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Int. J. Mol. Sci., Volume 21, Issue 21 (November-1 2020) – 607 articles

Cover Story (view full-size image): CaMKII and neuronal nitric oxide synthase (nNOS) co-localize in neurons, where CaMKII phosphorylates and inhibits nNOS via a specific Ser residue in transient forebrain ischemia, especially in hypothermic conditions. Meanwhile, CaMKII activities are reversibly regulated by oxidative environmental stress via its specific Cys residue. Thus, mutual regulation between CaMKII and NO might be potential therapeutic signals for neuronal injury. View this paper
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20 pages, 1072 KiB  
Review
How to Predict Metastasis in Luminal Breast Cancer? Current Solutions and Future Prospects
by Sylwia Tabor, Małgorzata Szostakowska-Rodzos, Anna Fabisiewicz and Ewa A. Grzybowska
Int. J. Mol. Sci. 2020, 21(21), 8415; https://doi.org/10.3390/ijms21218415 - 9 Nov 2020
Cited by 15 | Viewed by 4855
Abstract
Breast cancer metastasis is the main cause of breast cancer mortality. Luminal breast cancer represents the majority of breast cancer cases and, despite relatively good prognosis, its heterogeneity creates problems with a proper stratification of patients and correct identification of the group with [...] Read more.
Breast cancer metastasis is the main cause of breast cancer mortality. Luminal breast cancer represents the majority of breast cancer cases and, despite relatively good prognosis, its heterogeneity creates problems with a proper stratification of patients and correct identification of the group with a high risk of metastatic relapse. Current prognostic tools are based on the analysis of the primary tumor and, despite their undisputed power of prediction, they might be insufficient to foresee the relapse in an accurate and precise manner, especially if the relapse occurs after a long period of dormancy, which is very common in luminal breast cancer. New approaches tend to rely on body fluid analyses, which have the advantage of being non-invasive and versatile and may be repeated and used for monitoring the disease in the long run. In this review we describe the current, newly-developed, and only-just-discovered methods which are or may become useful in the assessment of the probability of the relapse. Full article
(This article belongs to the Special Issue Attacking Cancer Progression and Metastasis)
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21 pages, 1278 KiB  
Review
Liver Regeneration after Hepatectomy and Partial Liver Transplantation
by Shintaro Yagi, Masaaki Hirata, Yosuke Miyachi and Shinji Uemoto
Int. J. Mol. Sci. 2020, 21(21), 8414; https://doi.org/10.3390/ijms21218414 - 9 Nov 2020
Cited by 101 | Viewed by 11240
Abstract
The liver is a unique organ with an abundant regenerative capacity. Therefore, partial hepatectomy (PHx) or partial liver transplantation (PLTx) can be safely performed. Liver regeneration involves a complex network of numerous hepatotropic factors, cytokines, pathways, and transcriptional factors. Compared with liver regeneration [...] Read more.
The liver is a unique organ with an abundant regenerative capacity. Therefore, partial hepatectomy (PHx) or partial liver transplantation (PLTx) can be safely performed. Liver regeneration involves a complex network of numerous hepatotropic factors, cytokines, pathways, and transcriptional factors. Compared with liver regeneration after a viral- or drug-induced liver injury, that of post-PHx or -PLTx has several distinct features, such as hemodynamic changes in portal venous flow or pressure, tissue ischemia/hypoxia, and hemostasis/platelet activation. Although some of these changes also occur during liver regeneration after a viral- or drug-induced liver injury, they are more abrupt and drastic following PHx or PLTx, and can thus be the main trigger and driving force of liver regeneration. In this review, we first provide an overview of the molecular biology of liver regeneration post-PHx and -PLTx. Subsequently, we summarize some clinical conditions that negatively, or sometimes positively, interfere with liver regeneration after PHx or PLTx, such as marginal livers including aged or fatty liver and the influence of immunosuppression. Full article
(This article belongs to the Special Issue New Frontiers in Organ Preservation and Hepatoprotection)
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18 pages, 2783 KiB  
Article
Association Analysis in Children Born from Normal and Complicated Pregnancies—Cardiovascular Disease Associated microRNAs and the Incidence of Prehypertension/Hypertension, Overweight/Obesity, Valve Problems and Heart Defects
by Ilona Hromadnikova, Katerina Kotlabova, Ladislav Krofta and Jan Sirc
Int. J. Mol. Sci. 2020, 21(21), 8413; https://doi.org/10.3390/ijms21218413 - 9 Nov 2020
Cited by 5 | Viewed by 2804
Abstract
The goal was to assess how a history of any kind of pregnancy-related complication altered expression profile of microRNAs played a role in the pathogenesis of diabetes, cardiovascular and cerebrovascular diseases in the peripheral blood leukocytes of children at the age of 3–11 [...] Read more.
The goal was to assess how a history of any kind of pregnancy-related complication altered expression profile of microRNAs played a role in the pathogenesis of diabetes, cardiovascular and cerebrovascular diseases in the peripheral blood leukocytes of children at the age of 3–11 years. The prior exposure to gestational hypertension, preeclampsia, fetal growth restriction, gestational diabetes mellitus, preterm prelabor rupture of membranes or spontaneous preterm birth causes that a significant proportion of children (57.42% to 90.0% specifically) had a substantially altered microRNA expression profile, which might be the origin of a lifelong cardiovascular risk. A total of 23 out of 29 tested microRNAs were upregulated in children born from such complicated gestation. The occurrence of overweight, obesity, valve problems and heart defects even intensified upregulation of microRNAs already present in children exposed to such pregnancy complications. The occurrence of overweight/obesity (miR-92a-3p, and miR-210-3p) and valve problems or heart defects (miR-342-3p) induced microRNA upregulation in children affected with pregnancy complications. Overall, 42.86% overweight/obese children and 27.36% children with valve problems or heart defects had even higher microRNA levels than children with normal clinical findings after complicated pregnancies. In addition, the microRNA expression profile was also able to differentiate between children descending from normal gestation in relation to the occurrence of overweight and obesity. Screening on the base of the combination of 19 microRNAs identified 70.0% overweight/obese children at 90.0% specificity. In general, children after complicated pregnancies, just as children after normal pregnancies, with abnormal findings are at a higher risk of the onset of cardiovascular complications, and their dispensarization, with the aim to implement primary prevention strategies, would be beneficial. Full article
(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications 2.0)
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29 pages, 1373 KiB  
Review
CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of the Ligands of Receptors CCR1, CCR2, CCR3, and CCR4
by Jan Korbecki, Klaudyna Kojder, Donata Simińska, Romuald Bohatyrewicz, Izabela Gutowska, Dariusz Chlubek and Irena Baranowska-Bosiacka
Int. J. Mol. Sci. 2020, 21(21), 8412; https://doi.org/10.3390/ijms21218412 - 9 Nov 2020
Cited by 238 | Viewed by 18592
Abstract
CC chemokines, a subfamily of 27 chemotactic cytokines, are a component of intercellular communication, which is crucial for the functioning of the tumor microenvironment. Although many individual chemokines have been well researched, there has been no comprehensive review presenting the role of all [...] Read more.
CC chemokines, a subfamily of 27 chemotactic cytokines, are a component of intercellular communication, which is crucial for the functioning of the tumor microenvironment. Although many individual chemokines have been well researched, there has been no comprehensive review presenting the role of all known human CC chemokines in the hallmarks of cancer, and this paper aims at filling this gap. The first part of this review discusses the importance of CCL1, CCL3, CCL4, CCL5, CCL18, CCL19, CCL20, CCL21, CCL25, CCL27, and CCL28 in cancer. Here, we discuss the significance of CCL2 (MCP-1), CCL7, CCL8, CCL11, CCL13, CCL14, CCL15, CCL16, CCL17, CCL22, CCL23, CCL24, and CCL26. The presentation of each chemokine includes its physiological function and then the role in tumor, including proliferation, drug resistance, migration, invasion, and organ-specific metastasis of tumor cells, as well as the effects on angiogenesis and lymphangiogenesis. We also discuss the effects of each CC chemokine on the recruitment of cancer-associated cells to the tumor niche (eosinophils, myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAM), tumor-associated neutrophils (TAN), regulatory T cells (Treg)). On the other hand, we also present the anti-cancer properties of CC chemokines, consisting in the recruitment of tumor-infiltrating lymphocytes (TIL). Full article
(This article belongs to the Special Issue The Significance of Chemokines for Cancer Processes)
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23 pages, 2041 KiB  
Review
Molecular Mechanisms of “Antiphospholipid Antibodies” and Their Paradoxical Role in the Pathogenesis of “Seronegative APS”
by Roberta Misasi, Agostina Longo, Serena Recalchi, Daniela Caissutti, Gloria Riitano, Valeria Manganelli, Tina Garofalo, Maurizio Sorice and Antonella Capozzi
Int. J. Mol. Sci. 2020, 21(21), 8411; https://doi.org/10.3390/ijms21218411 - 9 Nov 2020
Cited by 25 | Viewed by 5960
Abstract
Antiphospholipid Syndrome (APS) is an autoimmune disease characterized by arterial and/or venous thrombosis and/or pregnancy morbidity, associated with circulating antiphospholipid antibodies (aPL). In some cases, patients with a clinical profile indicative of APS (thrombosis, recurrent miscarriages or fetal loss), who are persistently negative [...] Read more.
Antiphospholipid Syndrome (APS) is an autoimmune disease characterized by arterial and/or venous thrombosis and/or pregnancy morbidity, associated with circulating antiphospholipid antibodies (aPL). In some cases, patients with a clinical profile indicative of APS (thrombosis, recurrent miscarriages or fetal loss), who are persistently negative for conventional laboratory diagnostic criteria, are classified as “seronegative” APS patients (SN-APS). Several findings suggest that aPL, which target phospholipids and/or phospholipid binding proteins, mainly β-glycoprotein I (β-GPI), may contribute to thrombotic diathesis by interfering with hemostasis. Despite the strong association between aPL and thrombosis, the exact pathogenic mechanisms underlying thrombotic events and pregnancy morbidity in APS have not yet been fully elucidated and multiple mechanisms may be involved. Furthermore, in many SN-APS patients, it is possible to demonstrate the presence of unconventional aPL (“non-criteria” aPL) or to detect aPL with alternative laboratory methods. These findings allowed the scientists to study the pathogenic mechanism of SN-APS. This review is focused on the evidence showing that these antibodies may play a functional role in the signal transduction pathway(s) leading to thrombosis and pregnancy morbidity in SN-APS. A better comprehension of the molecular mechanisms triggered by aPL may drive development of potential therapeutic strategies in APS patients. Full article
(This article belongs to the Special Issue Molecular Mechanism and Pathogenesis of Antiphospholipid Syndrome)
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24 pages, 1975 KiB  
Review
Ketamine and Calcium Signaling—A Crosstalk for Neuronal Physiology and Pathology
by Malwina Lisek, Ludmila Zylinska and Tomasz Boczek
Int. J. Mol. Sci. 2020, 21(21), 8410; https://doi.org/10.3390/ijms21218410 - 9 Nov 2020
Cited by 20 | Viewed by 8712
Abstract
Ketamine is a non-competitive antagonist of NMDA (N-methyl-D-aspartate) receptor, which has been in clinical practice for over a half century. Despite recent data suggesting its harmful side effects, such as neuronal loss, synapse dysfunction or disturbed neural network formation, the drug is still [...] Read more.
Ketamine is a non-competitive antagonist of NMDA (N-methyl-D-aspartate) receptor, which has been in clinical practice for over a half century. Despite recent data suggesting its harmful side effects, such as neuronal loss, synapse dysfunction or disturbed neural network formation, the drug is still applied in veterinary medicine and specialist anesthesia. Several lines of evidence indicate that structural and functional abnormalities in the nervous system caused by ketamine are crosslinked with the imbalanced activity of multiple Ca2+-regulated signaling pathways. Due to its ubiquitous nature, Ca2+ is also frequently located in the center of ketamine action, although the precise mechanisms underlying drug’s negative or therapeutic properties remain mysterious for the large part. This review seeks to delineate the relationship between ketamine-triggered imbalance in Ca2+ homeostasis and functional consequences for downstream processes regulating key aspects of neuronal function. Full article
(This article belongs to the Special Issue Psychoactive Substances in Neuronal Development)
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17 pages, 348 KiB  
Review
Biomarkers in Rare Demyelinating Disease of the Central Nervous System
by Marina Boziki, Styliani-Aggeliki Sintila, Panagiotis Ioannidis and Nikolaos Grigoriadis
Int. J. Mol. Sci. 2020, 21(21), 8409; https://doi.org/10.3390/ijms21218409 - 9 Nov 2020
Cited by 7 | Viewed by 4036
Abstract
Rare neurological diseases are a heterogeneous group corresponding approximately to 50% of all rare diseases. Neurologists are among the main specialists involved in their diagnostic investigation. At the moment, a consensus guideline on which neurologists may base clinical suspicion is not available. Moreover, [...] Read more.
Rare neurological diseases are a heterogeneous group corresponding approximately to 50% of all rare diseases. Neurologists are among the main specialists involved in their diagnostic investigation. At the moment, a consensus guideline on which neurologists may base clinical suspicion is not available. Moreover, neurologists need guidance with respect to screening investigations that may be performed. In this respect, biomarker research has emerged as a particularly active field due to its potential applications in clinical practice. With respect to autoimmune demyelinating diseases of the Central Nervous System (CNS), although these diseases occur in the frame of organ-specific autoimmunity, pathology of the disease itself is orchestrated among several anatomical and functional compartments. The differential diagnosis is broad and includes, but is not limited to, rare neurological diseases. Multiple Sclerosis (MS) needs to be differentially diagnosed from rare MS variants, Acute Disseminated Encephalomyelitis (ADEM), the range of Neuromyelitis Optica Spectrum Disorders (NMOSDs), Myelin Oligodendrocyte Glycoprotein (MOG) antibody disease and other systemic inflammatory diseases. Diagnostic biomarkers may facilitate timely diagnosis and proper disease management, preventing disease exacerbation due to misdiagnosis and false treatment. In this review, we will describe advances in biomarker research with respect to rare neuroinflammatory disease of the CNS. Full article
(This article belongs to the Special Issue Biomarkers in Rare Diseases)
16 pages, 2041 KiB  
Communication
3D-Reconstructed Retinal Pigment Epithelial Cells Provide Insights into the Anatomy of the Outer Retina
by Eloise Keeling, David S. Chatelet, Nicole Y. T. Tan, Farihah Khan, Rhys Richards, Thibana Thisainathan, Patricia Goggin, Anton Page, David A. Tumbarello, Andrew J. Lotery and J. Arjuna Ratnayaka
Int. J. Mol. Sci. 2020, 21(21), 8408; https://doi.org/10.3390/ijms21218408 - 9 Nov 2020
Cited by 15 | Viewed by 5878
Abstract
The retinal pigment epithelium (RPE) is located between the neuroretina and the choroid, and plays a critical role in vision. RPE cells internalise outer segments (OS) from overlying photoreceptors in the daily photoreceptor renewal. Changes to RPE structure are linked with age and [...] Read more.
The retinal pigment epithelium (RPE) is located between the neuroretina and the choroid, and plays a critical role in vision. RPE cells internalise outer segments (OS) from overlying photoreceptors in the daily photoreceptor renewal. Changes to RPE structure are linked with age and retinopathy, which has been described in the past by conventional 2D electron microscopy. We used serial block face scanning electron microscopy (SBF-SEM) to reconstruct RPE cells from the central mouse retina. Three-dimensional-reconstructed OS revealed the RPE to support large numbers of photoreceptors (90–216 per RPE cell). Larger bi-nucleate RPE maintained more photoreceptors, although their cytoplasmic volume was comparable to smaller mono-nucleate RPE supporting fewer photoreceptors. Scrutiny of RPE microvilli and interdigitating OS revealed the angle and surface area of contact between RPE and photoreceptors. Bi-nucleate RPE contained more mitochondria compared to mono-nucleate RPE. Furthermore, bi-nucleate cells contained larger sub-RPE spaces, supporting a likely association with disease. Use of perfusion-fixed tissues ensured the highest possible standard of preservation, providing novel insights into the 3D RPE architecture and changes linked with retinopathy. This study serves as a benchmark for comparing retinal tissues from donor eyes with age-related macular degeneration (AMD) and other retinopathies. Full article
(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 2.0)
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12 pages, 3649 KiB  
Article
High Stroma T-Cell Infiltration is Associated with Better Survival in Stage pT1 Bladder Cancer
by Sabine Hülsen, Eleonora Lippolis, Fulvia Ferrazzi, Wolfgang Otto, Luitpold Distel, Rainer Fietkau, Stefan Denzinger, Johannes Breyer, Maximilian Burger, Simone Bertz, Markus Eckstein, Annette Ebner, Arndt Hartmann and Carol-I. Geppert
Int. J. Mol. Sci. 2020, 21(21), 8407; https://doi.org/10.3390/ijms21218407 - 9 Nov 2020
Cited by 15 | Viewed by 2696
Abstract
Stage pT1 bladder cancer (BC) shows highly diverse outcomes. Predictive markers are required to stratify patients for personalized treatment. The present study aimed to validate immune response quantification as a prognostic marker. Patients with pT1 BC (n = 167) treated by transurethral [...] Read more.
Stage pT1 bladder cancer (BC) shows highly diverse outcomes. Predictive markers are required to stratify patients for personalized treatment. The present study aimed to validate immune response quantification as a prognostic marker. Patients with pT1 BC (n = 167) treated by transurethral resection of the bladder (TURB) were enrolled. Formaldehyde-fixed paraffin-embedded material was stained for CD3 and CD8. Corresponding T cells were counted in three regions with the highest immune response. Numbers of tertiary lymphoid structures (TLS) and lymphocyte aggregates (LA) were quantified. High CD3+ stroma T-cell infiltration was associated with improved survival (p = 0.045), especially in the G3 subgroup (p = 0.01). Cluster with higher immune response showed less recurrence (p = 0.034) and favorable overall survival (OS) (p = 0.019). In contrast, higher CD3+ and CD8+ tumor T-cell infiltration seemed to have a negative impact on prognosis. TLS and LA were more frequently observed in G3 tumors, indicating an increased anti-tumoral immune response. We proved the role of immune cell infiltration and showed that higher infiltration numbers of CD3+ (not CD8+) lymphocytes in the stroma are associated with favorable outcome. Immune cell quantification could be used as a marker to help stratify patients’ risk and therefore, to optimize patients’ management and follow-up examination as well as possible therapies. Full article
(This article belongs to the Special Issue Biomarker-Oriented Treatment of Urogenital Cancers)
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26 pages, 1312 KiB  
Review
Molecular and Cellular Mechanisms of Itch in Psoriasis
by Eriko Komiya, Mitsutoshi Tominaga, Yayoi Kamata, Yasushi Suga and Kenji Takamori
Int. J. Mol. Sci. 2020, 21(21), 8406; https://doi.org/10.3390/ijms21218406 - 9 Nov 2020
Cited by 59 | Viewed by 10294
Abstract
Itch (or pruritus) was not previously recognized as a serious symptom of psoriasis. However, approximately 60–90% of psoriatic patients with pruritus have stated that it deteriorates their quality of life. Since conventional antipruritic therapies, such as antihistamines, only exert limited effects, the establishment [...] Read more.
Itch (or pruritus) was not previously recognized as a serious symptom of psoriasis. However, approximately 60–90% of psoriatic patients with pruritus have stated that it deteriorates their quality of life. Since conventional antipruritic therapies, such as antihistamines, only exert limited effects, the establishment of a treatment option for itch in psoriasis is urgently needed. Although a definitive drug is not currently available, various itch mediators are known to be involved in pruritus in psoriasis. In this review, we describe the clinical features of pruritus in psoriasis, classify a wide range of itch mediators into categories, such as the nervous, immune, endocrine, and vascular systems, and discuss the mechanisms by which these mediators induce or aggravate itch in the pathophysiology of psoriasis. Full article
(This article belongs to the Special Issue Psoriasis: Pathogenesis, Comorbidities, and Therapy Updated)
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18 pages, 4123 KiB  
Article
A Novel Inhibitor of Carbonic Anhydrases Prevents Hypoxia-Induced TNBC Cell Plasticity
by Annachiara Sarnella, Giuliana D’Avino, Billy Samuel Hill, Vincenzo Alterio, Jean-Yves Winum, Claudiu T. Supuran, Giuseppina De Simone and Antonella Zannetti
Int. J. Mol. Sci. 2020, 21(21), 8405; https://doi.org/10.3390/ijms21218405 - 9 Nov 2020
Cited by 15 | Viewed by 2873
Abstract
Cell plasticity is the ability that cells have to modify their phenotype, adapting to the environment. Cancer progression is under the strict control of the the tumor microenvironment that strongly determines its success by regulating the behavioral changes of tumor cells. The cross-talk [...] Read more.
Cell plasticity is the ability that cells have to modify their phenotype, adapting to the environment. Cancer progression is under the strict control of the the tumor microenvironment that strongly determines its success by regulating the behavioral changes of tumor cells. The cross-talk between cancer and stromal cells and the interactions with the extracellular matrix, hypoxia and acidosis contribute to trigger a new tumor cell identity and to enhance tumor heterogeneity and metastatic spread. In highly aggressive triple-negative breast cancer, tumor cells show a significant capability to change their phenotype under the pressure of the hypoxic microenvironment. In this study, we investigated whether targeting the hypoxia-induced protein carbonic anhydrase IX (CA IX) could reduce triple-negative breast cancer (TNBC) cell phenotypic switching involved in processes associated with poor prognosis such as vascular mimicry (VM) and cancer stem cells (CSCs). The treatment of two TNBC cell lines (BT-549 and MDA-MB-231) with a specific CA IX siRNA or with a novel inhibitor of carbonic anhydrases (RC44) severely impaired their ability to form a vascular-like network and mammospheres and reduced their metastatic potential. In addition, the RC44 inhibitor was able to hamper the signal pathways involved in triggering VM and CSC formation. These results demonstrate that targeting hypoxia-induced cell plasticity through CA IX inhibition could be a new opportunity to selectively reduce VM and CSCs, thus improving the efficiency of existing therapies in TNBC. Full article
(This article belongs to the Special Issue Breast Cancer: From Pathophysiology to Novel Therapeutic Approaches)
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24 pages, 4150 KiB  
Article
Ligand-Specific Factors Influencing GLP-1 Receptor Post-Endocytic Trafficking and Degradation in Pancreatic Beta Cells
by Zijian Fang, Shiqian Chen, Yusman Manchanda, Stavroula Bitsi, Philip Pickford, Alessia David, Maria M. Shchepinova, Ivan R. Corrêa Jr, David J. Hodson, Johannes Broichhagen, Edward W. Tate, Frank Reimann, Victoria Salem, Guy A. Rutter, Tricia Tan, Stephen R. Bloom, Alejandra Tomas and Ben Jones
Int. J. Mol. Sci. 2020, 21(21), 8404; https://doi.org/10.3390/ijms21218404 - 9 Nov 2020
Cited by 25 | Viewed by 5941
Abstract
The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of blood glucose homeostasis. Ligand-specific differences in membrane trafficking of the GLP-1R influence its signalling properties and therapeutic potential in type 2 diabetes. Here, we have evaluated how different factors combine to control the [...] Read more.
The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of blood glucose homeostasis. Ligand-specific differences in membrane trafficking of the GLP-1R influence its signalling properties and therapeutic potential in type 2 diabetes. Here, we have evaluated how different factors combine to control the post-endocytic trafficking of GLP-1R to recycling versus degradative pathways. Experiments were performed in primary islet cells, INS-1 832/3 clonal beta cells and HEK293 cells, using biorthogonal labelling of GLP-1R to determine its localisation and degradation after treatment with GLP-1, exendin-4 and several further GLP-1R agonist peptides. We also characterised the effect of a rare GLP1R coding variant, T149M, and the role of endosomal peptidase endothelin-converting enzyme-1 (ECE-1), in GLP1R trafficking. Our data reveal how treatment with GLP-1 versus exendin-4 is associated with preferential GLP-1R targeting towards a recycling pathway. GLP-1, but not exendin-4, is a substrate for ECE-1, and the resultant propensity to intra-endosomal degradation, in conjunction with differences in binding affinity, contributes to alterations in GLP-1R trafficking behaviours and degradation. The T149M GLP-1R variant shows reduced signalling and internalisation responses, which is likely to be due to disruption of the cytoplasmic region that couples to intracellular effectors. These observations provide insights into how ligand- and genotype-specific factors can influence GLP-1R trafficking. Full article
(This article belongs to the Special Issue Journey inside the Beta Cells in Type 2 Diabetes)
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11 pages, 963 KiB  
Communication
The FKBP4 Gene, Encoding a Regulator of the Androgen Receptor Signaling Pathway, Is a Novel Candidate Gene for Androgen Insensitivity Syndrome
by Erkut Ilaslan, Renata Markosyan, Patrick Sproll, Brian J. Stevenson, Malgorzata Sajek, Marcin P. Sajek, Hasmik Hayrapetyan, Tamara Sarkisian, Ludmila Livshits, Serge Nef, Jadwiga Jaruzelska and Kamila Kusz-Zamelczyk
Int. J. Mol. Sci. 2020, 21(21), 8403; https://doi.org/10.3390/ijms21218403 - 9 Nov 2020
Cited by 7 | Viewed by 3733
Abstract
Androgen insensitivity syndrome (AIS), manifesting incomplete virilization in 46,XY individuals, is caused mostly by androgen receptor (AR) gene mutations. Therefore, a search for AR mutations is a routine approach in AIS diagnosis. However, some AIS patients lack AR mutations, which complicates the diagnosis. [...] Read more.
Androgen insensitivity syndrome (AIS), manifesting incomplete virilization in 46,XY individuals, is caused mostly by androgen receptor (AR) gene mutations. Therefore, a search for AR mutations is a routine approach in AIS diagnosis. However, some AIS patients lack AR mutations, which complicates the diagnosis. Here, we describe a patient suffering from partial androgen insensitivity syndrome (PAIS) and lacking AR mutations. The whole exome sequencing of the patient and his family members identified a heterozygous FKBP4 gene mutation, c.956T>C (p.Leu319Pro), inherited from the mother. The gene encodes FKBP prolyl isomerase 4, a positive regulator of the AR signaling pathway. This is the first report describing a FKBP4 gene mutation in association with a human disorder of sexual development (DSD). Importantly, the dysfunction of a homologous gene was previously reported in mice, resulting in a phenotype corresponding to PAIS. Moreover, the Leu319Pro amino acid substitution occurred in a highly conserved position of the FKBP4 region, responsible for interaction with other proteins that are crucial for the AR functional heterocomplex formation and therefore the substitution is predicted to cause the disease. We proposed the FKBP4 gene as a candidate AIS gene and suggest screening that gene for the molecular diagnosis of AIS patients lacking AR gene mutations. Full article
(This article belongs to the Special Issue Sex Determination Mechanisms and Disease)
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16 pages, 2447 KiB  
Article
Enzyme Properties of a Laccase Obtained from the Transcriptome of the Marine-Derived Fungus Stemphylium lucomagnoense
by Wissal Ben Ali, Amal Ben Ayed, Annick Turbé-Doan, Emmanuel Bertrand, Yann Mathieu, Craig B. Faulds, Anne Lomascolo, Giuliano Sciara, Eric Record and Tahar Mechichi
Int. J. Mol. Sci. 2020, 21(21), 8402; https://doi.org/10.3390/ijms21218402 - 9 Nov 2020
Cited by 5 | Viewed by 3269
Abstract
Only a few studies have examined how marine-derived fungi and their enzymes adapt to salinity and plant biomass degradation. This work concerns the production and characterisation of an oxidative enzyme identified from the transcriptome of marine-derived fungus Stemphylium lucomagnoense. The laccase-encoding gene [...] Read more.
Only a few studies have examined how marine-derived fungi and their enzymes adapt to salinity and plant biomass degradation. This work concerns the production and characterisation of an oxidative enzyme identified from the transcriptome of marine-derived fungus Stemphylium lucomagnoense. The laccase-encoding gene SlLac2 from S. lucomagnoense was cloned for heterologous expression in Aspergillus niger D15#26 for protein production in the extracellular medium of around 30 mg L−1. The extracellular recombinant enzyme SlLac2 was successfully produced and purified in three steps protocol: ultrafiltration, anion-exchange chromatography, and size exclusion chromatography, with a final recovery yield of 24%. SlLac2 was characterised by physicochemical properties, kinetic parameters, and ability to oxidise diverse phenolic substrates. We also studied its activity in the presence and absence of sea salt. The molecular mass of SlLac2 was about 75 kDa, consistent with that of most ascomycete fungal laccases. With syringaldazine as substrate, SlLac2 showed an optimal activity at pH 6 and retained nearly 100% of its activity when incubated at 50°C for 180 min. SlLac2 exhibited more than 50% of its activity with 5% wt/vol of sea salt. Full article
(This article belongs to the Special Issue Carbohydrate-Active Enzymes: Structure, Activity and Reaction Products 2020)
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22 pages, 4583 KiB  
Review
Plant Non-Coding RNAs: Origin, Biogenesis, Mode of Action and Their Roles in Abiotic Stress
by Joram Kiriga Waititu, Chunyi Zhang, Jun Liu and Huan Wang
Int. J. Mol. Sci. 2020, 21(21), 8401; https://doi.org/10.3390/ijms21218401 - 9 Nov 2020
Cited by 64 | Viewed by 6081
Abstract
As sessile species, plants have to deal with the rapidly changing environment. In response to these environmental conditions, plants employ a plethora of response mechanisms that provide broad phenotypic plasticity to allow the fine-tuning of the external cues related reactions. Molecular biology has [...] Read more.
As sessile species, plants have to deal with the rapidly changing environment. In response to these environmental conditions, plants employ a plethora of response mechanisms that provide broad phenotypic plasticity to allow the fine-tuning of the external cues related reactions. Molecular biology has been transformed by the major breakthroughs in high-throughput transcriptome sequencing and expression analysis using next-generation sequencing (NGS) technologies. These innovations have provided substantial progress in the identification of genomic regions as well as underlying basis influencing transcriptional and post-transcriptional regulation of abiotic stress response. Non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs), short interfering RNAs (siRNAs), and long non-coding RNAs (lncRNAs), have emerged as essential regulators of plants abiotic stress response. However, shared traits in the biogenesis of ncRNAs and the coordinated cross-talk among ncRNAs mechanisms contribute to the complexity of these molecules and might play an essential part in regulating stress responses. Herein, we highlight the current knowledge of plant microRNAs, siRNAs, and lncRNAs, focusing on their origin, biogenesis, modes of action, and fundamental roles in plant response to abiotic stresses. Full article
(This article belongs to the Special Issue Molecular Bases of Stress Adaptation in Plants: The Contribute of Regulation by Small RNAs in Plant Development and Stress Response)
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20 pages, 3898 KiB  
Article
CDK5RAP3, a Novel Nucleoplasmic Shuttle, Deeply Regulates HSF1-Mediated Heat Stress Response and Protects Mammary Epithelial Cells from Heat Injury
by Yangyang Shen, Yan Zou, Jun Li, Fanghui Chen, Honglin Li and Yafei Cai
Int. J. Mol. Sci. 2020, 21(21), 8400; https://doi.org/10.3390/ijms21218400 - 9 Nov 2020
Cited by 7 | Viewed by 3133
Abstract
CDK5RAP3 was regarded as the most significant regulator of cellular responses against heat stress, which is associated with dysfunctions of the immune system and animal susceptibility to disease. Despite this, little known about how CDK5RAP3 regulates heat stress response. In this study, CDK5RAP3 [...] Read more.
CDK5RAP3 was regarded as the most significant regulator of cellular responses against heat stress, which is associated with dysfunctions of the immune system and animal susceptibility to disease. Despite this, little known about how CDK5RAP3 regulates heat stress response. In this study, CDK5RAP3 conditional Knockout (CKO) mice, CDK5RAP3-/- mouse embryo fibroblasts (MEFs) and bovine mammary epithelial cells (BMECs) were used as an in vitro and in vivo model, respectively to reveal the role of CDK5RAP3 in regulating the heat stress response. The deletion of CDK5RAP3 unexpectedly caused animal lethality after 1.5-h heat stimulations. Furthermore, BMECs were re-cultured for eight hours after heat stress and was found that the expression of CDK5RAP3 and HSPs showed a similar fluctuating pattern of increase (0–2, 4–6 h) and decrease (2–4, 6–8 h). In addition to the remarkably enhanced expression of heat shock protein, apoptosis rate and endoplasmic reticulum stress, the deletion of CDK5RAP3 also affected nucleoplasmic translocation and trimer formation of heat shock factor 1 (HSF1). These programs were further confirmed in the mammary gland of CDK5RAP3 CKO mice and CDK5RAP3-/- MEFs as well. Interestingly, genetic silencing of HSF1 downregulated CDK5RAP3 expression in BMECs. Immunostaining and immunoprecipitation studies suggested a physical interaction between CDK5RAP3 and HSF1 being co-localized in the cytoplasm and nucleus. Besides, CDK5RAP3 also interacted with HSP90, suggesting an operative machinery at both transcriptional level and protein functionality of HSP90 per se. Together, our findings suggested that CDK5RAP3 works like a novel nucleoplasmic shuttle or molecular chaperone, deeply participating in HSF1-mediated heat stress response and protecting cells from heat injury. Full article
(This article belongs to the Special Issue The Role of E3 Ligases and Deubiquitinating Enzymes in Cellular Signaling, Diseases, and Therapeutics)
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21 pages, 2958 KiB  
Hypothesis
Hypothesis: Single Actomyosin Properties Account for Ensemble Behavior in Active Muscle Shortening and Isometric Contraction
by Alf Månsson
Int. J. Mol. Sci. 2020, 21(21), 8399; https://doi.org/10.3390/ijms21218399 - 9 Nov 2020
Cited by 12 | Viewed by 3783
Abstract
Muscle contraction results from cyclic interactions between myosin II motors and actin with two sets of proteins organized in overlapping thick and thin filaments, respectively, in a nearly crystalline lattice in a muscle sarcomere. However, a sarcomere contains a huge number of other [...] Read more.
Muscle contraction results from cyclic interactions between myosin II motors and actin with two sets of proteins organized in overlapping thick and thin filaments, respectively, in a nearly crystalline lattice in a muscle sarcomere. However, a sarcomere contains a huge number of other proteins, some with important roles in muscle contraction. In particular, these include thin filament proteins, troponin and tropomyosin; thick filament proteins, myosin binding protein C; and the elastic protein, titin, that connects the thin and thick filaments. Furthermore, the order and 3D organization of the myofilament lattice may be important per se for contractile function. It is possible to model muscle contraction based on actin and myosin alone with properties derived in studies using single molecules and biochemical solution kinetics. It is also possible to reproduce several features of muscle contraction in experiments using only isolated actin and myosin, arguing against the importance of order and accessory proteins. Therefore, in this paper, it is hypothesized that “single molecule actomyosin properties account for the contractile properties of a half sarcomere during shortening and isometric contraction at almost saturating Ca concentrations”. In this paper, existing evidence for and against this hypothesis is reviewed and new modeling results to support the arguments are presented. Finally, further experimental tests are proposed, which if they corroborate, at least approximately, the hypothesis, should significantly benefit future effective analysis of a range of experimental studies, as well as drug discovery efforts. Full article
(This article belongs to the Special Issue Molecular Motors: From Single Molecules to Cooperative and Regulatory Mechanisms In Vivo)
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16 pages, 2841 KiB  
Article
Platelet-Reactive Antibodies in Patients after Ischaemic Stroke—An Epiphenomenon or a Natural Protective Mechanism
by Young Eun Park, Rushi Penumarthy, Paul P. Sun, Caroline Y. Kang, Marie-Christine Morel-Kopp, Jonathan Downing, Taryn N. Green, Tracey Immanuel, Christopher M. Ward, Deborah Young, Matthew J. During, P. Alan Barber and Maggie L. Kalev-Zylinska
Int. J. Mol. Sci. 2020, 21(21), 8398; https://doi.org/10.3390/ijms21218398 - 9 Nov 2020
Cited by 1 | Viewed by 2791
Abstract
Ischaemic brain damage induces autoimmune responses, including the production of autoantibodies with potential neuroprotective effects. Platelets share unexplained similarities with neurons, and the formation of anti-platelet antibodies has been documented in neurological disorders. The aim of this study was to investigate the presence [...] Read more.
Ischaemic brain damage induces autoimmune responses, including the production of autoantibodies with potential neuroprotective effects. Platelets share unexplained similarities with neurons, and the formation of anti-platelet antibodies has been documented in neurological disorders. The aim of this study was to investigate the presence of anti-platelet antibodies in the peripheral blood of patients after ischaemic stroke and determine any clinical correlations. Using a flow cytometry-based platelet immunofluorescence method, we detected platelet-reactive antibodies in 15 of 48 (31%) stroke patients and two of 50 (4%) controls (p < 0.001). Western blotting revealed heterogeneous reactivities with platelet proteins, some of which overlapped with brain proteins. Stroke patients who carried anti-platelet antibodies presented with larger infarcts and more severe neurological dysfunction, which manifested as higher scores on the National Institutes of Health Stroke Scale (NIHSS; p = 0.009), but they had a greater recovery in the NIHSS by the time of hospital discharge (day 7 ± 2) compared with antibody-negative patients (p = 0.043). Antibodies from stroke sera reacted more strongly with activated platelets (p = 0.031) and inhibited platelet aggregation by up to 30.1 ± 2.8% (p < 0.001), suggesting the potential to interfere with thrombus formation. In conclusion, platelet-reactive antibodies can be found in patients soon after ischaemic stroke and correlate with better short-term outcomes, suggesting a potential novel mechanism limiting thrombosis. Full article
(This article belongs to the Special Issue Advances in Biological Functions of Platelet)
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14 pages, 1534 KiB  
Review
Why Vitamin C Could Be an Excellent Complementary Remedy to Conventional Therapies for Breast Cancer
by Michela Codini
Int. J. Mol. Sci. 2020, 21(21), 8397; https://doi.org/10.3390/ijms21218397 - 9 Nov 2020
Cited by 15 | Viewed by 6054
Abstract
The most frequent cancer in women is breast cancer, which is a major cause of death. Currently, there are many pharmacological therapies that have made possible the cure and resolution of this tumor. However, these therapies are accompanied by numerous collateral effects that [...] Read more.
The most frequent cancer in women is breast cancer, which is a major cause of death. Currently, there are many pharmacological therapies that have made possible the cure and resolution of this tumor. However, these therapies are accompanied by numerous collateral effects that influence the quality of life (QoL) of the patients to varying degrees. For this reason, attention is turning to the use of complementary medicine to improve QoL. In particular, there are increased trials of intravenous injection of vitamin C at high doses to enhance the antitumor activity of drugs and/or decrease their side effects. This review intends to underline the anticancer mechanisms of vitamin C that could explain its efficacy for treating breast cancer, and why the use of vitamin C at high doses could help patients with breast cancer to enhance the efficacy of pharmacological therapies and/or decrease their side effects. Full article
(This article belongs to the Special Issue Dietary Bioactive Compounds and Breast Cancer)
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14 pages, 1470 KiB  
Article
Letrozole Suppresses the Fusion of Osteoclast Precursors through Inhibition of p38-Mediated DC-STAMP Pathway
by Hyung Joon Kim, Hwa-Sik Seong, YunJeong Choi, Soon Chul Heo and Yong-Deok Kim
Int. J. Mol. Sci. 2020, 21(21), 8396; https://doi.org/10.3390/ijms21218396 - 9 Nov 2020
Cited by 2 | Viewed by 2527
Abstract
Letrozole is a reversible nonsteroidal aromatase inhibitor that is widely used in postmenopausal breast cancer patients. It is well established that letrozole decreases bone density owing to estrogen depletion; however, few studies have reported its direct effect on bone cells in vitro. Therefore, [...] Read more.
Letrozole is a reversible nonsteroidal aromatase inhibitor that is widely used in postmenopausal breast cancer patients. It is well established that letrozole decreases bone density owing to estrogen depletion; however, few studies have reported its direct effect on bone cells in vitro. Therefore, we investigated the effect of letrozole on bone metabolism, focusing on osteoclastogenesis. Letrozole did not affect the viability, proliferation, or migration of bone marrow-derived macrophages (BMMs); however, it reduced the multinucleation of immature osteoclasts and subsequent bone resorption in vitro. Overall, letrozole inhibited the expression of dendritic cell-specific transmembrane protein (DC-STAMP), tartrate-resistant acid phosphatase, calcitonin receptor, and cathepsin K. Among them, the reduced expression of DC-STAMP was the most prominent. However, this downregulation of DC-STAMP expression following letrozole treatment was not related to the inhibition of major osteoclastogenesis pathways, such as the nuclear factor-κB (NF-κB), c-Fos, and nuclear factor of activated T cell c1 (NFATc1) pathways, but was attributed to the inhibition of p38, which is known to reside upstream of DC-STAMP expression. Notably, the anti-osteoclastogenic effect of letrozole was abolished following treatment with the p38 activator anisomycin. Contrary to our expectations, these results strongly suggest a previously unknown anti-osteoclastogenic activity of letrozole, mediated by the downregulation of the p38/DC-STAMP pathway. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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25 pages, 5588 KiB  
Article
Influence of Lipoxygenase Inhibition on Glioblastoma Cell Biology
by Felipe da Costa Souza, Matthew Thomas Ferreira and Alison Colquhoun
Int. J. Mol. Sci. 2020, 21(21), 8395; https://doi.org/10.3390/ijms21218395 - 9 Nov 2020
Cited by 16 | Viewed by 7406
Abstract
Background: The relationship between glioblastoma (GBM) and fatty acid metabolism could be the key to elucidate more effective therapeutic targets. 15-lipoxygenase-1 (15-LOX), a linolenic acid and arachidonic acid metabolizing enzyme, induces both pro- and antitumorigenic effects in different cancer types. Its role in [...] Read more.
Background: The relationship between glioblastoma (GBM) and fatty acid metabolism could be the key to elucidate more effective therapeutic targets. 15-lipoxygenase-1 (15-LOX), a linolenic acid and arachidonic acid metabolizing enzyme, induces both pro- and antitumorigenic effects in different cancer types. Its role in glioma activity has not yet been clearly described. The objective of this study was to identify the influence of 15-LOX and its metabolites on glioblastoma cell activity. Methods: GBM cell lines were examined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to identify 15-LOX metabolites. GBM cells treated with 15-LOX metabolites, 13-hydroxyoctadecadeinoic acid (HODE) and 9-HODE, and two 15-LOX inhibitors (luteolin and nordihydroguaiaretic acid) were also examined. Dose response/viability curves, RT-PCRs, flow cytometry, migration assays, and zymograms were performed to analyze GBM growth, migration, and invasion. Results: Higher quantities of 13-HODE were observed in five GBM cell lines compared to other lipids analyzed. Both 13-HODE and 9-HODE increased cell count in U87MG. 15-LOX inhibition decreased migration and increased cell cycle arrest in the G2/M phase. Conclusion: 15-LOX and its linoleic acid (LA)-derived metabolites exercise a protumorigenic influence on GBM cells in vitro. Elevated endogenous levels of 13-HODE called attention to the relationship between linoleic acid metabolism and GBM cell activity. Full article
(This article belongs to the Special Issue Bioactive Lipids and Lipidomics 2020)
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21 pages, 2444 KiB  
Article
Epigenetics of Muscle- and Brain-Specific Expression of KLHL Family Genes
by Kenneth C. Ehrlich, Carl Baribault and Melanie Ehrlich
Int. J. Mol. Sci. 2020, 21(21), 8394; https://doi.org/10.3390/ijms21218394 - 9 Nov 2020
Cited by 19 | Viewed by 4120
Abstract
KLHL and the related KBTBD genes encode components of the Cullin-E3 ubiquitin ligase complex and typically target tissue-specific proteins for degradation, thereby affecting differentiation, homeostasis, metabolism, cell signaling, and the oxidative stress response. Despite their importance in cell function and disease (especially, KLHL40 [...] Read more.
KLHL and the related KBTBD genes encode components of the Cullin-E3 ubiquitin ligase complex and typically target tissue-specific proteins for degradation, thereby affecting differentiation, homeostasis, metabolism, cell signaling, and the oxidative stress response. Despite their importance in cell function and disease (especially, KLHL40, KLHL41, KBTBD13, KEAP1, and ENC1), previous studies of epigenetic factors that affect transcription were predominantly limited to promoter DNA methylation. Using diverse tissue and cell culture whole-genome profiles, we examined 17 KLHL or KBTBD genes preferentially expressed in skeletal muscle or brain to identify tissue-specific enhancer and promoter chromatin, open chromatin (DNaseI hypersensitivity), and DNA hypomethylation. Sixteen of the 17 genes displayed muscle- or brain-specific enhancer chromatin in their gene bodies, and most exhibited specific intergenic enhancer chromatin as well. Seven genes were embedded in super-enhancers (particularly strong, tissue-specific clusters of enhancers). The enhancer chromatin regions typically displayed foci of DNA hypomethylation at peaks of open chromatin. In addition, we found evidence for an intragenic enhancer in one gene upregulating expression of its neighboring gene, specifically for KLHL40/HHATL and KLHL38/FBXO32 gene pairs. Many KLHL/KBTBD genes had tissue-specific promoter chromatin at their 5′ ends, but surprisingly, two (KBTBD11 and KLHL31) had constitutively unmethylated promoter chromatin in their 3′ exons that overlaps a retrotransposed KLHL gene. Our findings demonstrate the importance of expanding epigenetic analyses beyond the 5′ ends of genes in studies of normal and abnormal gene regulation. Full article
(This article belongs to the Special Issue Epigenetic Connections between the Gene Regulatory Network and Chromatin Dynamics)
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21 pages, 5103 KiB  
Article
The Function of Oncogene B-Cell Lymphoma 6 in the Regulation of the Migration and Invasion of Trophoblastic Cells
by Andreas Ritter, Babek Khan Safdar, Britta Jasmer, Nina-Naomi Kreis, Alexandra Friemel, Susanne Roth, Christine Solbach, Frank Louwen and Juping Yuan
Int. J. Mol. Sci. 2020, 21(21), 8393; https://doi.org/10.3390/ijms21218393 - 9 Nov 2020
Cited by 8 | Viewed by 2616
Abstract
Human placentation is a highly invasive process. Deficiency in the invasiveness of trophoblasts is associated with a spectrum of gestational diseases, such as preeclampsia (PE). The oncogene B-cell lymphoma 6 (BCL6) is involved in the migration and invasion of various malignant cells. Intriguingly, [...] Read more.
Human placentation is a highly invasive process. Deficiency in the invasiveness of trophoblasts is associated with a spectrum of gestational diseases, such as preeclampsia (PE). The oncogene B-cell lymphoma 6 (BCL6) is involved in the migration and invasion of various malignant cells. Intriguingly, its expression is deregulated in preeclamptic placentas. We have reported that BCL6 is required for the proliferation, survival, fusion, and syncytialization of trophoblasts. In the present work, we show that the inhibition of BCL6, either by its gene silencing or by using specific small molecule inhibitors, impairs the migration and invasion of trophoblastic cells, by reducing cell adhesion and compromising the dynamics of the actin cytoskeleton. Moreover, the suppression of BCL6 weakens the signals of the phosphorylated focal adhesion kinase, Akt/protein kinase B, and extracellular regulated kinase 1/2, accompanied by more stationary, but less migratory, cells. Interestingly, transcriptomic analyses reveal that a small interfering RNA-induced reduction of BCL6 decreases the levels of numerous genes, such as p21 activated kinase 1, myosin light chain kinase, and gamma actin related to cell adhesion, actin dynamics, and cell migration. These data suggest BCL6 as a crucial player in the migration and invasion of trophoblasts in the early stages of placental development through the regulation of various genes associated with the migratory machinery. Full article
(This article belongs to the Section Molecular Biology)
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12 pages, 4021 KiB  
Article
Human Microfibrillar-Associated Protein 4 (MFAP4) Gene Promoter: A TATA-Less Promoter That Is Regulated by Retinol and Coenzyme Q10 in Human Fibroblast Cells
by Ying-Ju Lin, An-Ni Chen, Xi Jiang Yin, Chunxiang Li and Chih-Chien Lin
Int. J. Mol. Sci. 2020, 21(21), 8392; https://doi.org/10.3390/ijms21218392 - 9 Nov 2020
Cited by 2 | Viewed by 2640
Abstract
Elastic fibers are one of the major structural components of the extracellular matrix (ECM) in human connective tissues. Among these fibers, microfibrillar-associated protein 4 (MFAP4) is one of the most important microfibril-associated glycoproteins. MFAP4 has been found to bind with elastin microfibrils and [...] Read more.
Elastic fibers are one of the major structural components of the extracellular matrix (ECM) in human connective tissues. Among these fibers, microfibrillar-associated protein 4 (MFAP4) is one of the most important microfibril-associated glycoproteins. MFAP4 has been found to bind with elastin microfibrils and interact directly with fibrillin-1, and then aid in elastic fiber formation. However, the regulations of the human MFAP4 gene are not so clear. Therefore, in this study, we firstly aimed to analyze and identify the promoter region of the human MFAP4 gene. The results indicate that the human MFAP4 promoter is a TATA-less promoter with tissue- and species-specific properties. Moreover, the promoter can be up-regulated by retinol and coenzyme Q10 (coQ10) in Detroit 551 cells. Full article
(This article belongs to the Section Molecular Biology)
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20 pages, 4102 KiB  
Article
Different Sensitivity of Macrophages to Phospholipidosis Induction by Amphiphilic Cationic Drugs
by Kristin Öhlinger, Markus Absenger-Novak, Claudia Meindl, Jennifer Ober and Eleonore Fröhlich
Int. J. Mol. Sci. 2020, 21(21), 8391; https://doi.org/10.3390/ijms21218391 - 9 Nov 2020
Cited by 7 | Viewed by 3443
Abstract
Phospholipidosis (PLD), the intracellular accumulation of phospholipids, is an adaptive response to toxic stimuli and serves as an important parameter in the biological assessment of compounds. Cationic amphiphilic drugs are the main inducers of PLD and may impair the function of alveolar macrophages. [...] Read more.
Phospholipidosis (PLD), the intracellular accumulation of phospholipids, is an adaptive response to toxic stimuli and serves as an important parameter in the biological assessment of compounds. Cationic amphiphilic drugs are the main inducers of PLD and may impair the function of alveolar macrophages. In vivo and in vitro models are used for PLD screening but the choice of the cellular model may be important because PLD develops in a cell- and species-specific manner. In this study, a panel of different staining (LysoSensor, Acridine Orange, Nile Red, HCS LipidTOX, LysoID) was evaluated in murine (DMBM-2, J774, RAW264.7) and human (THP-1, monocyte-derived macrophages from peripheral blood) cells to identify the most sensitive and easy to analyze staining method and to detect species-specific differences in the reaction pattern. Amiodarone and chloroquine served as inducers of PLD. High content screening was used to compare number, area, and intensity of the staining. Due to the fast staining protocol and the sensitivity of the detection, LysoID proved to be the most suitable dye of the testing. The lower induction of PLD by chloroquine reported in vivo was also seen in this study. THP-1 macrophages, followed by DMBM-2 cells, produced the most similar reaction pattern to human monocyte-derived macrophages. Full article
(This article belongs to the Special Issue Pulmonary Delivery of Drugs and Biologics)
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28 pages, 867 KiB  
Review
Advanced Medical Therapies in the Management of Non-Scarring Alopecia: Areata and Androgenic Alopecia
by Antonio Martinez-Lopez, Trinidad Montero-Vilchez, Álvaro Sierra-Sánchez, Alejandro Molina-Leyva and Salvador Arias-Santiago
Int. J. Mol. Sci. 2020, 21(21), 8390; https://doi.org/10.3390/ijms21218390 - 9 Nov 2020
Cited by 21 | Viewed by 10253
Abstract
Alopecia is a challenging condition for both physicians and patients. Several topical, intralesional, oral, and surgical treatments have been developed in recent decades, but some of those therapies only provide partial improvement. Advanced medical therapies are medical products based on genes, cells, and/or [...] Read more.
Alopecia is a challenging condition for both physicians and patients. Several topical, intralesional, oral, and surgical treatments have been developed in recent decades, but some of those therapies only provide partial improvement. Advanced medical therapies are medical products based on genes, cells, and/or tissue engineering products that have properties in regenerating, repairing, or replacing human tissue. In recent years, numerous applications have been described for advanced medical therapies. With this background, those therapies may have a role in the treatment of various types of alopecia such as alopecia areata and androgenic alopecia. The aim of this review is to provide dermatologists an overview of the different advanced medical therapies that have been applied in the treatment of alopecia, by reviewing clinical and basic research studies as well as ongoing clinical trials. Full article
(This article belongs to the Special Issue Inflammatory Skin Conditions 2020)
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25 pages, 5189 KiB  
Article
Phenotypic and Functional Characteristics of Exosomes Derived from Irradiated Mouse Organs and Their Role in the Mechanisms Driving Non-Targeted Effects
by Seda Tuncay Cagatay, Ammar Mayah, Mariateresa Mancuso, Paola Giardullo, Simonetta Pazzaglia, Anna Saran, Amuthachelvi Daniel, Damien Traynor, Aidan D. Meade, Fiona Lyng, Soile Tapio and Munira Kadhim
Int. J. Mol. Sci. 2020, 21(21), 8389; https://doi.org/10.3390/ijms21218389 - 9 Nov 2020
Cited by 32 | Viewed by 4189
Abstract
Molecular communication between irradiated and unirradiated neighbouring cells initiates radiation-induced bystander effects (RIBE) and out-of-field (abscopal) effects which are both an example of the non-targeted effects (NTE) of ionising radiation (IR). Exosomes are small membrane vesicles of endosomal origin and newly identified mediators [...] Read more.
Molecular communication between irradiated and unirradiated neighbouring cells initiates radiation-induced bystander effects (RIBE) and out-of-field (abscopal) effects which are both an example of the non-targeted effects (NTE) of ionising radiation (IR). Exosomes are small membrane vesicles of endosomal origin and newly identified mediators of NTE. Although exosome-mediated changes are well documented in radiation therapy and oncology, there is a lack of knowledge regarding the role of exosomes derived from inside and outside the radiation field in the early and delayed induction of NTE following IR. Therefore, here we investigated the changes in exosome profile and the role of exosomes as possible molecular signalling mediators of radiation damage. Exosomes derived from organs of whole body irradiated (WBI) or partial body irradiated (PBI) mice after 24 h and 15 days post-irradiation were transferred to recipient mouse embryonic fibroblast (MEF) cells and changes in cellular viability, DNA damage and calcium, reactive oxygen species and nitric oxide signalling were evaluated compared to that of MEF cells treated with exosomes derived from unirradiated mice. Taken together, our results show that whole and partial-body irradiation increases the number of exosomes, instigating changes in exosome-treated MEF cells, depending on the source organ and time after exposure. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics)
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21 pages, 6537 KiB  
Article
Polar Lipid Fraction E from Sulfolobus acidocaldarius and Dipalmitoylphosphatidylcholine Can Form Stable yet Thermo-Sensitive Tetraether/Diester Hybrid Archaeosomes with Controlled Release Capability
by Umme Ayesa and Parkson Lee-Gau Chong
Int. J. Mol. Sci. 2020, 21(21), 8388; https://doi.org/10.3390/ijms21218388 - 9 Nov 2020
Cited by 12 | Viewed by 3552
Abstract
Archaeosomes have drawn increasing attention in recent years as novel nano-carriers for therapeutics. The main obstacle of using archaeosomes for therapeutics delivery has been the lack of an efficient method to trigger the release of entrapped content from the otherwise extremely stable structure. [...] Read more.
Archaeosomes have drawn increasing attention in recent years as novel nano-carriers for therapeutics. The main obstacle of using archaeosomes for therapeutics delivery has been the lack of an efficient method to trigger the release of entrapped content from the otherwise extremely stable structure. Our present study tackles this long-standing problem. We made hybrid archaeosomes composed of tetraether lipids, called the polar lipid fraction E (PLFE) isolated from the thermoacidophilic archaeon Sulfolobus acidocaldarius, and the synthetic diester lipid dipalmitoylphosphatidylcholine (DPPC). Differential polarized phase-modulation and steady-state fluorometry, confocal fluorescence microscopy, zeta potential (ZP) measurements, and biochemical assays were employed to characterize the physical properties and drug behaviors in PLFE/DPPC hybrid archaeosomes in the presence and absence of live cells. We found that PLFE lipids have an ordering effect on fluid DPPC liposomal membranes, which can slow down the release of entrapped drugs, while PLFE provides high negative charges on the outer surface of liposomes, which can increase vesicle stability against coalescence among liposomes or with cells. Furthermore, we found that the zeta potential in hybrid archaeosomes with 30 mol% PLFE and 70 mol% DPPC (designated as PLFE/DPPC(3:7) archaeosomes) undergoes an abrupt increase from −48 mV at 37 °C to −16 mV at 44 °C (termed the ZP transition), which we hypothesize results from DPPC domain melting and PLFE lipid ‘flip-flop’. The anticancer drug doxorubicin (DXO) can be readily incorporated into PLFE/DPPC(3:7) archaeosomes. The rate constant of DXO release from PLFE/DPPC(3:7) archaeosomes into Tris buffer exhibited a sharp increase (~2.5 times), when the temperature was raised from 37 to 42 °C, which is believed to result from the liposomal structural changes associated with the ZP transition. This thermo-induced sharp increase in drug release was not affected by serum proteins as a similar temperature dependence of drug release kinetics was observed in human blood serum. A 15-min pre-incubation of PLFE/DPPC(3:7) archaeosomal DXO with MCF-7 breast cancer cells at 42 °C caused a significant increase in the amount of DXO entering into the nuclei and a considerable increase in the cell’s cytotoxicity under the 37 °C growth temperature. Taken together, our data suggests that PLFE/DPPC(3:7) archaeosomes are stable yet potentially useful thermo-sensitive liposomes wherein the temperature range (from 37 to 42–44 °C) clinically used for mild hyperthermia treatment of tumors can be used to trigger drug release for medical interventions. Full article
(This article belongs to the Collection Feature Papers in Molecular Biophysics)
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19 pages, 1396 KiB  
Review
The Regulation of Ferroptosis by Tumor Suppressor p53 and its Pathway
by Juan Liu, Cen Zhang, Jianming Wang, Wenwei Hu and Zhaohui Feng
Int. J. Mol. Sci. 2020, 21(21), 8387; https://doi.org/10.3390/ijms21218387 - 9 Nov 2020
Cited by 152 | Viewed by 13878
Abstract
Tumor suppressor p53 plays a key role in tumor suppression. In addition to tumor suppression, p53 is also involved in many other biological and pathological processes, such as immune response, maternal reproduction, tissue ischemia/reperfusion injuries and neurodegenerative diseases. While it has been widely [...] Read more.
Tumor suppressor p53 plays a key role in tumor suppression. In addition to tumor suppression, p53 is also involved in many other biological and pathological processes, such as immune response, maternal reproduction, tissue ischemia/reperfusion injuries and neurodegenerative diseases. While it has been widely accepted that the role of p53 in regulation of cell cycle arrest, senescence and apoptosis contributes greatly to the function of p53 in tumor suppression, emerging evidence has implicated that p53 also exerts its tumor suppressive function through regulation of many other cellular processes, such as metabolism, anti-oxidant defense and ferroptosis. Ferroptosis is a unique iron-dependent form of programmed cell death driven by lipid peroxidation in cells. Ferroptosis has been reported to be involved in cancer, tissue ischemia/reperfusion injuries and neurodegenerative diseases. Recent studies have shown that ferroptosis can be regulated by p53 and its signaling pathway as well as tumor-associated mutant p53. Interestingly, the regulation of ferroptosis by p53 appears to be highly context-dependent. In this review, we summarize recent advances in the regulation of ferroptosis by p53 and its signaling pathway. Further elucidation of the role and molecular mechanism of p53 in ferroptosis regulation will yield new therapeutic strategies for cancer and other diseases, including neurodegenerative diseases and tissue ischemia/reperfusion injuries. Full article
(This article belongs to the Special Issue The Interplay between Metabolism and Cancer and the Adipose Tissue Communication Signals)
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12 pages, 1834 KiB  
Article
Fluorescence Assay for the Determination of d-Panthenol Based on Novel Ring-Fused 2-Pyridone Derivative
by Wiktor Kasprzyk, Tomasz Świergosz and Filip Koper
Int. J. Mol. Sci. 2020, 21(21), 8386; https://doi.org/10.3390/ijms21218386 - 9 Nov 2020
Cited by 10 | Viewed by 3614
Abstract
Herein, a novel fluorescent method for the determination of d-panthenol (DP) level in solutions with no separate hydrolysis step has been revealed based on the utilization of citric acid (CA) as a derivatizing agent. Consequently, the essential parameters of the derivatization process [...] Read more.
Herein, a novel fluorescent method for the determination of d-panthenol (DP) level in solutions with no separate hydrolysis step has been revealed based on the utilization of citric acid (CA) as a derivatizing agent. Consequently, the essential parameters of the derivatization process were established, resulting in the development of sensitive, repeatable, and accurate determination of panthenol. The method was approved, and its usefulness in characterizing the concentration of DP in pharmaceutical formulations and selectivity in the determination of DP were validated. The chemical structure of the new fluorophore formulating in the reaction in DP with CA, i.e., 6-oxo-3,4-dihydro-2H,6H-pyrido[2,1-b][1,3]oxazine-8-carboxylic acid (ODPC), was elucidated using detailed NMR experiments: one-dimensional (1H, 13C) as well as two-dimensional NMR spectra (1H-1H COSY, 1H-13C HSQC, 1H-13C HMBC, 1H-15N HSQC, 1H-15N HMBC). Full article
(This article belongs to the Section Molecular Pharmacology)
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