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Volume 22
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Int. J. Mol. Sci., Volume 22, Issue 10 (May-2 2021) – 355 articles

Cover Story (view full-size image): Transport of ions and nutrients is a core mitochondrial function, without which there would be no mitochondrial metabolism and ATP production. Ion homeostasis and mitochondrial phenotype play key roles in driving the malignancy. This review comprehensively summarizes and critically discusses the role of the reciprocal relationship between ion transport and mitochondria in crucial cellular functions, including metabolism, signaling, and cell fate decisions. We focus on Ca2+, H+, and K+, which play essential and highly interconnected roles in mitochondrial function and are profoundly dysregulated in cancer. We describe the transport and roles of these ions in normal mitochondria, summarize the changes occurring during cancer development, and discuss how they might impact tumorigenesis. View this paper
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20 pages, 7535 KiB  
Article
KEAP1 Cancer Mutants: A Large-Scale Molecular Dynamics Study of Protein Stability
by Carter J. Wilson, Megan Chang, Mikko Karttunen and Wing-Yiu Choy
Int. J. Mol. Sci. 2021, 22(10), 5408; https://doi.org/10.3390/ijms22105408 - 20 May 2021
Cited by 6 | Viewed by 4275
Abstract
We have performed 280 μs of unbiased molecular dynamics (MD) simulations to investigate the effects of 12 different cancer mutations on Kelch-like ECH-associated protein 1 (KEAP1) (G333C, G350S, G364C, G379D, R413L, R415G, A427V, G430C, R470C, R470H, R470S and G476R), one of the [...] Read more.
We have performed 280 μs of unbiased molecular dynamics (MD) simulations to investigate the effects of 12 different cancer mutations on Kelch-like ECH-associated protein 1 (KEAP1) (G333C, G350S, G364C, G379D, R413L, R415G, A427V, G430C, R470C, R470H, R470S and G476R), one of the frequently mutated proteins in lung cancer. The aim was to provide structural insight into the effects of these mutants, including a new class of ANCHOR (additionally NRF2-complexed hypomorph) mutant variants. Our work provides additional insight into the structural dynamics of mutants that could not be analyzed experimentally, painting a more complete picture of their mutagenic effects. Notably, blade-wise analysis of the Kelch domain points to stability as a possible target of cancer in KEAP1. Interestingly, structural analysis of the R470C ANCHOR mutant, the most prevalent missense mutation in KEAP1, revealed no significant change in structural stability or NRF2 binding site dynamics, possibly indicating an covalent modification as this mutant’s mode of action. Full article
(This article belongs to the Collection Feature Papers in Molecular Biophysics)
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17 pages, 3744 KiB  
Review
An Analytical Review of the Structural Features of Pentatricopeptide Repeats: Strategic Amino Acids, Repeat Arrangements and Superhelical Architecture
by Sailen Barik
Int. J. Mol. Sci. 2021, 22(10), 5407; https://doi.org/10.3390/ijms22105407 - 20 May 2021
Cited by 1 | Viewed by 2591
Abstract
Tricopeptide repeats are common in natural proteins, and are exemplified by 34- and 35-residue repeats, known respectively as tetratricopeptide repeats (TPRs) and pentatricopeptide repeats (PPRs). In both classes, each repeat unit forms an antiparallel bihelical structure, so that multiple such units in a [...] Read more.
Tricopeptide repeats are common in natural proteins, and are exemplified by 34- and 35-residue repeats, known respectively as tetratricopeptide repeats (TPRs) and pentatricopeptide repeats (PPRs). In both classes, each repeat unit forms an antiparallel bihelical structure, so that multiple such units in a polypeptide are arranged in a parallel fashion. The primary structures of the motifs are nonidentical, but amino acids of similar properties occur in strategic positions. The focus of the present work was on PPR, but TPR, its better-studied cousin, is often included for comparison. The analyses revealed that critical amino acids, namely Gly, Pro, Ala and Trp, were placed at distinct locations in the higher order structure of PPR domains. While most TPRs occur in repeats of three, the PPRs exhibited a much greater diversity in repeat numbers, from 1 to 30 or more, separated by spacers of various sequences and lengths. Studies of PPR strings in proteins showed that the majority of PPR units are single, and that the longer tandems (i.e., without space in between) occurred in decreasing order. The multi-PPR domains also formed superhelical vortices, likely governed by interhelical angles rather than the spacers. These findings should be useful in designing and understanding the PPR domains. Full article
(This article belongs to the Special Issue Structure, Function and Evolution of Protein Domains)
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19 pages, 3171 KiB  
Article
Targeting Lactate Dehydrogenase A with Catechin Resensitizes SNU620/5FU Gastric Cancer Cells to 5-Fluorouracil
by Jung Ho Han, MinJeong Kim, Hyeon Jin Kim, Se Bok Jang, Sung-Jin Bae, In-Kyu Lee, Dongryeol Ryu and Ki-Tae Ha
Int. J. Mol. Sci. 2021, 22(10), 5406; https://doi.org/10.3390/ijms22105406 - 20 May 2021
Cited by 31 | Viewed by 5177
Abstract
Resistance to anticancer therapeutics occurs in virtually every type of cancer and becomes a major difficulty in cancer treatment. Although 5-fluorouracil (5FU) is the first-line choice of anticancer therapy for gastric cancer, its effectiveness is limited owing to drug resistance. Recently, altered cancer [...] Read more.
Resistance to anticancer therapeutics occurs in virtually every type of cancer and becomes a major difficulty in cancer treatment. Although 5-fluorouracil (5FU) is the first-line choice of anticancer therapy for gastric cancer, its effectiveness is limited owing to drug resistance. Recently, altered cancer metabolism, including the Warburg effect, a preference for glycolysis rather than oxidative phosphorylation for energy production, has been accepted as a pivotal mechanism regulating resistance to chemotherapy. Thus, we investigated the detailed mechanism and possible usefulness of antiglycolytic agents in ameliorating 5FU resistance using established gastric cancer cell lines, SNU620 and SNU620/5FU. SNU620/5FU, a gastric cancer cell harboring resistance to 5FU, showed much higher lactate production and expression of glycolysis-related enzymes, such as lactate dehydrogenase A (LDHA), than those of the parent SNU620 cells. To limit glycolysis, we examined catechin and its derivatives, which are known anti-inflammatory and anticancer natural products because epigallocatechin gallate has been previously reported as a suppressor of LDHA expression. Catechin, the simplest compound among them, had the highest inhibitory effect on lactate production and LDHA activity. In addition, the combination of 5FU and catechin showed additional cytotoxicity and induced reactive oxygen species (ROS)-mediated apoptosis in SNU620/5FU cells. Thus, based on these results, we suggest catechin as a candidate for the development of a novel adjuvant drug that reduces chemoresistance to 5FU by restricting LDHA. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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16 pages, 2302 KiB  
Article
Curcumin at Low Doses Potentiates and at High Doses Inhibits ABT-737-Induced Platelet Apoptosis
by Natalia Rukoyatkina, Valentina Shpakova, Julia Sudnitsyna, Michael Panteleev, Stephanie Makhoul, Stepan Gambaryan and Kerstin Jurk
Int. J. Mol. Sci. 2021, 22(10), 5405; https://doi.org/10.3390/ijms22105405 - 20 May 2021
Cited by 8 | Viewed by 3677
Abstract
Curcumin is a natural bioactive component derived from the turmeric plant Curcuma longa, which exhibits a range of beneficial activities on human cells. Previously, an inhibitory effect of curcumin on platelets was demonstrated. However, it is unknown whether this inhibitory effect is [...] Read more.
Curcumin is a natural bioactive component derived from the turmeric plant Curcuma longa, which exhibits a range of beneficial activities on human cells. Previously, an inhibitory effect of curcumin on platelets was demonstrated. However, it is unknown whether this inhibitory effect is due to platelet apoptosis or procoagulant platelet formation. In this study, curcumin did not activate caspase 3-dependent apoptosis of human platelets, but rather induced the formation of procoagulant platelets. Interestingly, curcumin at low concentration (5 µM) potentiated, and at high concentration (50 µM) inhibited ABT-737-induced platelet apoptosis, which was accompanied by inhibition of ABT-737-mediated thrombin generation. Platelet viability was not affected by curcumin at low concentration and was reduced by 17% at high concentration. Furthermore, curcumin-induced autophagy in human platelets via increased translocation of LC3I to LC3II, which was associated with activation of adenosine monophosphate (AMP) kinase and inhibition of protein kinase B activity. Because curcumin inhibits P-glycoprotein (P-gp) in cancer cells and contributes to overcoming multidrug resistance, we showed that curcumin similarly inhibited platelet P-gp activity. Our results revealed that the platelet inhibitory effect of curcumin is mediated by complex processes, including procoagulant platelet formation. Thus, curcumin may protect against or enhance caspase-dependent apoptosis in platelets under certain conditions. Full article
(This article belongs to the Special Issue Molecular Research on Platelet Function in Disease)
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18 pages, 4184 KiB  
Article
Osteogenic Potential of Mesenchymal Stem Cells from Adipose Tissue, Bone Marrow and Hair Follicle Outer Root Sheath in a 3D Crosslinked Gelatin-Based Hydrogel
by Hanluo Li, Hafiz Awais Nawaz, Federica Francesca Masieri, Sarah Vogel, Ute Hempel, Alexander K. Bartella, Rüdiger Zimmerer, Jan-Christoph Simon, Michaela Schulz-Siegmund, Michael Hacker, Bernd Lethaus and Vuk Savković
Int. J. Mol. Sci. 2021, 22(10), 5404; https://doi.org/10.3390/ijms22105404 - 20 May 2021
Cited by 4 | Viewed by 3871
Abstract
Bone transplantation is regarded as the preferred therapy to treat a variety of bone defects. Autologous bone tissue is often lacking at the source, and the mesenchymal stem cells (MSCs) responsible for bone repair mechanisms are extracted by invasive procedures. This study explores [...] Read more.
Bone transplantation is regarded as the preferred therapy to treat a variety of bone defects. Autologous bone tissue is often lacking at the source, and the mesenchymal stem cells (MSCs) responsible for bone repair mechanisms are extracted by invasive procedures. This study explores the potential of autologous mesenchymal stem cells derived from the hair follicle outer root sheath (MSCORS). We demonstrated that MSCORS have a remarkable capacity to differentiate in vitro towards the osteogenic lineage. Indeed, when combined with a novel gelatin-based hydrogel called Osteogel, they provided additional osteoinductive cues in vitro that may pave the way for future application in bone regeneration. MSCORS were also compared to MSCs from adipose tissue (ADMSC) and bone marrow (BMMSC) in a 3D Osteogel model. We analyzed gel plasticity, cell phenotype, cell viability, and differentiation capacity towards the osteogenic lineage by measuring alkaline phosphatase (ALP) activity, calcium deposition, and specific gene expression. The novel injectable hydrogel filled an irregularly shaped lesion in a porcine wound model displaying high plasticity. MSCORS in Osteogel showed a higher osteo-commitment in terms of calcium deposition and expression dynamics of OCN, BMP2, and PPARG when compared to ADMSC and BMMSC, whilst displaying comparable cell viability and ALP activity. In conclusion, autologous MSCORS combined with our novel gelatin-based hydrogel displayed a high capacity for differentiation towards the osteogenic lineage and are acquired by non-invasive procedures, therefore qualifying as a suitable and expandable novel approach in the field of bone regeneration therapy. Full article
(This article belongs to the Special Issue Different Strategies for Osteogenic Differentiation and Bone Regeneration)
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18 pages, 1893 KiB  
Article
Early-Pregnancy Dydrogesterone Supplementation Mimicking Luteal-Phase Support in ART Patients Did Not Provoke Major Reproductive Disorders in Pregnant Mice and Their Progeny
by Laura Jeschke, Clarisa Guillermina Santamaria, Nicole Meyer, Ana Claudia Zenclussen, Julia Bartley and Anne Schumacher
Int. J. Mol. Sci. 2021, 22(10), 5403; https://doi.org/10.3390/ijms22105403 - 20 May 2021
Cited by 4 | Viewed by 4233
Abstract
Progestogens are frequently administered during early pregnancy to patients undergoing assisted reproductive techniques (ART) to overcome progesterone deficits following ART procedures. Orally administered dydrogesterone (DG) shows equal efficacy to other progestogens with a higher level of patient compliance. However, potential harmful effects of [...] Read more.
Progestogens are frequently administered during early pregnancy to patients undergoing assisted reproductive techniques (ART) to overcome progesterone deficits following ART procedures. Orally administered dydrogesterone (DG) shows equal efficacy to other progestogens with a higher level of patient compliance. However, potential harmful effects of DG on critical pregnancy processes and on the health of the progeny are not yet completely ruled out. We treated pregnant mice with DG in the mode, duration, and doses comparable to ART patients. Subsequently, we studied DG effects on embryo implantation, placental and fetal growth, fetal-maternal circulation, fetal survival, and the uterine immune status. After birth of in utero DG-exposed progeny, we assessed their sex ratios, weight gain, and reproductive performance. Early-pregnancy DG administration did not interfere with placental and fetal development, fetal-maternal circulation, or fetal survival, and provoked only minor changes in the uterine immune compartment. DG-exposed offspring grew normally, were fertile, and showed no reproductive abnormalities with the exception of an altered spermiogram in male progeny. Notably, DG shifted the sex ratio in favor of female progeny. Even though our data may be reassuring for the use of DG in ART patients, the detrimental effects on spermatogenesis in mice warrants further investigations and may be a reason for caution for routine DG supplementation in early pregnancy. Full article
(This article belongs to the Special Issue The Role of Progesterone in the Feto-Maternal Immunological Relationship)
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13 pages, 654 KiB  
Review
Angiogenic Properties of Placenta-Derived Extracellular Vesicles in Normal Pregnancy and in Preeclampsia
by Natalia Gebara, Yolanda Correia, Keqing Wang and Benedetta Bussolati
Int. J. Mol. Sci. 2021, 22(10), 5402; https://doi.org/10.3390/ijms22105402 - 20 May 2021
Cited by 22 | Viewed by 6796
Abstract
Angiogenesis is one of the main processes that coordinate the biological events leading to a successful pregnancy, and its imbalance characterizes several pregnancy-related diseases, including preeclampsia. Intracellular interactions via extracellular vesicles (EVs) contribute to pregnancy’s physiology and pathophysiology, and to the fetal–maternal interaction. [...] Read more.
Angiogenesis is one of the main processes that coordinate the biological events leading to a successful pregnancy, and its imbalance characterizes several pregnancy-related diseases, including preeclampsia. Intracellular interactions via extracellular vesicles (EVs) contribute to pregnancy’s physiology and pathophysiology, and to the fetal–maternal interaction. The present review outlines the implications of EV-mediated crosstalk in the angiogenic process in healthy pregnancy and its dysregulation in preeclampsia. In particular, the effect of EVs derived from gestational tissues in pro and anti-angiogenic processes in the physiological and pathological setting is described. Moreover, the application of EVs from placental stem cells in the clinical setting is reported. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Reproduction—2nd Edition)
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23 pages, 6378 KiB  
Article
The Structure–Properties–Cytotoxicity Interplay: A Crucial Pathway to Determining Graphene Oxide Biocompatibility
by Marta Dziewięcka, Mirosława Pawlyta, Łukasz Majchrzycki, Katarzyna Balin, Sylwia Barteczko, Martyna Czerkawska and Maria Augustyniak
Int. J. Mol. Sci. 2021, 22(10), 5401; https://doi.org/10.3390/ijms22105401 - 20 May 2021
Cited by 16 | Viewed by 2981
Abstract
Interest in graphene oxide nature and potential applications (especially nanocarriers) has resulted in numerous studies, but the results do not lead to clear conclusions. In this paper, graphene oxide is obtained by multiple synthesis methods and generally characterized. The mechanism of GO interaction [...] Read more.
Interest in graphene oxide nature and potential applications (especially nanocarriers) has resulted in numerous studies, but the results do not lead to clear conclusions. In this paper, graphene oxide is obtained by multiple synthesis methods and generally characterized. The mechanism of GO interaction with the organism is hard to summarize due to its high chemical activity and variability during the synthesis process and in biological buffers’ environments. When assessing the biocompatibility of GO, it is necessary to take into account many factors derived from nanoparticles (structure, morphology, chemical composition) and the organism (species, defense mechanisms, adaptation). This research aims to determine and compare the in vivo toxicity potential of GO samples from various manufacturers. Each GO sample is analyzed in two concentrations and applied with food. The physiological reactions of an easy model Acheta domesticus (cell viability, apoptosis, oxidative defense, DNA damage) during ten-day lasting exposure were observed. This study emphasizes the variability of the GO nature and complements the biocompatibility aspect, especially in the context of various GO-based experimental models. Changes in the cell biomarkers are discussed in light of detailed physicochemical analysis. Full article
(This article belongs to the Section Molecular Toxicology)
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20 pages, 3082 KiB  
Article
Metabolic Disturbances in Rat Sublines with Constitutionally Altered Serotonin Homeostasis
by Maja Kesić, Petra Baković, Ranko Stojković, Jasminka Štefulj and Lipa Čičin-Šain
Int. J. Mol. Sci. 2021, 22(10), 5400; https://doi.org/10.3390/ijms22105400 - 20 May 2021
Cited by 4 | Viewed by 3148
Abstract
Central and peripheral serotonin (5HT) have opposing functions in the regulation of energy homeostasis. Both increasing 5HT signaling in the brain and decreasing 5HT signaling in the periphery have been proposed as potential treatments for obesity. This study investigates the relationship between constitutionally [...] Read more.
Central and peripheral serotonin (5HT) have opposing functions in the regulation of energy homeostasis. Both increasing 5HT signaling in the brain and decreasing 5HT signaling in the periphery have been proposed as potential treatments for obesity. This study investigates the relationship between constitutionally high or low 5HT activity and systemic net energy balance. Two sublines of rats with high and low whole-body 5HT tone, obtained by selective breeding for platelet 5HT parameters, were examined for fat accumulation in different white adipose tissue (WAT) depots, glucose/insulin tolerance, blood metabolic parameters, and expression of various metabolic genes. High-5HT animals, unlike their low-5HT counterparts, developed widespread intra-abdominal obesity associated with glucose and insulin intolerance, which worsened with age. They also had elevated blood glucose and lipid parameters but showed no significant changes in circulating leptin, resistin, and adipsin levels. Surprisingly, adiponectin levels were increased in plasma but reduced in the WAT of high-5HT rats. A limited number of metabolic genes belonging to different functional classes showed differential expression in WAT of high-5HT compared to low-5HT rats. Overall, a constitutive increase in 5HT tone is associated with a positive energy balance acting through subtle dysregulation of a broad spectrum of metabolic pathways. Full article
(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation 2.0)
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22 pages, 4295 KiB  
Review
Viruses and Skin Cancer
by Sara Becerril, Roberto Corchado-Cobos, Natalia García-Sancha, Leonor Revelles, David Revilla, Tatiana Ugalde, Concepción Román-Curto, Jesús Pérez-Losada and Javier Cañueto
Int. J. Mol. Sci. 2021, 22(10), 5399; https://doi.org/10.3390/ijms22105399 - 20 May 2021
Cited by 16 | Viewed by 5216
Abstract
Advances in virology and skin cancer over recent decades have produced achievements that have been recognized not only in the field of dermatology, but also in other areas of medicine. They have modified the therapeutic and preventive solutions that can be offered to [...] Read more.
Advances in virology and skin cancer over recent decades have produced achievements that have been recognized not only in the field of dermatology, but also in other areas of medicine. They have modified the therapeutic and preventive solutions that can be offered to some patients and represent a significant step forward in our knowledge of the biology of skin cancer. In this paper, we review the viral agents responsible for different types of skin cancer, especially for solid skin tumors. We focus on human papillomavirus and squamous cell cancers, Merkel cell polyomavirus and Merkel cell carcinoma, and human herpesvirus 8 and Kaposi’s sarcoma. Full article
(This article belongs to the Special Issue The Influence of Genetics and Environmental Risk Factors in Cutaneous and Mucosal Neoplasms)
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16 pages, 683 KiB  
Review
Epigenetic Targeting of Histone Deacetylases in Diagnostics and Treatment of Depression
by Hyun-Sun Park, Jongmin Kim, Seong Hoon Ahn and Hong-Yeoul Ryu
Int. J. Mol. Sci. 2021, 22(10), 5398; https://doi.org/10.3390/ijms22105398 - 20 May 2021
Cited by 27 | Viewed by 4781
Abstract
Depression is a highly prevalent, disabling, and often chronic illness that places substantial burdens on patients, families, healthcare systems, and the economy. A substantial minority of patients are unresponsive to current therapies, so there is an urgent need to develop more broadly effective, [...] Read more.
Depression is a highly prevalent, disabling, and often chronic illness that places substantial burdens on patients, families, healthcare systems, and the economy. A substantial minority of patients are unresponsive to current therapies, so there is an urgent need to develop more broadly effective, accessible, and tolerable therapies. Pharmacological regulation of histone acetylation level has been investigated as one potential clinical strategy. Histone acetylation status is considered a potential diagnostic biomarker for depression, while inhibitors of histone deacetylases (HDACs) have garnered interest as novel therapeutics. This review describes recent advances in our knowledge of histone acetylation status in depression and the therapeutic potential of HDAC inhibitors. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers)
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17 pages, 572 KiB  
Review
Human Genomics and the Biocultural Origin of Music
by Livia Beccacece, Paolo Abondio, Elisabetta Cilli, Donatella Restani and Donata Luiselli
Int. J. Mol. Sci. 2021, 22(10), 5397; https://doi.org/10.3390/ijms22105397 - 20 May 2021
Cited by 12 | Viewed by 6463
Abstract
Music is an exclusive feature of humankind. It can be considered as a form of universal communication, only partly comparable to the vocalizations of songbirds. Many trends of research in this field try to address music origins, as well as the genetic bases [...] Read more.
Music is an exclusive feature of humankind. It can be considered as a form of universal communication, only partly comparable to the vocalizations of songbirds. Many trends of research in this field try to address music origins, as well as the genetic bases of musicality. On one hand, several hypotheses have been made on the evolution of music and its role, but there is still debate, and comparative studies suggest a gradual evolution of some abilities underlying musicality in primates. On the other hand, genome-wide studies highlight several genes associated with musical aptitude, confirming a genetic basis for different musical skills which humans show. Moreover, some genes associated with musicality are involved also in singing and song learning in songbirds, suggesting a likely evolutionary convergence between humans and songbirds. This comprehensive review aims at presenting the concept of music as a sociocultural manifestation within the current debate about its biocultural origin and evolutionary function, in the context of the most recent discoveries related to the cross-species genetics of musical production and perception. Full article
(This article belongs to the Collection Feature Papers in Molecular Genetics and Genomics)
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15 pages, 6188 KiB  
Article
Clinical Characteristics of POC1B-Associated Retinopathy and Assignment of Pathogenicity to Novel Deep Intronic and Non-Canonical Splice Site Variants
by Nicole Weisschuh, Pascale Mazzola, Miriam Bertrand, Tobias B. Haack, Bernd Wissinger, Susanne Kohl and Katarina Stingl
Int. J. Mol. Sci. 2021, 22(10), 5396; https://doi.org/10.3390/ijms22105396 - 20 May 2021
Cited by 15 | Viewed by 2697
Abstract
Mutations in POC1B are a rare cause of inherited retinal degeneration. In this study, we present a thorough phenotypic and genotypic characterization of three individuals harboring putatively pathogenic variants in the POC1B gene. All patients displayed a similar, slowly progressive retinopathy (cone dystrophy [...] Read more.
Mutations in POC1B are a rare cause of inherited retinal degeneration. In this study, we present a thorough phenotypic and genotypic characterization of three individuals harboring putatively pathogenic variants in the POC1B gene. All patients displayed a similar, slowly progressive retinopathy (cone dystrophy or cone-rod dystrophy) with normal funduscopy but disrupted outer retinal layers on optical coherence tomography and variable age of onset. Other symptoms were decreased visual acuity and photophobia. Whole genome sequencing revealed a novel homozygous frameshift variant in one patient. Another patient was shown to harbor a novel deep intronic variant in compound heterozygous state with a previously reported canonical splice site variant. The third patient showed a novel nonsense variant and a novel non-canonical splice site variant. We aimed to validate the effect of the deep intronic variant and the non-canonical splice site variant by means of in vitro splice assays. In addition, direct RNA analysis was performed in one patient. Splicing analysis revealed that the non-canonical splice site variant c.561-3T>C leads to exon skipping while the novel deep intronic variant c.1033-327T>A causes pseudoexon activation. Our data expand the genetic landscape of POC1B mutations and confirm the benefit of genome sequencing in combination with downstream functional validation using minigene assays for the analysis of putative splice variants. In addition, we provide clinical multimodal phenotyping of the affected individuals. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases)
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27 pages, 27333 KiB  
Article
The Study on Molecular Profile Changes of Pathogens via Zinc Nanocomposites Immobilization Approach
by Agnieszka Rogowska, Viorica Railean-Plugaru, Paweł Pomastowski, Justyna Walczak-Skierska, Anna Król-Górniak, Adrian Gołębiowski and Bogusław Buszewski
Int. J. Mol. Sci. 2021, 22(10), 5395; https://doi.org/10.3390/ijms22105395 - 20 May 2021
Cited by 7 | Viewed by 2548
Abstract
The most critical group of all includes multidrug resistant bacteria that pose a particular threat in hospitals, as they can cause severe and often deadly infections. Modern medicine still faces the difficult task of developing new agents for the effective control of bacterial-based [...] Read more.
The most critical group of all includes multidrug resistant bacteria that pose a particular threat in hospitals, as they can cause severe and often deadly infections. Modern medicine still faces the difficult task of developing new agents for the effective control of bacterial-based diseases. The targeted administration of nanoparticles can enhance the efficiency of conventional pharmaceutical agents. However, the interpretation of interfaces’ interactions between nanoparticles and biological systems still remains a challenge for researchers. In fact, the current research presents a strategy for using ZnO NPs immobilization with ampicillin and tetracycline. Firstly, the study provides the mechanism of the ampicillin and tetracycline binding on the surface of ZnO NPs. Secondly, it examines the effect of non-immobilized ZnO NPs, immobilized with ampicillin (ZnONPs/AMP) and tetracycline (ZnONPs/TET), on the cells’ metabolism and morphology, based on the protein and lipid profiles. A sorption kinetics study showed that the antibiotics binding on the surface of ZnONPs depend on their structure. The efficiency of the process was definitely higher in the case of ampicillin. In addition, flow cytometry results showed that immobilized nanoparticles present a different mechanism of action. Moreover, according to the MALDI approach, the antibacterial activity mechanism of the investigated ZnO complexes is mainly based on the destruction of cell membrane integrity by lipids and proteins, which is necessary for proper cell function. Additionally, it was noticed that some of the identified changes indicate the activation of defense mechanisms by cells, leading to a decrease in the permeability of a cell’s external barriers or the synthesis of repair proteins. Full article
(This article belongs to the Collection Feature Papers in Molecular Biophysics)
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25 pages, 8163 KiB  
Article
CRL4-DCAF12 Ubiquitin Ligase Controls MOV10 RNA Helicase during Spermatogenesis and T Cell Activation
by Tomas Lidak, Nikol Baloghova, Vladimir Korinek, Radislav Sedlacek, Jana Balounova, Petr Kasparek and Lukas Cermak
Int. J. Mol. Sci. 2021, 22(10), 5394; https://doi.org/10.3390/ijms22105394 - 20 May 2021
Cited by 14 | Viewed by 4900
Abstract
Multisubunit cullin-RING ubiquitin ligase 4 (CRL4)-DCAF12 recognizes the C-terminal degron containing acidic amino acid residues. However, its physiological roles and substrates are largely unknown. Purification of CRL4-DCAF12 complexes revealed a wide range of potential substrates, including MOV10, an “ancient” RNA-induced silencing complex (RISC) [...] Read more.
Multisubunit cullin-RING ubiquitin ligase 4 (CRL4)-DCAF12 recognizes the C-terminal degron containing acidic amino acid residues. However, its physiological roles and substrates are largely unknown. Purification of CRL4-DCAF12 complexes revealed a wide range of potential substrates, including MOV10, an “ancient” RNA-induced silencing complex (RISC) complex RNA helicase. We show that DCAF12 controls the MOV10 protein level via its C-terminal motif in a proteasome- and CRL-dependent manner. Next, we generated Dcaf12 knockout mice and demonstrated that the DCAF12-mediated degradation of MOV10 is conserved in mice and humans. Detailed analysis of Dcaf12-deficient mice revealed that their testes produce fewer mature sperms, phenotype accompanied by elevated MOV10 and imbalance in meiotic markers SCP3 and γ-H2AX. Additionally, the percentages of splenic CD4+ T and natural killer T (NKT) cell populations were significantly altered. In vitro, activated Dcaf12-deficient T cells displayed inappropriately stabilized MOV10 and increased levels of activated caspases. In summary, we identified MOV10 as a novel substrate of CRL4-DCAF12 and demonstrated the biological relevance of the DCAF12-MOV10 pathway in spermatogenesis and T cell activation. Full article
(This article belongs to the Special Issue Ubiquitin-Conjugating or Deubiquitinating Enzymes in Signal Transduction Pathways)
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19 pages, 29876 KiB  
Article
Transcriptome and Metabolomic Analyses Reveal Regulatory Networks Controlling Maize Stomatal Development in Response to Blue Light
by Tiedong Liu and Xiwen Zhang
Int. J. Mol. Sci. 2021, 22(10), 5393; https://doi.org/10.3390/ijms22105393 - 20 May 2021
Cited by 9 | Viewed by 2943
Abstract
(1) Background: Blue light is important for the formation of maize stomata, but the signal network remains unclear. (2) Methods: We replaced red light with blue light in an experiment and provided a complementary regulatory network for the stomatal development of maize by [...] Read more.
(1) Background: Blue light is important for the formation of maize stomata, but the signal network remains unclear. (2) Methods: We replaced red light with blue light in an experiment and provided a complementary regulatory network for the stomatal development of maize by using transcriptome and metabolomics analysis. (3) Results: Exposure to blue light led to 1296 differentially expressed genes and 419 differential metabolites. Transcriptome comparisons and correlation signaling network analysis detected 55 genes, and identified 6 genes that work in the regulation of the HY5 module and MAPK cascade, that interact with PTI1, COI1, MPK2, and MPK3, in response to the substitution of blue light in environmental adaptation and signaling transduction pathways. Metabolomics analysis showed that two genes involved in carotenoid biosynthesis and starch and sucrose metabolism participate in stomatal development. Their signaling sites located on the PHI1 and MPK2 sites of the MAPK cascade respond to blue light signaling. (4) Conclusions: Blue light remarkably changed the transcriptional signal transduction and metabolism of metabolites, and eight obtained genes worked in the HY5 module and MAPK cascade. Full article
(This article belongs to the Special Issue Transcriptomic Basis and Nutrient Dependent Signaling Pathways in Plant Development 2.0)
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16 pages, 21910 KiB  
Article
α-Synuclein A53T Binds to Transcriptional Adapter 2-Alpha and Blocks Histone H3 Acetylation
by Ji-Yeong Lee, Hanna Kim, Areum Jo, Rin Khang, Chi-Hu Park, Soo-Jeong Park, Eunsang Kwag and Joo-Ho Shin
Int. J. Mol. Sci. 2021, 22(10), 5392; https://doi.org/10.3390/ijms22105392 - 20 May 2021
Cited by 16 | Viewed by 3663
Abstract
α-Synuclein (α-syn) is a hallmark amyloidogenic protein component of Lewy bodies in dopaminergic neurons affected by Parkinson’s disease (PD). Despite the multi-faceted gene regulation of α-syn in the nucleus, the mechanism underlying α-syn crosstalk in chromatin remodeling in PD pathogenesis remains elusive. Here, [...] Read more.
α-Synuclein (α-syn) is a hallmark amyloidogenic protein component of Lewy bodies in dopaminergic neurons affected by Parkinson’s disease (PD). Despite the multi-faceted gene regulation of α-syn in the nucleus, the mechanism underlying α-syn crosstalk in chromatin remodeling in PD pathogenesis remains elusive. Here, we identified transcriptional adapter 2-alpha (TADA2a) as a novel binding partner of α-syn using the BioID system. TADA2a is a component of the p300/CBP-associated factor and is related to histone H3/H4 acetylation. We found that α-syn A53T was more preferentially localized in the nucleus than the α-syn wild-type (WT), leading to a stronger disturbance of TADA2a. Indeed, α-syn A53T significantly reduced the level of histone H3 acetylation in SH-SY5Y cells; its reduction was also evident in the striatum (STR) and substantia nigra (SN) of mice that were stereotaxically injected with α-syn preformed fibrils (PFFs). Interestingly, α-syn PFF injection resulted in a decrease in TADA2a in the STR and SN of α-syn PFF-injected mice. Furthermore, the levels of TADA2a and acetylated histone H3 were significantly decreased in the SN of patients with PD. Therefore, histone modification through α-syn A53T-TADA2a interaction may be associated with α-syn-mediated neurotoxicity in PD pathology. Full article
(This article belongs to the Section Biochemistry)
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36 pages, 2107 KiB  
Review
SUMO-Targeted Ubiquitin Ligases and Their Functions in Maintaining Genome Stability
by Ya-Chu Chang, Marissa K. Oram and Anja-Katrin Bielinsky
Int. J. Mol. Sci. 2021, 22(10), 5391; https://doi.org/10.3390/ijms22105391 - 20 May 2021
Cited by 29 | Viewed by 6856
Abstract
Small ubiquitin-like modifier (SUMO)-targeted E3 ubiquitin ligases (STUbLs) are specialized enzymes that recognize SUMOylated proteins and attach ubiquitin to them. They therefore connect the cellular SUMOylation and ubiquitination circuits. STUbLs participate in diverse molecular processes that span cell cycle regulated events, including DNA [...] Read more.
Small ubiquitin-like modifier (SUMO)-targeted E3 ubiquitin ligases (STUbLs) are specialized enzymes that recognize SUMOylated proteins and attach ubiquitin to them. They therefore connect the cellular SUMOylation and ubiquitination circuits. STUbLs participate in diverse molecular processes that span cell cycle regulated events, including DNA repair, replication, mitosis, and transcription. They operate during unperturbed conditions and in response to challenges, such as genotoxic stress. These E3 ubiquitin ligases modify their target substrates by catalyzing ubiquitin chains that form different linkages, resulting in proteolytic or non-proteolytic outcomes. Often, STUbLs function in compartmentalized environments, such as the nuclear envelope or kinetochore, and actively aid in nuclear relocalization of damaged DNA and stalled replication forks to promote DNA repair or fork restart. Furthermore, STUbLs reside in the same vicinity as SUMO proteases and deubiquitinases (DUBs), providing spatiotemporal control of their targets. In this review, we focus on the molecular mechanisms by which STUbLs help to maintain genome stability across different species. Full article
(This article belongs to the Special Issue DNA Replication Stress and Chromosomal Instability)
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15 pages, 2568 KiB  
Article
Partial Deficiency of Zfp217 Resists High-Fat Diet-Induced Obesity by Increasing Energy Metabolism in Mice
by Qianhui Zeng, Nannan Wang, Yaru Zhang, Yuxuan Yang, Shuangshuang Li, Rong Zheng, Jin Chai, Tong Qiao and Siwen Jiang
Int. J. Mol. Sci. 2021, 22(10), 5390; https://doi.org/10.3390/ijms22105390 - 20 May 2021
Cited by 6 | Viewed by 2678
Abstract
Obesity-induced adipose tissue dysfunction and disorders of glycolipid metabolism have become a worldwide research priority. Zfp217 plays a crucial role in adipogenesis of 3T3-L1 preadipocytes, but about its functions in animal models are not yet clear. To explore the role of Zfp217 in [...] Read more.
Obesity-induced adipose tissue dysfunction and disorders of glycolipid metabolism have become a worldwide research priority. Zfp217 plays a crucial role in adipogenesis of 3T3-L1 preadipocytes, but about its functions in animal models are not yet clear. To explore the role of Zfp217 in high-fat diet (HFD)-induced obese mice, global Zfp217 heterozygous knockout (Zfp217+/−) mice were constructed. Zfp217+/− mice and Zfp217+/+ mice fed a normal chow diet (NC) did not differ significantly in weight gain, percent body fat mass, glucose tolerance, or insulin sensitivity. When challenged with HFD, Zfp217+/− mice had less weight gain than Zfp217+/+ mice. Histological observations revealed that Zfp217+/− mice fed a high-fat diet had much smaller white adipocytes in inguinal white adipose tissue (iWAT). Zfp217+/− mice had improved metabolic profiles, including improved glucose tolerance, enhanced insulin sensitivity, and increased energy expenditure compared to the Zfp217+/+ mice under HFD. We found that adipogenesis-related genes were increased and metabolic thermogenesis-related genes were decreased in the iWAT of HFD-fed Zfp217+/+ mice compared to Zfp217+/− mice. In addition, adipogenesis was markedly reduced in mouse embryonic fibroblasts (MEFs) from Zfp217-deleted mice. Together, these data indicate that Zfp217 is a regulator of energy metabolism and it is likely to provide novel insight into treatment for obesity. Full article
(This article belongs to the Special Issue Obesity, Genes, and Obesity-Related Disorders)
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13 pages, 656 KiB  
Review
Neuroprotection of the Perinatal Brain by Early Information of Cerebral Oxygenation and Perfusion Patterns
by Filipe Gonçalves Costa, Naser Hakimi and Frank Van Bel
Int. J. Mol. Sci. 2021, 22(10), 5389; https://doi.org/10.3390/ijms22105389 - 20 May 2021
Cited by 14 | Viewed by 3473
Abstract
Abnormal patterns of cerebral perfusion/oxygenation are associated with neuronal damage. In preterm neonates, hypoxemia, hypo-/hypercapnia and lack of cerebral autoregulation are related to peri-intraventricular hemorrhages and white matter injury. Reperfusion damage after perinatal hypoxic ischemia in term neonates seems related with cerebral hyperoxygenation. [...] Read more.
Abnormal patterns of cerebral perfusion/oxygenation are associated with neuronal damage. In preterm neonates, hypoxemia, hypo-/hypercapnia and lack of cerebral autoregulation are related to peri-intraventricular hemorrhages and white matter injury. Reperfusion damage after perinatal hypoxic ischemia in term neonates seems related with cerebral hyperoxygenation. Since biological tissue is transparent for near infrared (NIR) light, NIR-spectroscopy (NIRS) is a noninvasive bedside tool to monitor brain oxygenation and perfusion. This review focuses on early assessment and guiding abnormal cerebral oxygenation/perfusion patterns to possibly reduce brain injury. In term infants, early patterns of brain oxygenation helps to decide whether or not therapy (hypothermia) and add-on therapies should be considered. Further NIRS-related technical advances such as the use of (functional) NIRS allowing simultaneous estimation and integrating of heart rate, respiration rate and monitoring cerebral autoregulation will be discussed. Full article
(This article belongs to the Special Issue New Strategies of Neuroprotection and Repair in the Developing Brain)
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14 pages, 1069 KiB  
Article
Effects of Virgin Olive Oil on Blood Pressure and Renal Aminopeptidase Activities in Male Wistar Rats
by Germán Domínguez-Vías, Ana Belén Segarra, Manuel Ramírez-Sánchez and Isabel Prieto
Int. J. Mol. Sci. 2021, 22(10), 5388; https://doi.org/10.3390/ijms22105388 - 20 May 2021
Cited by 7 | Viewed by 3825
Abstract
High saturated fat diets have been associated with the development of obesity and hypertension, along with other pathologies related to the metabolic syndrome. In contrast, the Mediterranean diet, characterized by its high content of monounsaturated fatty acids, has been proposed as a dietary [...] Read more.
High saturated fat diets have been associated with the development of obesity and hypertension, along with other pathologies related to the metabolic syndrome. In contrast, the Mediterranean diet, characterized by its high content of monounsaturated fatty acids, has been proposed as a dietary factor capable of positively regulating cardiovascular function. These effects have been linked to changes in the local renal renin angiotensin system (RAS) and the activity of the sympathetic nervous system. The main goal of this study was to analyze the role of two dietary fat sources on aminopeptidases activities involved in local kidney RAS. Male Wistar rats (six months old) were fed during 24 weeks with three different diets: the standard diet (S), the standard diet supplemented with virgin olive oil (20%) (VOO), or the standard diet enriched with butter (20%) plus cholesterol (0.1%) (Bch). Kidney samples were separated in medulla and cortex for aminopeptidase activities (AP) assay. Urine samples were collected for routine analysis by chemical tests. Aminopeptidase activities were determined by fluorometric methods in soluble (sol) and membrane-bound (mb) fractions of renal tissue, using arylamide derivatives as substrates. After the experimental period, the systolic blood pressure (SBP) values were similar in standard and VOO animals, and significantly lower than in the Bch group. At the same time, a significant increase in GluAP and IRAP activities were found in renal medulla of Bch animals. However, in VOO group the increase of GluAP activity in renal medulla was lower, while AspAP activity decreased in the renal cortex. Furthermore, the VOO diet also affected other aminopeptidase activities, such as TyrAP and pGluAP, related to the regulation of the sympathetic nervous system and the metabolic rate. These results support the beneficial effect of VOO in the regulation of SBP through changes in local AP activities of the kidney. Full article
(This article belongs to the Special Issue Molecular Interactions of Arterial Hypertension in Its Target Organs)
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17 pages, 507 KiB  
Review
Vascular Endothelial Growth Factor Biology and Its Potential as a Therapeutic Target in Rheumatic Diseases
by Thi Hong Van Le and Sang-Mo Kwon
Int. J. Mol. Sci. 2021, 22(10), 5387; https://doi.org/10.3390/ijms22105387 - 20 May 2021
Cited by 25 | Viewed by 5177
Abstract
Rheumatic diseases constitute a diversified group of diseases distinguished by arthritis and often involve other organs. The affected individual has low quality of life, productivity even life-threatening in some severe conditions. Moreover, they impose significant economic and social burdens. In recent years, the [...] Read more.
Rheumatic diseases constitute a diversified group of diseases distinguished by arthritis and often involve other organs. The affected individual has low quality of life, productivity even life-threatening in some severe conditions. Moreover, they impose significant economic and social burdens. In recent years, the patient outcome has been improved significantly due to clearer comprehension of the pathology of rheumatic diseases and the effectiveness of “treat to target” therapies. However, the high cost and the adverse effects are the concerns and full remissions are not often observed. One of the main processes that contributes to the pathogenesis of rheumatic diseases is angiogenesis. Vascular endothelial growth factor (VEGF), a central mediator that regulates angiogenesis, has different isoforms and functions in various physiological processes. Increasing evidence suggests an association between the VEGF system and rheumatic diseases. Anti-VEGF and VEGF receptor (VEGFR) therapies have been used to treat several cancers and eye diseases. This review summarizes the current understanding of VEGF biology and its role in the context of rheumatic diseases, the contribution of VEGF bioavailability in the pathogenesis of rheumatic diseases, and the potential implications of therapeutic approaches targeting VEGF for these diseases. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis 3.0)
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23 pages, 45236 KiB  
Article
Rapamycin Alternatively Modifies Mitochondrial Dynamics in Dendritic Cells to Reduce Kidney Ischemic Reperfusion Injury
by Maria Namwanje, Bijay Bisunke, Thomas V. Rousselle, Gene G. Lamanilao, Venkatadri S. Sunder, Elizabeth C. Patterson, Canan Kuscu, Cem Kuscu, Daniel Maluf, Manjari Kiran, Valeria Mas, James D. Eason and Amandeep Bajwa
Int. J. Mol. Sci. 2021, 22(10), 5386; https://doi.org/10.3390/ijms22105386 - 20 May 2021
Cited by 10 | Viewed by 4079
Abstract
Dendritic cells (DCs) are unique immune cells that can link innate and adaptive immune responses and Immunometabolism greatly impacts their phenotype. Rapamycin is a macrolide compound that has immunosuppressant functions and is used to prevent graft loss in kidney transplantation. The current study [...] Read more.
Dendritic cells (DCs) are unique immune cells that can link innate and adaptive immune responses and Immunometabolism greatly impacts their phenotype. Rapamycin is a macrolide compound that has immunosuppressant functions and is used to prevent graft loss in kidney transplantation. The current study evaluated the therapeutic potential of ex-vivo rapamycin treated DCs to protect kidneys in a mouse model of acute kidney injury (AKI). For the rapamycin single (S) treatment (Rapa-S-DC), Veh-DCs were treated with rapamycin (10 ng/mL) for 1 h before LPS. In contrast, rapamycin multiple (M) treatment (Rapa-M-DC) were exposed to 3 treatments over 7 days. Only multiple ex-vivo rapamycin treatments of DCs induced a persistent reprogramming of mitochondrial metabolism. These DCs had 18-fold more mitochondria, had almost 4-fold higher oxygen consumption rates, and produced more ATP compared to Veh-DCs (Veh treated control DCs). Pathway analysis showed IL10 signaling as a major contributing pathway to the altered immunophenotype after Rapamycin treatment compared to vehicle with significantly lower cytokines Tnfa, Il1b, and Il6, while regulators of mitochondrial content Pgc1a, Tfam, and Ho1 remained elevated. Critically, adoptive transfer of rapamycin-treated DCs to WT recipients 24 h before bilateral kidney ischemia significantly protected the kidneys from injury with a significant 3-fold improvement in kidney function. Last, the infusion of DCs containing higher mitochondria numbers (treated ex-vivo with healthy isolated mitochondria (10 µg/mL) one day before) also partially protected the kidneys from IRI. These studies demonstrate that pre-emptive infusion of ex-vivo reprogrammed DCs that have higher mitochondria content has therapeutic capacity to induce an anti-inflammatory regulatory phenotype to protect kidneys from injury. Full article
(This article belongs to the Special Issue Pathobiology of Acute Kidney Injury)
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14 pages, 6797 KiB  
Article
Deep Learning in Pancreatic Tissue: Identification of Anatomical Structures, Pancreatic Intraepithelial Neoplasia, and Ductal Adenocarcinoma
by Mark Kriegsmann, Katharina Kriegsmann, Georg Steinbuss, Christiane Zgorzelski, Anne Kraft and Matthias M. Gaida
Int. J. Mol. Sci. 2021, 22(10), 5385; https://doi.org/10.3390/ijms22105385 - 20 May 2021
Cited by 24 | Viewed by 3670
Abstract
Identification of pancreatic ductal adenocarcinoma (PDAC) and precursor lesions in histological tissue slides can be challenging and elaborate, especially due to tumor heterogeneity. Thus, supportive tools for the identification of anatomical and pathological tissue structures are desired. Deep learning methods recently emerged, which [...] Read more.
Identification of pancreatic ductal adenocarcinoma (PDAC) and precursor lesions in histological tissue slides can be challenging and elaborate, especially due to tumor heterogeneity. Thus, supportive tools for the identification of anatomical and pathological tissue structures are desired. Deep learning methods recently emerged, which classify histological structures into image categories with high accuracy. However, to date, only a limited number of classes and patients have been included in histopathological studies. In this study, scanned histopathological tissue slides from tissue microarrays of PDAC patients (n = 201, image patches n = 81.165) were extracted and assigned to a training, validation, and test set. With these patches, we implemented a convolutional neuronal network, established quality control measures and a method to interpret the model, and implemented a workflow for whole tissue slides. An optimized EfficientNet algorithm achieved high accuracies that allowed automatically localizing and quantifying tissue categories including pancreatic intraepithelial neoplasia and PDAC in whole tissue slides. SmoothGrad heatmaps allowed explaining image classification results. This is the first study that utilizes deep learning for automatic identification of different anatomical tissue structures and diseases on histopathological images of pancreatic tissue specimens. The proposed approach is a valuable tool to support routine diagnostic review and pancreatic cancer research. Full article
(This article belongs to the Special Issue The Immune Landscape in Solid Tumors)
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18 pages, 2473 KiB  
Article
KRAS and EGFR Mutations Differentially Alter ABC Drug Transporter Expression in Cisplatin-Resistant Non-Small Cell Lung Cancer
by Luca Jaromi, Veronika Csongei, Monika Vesel, ElHusseiny Mohamed Mahmud Abdelwahab, Amina Soltani, Zsofia Torok, Gabor Smuk, Veronika Sarosi and Judit Erzsebet Pongracz
Int. J. Mol. Sci. 2021, 22(10), 5384; https://doi.org/10.3390/ijms22105384 - 20 May 2021
Cited by 15 | Viewed by 3871
Abstract
Lung carcinoma is still the most common malignancy worldwide. One of the major subtypes of non-small cell lung cancer (NSCLC) is adenocarcinoma (AC). As driver mutations and hence therapies differ in AC subtypes, we theorized that the expression and function of ABC drug [...] Read more.
Lung carcinoma is still the most common malignancy worldwide. One of the major subtypes of non-small cell lung cancer (NSCLC) is adenocarcinoma (AC). As driver mutations and hence therapies differ in AC subtypes, we theorized that the expression and function of ABC drug transporters important in multidrug resistance (MDR) would correlate with characteristic driver mutations KRAS or EGFR. Cisplatin resistance (CR) was generated in A549 (KRAS) and PC9 (EGFR) cell lines and gene expression was tested. In three-dimensional (3D) multicellular aggregate cultures, both ABCB1 and ABCG2 transporters, as well as the WNT microenvironment, were investigated. ABCB1 and ABCG2 gene expression levels were different in primary AC samples and correlated with specific driver mutations. The drug transporter expression pattern of parental A549 and PC9, as well as A549-CR and PC9-CR, cell lines differed. Increased mRNA levels of ABCB1 and ABCG2 were detected in A549-CR cells, compared to parental A549, while the trend observed in the case of PC9 cells was different. Dominant alterations were observed in LEF1, RHOU and DACT1 genes of the WNT signalling pathway in a mutation-dependent manner. The study confirmed that, in lung AC-s, KRAS and EGFR driver mutations differentially affect both drug transporter expression and the cisplatin-induced WNT signalling microenvironment. Full article
(This article belongs to the Special Issue Molecular Regulation of Cancer Cell Migration, Invasion, and Metastasis)
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13 pages, 552 KiB  
Review
Programmed Death-Ligand 1 as a Regulator of Tumor Progression and Metastasis
by Ioannis A. Vathiotis, Georgia Gomatou, Dimitrios J. Stravopodis and Nikolaos Syrigos
Int. J. Mol. Sci. 2021, 22(10), 5383; https://doi.org/10.3390/ijms22105383 - 20 May 2021
Cited by 12 | Viewed by 2938
Abstract
Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint has long been implicated in modeling antitumor immunity; PD-1/PD-L1 axis inhibitors exert their antitumor effects by relieving PD-L1-mediated suppression on tumor-infiltrating T lymphocytes. However, recent studies have unveiled a distinct, tumor-intrinsic, potential [...] Read more.
Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint has long been implicated in modeling antitumor immunity; PD-1/PD-L1 axis inhibitors exert their antitumor effects by relieving PD-L1-mediated suppression on tumor-infiltrating T lymphocytes. However, recent studies have unveiled a distinct, tumor-intrinsic, potential role for PD-L1. In this review, we focus on tumor-intrinsic PD-L1 signaling and delve into preclinical evidence linking PD-L1 protein expression with features of epithelial-to-mesenchymal transition program, cancer stemness and known oncogenic pathways. We further summarize data from studies supporting the prognostic significance of PD-L1 in different tumor types. We show that PD-L1 may indeed have oncogenic potential and act as a regulator of tumor progression and metastasis. Full article
(This article belongs to the Special Issue Causalities and Regulations of Tumor Metastasis — in Memory of Professor Isaiah J. Fidler (1936–2020))
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14 pages, 1259 KiB  
Article
MAT2A Localization and Its Independently Prognostic Relevance in Breast Cancer Patients
by Pei-Yi Chu, Hsing-Ju Wu, Shin-Mae Wang, Po-Ming Chen, Feng-Yao Tang and En-Pei Isabel Chiang
Int. J. Mol. Sci. 2021, 22(10), 5382; https://doi.org/10.3390/ijms22105382 - 20 May 2021
Cited by 17 | Viewed by 4090
Abstract
(1) Background: methionine cycle is not only essential for cancer cell proliferation but is also critical for metabolic reprogramming, a cancer hallmark. Hepatic and extrahepatic tissues methionine adenosyltransferases (MATs) are products of two genes, MAT1A and MAT2A that catalyze the formation of S [...] Read more.
(1) Background: methionine cycle is not only essential for cancer cell proliferation but is also critical for metabolic reprogramming, a cancer hallmark. Hepatic and extrahepatic tissues methionine adenosyltransferases (MATs) are products of two genes, MAT1A and MAT2A that catalyze the formation of S-adenosylmethionine (SAM), the principal biological methyl donor. Glycine N-methyltransferase (GNMT) further utilizes SAM for sarcosine formation, thus it regulates the ratio of SAM:S-adenosylhomocysteine (SAH). (2) Methods: by analyzing the TCGA/GTEx datasets available within GEPIA2, we discovered that breast cancer patients with higher MAT2A had worse survival rate (p = 0.0057). Protein expression pattern of MAT1AA, MAT2A and GNMT were investigated in the tissue microarray in our own cohort (n = 252) by immunohistochemistry. MAT2A C/N expression ratio and cell invasion activity were further investigated in a panel of breast cancer cell lines. (3) Results: GNMT and MAT1A were detected in the cytoplasm, whereas MAT2A showed both cytoplasmic and nuclear immunoreactivity. Neither GNMT nor MAT1A protein expression was associated with patient survival rate in our cohort. Kaplan–Meier survival curves showed that a higher cytoplasmic/nuclear (C/N) MAT2A protein expression ratio correlated with poor overall survival (5 year survival rate: 93.7% vs. 83.3%, C/N ratio ≥ 1.0 vs. C/N ratio < 1.0, log-rank p = 0.004). Accordingly, a MAT2A C/N expression ratio ≥ 1.0 was determined as an independent risk factor by Cox regression analysis (hazard ratio = 2.771, p = 0.018, n = 252). In vitro studies found that breast cancer cell lines with a higher MAT2A C/N ratio were more invasive. (4) Conclusions: the subcellular localization of MAT2A may affect its functions, and elevated MAT2A C/N ratio in breast cancer cells is associated with increased invasiveness. MAT2A C/N expression ratio determined by IHC staining could serve as a novel independent prognostic marker for breast cancer. Full article
(This article belongs to the Special Issue Breast Cancer: From Pathophysiology to Novel Therapeutic Approaches 2.0)
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18 pages, 6691 KiB  
Article
Retinal Pigment Epithelium Remodeling in Mouse Models of Retinitis Pigmentosa
by Debora Napoli, Martina Biagioni, Federico Billeri, Beatrice Di Marco, Noemi Orsini, Elena Novelli and Enrica Strettoi
Int. J. Mol. Sci. 2021, 22(10), 5381; https://doi.org/10.3390/ijms22105381 - 20 May 2021
Cited by 23 | Viewed by 4804
Abstract
In retinitis pigmentosa (RP), one of many possible genetic mutations causes rod degeneration, followed by cone secondary death leading to blindness. Accumulating evidence indicates that rod death triggers multiple, non-cell-autonomous processes, which include oxidative stress and inflammation/immune responses, all contributing to cone demise. [...] Read more.
In retinitis pigmentosa (RP), one of many possible genetic mutations causes rod degeneration, followed by cone secondary death leading to blindness. Accumulating evidence indicates that rod death triggers multiple, non-cell-autonomous processes, which include oxidative stress and inflammation/immune responses, all contributing to cone demise. Inflammation relies on local microglia and recruitment of immune cells, reaching the retina through breakdowns of the inner blood retinal barrier (iBRB). Leakage in the inner retina vasculature suggests similarly altered outer BRB, formed by junctions between retinal pigment epithelium (RPE) cells, which are crucial for retinal homeostasis, immune response, and privilege. We investigated the RPE structural integrity in three models of RP (rd9, rd10, and Tvrm4 mice) by immunostaining for zonula occludens-1 (ZO-1), an essential regulatory component of tight junctions. Quantitative image analysis demonstrated discontinuities in ZO-1 profiles in all mutants, despite different degrees of photoreceptor loss. ZO-1 interruption zones corresponded to leakage of in vivo administered, fluorescent dextran through the choroid-RPE interface, demonstrating barrier dysfunction. Dexamethasone, administered to rd10 mice for rescuing cones, also rescued RPE structure. Thus, previously undetected, stereotyped abnormalities occur in the RPE of RP mice; pharmacological targeting of inflammation supports a feedback loop leading to simultaneous protection of cones and the RPE. Full article
(This article belongs to the Special Issue Retinal Degeneration: Molecular Mechanism, Pathogenesis and Treatment)
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35 pages, 5240 KiB  
Article
Hydrogen Bonds: Raman Spectroscopic Study
by Boris A. Kolesov
Int. J. Mol. Sci. 2021, 22(10), 5380; https://doi.org/10.3390/ijms22105380 - 20 May 2021
Cited by 34 | Viewed by 5542
Abstract
The work outlines general ideas on how the frequency and the intensity of proton vibrations of X–H···Y hydrogen bonding are formed as the bond evolves from weak to maximally strong bonding. For this purpose, the Raman spectra of different chemical compounds with moderate, [...] Read more.
The work outlines general ideas on how the frequency and the intensity of proton vibrations of X–H···Y hydrogen bonding are formed as the bond evolves from weak to maximally strong bonding. For this purpose, the Raman spectra of different chemical compounds with moderate, strong, and extremely strong hydrogen bonds were obtained in the temperature region of 5 K–300 K. The dependence of the proton vibrational frequency is schematically presented as a function of the rigidity of O-H···O bonding. The problems of proton dynamics on tautomeric O–H···O bonds are considered. A brief description of the N–H···O and C–H···Y hydrogen bonds is given. Full article
(This article belongs to the Section Molecular Biophysics)
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22 pages, 7151 KiB  
Article
Rapamycin Ameliorates Defects in Mitochondrial Fission and Mitophagy in Glioblastoma Cells
by Paola Lenzi, Rosangela Ferese, Francesca Biagioni, Federica Fulceri, Carla L. Busceti, Alessandra Falleni, Stefano Gambardella, Alessandro Frati and Francesco Fornai
Int. J. Mol. Sci. 2021, 22(10), 5379; https://doi.org/10.3390/ijms22105379 - 20 May 2021
Cited by 27 | Viewed by 3912
Abstract
Glioblastoma (GBM) cells feature mitochondrial alterations, which are documented and quantified in the present study, by using ultrastructural morphometry. Mitochondrial impairment, which roughly occurs in half of the organelles, is shown to be related to mTOR overexpression and autophagy suppression. The novelty of [...] Read more.
Glioblastoma (GBM) cells feature mitochondrial alterations, which are documented and quantified in the present study, by using ultrastructural morphometry. Mitochondrial impairment, which roughly occurs in half of the organelles, is shown to be related to mTOR overexpression and autophagy suppression. The novelty of the present study consists of detailing an mTOR-dependent mitophagy occlusion, along with suppression of mitochondrial fission. These phenomena contribute to explain the increase in altered mitochondria reported here. Administration of the mTOR inhibitor rapamycin rescues mitochondrial alterations. In detail, rapamycin induces the expression of genes promoting mitophagy (PINK1, PARKIN, ULK1, AMBRA1) and mitochondrial fission (FIS1, DRP1). This occurs along with over-expression of VPS34, an early gene placed upstream in the autophagy pathway. The topographic stoichiometry of proteins coded by these genes within mitochondria indicates that, a remarkable polarization of proteins involved in fission and mitophagy within mitochondria including LC3 takes place. Co-localization of these proteins within mitochondria, persists for weeks following rapamycin, which produces long-lasting mitochondrial plasticity. Thus, rapamycin restores mitochondrial status in GBM cells. These findings add novel evidence about mitochondria and GBM, while fostering a novel therapeutic approach to restore healthy mitochondria through mTOR inhibition. Full article
(This article belongs to the Special Issue mTOR, Metabolism, and Diseases)
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