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Int. J. Mol. Sci., Volume 22, Issue 19 (October-1 2021) – 721 articles

Cover Story (view full-size image): Data in this report support the model that chemotherapy modifies the blood vessel wall by a two-prong mechanism: (a) increasing vascular permeability and (b) inducing the remodeling of the basement membrane underlying the blood vessel wall via an MMP2-dependent process. The net result is an increase in the adhesiveness of vascular wall, allowing cancer cells—shortly after their arrival at the lung—to adhere, at least in part, through integrin β1 on the cells. Since vascular adhesion is an important step in the metastatic cascade and since metastasis is the major cause of cancer death, understanding how chemotherapy, the very treatment to combat cancer, enhances this step may provide strategies to improve the efficacy of chemotherapy. View this paper
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23 pages, 1843 KiB  
Review
Exosomes and Brain Metastases: A Review on Their Role and Potential Applications
by Filipa D. Oliveira, Miguel A. R. B. Castanho and Vera Neves
Int. J. Mol. Sci. 2021, 22(19), 10899; https://doi.org/10.3390/ijms221910899 - 8 Oct 2021
Cited by 15 | Viewed by 4239
Abstract
Brain metastases (BM) are a frequent complication in patients with advanced stages of cancer, associated with impairment of the neurological function, quality of life, prognosis, and survival. BM treatment consists of a combination of the available cancer therapies, such as surgery, radiotherapy, chemotherapy, [...] Read more.
Brain metastases (BM) are a frequent complication in patients with advanced stages of cancer, associated with impairment of the neurological function, quality of life, prognosis, and survival. BM treatment consists of a combination of the available cancer therapies, such as surgery, radiotherapy, chemotherapy, immunotherapy and targeted therapies. Even so, cancer patients with BM are still linked to poor prognosis, with overall survival being reported as 12 months or less. Intercellular communication has a pivotal role in the development of metastases, therefore, it has been extensively studied not only to better understand the metastization process, but also to further develop new therapeutic strategies. Exosomes have emerged as key players in intercellular communication being potential therapeutic targets, drug delivery systems (DDS) or biomarkers. In this Review, we focus on the role of these extracellular vesicles (EVs) in BM formation and their promising application in the development of new BM therapeutic strategies. Full article
(This article belongs to the Special Issue Nanoparticles in CNS Diseases)
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15 pages, 1671 KiB  
Article
Characterizing Binding Interactions That Are Essential for Selective Transport through the Nuclear Pore Complex
by Kathleen M. Lennon, Mohammad Soheilypour, Mohaddeseh Peyro, Devin L. Wakefield, Grace E. Choo, Mohammad R. K. Mofrad and Tijana Jovanovic-Talisman
Int. J. Mol. Sci. 2021, 22(19), 10898; https://doi.org/10.3390/ijms221910898 - 8 Oct 2021
Cited by 7 | Viewed by 2578
Abstract
Specific macromolecules are rapidly transported across the nuclear envelope via the nuclear pore complex (NPC). The selective transport process is facilitated when nuclear transport receptors (NTRs) weakly and transiently bind to intrinsically disordered constituents of the NPC, FG Nups. These two types of [...] Read more.
Specific macromolecules are rapidly transported across the nuclear envelope via the nuclear pore complex (NPC). The selective transport process is facilitated when nuclear transport receptors (NTRs) weakly and transiently bind to intrinsically disordered constituents of the NPC, FG Nups. These two types of proteins help maintain the selective NPC barrier. To interrogate their binding interactions in vitro, we deployed an NPC barrier mimic. We created the stationary phase by covalently attaching fragments of a yeast FG Nup called Nsp1 to glass coverslips. We used a tunable mobile phase containing NTR, nuclear transport factor 2 (NTF2). In the stationary phase, three main factors affected binding: the number of FG repeats, the charge of fragments, and the fragment density. We also identified three main factors affecting binding in the mobile phase: the avidity of the NTF2 variant for Nsp1, the presence of nonspecific proteins, and the presence of additional NTRs. We used both experimentally determined binding parameters and molecular dynamics simulations of Nsp1FG fragments to create an agent-based model. The results suggest that NTF2 binding is negatively cooperative and dependent on the density of Nsp1FG molecules. Our results demonstrate the strengths of combining experimental and physical modeling approaches to study NPC-mediated transport. Full article
(This article belongs to the Special Issue The Molecular Mechanisms of Nuclear Transport in Health and Disease)
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12 pages, 1597 KiB  
Article
GreeningDB: A Database of Host–Pathogen Protein–Protein Interactions and Annotation Features of the Bacteria Causing Huanglongbing HLB Disease
by Cristian D. Loaiza, Naveen Duhan and Rakesh Kaundal
Int. J. Mol. Sci. 2021, 22(19), 10897; https://doi.org/10.3390/ijms221910897 - 8 Oct 2021
Cited by 3 | Viewed by 2751
Abstract
The Citrus genus comprises some of the most important and commonly cultivated fruit plants. Within the last decade, citrus greening disease (also known as huanglongbing or HLB) has emerged as the biggest threat for the citrus industry. This disease does not have a [...] Read more.
The Citrus genus comprises some of the most important and commonly cultivated fruit plants. Within the last decade, citrus greening disease (also known as huanglongbing or HLB) has emerged as the biggest threat for the citrus industry. This disease does not have a cure yet and, thus, many efforts have been made to find a solution to this devastating condition. There are challenges in the generation of high-yield resistant cultivars, in part due to the limited and sparse knowledge about the mechanisms that are used by the Liberibacter bacteria to proliferate the infection in Citrus plants. Here, we present GreeningDB, a database implemented to provide the annotation of Liberibacter proteomes, as well as the host–pathogen comparactomics tool, a novel platform to compare the predicted interactomes of two HLB host–pathogen systems. GreeningDB is built to deliver a user-friendly interface, including network visualization and links to other resources. We hope that by providing these characteristics, GreeningDB can become a central resource to retrieve HLB-related protein annotations, and thus, aid the community that is pursuing the development of molecular-based strategies to mitigate this disease’s impact. The database is freely available at http://bioinfo.usu.edu/GreeningDB/ (accessed on 11 August 2021). Full article
(This article belongs to the Special Issue Applied and Advanced Research in Plant Bioinformatics)
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15 pages, 4088 KiB  
Article
7,8-Dihydroxiflavone Protects Adult Rat Axotomized Retinal Ganglion Cells through MAPK/ERK and PI3K/AKT Activation
by Caridad Galindo-Romero, Beatriz Vidal-Villegas, Javier Asís-Martínez, Fernando Lucas-Ruiz, Alejandro Gallego-Ortega and Manuel Vidal-Sanz
Int. J. Mol. Sci. 2021, 22(19), 10896; https://doi.org/10.3390/ijms221910896 - 8 Oct 2021
Cited by 11 | Viewed by 2209
Abstract
We analyze the 7,8-dihydroxyflavone (DHF)/TrkB signaling activation of two main intracellular pathways, mitogen-activated protein kinase (MAPK)/ERK and phosphatidylinositol 3 kinase (PI3K)/AKT, in the neuroprotection of axotomized retinal ganglion cells (RGCs). Methods: Adult albino Sprague-Dawley rats received left intraorbital optic nerve transection (IONT) and [...] Read more.
We analyze the 7,8-dihydroxyflavone (DHF)/TrkB signaling activation of two main intracellular pathways, mitogen-activated protein kinase (MAPK)/ERK and phosphatidylinositol 3 kinase (PI3K)/AKT, in the neuroprotection of axotomized retinal ganglion cells (RGCs). Methods: Adult albino Sprague-Dawley rats received left intraorbital optic nerve transection (IONT) and were divided in two groups. One group received daily intraperitoneal DHF (5 mg/kg) and another vehicle (1%DMSO in 0.9%NaCl) from one day before IONT until processing. Additional intact rats were employed as control (n = 4). At 1, 3 or 7 days (d) after IONT, phosphorylated (p)AKT, p-MAPK, and non-phosphorylated AKT and MAPK expression levels were analyzed in the retina by Western blotting (n = 4/group). Radial sections were also immunodetected for the above-mentioned proteins, and for Brn3a and vimentin to identify RGCs and Müller cells (MCs), respectively (n = 3/group). Results: IONT induced increased levels of p-MAPK and MAPK at 3d in DHF- or vehicle-treated retinas and at 7d in DHF-treated retinas. IONT induced a fast decrease in AKT in retinas treated with DHF or vehicle, with higher levels of phosphorylation in DHF-treated retinas at 7d. In intact retinas and vehicle-treated groups, no p-MAPK or MAPK expression in RGCs was observed. In DHF- treated retinas p-MAPK and MAPK were expressed in the ganglion cell layer and in the RGC nuclei 3 and 7d after IONT. AKT was observed in intact and axotomized RGCs, but the signal intensity of p-AKT was stronger in DHF-treated retinas. Finally, MCs expressed higher quantities of both MAPK and AKT at 3d in both DHF- and vehicle-treated retinas, and at 7d the phosphorylation of p-MAPK was higher in DHF-treated groups. Conclusions: Phosphorylation and increased levels of AKT and MAPK through MCs and RGCs in retinas after DHF-treatment may be responsible for the increased and long-lasting RGC protection afforded by DHF after IONT. Full article
(This article belongs to the Special Issue Retina Degeneration, Neuroprotection and Repair)
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16 pages, 4474 KiB  
Article
Structural Alterations of Antigens at the Material Interface: An Early Decision Toolbox Facilitating Safe-by-Design Nanovaccine Development
by Litty Johnson, Lorenz Aglas, Wai Tuck Soh, Mark Geppert, Sabine Hofer, Norbert Hofstätter, Peter Briza, Fatima Ferreira, Richard Weiss, Hans Brandstetter, Albert Duschl and Martin Himly
Int. J. Mol. Sci. 2021, 22(19), 10895; https://doi.org/10.3390/ijms221910895 - 8 Oct 2021
Cited by 4 | Viewed by 2711
Abstract
Nanomaterials have found extensive interest in the development of novel vaccines, as adjuvants and/or carriers in vaccination platforms. Conjugation of protein antigens at the particle surface by non-covalent adsorption is the most widely used approach in licensed particulate vaccines. Hence, it is essential [...] Read more.
Nanomaterials have found extensive interest in the development of novel vaccines, as adjuvants and/or carriers in vaccination platforms. Conjugation of protein antigens at the particle surface by non-covalent adsorption is the most widely used approach in licensed particulate vaccines. Hence, it is essential to understand proteins’ structural integrity at the material interface in order to develop safe-by-design nanovaccines. In this study, we utilized two model proteins, the wild-type allergen Bet v 1 and its hypoallergenic fold variant (BM4), to compare SiO2 nanoparticles with Alhydrogel® as particulate systems. A set of biophysical and functional assays including circular dichroism spectroscopy and proteolytic degradation was used to examine the antigens’ structural integrity at the material interface. Conjugation of both biomolecules to the particulate systems decreased their proteolytic stability. However, we observed qualitative and quantitative differences in antigen processing concomitant with differences in their fold stability. These changes further led to an alteration in IgE epitope recognition. Here, we propose a toolbox of biophysical and functional in vitro assays for the suitability assessment of nanomaterials in the early stages of vaccine development. These tools will aid in safe-by-design innovations and allow fine-tuning the properties of nanoparticle candidates to shape a specific immune response. Full article
(This article belongs to the Special Issue Functional Nanomaterials for Healthcare)
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15 pages, 4499 KiB  
Article
Aging Resistance of Biocomposites Crosslinked with Silica and Quercetin
by Anna Masek and Olga Olejnik
Int. J. Mol. Sci. 2021, 22(19), 10894; https://doi.org/10.3390/ijms221910894 - 8 Oct 2021
Cited by 9 | Viewed by 2392
Abstract
This research focuses on revealing the double role of quercetin accompanied by silica in epoxidized natural rubber. A crosslinking ability with antioxidative properties exists and reveals the dependence of these functions on quercetin content. Here, the aging resistance of self-healable biocomposites was analyzed. [...] Read more.
This research focuses on revealing the double role of quercetin accompanied by silica in epoxidized natural rubber. A crosslinking ability with antioxidative properties exists and reveals the dependence of these functions on quercetin content. Here, the aging resistance of self-healable biocomposites was analyzed. The self-healing properties were presented in our previous work. The stabilizing effect of quercetin applied as a crosslinking agent has been studied in epoxidized natural rubber with a 50 mol% of epoxidation (ENR-50). Some of five -OH moiety groups existing in the quercetin structure are able to react with epoxy rings of ENR-50 and cure this elastomer, whereas other free hydroxyl groups can donate the hydrogen molecule to a radical molecule, stabilizing it. The aging resistance of prepared composites was estimated by mechanical tests conducted before and after different types of aging, as well as by differences in color and surface energy between aged and un-aged samples. Changes within the oxygen function, which occurred as a result of the aging process, were observed using FT-IR absorbance spectroscopy. Furthermore, the impact of quercetin content on composites’ thermal stability was investigated by thermogravimetry (TGA). According to the results, a proper dose of quercetin can act as a crosslinker and antioxidant in ENR-50 at the same time. Full article
(This article belongs to the Special Issue Advanced Polymer Composite Materials III)
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18 pages, 1986 KiB  
Article
Sphingosine-1 Phosphate Lyase Regulates Sensitivity of Pancreatic Beta-Cells to Lipotoxicity
by Yadi Tang, Thomas Plötz, Markus H. Gräler and Ewa Gurgul-Convey
Int. J. Mol. Sci. 2021, 22(19), 10893; https://doi.org/10.3390/ijms221910893 - 8 Oct 2021
Cited by 5 | Viewed by 2445
Abstract
Elevated levels of free fatty acids (FFAs) have been related to pancreatic beta-cell failure in type 2 diabetes (T2DM), though the underlying mechanisms are not yet fully understood. FFAs have been shown to dysregulate formation of bioactive sphingolipids, such as ceramides and sphingosine-1 [...] Read more.
Elevated levels of free fatty acids (FFAs) have been related to pancreatic beta-cell failure in type 2 diabetes (T2DM), though the underlying mechanisms are not yet fully understood. FFAs have been shown to dysregulate formation of bioactive sphingolipids, such as ceramides and sphingosine-1 phosphate (S1P) in beta-cells. The aim of this study was to analyze the role of sphingosine-1 phosphate lyase (SPL), a key enzyme of the sphingolipid pathway that catalyzes an irreversible degradation of S1P, in the sensitivity of beta-cells to lipotoxicity. To validate the role of SPL in lipotoxicity, we modulated SPL expression in rat INS1E cells and in human EndoC-βH1 beta-cells. SPL overexpression in INS1E cells (INS1E-SPL), which are characterized by a moderate basal expression level of SPL, resulted in an acceleration of palmitate-mediated cell viability loss, proliferation inhibition and induction of oxidative stress. SPL overexpression affected the mRNA expression of ER stress markers and mitochondrial chaperones. In contrast to control cells, in INS1E-SPL cells no protective effect of oleate was detected. Moreover, Plin2 expression and lipid droplet formation were strongly reduced in OA-treated INS1E-SPL cells. Silencing of SPL in human EndoC-βH1 beta-cells, which are characterized by a significantly higher SPL expression as compared to rodent beta-cells, resulted in prevention of FFA-mediated caspase-3/7 activation. Our findings indicate that an adequate control of S1P degradation by SPL might be crucially involved in the susceptibility of pancreatic beta-cells to lipotoxicity. Full article
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 2.0)
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13 pages, 3133 KiB  
Article
Salt Stress Promotes Abscisic Acid Accumulation to Affect Cell Proliferation and Expansion of Primary Roots in Rice
by Yingying Huang, Jiahao Zhou, Yuxiang Li, Ruidang Quan, Juan Wang, Rongfeng Huang and Hua Qin
Int. J. Mol. Sci. 2021, 22(19), 10892; https://doi.org/10.3390/ijms221910892 - 8 Oct 2021
Cited by 32 | Viewed by 3392
Abstract
The primary root is the basic component of the root system and plays a key role in early seedling growth in rice. Its growth is easily affected by environmental cues, such as salt stress. Abscisic acid (ABA) plays an essential role in root [...] Read more.
The primary root is the basic component of the root system and plays a key role in early seedling growth in rice. Its growth is easily affected by environmental cues, such as salt stress. Abscisic acid (ABA) plays an essential role in root development, but the molecular mechanism underlying ABA-regulated root growth in response to salt stress remains poorly understood. In this study, we report that salt stress inhibits primary root elongation and promotes primary root swelling. Moreover, salt stress induces the expression of ABA-responsive genes and ABA accumulation in the primary root, revealing that ABA plays an essential role in salt-modulated root growth. Transgenic lines of OsSAPK10-OE and OsABIL2-OE, which constitutively express OsSAPK10 or OsABIL2, with enhanced or attenuated ABA signaling, show increased and decreased sensitivity to salt, correspondingly. Microscopic analysis indicates that salt and ABA inhibits cell proliferation and promotes cell expansion in the root apical meristem. Transcriptome analysis showed that ABA induces the expression of EXPANSIN genes. Further investigations indicate that ABA exerts these effects largely through ABA signaling. Thus, our findings deepen our understanding of the role of ABA in controlling primary root growth in response to salt stress, and this knowledge can be used by breeders to cultivate rice varieties suitable for saline–alkali land. Full article
(This article belongs to the Special Issue Hormonal Regulations of Plant Development)
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14 pages, 2166 KiB  
Review
A Survey of Autoencoder Algorithms to Pave the Diagnosis of Rare Diseases
by David Pratella, Samira Ait-El-Mkadem Saadi, Sylvie Bannwarth, Véronique Paquis-Fluckinger and Silvia Bottini
Int. J. Mol. Sci. 2021, 22(19), 10891; https://doi.org/10.3390/ijms221910891 - 8 Oct 2021
Cited by 17 | Viewed by 4175
Abstract
Rare diseases (RDs) concern a broad range of disorders and can result from various origins. For a long time, the scientific community was unaware of RDs. Impressive progress has already been made for certain RDs; however, due to the lack of sufficient knowledge, [...] Read more.
Rare diseases (RDs) concern a broad range of disorders and can result from various origins. For a long time, the scientific community was unaware of RDs. Impressive progress has already been made for certain RDs; however, due to the lack of sufficient knowledge, many patients are not diagnosed. Nowadays, the advances in high-throughput sequencing technologies such as whole genome sequencing, single-cell and others, have boosted the understanding of RDs. To extract biological meaning using the data generated by these methods, different analysis techniques have been proposed, including machine learning algorithms. These methods have recently proven to be valuable in the medical field. Among such approaches, unsupervised learning methods via neural networks including autoencoders (AEs) or variational autoencoders (VAEs) have shown promising performances with applications on various type of data and in different contexts, from cancer to healthy patient tissues. In this review, we discuss how AEs and VAEs have been used in biomedical settings. Specifically, we discuss their current applications and the improvements achieved in diagnostic and survival of patients. We focus on the applications in the field of RDs, and we discuss how the employment of AEs and VAEs would enhance RD understanding and diagnosis. Full article
(This article belongs to the Special Issue Computational and Omics Research on Rare Diseases)
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33 pages, 1466 KiB  
Review
Angiogenic Effects and Crosstalk of Adipose-Derived Mesenchymal Stem/Stromal Cells and Their Extracellular Vesicles with Endothelial Cells
by Swarna Rautiainen, Timo Laaksonen and Raili Koivuniemi
Int. J. Mol. Sci. 2021, 22(19), 10890; https://doi.org/10.3390/ijms221910890 - 8 Oct 2021
Cited by 48 | Viewed by 5256
Abstract
Adipose-derived mesenchymal stem/stromal cells (ASCs) are an adult stem cell population able to self-renew and differentiate into numerous cell lineages. ASCs provide a promising future for therapeutic angiogenesis due to their ability to promote blood vessel formation. Specifically, their ability to differentiate into [...] Read more.
Adipose-derived mesenchymal stem/stromal cells (ASCs) are an adult stem cell population able to self-renew and differentiate into numerous cell lineages. ASCs provide a promising future for therapeutic angiogenesis due to their ability to promote blood vessel formation. Specifically, their ability to differentiate into endothelial cells (ECs) and pericyte-like cells and to secrete angiogenesis-promoting growth factors and extracellular vesicles (EVs) makes them an ideal option in cell therapy and in regenerative medicine in conditions including tissue ischemia. In recent angiogenesis research, ASCs have often been co-cultured with an endothelial cell (EC) type in order to form mature vessel-like networks in specific culture conditions. In this review, we introduce co-culture systems and co-transplantation studies between ASCs and ECs. In co-cultures, the cells communicate via direct cell–cell contact or via paracrine signaling. Most often, ASCs are found in the perivascular niche lining the vessels, where they stabilize the vascular structures and express common pericyte surface proteins. In co-cultures, ASCs modulate endothelial cells and induce angiogenesis by promoting tube formation, partly via secretion of EVs. In vivo co-transplantation of ASCs and ECs showed improved formation of functional vessels over a single cell type transplantation. Adipose tissue as a cell source for both mesenchymal stem cells and ECs for co-transplantation serves as a prominent option for therapeutic angiogenesis and blood perfusion in vivo. Full article
(This article belongs to the Special Issue Molecular Morphology and Function of Stromal Cells)
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22 pages, 367 KiB  
Review
Electroencephalography as a Non-Invasive Biomarker of Alzheimer’s Disease: A Forgotten Candidate to Substitute CSF Molecules?
by Paloma Monllor, Ana Cervera-Ferri, Maria-Angeles Lloret, Daniel Esteve, Begoña Lopez, Jose-Luis Leon and Ana Lloret
Int. J. Mol. Sci. 2021, 22(19), 10889; https://doi.org/10.3390/ijms221910889 - 8 Oct 2021
Cited by 19 | Viewed by 3428
Abstract
Biomarkers for disease diagnosis and prognosis are crucial in clinical practice. They should be objective and quantifiable and respond to specific therapeutic interventions. Optimal biomarkers should reflect the underlying process (pathological or not), be reproducible, widely available, and allow measurements repeatedly over time. [...] Read more.
Biomarkers for disease diagnosis and prognosis are crucial in clinical practice. They should be objective and quantifiable and respond to specific therapeutic interventions. Optimal biomarkers should reflect the underlying process (pathological or not), be reproducible, widely available, and allow measurements repeatedly over time. Ideally, biomarkers should also be non-invasive and cost-effective. This review aims to focus on the usefulness and limitations of electroencephalography (EEG) in the search for Alzheimer’s disease (AD) biomarkers. The main aim of this article is to review the evolution of the most used biomarkers in AD and the need for new peripheral and, ideally, non-invasive biomarkers. The characteristics of the EEG as a possible source for biomarkers will be revised, highlighting its advantages compared to the molecular markers available so far. Full article
(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 2.0)
18 pages, 6378 KiB  
Article
TmSpz-like Plays a Fundamental Role in Response to E. coli but Not S. aureus or C. albican Infection in Tenebrio molitor via Regulation of Antimicrobial Peptide Production
by Ho Am Jang, Bharat Bhusan Patnaik, Maryam Ali Mohammadie Kojour, Bo Bae Kim, Young Min Bae, Ki Beom Park, Yong Seok Lee, Yong Hun Jo and Yeon Soo Han
Int. J. Mol. Sci. 2021, 22(19), 10888; https://doi.org/10.3390/ijms221910888 - 8 Oct 2021
Cited by 16 | Viewed by 3044
Abstract
The cystine knot protein Spätzle is a Toll receptor ligand that modulates the intracellular signaling cascade involved in the nuclear factor kappa B (NF-κB)-mediated regulation of antimicrobial peptide (AMP)-encoding genes. Spätzle-mediated activation of the Toll pathway is critical for the innate immune responses [...] Read more.
The cystine knot protein Spätzle is a Toll receptor ligand that modulates the intracellular signaling cascade involved in the nuclear factor kappa B (NF-κB)-mediated regulation of antimicrobial peptide (AMP)-encoding genes. Spätzle-mediated activation of the Toll pathway is critical for the innate immune responses of insects against Gram-positive bacteria and fungi. In this study, the open reading frame (ORF) sequence of Spätzle-like from T. molitor (TmSpz-like) identified from the RNA sequencing dataset was cloned and sequenced. The 885-bp TmSpz-like ORF encoded a polypeptide of 294 amino acid residues. TmSpz-like comprised a cystine knot domain with six conserved cysteine residues that formed three disulfide bonds. Additionally, TmSpz-like exhibited the highest amino acid sequence similarity with T. castaneum Spätzle (TcSpz). In the phylogenetic tree, TmSpz-like and TcSpz were located within a single cluster. The expression of TmSpz-like was upregulated in the Malpighian tubules and gut tissues of T. molitor. Additionally, the expression of TmSpz-like in the whole body and gut of the larvae was upregulated at 24 h post-E. coli infection. The results of RNA interference experiments revealed that TmSpz-like is critical for the viability of E. coli-infected T. molitor larvae. Eleven AMP-encoding genes were downregulated in the E. coli-infected TmSpz-like knockdown larvae, which suggested that TmSpz-like positively regulated these genes. Additionally, the NF-κB-encoding genes (TmDorX1, TmDorX2, and TmRelish) were downregulated in the E. coli-infected TmSpz-like knockdown larvae. Thus, TmSpz-like plays a critical role in the regulation of AMP production in T. molitor in response to E. coli infection. Full article
(This article belongs to the Special Issue Host-Pathogen Interaction 3.0)
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10 pages, 1355 KiB  
Article
Complex Transposon Insertion as a Novel Cause of Pompe Disease
by Igor Bychkov, Galina Baydakova, Alexandra Filatova, Ochir Migiaev, Andrey Marakhonov, Nataliya Pechatnikova, Ekaterina Pomerantseva, Fedor Konovalov, Maria Ampleeva, Vladimir Kaimonov, Mikhail Skoblov and Ekaterina Zakharova
Int. J. Mol. Sci. 2021, 22(19), 10887; https://doi.org/10.3390/ijms221910887 - 8 Oct 2021
Cited by 9 | Viewed by 2673
Abstract
Pompe disease (OMIM#232300) is an autosomal recessive lysosomal storage disorder caused by mutations in the GAA gene. According to public mutation databases, more than 679 pathogenic variants have been described in GAA, none of which are associated with mobile genetic elements. In [...] Read more.
Pompe disease (OMIM#232300) is an autosomal recessive lysosomal storage disorder caused by mutations in the GAA gene. According to public mutation databases, more than 679 pathogenic variants have been described in GAA, none of which are associated with mobile genetic elements. In this article, we report a novel molecular genetic cause of Pompe disease, which could be hardly detected using routine molecular genetic analysis. Whole genome sequencing followed by comprehensive functional analysis allowed us to discover and characterize a complex mobile genetic element insertion deep in the intron 15 of the GAA gene in a patient with infantile onset Pompe disease. Full article
(This article belongs to the Special Issue Molecular Mechanism Underlying Rare Inherited Neurological Diseases)
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16 pages, 2211 KiB  
Review
Actin Cytoskeletal Dynamics in Single-Cell Wound Repair
by Malene Laage Ebstrup, Catarina Dias, Anne Sofie Busk Heitmann, Stine Lauritzen Sønder and Jesper Nylandsted
Int. J. Mol. Sci. 2021, 22(19), 10886; https://doi.org/10.3390/ijms221910886 - 8 Oct 2021
Cited by 16 | Viewed by 3969
Abstract
The plasma membrane protects the eukaryotic cell from its surroundings and is essential for cell viability; thus, it is crucial that membrane disruptions are repaired quickly to prevent immediate dyshomeostasis and cell death. Accordingly, cells have developed efficient repair mechanisms to rapidly reseal [...] Read more.
The plasma membrane protects the eukaryotic cell from its surroundings and is essential for cell viability; thus, it is crucial that membrane disruptions are repaired quickly to prevent immediate dyshomeostasis and cell death. Accordingly, cells have developed efficient repair mechanisms to rapidly reseal ruptures and reestablish membrane integrity. The cortical actin cytoskeleton plays an instrumental role in both plasma membrane resealing and restructuring in response to damage. Actin directly aids membrane repair or indirectly assists auxiliary repair mechanisms. Studies investigating single-cell wound repair have often focused on the recruitment and activation of specialized repair machinery, despite the undeniable need for rapid and dynamic cortical actin modulation; thus, the role of the cortical actin cytoskeleton during wound repair has received limited attention. This review aims to provide a comprehensive overview of membrane repair mechanisms directly or indirectly involving cortical actin cytoskeletal remodeling. Full article
(This article belongs to the Special Issue The Plasma Membrane-Cytoskeleton Interface)
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20 pages, 19733 KiB  
Article
Molecular Imaging of Human Skeletal Myoblasts (huSKM) in Mouse Post-Infarction Myocardium
by Katarzyna Fiedorowicz, Weronika Wargocka-Matuszewska, Karolina A. Ambrożkiewicz, Anna Rugowska, Łukasz Cheda, Michał Fiedorowicz, Agnieszka Zimna, Monika Drabik, Szymon Borkowski, Maciej Świątkiewicz, Piotr Bogorodzki, Paweł Grieb, Paulina Hamankiewicz, Tomasz J. Kolanowski, Natalia Rozwadowska, Urszula Kozłowska, Aleksandra Klimczak, Jerzy Kolasiński, Zbigniew Rogulski and Maciej Kurpisz
Int. J. Mol. Sci. 2021, 22(19), 10885; https://doi.org/10.3390/ijms221910885 - 8 Oct 2021
Cited by 2 | Viewed by 2736
Abstract
Current treatment protocols for myocardial infarction improve the outcome of disease to some extent but do not provide the clue for full regeneration of the heart tissues. An increasing body of evidence has shown that transplantation of cells may lead to some organ [...] Read more.
Current treatment protocols for myocardial infarction improve the outcome of disease to some extent but do not provide the clue for full regeneration of the heart tissues. An increasing body of evidence has shown that transplantation of cells may lead to some organ recovery. However, the optimal stem cell population has not been yet identified. We would like to propose a novel pro-regenerative treatment for post-infarction heart based on the combination of human skeletal myoblasts (huSkM) and mesenchymal stem cells (MSCs). huSkM native or overexpressing gene coding for Cx43 (huSKMCx43) alone or combined with MSCs were delivered in four cellular therapeutic variants into the healthy and post-infarction heart of mice while using molecular reporter probes. Single-Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) performed right after cell delivery and 24 h later revealed a trend towards an increase in the isotopic uptake in the post-infarction group of animals treated by a combination of huSkMCx43 with MSC. Bioluminescent imaging (BLI) showed the highest increase in firefly luciferase (fluc) signal intensity in post-infarction heart treated with combination of huSkM and MSCs vs. huSkM alone (p < 0.0001). In healthy myocardium, however, nanoluciferase signal (nanoluc) intensity varied markedly between animals treated with stem cell populations either alone or in combinations with the tendency to be simply decreased. Therefore, our observations seem to show that MSCs supported viability, engraftment, and even proliferation of huSkM in the post-infarction heart. Full article
(This article belongs to the Section Biochemistry)
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20 pages, 5233 KiB  
Article
Cheonggukjang-Specific Component 1,3-Diphenyl-2-Propanone as a Novel PPARα/γ Dual Agonist: An In Vitro and In Silico Study
by Radha Arulkumar, Hee-Jin Jung, Sang-Gyun Noh, Daeui Park and Hae-Young Chung
Int. J. Mol. Sci. 2021, 22(19), 10884; https://doi.org/10.3390/ijms221910884 - 8 Oct 2021
Cited by 1 | Viewed by 2975
Abstract
Background: Cheonggukjang is a traditional fermented soybean paste that is mostly consumed in Korea. However, the biological activities of Cheonggukjang specific compounds have not been studied. Thus, we aimed to discover a novel dual agonist for PPARα/γ from dietary sources such as Cheonggukjang [...] Read more.
Background: Cheonggukjang is a traditional fermented soybean paste that is mostly consumed in Korea. However, the biological activities of Cheonggukjang specific compounds have not been studied. Thus, we aimed to discover a novel dual agonist for PPARα/γ from dietary sources such as Cheonggukjang specific volatile compounds and explore the potential role of PPARα/γ dual agonists using in vitro and in silico tools. Methods: A total of 35 compounds were selected from non-fermented and fermented soybean products cultured with Bacillus subtilis, namely Cheonggukjang, for analysis by in vitro and in silico studies. Results: Molecular docking results showed that 1,3-diphenyl-2-propanone (DPP) had the lowest docking score for activating PPARα (1K7L) and PPARγ (3DZY) with non-toxic effects. Moreover, DPP significantly increased the transcriptional activities of both PPARα and PPARγ and highly activated its expression in Ac2F liver cells, in vitro. Here, we demonstrated for the first time that DPP can act as a dual agonist of PPARα/γ using in vitro and in silico tools. Conclusions: The Cheonggukjang-specific compound DPP could be a novel PPARα/γ dual agonist and it is warranted to determine the therapeutic potential of PPARα/γ activation by dietary intervention and/or supplementation in the treatment of metabolic disorders without causing any adverse effects. Full article
(This article belongs to the Special Issue Natural Medicines, Functional Foods and Nutrients for Healthcare)
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19 pages, 1922 KiB  
Review
At a Crossroads to Cancer: How p53-Induced Cell Fate Decisions Secure Genome Integrity
by Dario Rizzotto, Lukas Englmaier and Andreas Villunger
Int. J. Mol. Sci. 2021, 22(19), 10883; https://doi.org/10.3390/ijms221910883 - 8 Oct 2021
Cited by 43 | Viewed by 8224
Abstract
P53 is known as the most critical tumor suppressor and is often referred to as the guardian of our genome. More than 40 years after its discovery, we are still struggling to understand all molecular details on how this transcription factor prevents oncogenesis [...] Read more.
P53 is known as the most critical tumor suppressor and is often referred to as the guardian of our genome. More than 40 years after its discovery, we are still struggling to understand all molecular details on how this transcription factor prevents oncogenesis or how to leverage current knowledge about its function to improve cancer treatment. Multiple cues, including DNA-damage or mitotic errors, can lead to the stabilization and nuclear translocation of p53, initiating the expression of multiple target genes. These transcriptional programs may be cell-type- and stimulus-specific, as is their outcome that ultimately imposes a barrier to cellular transformation. Cell cycle arrest and cell death are two well-studied consequences of p53 activation, but, while being considered critical, they do not fully explain the consequences of p53 loss-of-function phenotypes in cancer. Here, we discuss how mitotic errors alert the p53 network and give an overview of multiple ways that p53 can trigger cell death. We argue that a comparative analysis of different types of p53 responses, elicited by different triggers in a time-resolved manner in well-defined model systems, is critical to understand the cell-type-specific cell fate induced by p53 upon its activation in order to resolve the remaining mystery of its tumor-suppressive function. Full article
(This article belongs to the Special Issue The Functional Landscape of p53)
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35 pages, 1236 KiB  
Review
Agroinfiltration Mediated Scalable Transient Gene Expression in Genome Edited Crop Plants
by Maninder Kaur, Pooja Manchanda, Anu Kalia, Farah K. Ahmed, Eugenie Nepovimova, Kamil Kuca and Kamel A. Abd-Elsalam
Int. J. Mol. Sci. 2021, 22(19), 10882; https://doi.org/10.3390/ijms221910882 - 8 Oct 2021
Cited by 22 | Viewed by 8814
Abstract
Agrobacterium-mediated transformation is one of the most commonly used genetic transformation method that involves transfer of foreign genes into target plants. Agroinfiltration, an Agrobacterium-based transient approach and the breakthrough discovery of CRISPR/Cas9 holds trending stature to perform targeted and efficient genome [...] Read more.
Agrobacterium-mediated transformation is one of the most commonly used genetic transformation method that involves transfer of foreign genes into target plants. Agroinfiltration, an Agrobacterium-based transient approach and the breakthrough discovery of CRISPR/Cas9 holds trending stature to perform targeted and efficient genome editing (GE). The predominant feature of agroinfiltration is the abolishment of Transfer-DNA (T-DNA) integration event to ensure fewer biosafety and regulatory issues besides showcasing the capability to perform transcription and translation efficiently, hence providing a large picture through pilot-scale experiment via transient approach. The direct delivery of recombinant agrobacteria through this approach carrying CRISPR/Cas cassette to knockout the expression of the target gene in the intercellular tissue spaces by physical or vacuum infiltration can simplify the targeted site modification. This review aims to provide information on Agrobacterium-mediated transformation and implementation of agroinfiltration with GE to widen the horizon of targeted genome editing before a stable genome editing approach. This will ease the screening of numerous functions of genes in different plant species with wider applicability in future. Full article
(This article belongs to the Special Issue Plant Genomics and Genome Editing)
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2 pages, 750 KiB  
Correction
Correction: Feng et al. Nicotinamide Phosphoribosyltransferase (Nampt)/Nicotinamide Adenine Dinucleotide (NAD) Axis Suppresses Atrial Fibrillation by Modulating the Calcium Handling Pathway. Int. J. Mol. Sci. 2020, 21, 4655
by Duo Feng, DongZhu Xu, Nobuyuki Murakoshi, Kazuko Tajiri, Rujie Qin, Saori Yonebayashi, Yuta Okabe, Siqi Li, Zixun Yuan, Kazutaka Aonuma and Masaki Ieda
Int. J. Mol. Sci. 2021, 22(19), 10881; https://doi.org/10.3390/ijms221910881 - 8 Oct 2021
Viewed by 1741
Abstract
The authors wish to make the following corrections to this paper [...] Full article
(This article belongs to the Special Issue Electrophysiology)
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15 pages, 1131 KiB  
Review
Utilization of Pharmacological Ascorbate to Enhance Hydrogen Peroxide-Mediated Radiosensitivity in Cancer Therapy
by Zain Mehdi, Michael S. Petronek, Jeffrey M. Stolwijk, Kranti A. Mapuskar, Amanda L. Kalen, Garry R. Buettner, Joseph J. Cullen, Douglas R. Spitz, John M. Buatti and Bryan G. Allen
Int. J. Mol. Sci. 2021, 22(19), 10880; https://doi.org/10.3390/ijms221910880 - 8 Oct 2021
Cited by 13 | Viewed by 3692
Abstract
Interest in the use of pharmacological ascorbate as a treatment for cancer has increased considerably since it was introduced by Cameron and Pauling in the 1970s. Recently, pharmacological ascorbate has been used in preclinical and early-phase clinical trials as a selective radiation sensitizer [...] Read more.
Interest in the use of pharmacological ascorbate as a treatment for cancer has increased considerably since it was introduced by Cameron and Pauling in the 1970s. Recently, pharmacological ascorbate has been used in preclinical and early-phase clinical trials as a selective radiation sensitizer in cancer. The results of these studies are promising. This review summarizes data on pharmacological ascorbate (1) as a safe and efficacious adjuvant to cancer therapy; (2) as a selective radiosensitizer of cancer via a mechanism involving hydrogen peroxide; and (3) as a radioprotector in normal tissues. Additionally, we present new data demonstrating the ability of pharmacological ascorbate to enhance radiation-induced DNA damage in glioblastoma cells, facilitating cancer cell death. We propose that pharmacological ascorbate may be a general radiosensitizer in cancer therapy and simultaneously a radioprotector of normal tissue. Full article
(This article belongs to the Special Issue Radiation Biology and Molecular Radiation Oncology)
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11 pages, 1261 KiB  
Article
Synthesis of Demissidine Analogues from Tigogenin via Imine Intermediates
by Agnieszka Wojtkielewicz, Urszula Kiełczewska, Aneta Baj and Jacek W. Morzycki
Int. J. Mol. Sci. 2021, 22(19), 10879; https://doi.org/10.3390/ijms221910879 - 8 Oct 2021
Cited by 2 | Viewed by 2200
Abstract
A five-step transformation of a spiroketal side chain of tigogenin into an indolizidine system present in solanidane alkaloids such as demissidine and solanidine was elaborated. The key intermediate in the synthesis was spiroimine 3 readily obtained from tigogenin by its RuO4 oxidation [...] Read more.
A five-step transformation of a spiroketal side chain of tigogenin into an indolizidine system present in solanidane alkaloids such as demissidine and solanidine was elaborated. The key intermediate in the synthesis was spiroimine 3 readily obtained from tigogenin by its RuO4 oxidation to 5,6-dihydrokryptogenin followed by amination with aluminum amide generated in situ from DIBAlH and ammonium chloride. The mild reduction of spiroimine to a 26-hydroxy-dihydropyrrole derivative and subsequent mesylation resulted in the formation of 25-epidemissidinium salt or 23-sulfone depending on reaction conditions. Full article
(This article belongs to the Special Issue Theme Issue Honoring Prof. Dr. Ludger Wessjohann’s 60th Birthday: Natural Products in Modern Drug Discovery)
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21 pages, 2042 KiB  
Review
Parasite Survival and Disease Persistence in Cystic Fibrosis, Schistosomiasis and Pathogenic Bacterial Diseases: A Role for Universal Stress Proteins?
by Priscilla Masamba and Abidemi Paul Kappo
Int. J. Mol. Sci. 2021, 22(19), 10878; https://doi.org/10.3390/ijms221910878 - 8 Oct 2021
Cited by 5 | Viewed by 2934
Abstract
Universal stress proteins (USPs) were originally discovered in Escherichia coli over two decades ago and since then their presence has been detected in various organisms that include plants, archaea, metazoans, and bacteria. As their name suggests, they function in a series of various [...] Read more.
Universal stress proteins (USPs) were originally discovered in Escherichia coli over two decades ago and since then their presence has been detected in various organisms that include plants, archaea, metazoans, and bacteria. As their name suggests, they function in a series of various cellular responses in both abiotic and biotic stressful conditions such as oxidative stress, exposure to DNA damaging agents, nutrient starvation, high temperature and acidic stress, among others. Although a highly conserved group of proteins, the molecular and biochemical aspects of their functions are largely evasive. This is concerning, as it was observed that USPs act as essential contributors to the survival/persistence of various infectious pathogens. Their ubiquitous nature in various organisms, as well as their augmentation during conditions of stress, is a clear indication of their direct or indirect importance in providing resilience against such conditions. This paper seeks to clarify what has already been reported in the literature on the proposed mechanism of action of USPs in pathogenic organisms. Full article
(This article belongs to the Section Biochemistry)
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12 pages, 2320 KiB  
Article
Healthy Tissue Damage Following Cancer Ion Therapy: A Radiobiological Database Predicting Lymphocyte Chromosome Aberrations Based on the BIANCA Biophysical Model
by Alessia Embriaco, Ricardo Ramos, Mario Carante, Alfredo Ferrari, Paola Sala, Valerio Vercesi and Francesca Ballarini
Int. J. Mol. Sci. 2021, 22(19), 10877; https://doi.org/10.3390/ijms221910877 - 8 Oct 2021
Cited by 7 | Viewed by 2139
Abstract
Chromosome aberrations are widely considered among the best biomarkers of radiation health risk due to their relationship with late cancer incidence. In particular, aberrations in peripheral blood lymphocytes (PBL) can be regarded as indicators of hematologic toxicity, which is a major limiting factor [...] Read more.
Chromosome aberrations are widely considered among the best biomarkers of radiation health risk due to their relationship with late cancer incidence. In particular, aberrations in peripheral blood lymphocytes (PBL) can be regarded as indicators of hematologic toxicity, which is a major limiting factor of radiotherapy total dose. In this framework, a radiobiological database describing the induction of PBL dicentrics as a function of ion type and energy was developed by means of the BIANCA (BIophysical ANalysis of Cell death and chromosome Aberrations) biophysical model, which has been previously applied to predict the effectiveness of therapeutic-like ion beams at killing tumour cells. This database was then read by the FLUKA Monte Carlo transport code, thus allowing us to calculate the Relative Biological Effectiveness (RBE) for dicentric induction along therapeutic C-ion beams. A comparison with previous results showed that, while in the higher-dose regions (e.g., the Spread-Out Bragg Peak, SOBP), the RBE for dicentrics was lower than that for cell survival. In the lower-dose regions (e.g., the fragmentation tail), the opposite trend was observed. This work suggests that, at least for some irradiation scenarios, calculating the biological effectiveness of a hadrontherapy beam solely based on the RBE for cell survival may lead to an underestimation of the risk of (late) damage to healthy tissues. More generally, following this work, BIANCA has gained the capability of providing RBE predictions not only for cell killing, but also for healthy tissue damage. Full article
(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells 2.0)
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20 pages, 5822 KiB  
Article
Genetically Encoded Biosensors to Monitor Intracellular Reactive Oxygen and Nitrogen Species and Glutathione Redox Potential in Skeletal Muscle Cells
by Escarlata Fernández-Puente and Jesús Palomero
Int. J. Mol. Sci. 2021, 22(19), 10876; https://doi.org/10.3390/ijms221910876 - 8 Oct 2021
Cited by 8 | Viewed by 2745
Abstract
Reactive oxygen and nitrogen species (RONS) play an important role in the pathophysiology of skeletal muscle and are involved in the regulation of intracellular signaling pathways, which drive metabolism, regeneration, and adaptation in skeletal muscle. However, the molecular mechanisms underlying these processes are [...] Read more.
Reactive oxygen and nitrogen species (RONS) play an important role in the pathophysiology of skeletal muscle and are involved in the regulation of intracellular signaling pathways, which drive metabolism, regeneration, and adaptation in skeletal muscle. However, the molecular mechanisms underlying these processes are unknown or partially uncovered. We implemented a combination of methodological approaches that are funded for the use of genetically encoded biosensors associated with quantitative fluorescence microscopy imaging to study redox biology in skeletal muscle. Therefore, it was possible to detect and monitor RONS and glutathione redox potential with high specificity and spatio-temporal resolution in two models, isolated skeletal muscle fibers and C2C12 myoblasts/myotubes. Biosensors HyPer3 and roGFP2-Orp1 were examined for the detection of cytosolic hydrogen peroxide; HyPer-mito and HyPer-nuc for the detection of mitochondrial and nuclear hydrogen peroxide; Mito-Grx1-roGFP2 and cyto-Grx1-roGFP2 were used for registration of the glutathione redox potential in mitochondria and cytosol. G-geNOp was proven to detect cytosolic nitric oxide. The fluorescence emitted by the biosensors is affected by pH, and this might have masked the results; therefore, environmental CO2 must be controlled to avoid pH fluctuations. In conclusion, genetically encoded biosensors and quantitative fluorescence microscopy provide a robust methodology to investigate the pathophysiological processes associated with the redox biology of skeletal muscle. Full article
(This article belongs to the Special Issue Muscular Structure, Physiology and Metabolism)
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19 pages, 3564 KiB  
Article
Differences in Glycolysis and Mitochondrial Respiration between Cytotrophoblast and Syncytiotrophoblast In-Vitro: Evidence for Sexual Dimorphism
by Matthew Bucher, Leena Kadam, Kylia Ahuna and Leslie Myatt
Int. J. Mol. Sci. 2021, 22(19), 10875; https://doi.org/10.3390/ijms221910875 - 8 Oct 2021
Cited by 14 | Viewed by 5569
Abstract
In the placenta the proliferative cytotrophoblast cells fuse into the terminally differentiated syncytiotrophoblast layer which undertakes several energy-intensive functions including nutrient uptake and transfer and hormone synthesis. We used Seahorse glycolytic and mitochondrial stress tests on trophoblast cells isolated at term from women [...] Read more.
In the placenta the proliferative cytotrophoblast cells fuse into the terminally differentiated syncytiotrophoblast layer which undertakes several energy-intensive functions including nutrient uptake and transfer and hormone synthesis. We used Seahorse glycolytic and mitochondrial stress tests on trophoblast cells isolated at term from women of healthy weight to evaluate if cytotrophoblast (CT) and syncytiotrophoblast (ST) have different bioenergetic strategies, given their different functions. Whereas there are no differences in basal glycolysis, CT have significantly greater glycolytic capacity and reserve than ST. In contrast, ST have significantly higher basal, ATP-coupled and maximal mitochondrial respiration and spare capacity than CT. Consequently, under stress conditions CT can increase energy generation via its higher glycolytic capacity whereas ST can use its higher and more efficient mitochondrial respiration capacity. We have previously shown that with adverse in utero conditions of diabetes and obesity trophoblast respiration is sexually dimorphic. We found no differences in glycolytic parameters between sexes and no difference in mitochondrial respiration parameters other than increases seen upon syncytialization appear to be greater in females. There were differences in metabolic flexibility, i.e., the ability to use glucose, glutamine, or fatty acids, seen upon syncytialization between the sexes with increased flexibility in female trophoblast suggesting a better ability to adapt to changes in nutrient supply. Full article
(This article belongs to the Special Issue Placental Related Disorders of Pregnancy)
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14 pages, 931 KiB  
Review
Melatonin as a Therapeutic Agent for the Inhibition of Hypoxia-Induced Tumor Progression: A Description of Possible Mechanisms Involved
by Sepideh Bastani, Moloud Akbarzadeh, Yeganeh Rastgar Rezaei, Ali Farzane, Mohammad Nouri, Mahsa Mollapour Sisakht, Amir Fattahi, Maryam Akbarzadeh and Russel J. Reiter
Int. J. Mol. Sci. 2021, 22(19), 10874; https://doi.org/10.3390/ijms221910874 - 8 Oct 2021
Cited by 16 | Viewed by 2964
Abstract
Hypoxia has an important role in tumor progression via the up-regulation of growth factors and cellular adaptation genes. These changes promote cell survival, proliferation, invasion, metastasis, angiogenesis, and energy metabolism in favor of cancer development. Hypoxia also plays a central role in determining [...] Read more.
Hypoxia has an important role in tumor progression via the up-regulation of growth factors and cellular adaptation genes. These changes promote cell survival, proliferation, invasion, metastasis, angiogenesis, and energy metabolism in favor of cancer development. Hypoxia also plays a central role in determining the resistance of tumors to chemotherapy. Hypoxia of the tumor microenvironment provides an opportunity to develop new therapeutic strategies that may selectively induce apoptosis of the hypoxic cancer cells. Melatonin is well known for its role in the regulation of circadian rhythms and seasonal reproduction. Numerous studies have also documented the anti-cancer properties of melatonin, including anti-proliferation, anti-angiogenesis, and apoptosis promotion. In this paper, we hypothesized that melatonin exerts anti-cancer effects by inhibiting hypoxia-induced pathways. Considering this action, co-administration of melatonin in combination with other therapeutic medications might increase the effectiveness of anti-cancer drugs. In this review, we discussed the possible signaling pathways by which melatonin inhibits hypoxia-induced cancer cell survival, invasion, migration, and metabolism, as well as tumor angiogenesis. Full article
(This article belongs to the Special Issue Melatonin: Molecular Mechanisms and Biological Functions. A 2021 Update)
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27 pages, 927 KiB  
Review
Potential of Salivary Biomarkers in Autism Research: A Systematic Review
by Katarína Janšáková, Klaudia Kyselicová, Daniela Ostatníková and Gabriela Repiská
Int. J. Mol. Sci. 2021, 22(19), 10873; https://doi.org/10.3390/ijms221910873 - 8 Oct 2021
Cited by 11 | Viewed by 3927
Abstract
The diagnostic process for autism spectrum disorders (ASD) is based on a behavioral analysis of the suspected individual. Despite intensive research, no specific and valid biomarker has been identified for ASD, but saliva, with its advantages such as non-invasive collection, could serve as [...] Read more.
The diagnostic process for autism spectrum disorders (ASD) is based on a behavioral analysis of the suspected individual. Despite intensive research, no specific and valid biomarker has been identified for ASD, but saliva, with its advantages such as non-invasive collection, could serve as a suitable alternative to other body fluids. As a source of nucleic acid of both human and microbial origin, protein and non-protein molecules, saliva offers a complex view on the current state of the organism. Additionally, the use of salivary markers seems to be less complicated not only for ASD screening but also for revealing the etiopathogenesis of ASD, since enrolling neurotypical counterparts willing to participate in studies may be more feasible. The aim of the presented review is to provide an overview of the current research performed on saliva in relation to ASD, mutual complementing, and discrepancies that result in difficulties applying the observed markers in clinical practice. We emphasize the methodological limitations of saliva collection and processing as well as the lack of information regarding ASD diagnosis, which is critically discussed. Full article
(This article belongs to the Special Issue Molecular Genetics of Autism and Intellectual Disability)
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13 pages, 685 KiB  
Review
The Lung Microbiome during Health and Disease
by Kazuma Yagi, Gary B. Huffnagle, Nicholas W. Lukacs and Nobuhiro Asai
Int. J. Mol. Sci. 2021, 22(19), 10872; https://doi.org/10.3390/ijms221910872 - 8 Oct 2021
Cited by 105 | Viewed by 8235
Abstract
Healthy human lungs have traditionally been considered to be a sterile organ. However, culture-independent molecular techniques have reported that large numbers of microbes coexist in the lung and airways. The lungs harbor diverse microbial composition that are undetected by previous approaches. Many studies [...] Read more.
Healthy human lungs have traditionally been considered to be a sterile organ. However, culture-independent molecular techniques have reported that large numbers of microbes coexist in the lung and airways. The lungs harbor diverse microbial composition that are undetected by previous approaches. Many studies have found significant differences in microbial composition between during health and respiratory disease. The lung microbiome is likely to not only influence susceptibility or causes of diseases but be affected by disease activities or responses to treatment. Although lung microbiome research has some limitations from study design to reporting, it can add further dimensionality to host-microbe interactions. Moreover, there is a possibility that extending understanding to the lung microbiome with new multiple omics approaches would be useful for developing both diagnostic and prognostic biomarkers for respiratory diseases in clinical settings. Full article
(This article belongs to the Special Issue Host-Microbe Interaction 3.0)
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17 pages, 2809 KiB  
Article
Characterization of the Human Eccrine Sweat Proteome—A Focus on the Biological Variability of Individual Sweat Protein Profiles
by Bastien Burat, Audrey Reynaerts, Dominique Baiwir, Maximilien Fléron, Gauthier Eppe, Teresinha Leal and Gabriel Mazzucchelli
Int. J. Mol. Sci. 2021, 22(19), 10871; https://doi.org/10.3390/ijms221910871 - 8 Oct 2021
Cited by 10 | Viewed by 3354
Abstract
The potential of eccrine sweat as a bio-fluid of interest for diagnosis and personalized therapy has not yet been fully evaluated, due to the lack of in-depth sweat characterization studies. Thanks to recent developments in omics, together with the availability of accredited sweat [...] Read more.
The potential of eccrine sweat as a bio-fluid of interest for diagnosis and personalized therapy has not yet been fully evaluated, due to the lack of in-depth sweat characterization studies. Thanks to recent developments in omics, together with the availability of accredited sweat collection methods, the analysis of human sweat may now be envisioned as a standardized, non-invasive test for individualized monitoring and personalized medicine. Here, we characterized individual sweat samples, collected from 28 healthy adult volunteers under the most standardized sampling methodology, by applying optimized shotgun proteomics. The thorough characterization of the sweat proteome allowed the identification of 983 unique proteins from which 344 were identified across all samples. Annotation-wise, the study of the sweat proteome unveiled the over-representation of newly addressed actin dynamics, oxidative stress and proteasome-related functions, in addition to well-described proteolysis and anti-microbial immunity. The sweat proteome composition correlated with the inter-individual variability of sweat secretion parameters. In addition, both gender-exclusive proteins and gender-specific protein abundances were highlighted, despite the high similarity between human female and male sweat proteomes. In conclusion, standardized sample collection coupled with optimized shotgun proteomics significantly improved the depth of sweat proteome coverage, far beyond previous similar studies. The identified proteins were involved in many diverse biological processes and molecular functions, indicating the potential of this bio-fluid as a valuable biological matrix for further studies. Addressing sweat variability, our results prove the proteomic profiling of sweat to be a promising bio-fluid analysis for individualized, non-invasive monitoring and personalized medicine. Full article
(This article belongs to the Special Issue Mass Spectrometric Proteomics 2022)
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14 pages, 6779 KiB  
Article
LEF1 Enhances the Progression of Colonic Adenocarcinoma via Remodeling the Cell Motility Associated Structures
by Li Xiao, Caixia Zhang, Xinyao Li, Chenshuang Jia, Lirong Chen, Yue Yuan, Qian Gao, Zheng Lu, Yang Feng, Ruixia Zhao, Xuewei Zhao, Sinan Cheng, Zhan Shu, Jie Xu, Wei Duan, Guochao Nie and Yingchun Hou
Int. J. Mol. Sci. 2021, 22(19), 10870; https://doi.org/10.3390/ijms221910870 - 8 Oct 2021
Cited by 15 | Viewed by 2279
Abstract
Lymphoid enhancer-binding factor 1 (LEF1) is a key transcription factor mediating the Wnt signaling pathway. LEF1 is a regulator that is closely associated with tumor malignancy and is usually upregulated in cancers, including colonic adenocarcinoma. The underlying molecular mechanisms of LEF1 regulation for [...] Read more.
Lymphoid enhancer-binding factor 1 (LEF1) is a key transcription factor mediating the Wnt signaling pathway. LEF1 is a regulator that is closely associated with tumor malignancy and is usually upregulated in cancers, including colonic adenocarcinoma. The underlying molecular mechanisms of LEF1 regulation for colonic adenocarcinoma progression remain unknown. To explore it, the LEF1 expression in caco2 cells was inhibited using an shRNA approach. The results showed that downregulation of LEF1 inhibited the malignancy and motility associated microstructures, such as polymerization of F-actin, β-tubulin, and Lamin B1 in caco2 cells. LEF1 inhibition suppressed the expression of epithelial/endothelial-mesenchymal transition (EMT) relevant genes. Overall, the current results demonstrated that LEF1 plays a pivotal role in maintaining the malignancy of colonic adenocarcinoma by remodeling motility correlated microstructures and suppressing the expression of EMT-relevant genes. Our study provided evidence of the roles LEF1 played in colonic adenocarcinoma progression, and suggest LEF1 as a potential target for colonic adenocarcinoma therapy. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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