Abstract

The neuropathological hallmarks of Alzheimer’s disease (AD) are senile plaques (SPs), which are composed of amyloid β protein (Aβ), and neurofibrillary tangles (NFTs), which consist of highly phosphorylated tau protein. As bio-metal imbalance may be involved in the formation of NFT and SPs, [...] Read more.

The neuropathological hallmarks of Alzheimer’s disease (AD) are senile plaques (SPs), which are composed of amyloid β protein (Aβ), and neurofibrillary tangles (NFTs), which consist of highly phosphorylated tau protein. As bio-metal imbalance may be involved in the formation of NFT and SPs, metal regulation may be a direction for AD treatment. Clioquinol (CQ) is a metal-protein attenuating compound with mild chelating effects for Zn²⁺ and Cu²⁺, and CQ can not only detach metals from SPs, but also decrease amyloid aggregation in the brain. Previous studies suggested that Cu²⁺ induces the hyperphosphorylation of tau. However, the effects of CQ on tau were not fully explored. To examine the effects of CQ on tau metabolism, we used a human neuroblastoma cell line, M1C cells, which express wild-type tau protein (4R0N) via tetracycline-off (TetOff) induction. In a morphological study and ATP assay, up to 10 μM CQ had no effect on cell viability; however, 100 μM CQ had cytotoxic effects. CQ decreased accumulation of Cu⁺ in the M1C cells (39.4% of the control), and both total and phosphorylated tau protein. It also decreased the activity of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) (37.3% and 60.7% levels of the control, respectively), which are tau kinases. Of note, activation of protein phosphatase 2A (PP2A), which is a tau phosphatase, was also observed after CQ treatment. Fractionation experiments demonstrated a reduction of oligomeric tau in the tris insoluble, sarkosyl soluble fraction by CQ treatment. CQ also decreased caspase-cleaved tau, which accelerated the aggregation of tau protein. CQ activated autophagy and proteasome pathways, which are considered important for the degradation of tau protein. Although further studies are needed to elucidate the mechanisms responsible for the effects of CQ on tau, CQ may shed light on possible AD therapeutics. Full article

(This article belongs to the Special Issue Autophagy in the Nervous System)

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15 pages, 4457 KiB

Open AccessArticle

Hetero/Homo-Complexes of Sucrose Transporters May Be a Subtle Mode to Regulate Sucrose Transportation in Grape Berries

by Yumeng Cai, Ling Yin, Jie Wang, Wenjie Dong, Han Gao, Jinxu Xu, Zhefang Deng, Wenrui Tu, Jing Yan, Qingyong Meng and Yali Zhang

Int. J. Mol. Sci. 2021, 22(21), 12062; https://doi.org/10.3390/ijms222112062 - 08 Nov 2021

Cited by 4 | Viewed by 1588

Abstract

The sugar distribution mechanism in fruits has been the focus of research worldwide; however, it remains unclear. In order to elucidate the relevant mechanisms in grape berries, the expression, localization, function, and regulation of three sucrose transporters were studied in three representative Vitis [...] Read more.

The sugar distribution mechanism in fruits has been the focus of research worldwide; however, it remains unclear. In order to elucidate the relevant mechanisms in grape berries, the expression, localization, function, and regulation of three sucrose transporters were studied in three representative Vitis varieties. Both SUC11 and SUC12 expression levels were positively correlated with sugar accumulation in grape berries, whereas SUC27 showed a negative relationship. The alignment analysis and sucrose transport ability of isolated SUCs were determined to reflect coding region variations among V. vinifera, V. amurensis Ruper, and V. riparia, indicating that functional variation existed in one SUT from different varieties. Furthermore, potentially oligomerized abilities of VvSUCs colocalized in the sieve elements of the phloem as plasma membrane proteins were verified. The effects of oligomerization on transport properties were characterized in yeast. VvSUC11 and VvSUC12 are high-affinity/low-capacity types of SUTs that stimulate each other by upregulating V_max and K_m, inhibiting sucrose transport, and downregulating the K_m of VvSUC27. Thus, changes in the distribution of different SUTs in the same cell govern functional regulation. The activation and inhibition of sucrose transport could be achieved in different stages and tissues of grape development to achieve an effective distribution of sugar. Full article

(This article belongs to the Special Issue Sugar Transport in Plants)

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