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Volume 21
Issue 24
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Int. J. Mol. Sci., Volume 21, Issue 24 (December-2 2020) – 444 articles

Cover Story (view full-size image): The hippocampus is a structure in the brain crucial for learning, memory, and emotion processing. It is also involved in the development of neurological and neuropsychological disorders. Epigenetic regulation plays significant and influential roles in biological systems throughout different stages of life, from development through to adulthood. These include DNA methylation, histone modifications, and noncoding RNAs, which have been shown to regulate the development and function of the hippocampus and may play pivotal roles in the development of neurocognitive and neurodegenerative diseases. This review summarizes the epigenetic modifications of various cell types and processes within the hippocampus and their resulting effects. The effects of radiation exposure that may induce a myriad of epigenetic changes in the hippocampus are also reviewed. View this paper
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23 pages, 3810 KiB  
Article
Synthesis and Characterization of Store-Operated Calcium Entry Inhibitors Active in the Submicromolar Range
by Camille Le Guilcher, Tomas Luyten, Jan B. Parys, Mathieu Pucheault and Olivier Dellis
Int. J. Mol. Sci. 2020, 21(24), 9777; https://doi.org/10.3390/ijms21249777 - 21 Dec 2020
Cited by 2 | Viewed by 3075
Abstract
The store-operated calcium entry, better known as SOCE, forms the main Ca2+ influx pathway in non-excitable cells, especially in leukocytes, where it is required for cell activation and the immune response. During the past decades, several inhibitors were developed, but they lack [...] Read more.
The store-operated calcium entry, better known as SOCE, forms the main Ca2+ influx pathway in non-excitable cells, especially in leukocytes, where it is required for cell activation and the immune response. During the past decades, several inhibitors were developed, but they lack specificity or efficacy. From the non-specific SOCE inhibitor 2-aminoethyl diphenylborinate (2-APB), we synthetized 16 new analogues by replacing/modifying the phenyl groups. Among them, our compound P11 showed the best inhibitory capacity with a Ki ≈ 75 nM. Furthermore, below 1 µM, P11 was devoid of any inhibitory activity on the two other main cellular targets of 2-APB, the IP3 receptors, and the SERCA pumps. Interestingly, Jurkat T cells secrete interleukin-2 under phytohemagglutinin stimulation but undergo cell death and stop IL-2 synthesis when stimulated in the presence of increasing P11 concentrations. Thus, P11 could represent the first member of a new and potent family of immunosuppressors. Full article
(This article belongs to the Special Issue STIMulating Ca2+ Homeostasis)
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14 pages, 4760 KiB  
Article
Microphthalmia-Associated Transcription Factor-Dependent Melanoma Cell Adhesion Molecule Activation Promotes Peritoneal Metastasis of Ovarian Cancer
by Kazuhisa Kitami, Masato Yoshihara, Yoshihiro Koya, Mai Sugiyama, Shohei Iyoshi, Kaname Uno, Kazumasa Mogi, Sho Tano, Hiroki Fujimoto, Akihiro Nawa, Fumitaka Kikkawa and Hiroaki Kajiyama
Int. J. Mol. Sci. 2020, 21(24), 9776; https://doi.org/10.3390/ijms21249776 - 21 Dec 2020
Cited by 4 | Viewed by 2716
Abstract
Ovarian cancer (OvCa) is one of the leading causes of death due to its high metastasis rate to the peritoneum. Recurrent peritoneal tumors also develop despite the use of conventional platinum-based chemotherapies. Therefore, it is still important to explore the factors associated with [...] Read more.
Ovarian cancer (OvCa) is one of the leading causes of death due to its high metastasis rate to the peritoneum. Recurrent peritoneal tumors also develop despite the use of conventional platinum-based chemotherapies. Therefore, it is still important to explore the factors associated with peritoneal metastasis, as these predict the prognosis of patients with OvCa. In this study, we investigated the function of microphthalmia-associated transcription factor (MITF), which contributes to the development of melanoma, in epithelial ovarian cancer (OvCa). High MITF expression was significantly associated with a poor prognosis in OvCa. Notably, MITF contributed to the motility and invasion of OvCa cells, and specifically with their peri-mesothelial migration. In addition, MITF-positive cells expressed the melanoma cell adhesion molecule (MCAM/CD146), which was initially identified as a marker of melanoma progression and metastasis, and MCAM expression was regulated by MITF. MCAM was also identified as a significant prognostic factor for poor progression-free survival in patients with OvCa. Collectively, our results suggest that MITF is a novel therapeutic target that potentially promotes peritoneal metastasis of OvCa. Full article
(This article belongs to the Special Issue Gynecologic Oncology: From Molecular Mechanisms to Targeted Therapies 2.0)
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17 pages, 1206 KiB  
Review
The Current Status of Drug Repositioning and Vaccine Developments for the COVID-19 Pandemic
by Jung-Hyun Won and Howard Lee
Int. J. Mol. Sci. 2020, 21(24), 9775; https://doi.org/10.3390/ijms21249775 - 21 Dec 2020
Cited by 90 | Viewed by 9742
Abstract
Since the outbreak of coronavirus disease 2019 (COVID-19) was first identified, the world has vehemently worked to develop treatments and vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at an unprecedented speed. Few of the repositioned drugs for COVID-19 have shown that [...] Read more.
Since the outbreak of coronavirus disease 2019 (COVID-19) was first identified, the world has vehemently worked to develop treatments and vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at an unprecedented speed. Few of the repositioned drugs for COVID-19 have shown that they were efficacious and safe. In contrast, a couple of vaccines against SARS-CoV-2 will be ready for mass rollout early next year. Despite successful vaccine development for COVID-19, the world will face a whole new set of challenges including scale-up manufacturing, cold-chain logistics, long-term safety, and low vaccine acceptance. We highlighted the importance of knowledge sharing and collaboration to find innovative answers to these challenges and to prepare for newly emerging viruses. Full article
(This article belongs to the Section Molecular Pharmacology)
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11 pages, 1517 KiB  
Article
Detection of Telomeric DNA:RNA Hybrids Using TeloDRIP-qPCR
by Ilaria Rosso and Fabrizio d’Adda di Fagagna
Int. J. Mol. Sci. 2020, 21(24), 9774; https://doi.org/10.3390/ijms21249774 - 21 Dec 2020
Cited by 2 | Viewed by 3428
Abstract
Because of their intrinsic characteristics, telomeres are genomic loci that pose significant problems during the replication of the genome. In particular, it has been observed that telomeres that are maintained in cancer cells by the alternative mechanism of the lengthening of telomeres (ALT) [...] Read more.
Because of their intrinsic characteristics, telomeres are genomic loci that pose significant problems during the replication of the genome. In particular, it has been observed that telomeres that are maintained in cancer cells by the alternative mechanism of the lengthening of telomeres (ALT) harbor higher levels of replicative stress compared with telomerase-positive cancer cells. R-loops are three-stranded structures formed by a DNA:RNA hybrid and a displaced ssDNA. Emerging evidence suggests that controlling the levels of R-loops at ALT telomeres is critical for telomere maintenance. In fact, on the one hand, they favor telomere recombination, but on the other, they are a source of detrimental replicative stress. DRIP (DNA:RNA immunoprecipitation) is the main technique used for the detection of R-loops, and it is based on the use of the S9.6 antibody, which recognizes preferentially DNA:RNA hybrids in a sequence-independent manner. The detection of DNA:RNA hybrids in repetitive sequences such as telomeres requires some additional precautions as a result of their repetitive nature. Here, we share an optimized protocol for the detection of telomeric DNA:RNA hybrids, and we demonstrate its application in an ALT and in a telomerase-positive cell line. We demonstrate that ALT telomeres bear higher levels of DNA:RNA hybrids, and we propose this method as a reliable way to detect them in telomeres. Full article
(This article belongs to the Special Issue DNA Polymerases and Beyond: Molecular Machines Responding to Replication Stress)
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16 pages, 877 KiB  
Review
Running to Stand Still: Naive CD8+ T Cells Actively Maintain a Program of Quiescence
by Taylah J. Bennett, Vibha A. V. Udupa and Stephen J. Turner
Int. J. Mol. Sci. 2020, 21(24), 9773; https://doi.org/10.3390/ijms21249773 - 21 Dec 2020
Cited by 7 | Viewed by 4579
Abstract
CD8+ T cells play a pivotal role in clearing intracellular pathogens and combatting tumours. Upon infection, naïve CD8+ T cells differentiate into effector and memory cells, and this program is underscored by large-scale and coordinated changes in the chromatin architecture and [...] Read more.
CD8+ T cells play a pivotal role in clearing intracellular pathogens and combatting tumours. Upon infection, naïve CD8+ T cells differentiate into effector and memory cells, and this program is underscored by large-scale and coordinated changes in the chromatin architecture and gene expression. Importantly, recent evidence demonstrates that the epigenetic mechanisms that regulate the capacity for rapid effector function of memory T cells are shared by innate immune cells such as natural killer (NK) cells. Thus, it appears that the crucial difference between innate and adaptive immunity is the presence of the naïve state. This important distinction raises an intriguing new hypothesis, that the naïve state was evolutionary installed to restrain a default program of effector and memory differentiation in response to antigen recognition. We argue that the hallmark of adaptive T immunity is therefore the naïve program, which actively maintains CD8+ T cell quiescence until receipt of appropriate activation signals. In this review, we examine the mechanistic control of naïve CD8+ T cell quiescence and summarise the multiple levels of restraint imposed in naïve cells in to limit spontaneous and inappropriate activation. This includes epigenetic mechanisms and transcription factor (TF) regulation of gene expression, in addition to novel inhibitory receptors, abundance of RNA, and protein degradation. Full article
(This article belongs to the Special Issue Recent Advances in T Cell Immunity)
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24 pages, 4379 KiB  
Review
The Regulation of Intestinal Inflammation and Cancer Development by Type 2 Immune Responses
by Reyes Gamez-Belmonte, Lena Erkert, Stefan Wirtz and Christoph Becker
Int. J. Mol. Sci. 2020, 21(24), 9772; https://doi.org/10.3390/ijms21249772 - 21 Dec 2020
Cited by 11 | Viewed by 5163
Abstract
The gut is among the most complex organs of the human body. It has to exert several functions including food and water absorption while setting up an efficient barrier to the outside world. Dysfunction of the gut can be life-threatening. Diseases of the [...] Read more.
The gut is among the most complex organs of the human body. It has to exert several functions including food and water absorption while setting up an efficient barrier to the outside world. Dysfunction of the gut can be life-threatening. Diseases of the gastrointestinal tract such as inflammatory bowel disease, infections, or colorectal cancer, therefore, pose substantial challenges to clinical care. The intestinal epithelium plays an important role in intestinal disease development. It not only establishes an important barrier against the gut lumen but also constantly signals information about the gut lumen and its composition to immune cells in the bowel wall. Such signaling across the epithelial barrier also occurs in the other direction. Intestinal epithelial cells respond to cytokines and other mediators of immune cells in the lamina propria and shape the microbial community within the gut by producing various antimicrobial peptides. Thus, the epithelium can be considered as an interpreter between the microbiota and the mucosal immune system, safeguarding and moderating communication to the benefit of the host. Type 2 immune responses play important roles in immune-epithelial communication. They contribute to gut tissue homeostasis and protect the host against infections with helminths. However, they are also involved in pathogenic pathways in inflammatory bowel disease and colorectal cancer. The current review provides an overview of current concepts regarding type 2 immune responses in intestinal physiology and pathophysiology. Full article
(This article belongs to the Special Issue Inflammation and Gastrointestinal Cancers: Molecular Mechanisms and Therapies 1.0)
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15 pages, 3033 KiB  
Article
TGFβ1 Suppressed Matrix Mineralization of Osteoblasts Differentiation by Regulating SMURF1–C/EBPβ–DKK1 Axis
by Bora Nam, Hyosun Park, Young Lim Lee, Younseo Oh, Jinsung Park, So Yeon Kim, Subin Weon, Sung Hoon Choi, Jae-Hyuk Yang, Sungsin Jo and Tae-Hwan Kim
Int. J. Mol. Sci. 2020, 21(24), 9771; https://doi.org/10.3390/ijms21249771 - 21 Dec 2020
Cited by 30 | Viewed by 3077
Abstract
Transforming growth factor β1 (TGFβ1) is a major mediator in the modulation of osteoblast differentiation. However, the underlying molecular mechanism is still not fully understood. Here, we show that TGFβ1 has a dual stage-dependent role in osteoblast differentiation; TGFβ1 induced matrix maturation but [...] Read more.
Transforming growth factor β1 (TGFβ1) is a major mediator in the modulation of osteoblast differentiation. However, the underlying molecular mechanism is still not fully understood. Here, we show that TGFβ1 has a dual stage-dependent role in osteoblast differentiation; TGFβ1 induced matrix maturation but inhibited matrix mineralization. We discovered the underlying mechanism of the TGFβ1 inhibitory role in mineralization using human osteoprogenitors. In particular, the matrix mineralization-related genes of osteoblasts such as osteocalcin (OCN), Dickkopf 1 (DKK1), and CCAAT/enhancer-binding protein beta (C/EBPβ) were dramatically suppressed by TGFβ1 treatment. The suppressive effects of TGFβ1 were reversed with anti-TGFβ1 treatment. Mechanically, TGFβ1 decreased protein levels of C/EBPβ without changing mRNA levels and reduced both mRNA and protein levels of DKK1. The degradation of the C/EBPβ protein by TGFβ1 was dependent on the ubiquitin–proteasome pathway. TGFβ1 degraded the C/EBPβ protein by inducing the expression of the E3 ubiquitin ligase Smad ubiquitin regulatory factor 1 (SMURF1) at the transcript level, thereby reducing the C/EBPβ-DKK1 regulatory mechanism. Collectively, our findings suggest that TGFβ1 suppressed the matrix mineralization of osteoblast differentiation by regulating the SMURF1-C/EBPβ-DKK1 axis. Full article
(This article belongs to the Special Issue Osteoblast Differentiation and Activity in Skeletal Diseases)
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12 pages, 16201 KiB  
Review
Leaky Gut and Autoimmunity: An Intricate Balance in Individuals Health and the Diseased State
by Bilal Ahmad Paray, Mohammed Fahad Albeshr, Arif Tasleem Jan and Irfan A. Rather
Int. J. Mol. Sci. 2020, 21(24), 9770; https://doi.org/10.3390/ijms21249770 - 21 Dec 2020
Cited by 59 | Viewed by 17871
Abstract
Damage to the tissue and the ruining of functions characterize autoimmune syndromes. This review centers around leaky gut syndromes and how they stimulate autoimmune pathogenesis. Lymphoid tissue commonly associated with the gut, together with the neuroendocrine network, collaborates with the intestinal epithelial wall, [...] Read more.
Damage to the tissue and the ruining of functions characterize autoimmune syndromes. This review centers around leaky gut syndromes and how they stimulate autoimmune pathogenesis. Lymphoid tissue commonly associated with the gut, together with the neuroendocrine network, collaborates with the intestinal epithelial wall, with its paracellular tight junctions, to maintain the balance, tolerance, and resistance to foreign/neo-antigens. The physiological regulator of paracellular tight junctions plays a vital role in transferring macromolecules across the intestinal barrier and thereby maintains immune response equilibrium. A new paradigm has explained the intricacies of disease development and proposed that the processes can be prevented if the interaction between the genetic factor and environmental causes is barred by re-instituting the intestinal wall function. The latest clinical evidence and animal models reinforce this current thought and offer the basis for innovative methodologies to thwart and treat autoimmune syndromes. Full article
(This article belongs to the Special Issue Gut Microbes and Gut Metabolites)
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18 pages, 15268 KiB  
Review
Melanogenesis Connection with Innate Immunity and Toll-Like Receptors
by Saaya Koike and Kenshi Yamasaki
Int. J. Mol. Sci. 2020, 21(24), 9769; https://doi.org/10.3390/ijms21249769 - 21 Dec 2020
Cited by 34 | Viewed by 7920
Abstract
The epidermis is located in the outermost layer of the living body and is the place where external stimuli such as ultraviolet rays and microorganisms first come into contact. Melanocytes and melanin play a wide range of roles such as adsorption of metals, [...] Read more.
The epidermis is located in the outermost layer of the living body and is the place where external stimuli such as ultraviolet rays and microorganisms first come into contact. Melanocytes and melanin play a wide range of roles such as adsorption of metals, thermoregulation, and protection from foreign enemies by camouflage. Pigmentary disorders are observed in diseases associated with immunodeficiency such as Griscelli syndrome, indicating molecular sharing between immune systems and the machineries of pigment formation. Melanocytes express functional toll-like receptors (TLRs), and innate immune stimulation via TLRs affects melanin synthesis and melanosome transport to modulate skin pigmentation. TLR2 enhances melanogenetic gene expression to augment melanogenesis. In contrast, TLR3 increases melanosome transport to transfer to keratinocytes through Rab27A, the responsible molecule of Griscelli syndrome. TLR4 and TLR9 enhance tyrosinase expression and melanogenesis through p38 MAPK (mitogen-activated protein kinase) and NFκB signaling pathway, respectively. TLR7 suppresses microphthalmia-associated transcription factor (MITF), and MITF reduction leads to melanocyte apoptosis. Accumulating knowledge of the TLRs function of melanocytes has enlightened the link between melanogenesis and innate immune system. Full article
(This article belongs to the Special Issue Melanosome Transport/Transfer and Melanin Pigmentation in the Skin)
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10 pages, 258 KiB  
Article
Assessment of Endothelial Injury and Pro-Coagulant Activity Using Circulating Microvesicles in Survivors of Allogeneic Hematopoietic Cell Transplantation
by Eleni Gavriilaki, Ioanna Sakellari, Panagiota Anyfanti, Ioannis Batsis, Anna Vardi, Zoi Bousiou, Antonios Lazaridis, Barbara Nikolaidou, Ippokratis Zarifis, Marianna Masmanidou, Efthalia Yiannaki, Dimitra Markala, Achilles Anagnostopoulos, Stella Douma and Eugenia Gkaliagkousi
Int. J. Mol. Sci. 2020, 21(24), 9768; https://doi.org/10.3390/ijms21249768 - 21 Dec 2020
Cited by 13 | Viewed by 2455
Abstract
(1) Background: survivors of allogeneic hematopoietic cell transplantation (alloHCT) suffer from morbidity and mortality due to cardiovascular events. We hypothesized that vascular injury and pro-coagulant activity are evident in alloHCT survivors without existing alloHCT complications or relapse. (2) Methods: we enrolled consecutive adult [...] Read more.
(1) Background: survivors of allogeneic hematopoietic cell transplantation (alloHCT) suffer from morbidity and mortality due to cardiovascular events. We hypothesized that vascular injury and pro-coagulant activity are evident in alloHCT survivors without existing alloHCT complications or relapse. (2) Methods: we enrolled consecutive adult alloHCT survivors without established cardiovascular disease and control individuals matched for traditional cardiovascular risk factors (January–December 2019). Circulating microvesicles (MVs) of different cellular origins (platelet, erythrocyte, and endothelial) were measured by a standardized flow cytometry protocol as novel markers of vascular injury and pro-coagulant activity. (3) Results: we recruited 45 survivors after a median of 2.3 (range 1.1–13.2) years from alloHCT, and 45 controls. The majority of patients suffered from acute (44%) and/or chronic (66%) graft-versus-host disease (GVHD). Although the two groups were matched for traditional cardiovascular risk factors, alloHCT survivors showed significantly increased platelet and erythrocyte MVs compared to controls. Within alloHCT survivors, erythrocyte MVs were significantly increased in patients with a previous history of thrombotic microangiopathy. Interestingly, endothelial MVs were significantly increased only in alloHCT recipients of a myeloablative conditioning. Furthermore, MVs of different origins showed a positive association with each other. (4) Conclusions: endothelial dysfunction and increased thrombotic risk are evident in alloHCT recipients long after alloHCT, independently of traditional cardiovascular risk factors. An apparent synergism of these pathophysiological processes may be strongly involved in the subsequent establishment of cardiovascular disease. Full article
(This article belongs to the Special Issue Molecular Advances in Hypertension and Blood)
14 pages, 3454 KiB  
Article
Chlorinated Guaiane-Type Sesquiterpene Lactones as Cytotoxic Agents against Human Tumor Cells
by Francisco Estévez-Sarmiento, Ester Saavedra, Mercedes Ruiz-Estévez, Francisco León, José Quintana, Ignacio Brouard and Francisco Estévez
Int. J. Mol. Sci. 2020, 21(24), 9767; https://doi.org/10.3390/ijms21249767 - 21 Dec 2020
Cited by 11 | Viewed by 2258
Abstract
Guaiane-type sesquiterpene lactones are naturally occurring compounds which have attracted attention due to their array of biological activities. In this study, chlorinated guaianolides 1–8, isolated from plants of the genus Centaurea, were evaluated against the human leukemia cell lines [...] Read more.
Guaiane-type sesquiterpene lactones are naturally occurring compounds which have attracted attention due to their array of biological activities. In this study, chlorinated guaianolides 1–8, isolated from plants of the genus Centaurea, were evaluated against the human leukemia cell lines HL-60, U-937, a specific U-937 cell line that overexpresses the anti-apoptotic Bcl-2 protein and the human melanoma cell line SK-MEL-1. This established the relevant structure-growth inhibition relationships. Chlorohyssopifolins A (1), C (3) and D (4) and linichlorin A (6) were the most potent compounds in terms of inducing growth inhibition in the four cell lines. IC50 values were below 10 μM in all cases. Chlorohyssopifolins A (1) and D (4) and linichlorin A (6) were potent apoptotic inducers in human U-937 leukemia cells, as determined by fluorescent microscopy and flow cytometry, and their mechanism of action was associated with cytochrome c release, caspase activation and poly(ADP-ribose)polymerase cleavage. Overall this study shows that guaianolides induce cytotoxicity against human tumor cells and provides important insights into the cell death pathways that are involved. Full article
(This article belongs to the Section Bioactives and Nutraceuticals)
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19 pages, 2301 KiB  
Review
Influence of Natural Killer Cells and Natural Killer T Cells on Periodontal Disease: A Systematic Review of the Current Literature
by Andreas Seidel, Corinna L. Seidel, Matthias Weider, Rüdiger Junker, Lina Gölz and Helga Schmetzer
Int. J. Mol. Sci. 2020, 21(24), 9766; https://doi.org/10.3390/ijms21249766 - 21 Dec 2020
Cited by 13 | Viewed by 3646
Abstract
Natural killer (NK) cells, as members of the innate immune system, and natural killer T (NKT) cells, bridging innate and adaptive immunity, play a prominent role in chronic inflammatory diseases and cancerogenesis, yet have scarcely been examined in oral diseases. Therefore, systematic research [...] Read more.
Natural killer (NK) cells, as members of the innate immune system, and natural killer T (NKT) cells, bridging innate and adaptive immunity, play a prominent role in chronic inflammatory diseases and cancerogenesis, yet have scarcely been examined in oral diseases. Therefore, systematic research on the latest literature focusing on NK/NKT cell-mediated mechanisms in periodontal disease, including the time period 1988–2020, was carried out in MEDLINE (PubMed) using a predetermined search strategy, with a final selection of 25 studies. The results showed that NK cells tend to have rather proinflammatory influences via cytokine production, cytotoxic effects, dendritic-cell-crosstalk, and autoimmune reactions, while contrarily, NKT cell-mediated mechanisms were proinflammatory and immunoregulatory, ranging from protective effects via B-cell-regulation, specific antibody production, and the suppression of autoimmunity to destructive effects via cytokine production, dendritic-cell-crosstalk, and T-/B-cell interactions. Since NK cells seem to have a proinflammatory role in periodontitis, further research should focus on the proinflammatory and immunoregulatory properties of NKT cells in order to create, in addition to antibacterial strategies in dental inflammatory disease, novel anti-inflammatory therapeutic approaches modulating host immunity towards dental health. Full article
(This article belongs to the Special Issue Oral Inflammation—Environment, Molecules, and Cells in Oral Physiology and Pathology)
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20 pages, 3605 KiB  
Review
Synthetic Scaffold/Dental Pulp Stem Cell (DPSC) Tissue Engineering Constructs for Bone Defect Treatment: An Animal Studies Literature Review
by Felice Lorusso, Francesco Inchingolo, Gianna Dipalma, Francesca Postiglione, Stefania Fulle and Antonio Scarano
Int. J. Mol. Sci. 2020, 21(24), 9765; https://doi.org/10.3390/ijms21249765 - 21 Dec 2020
Cited by 33 | Viewed by 4958
Abstract
Background: Recently a greater interest in tissue engineering for the treatment of large bone defect has been reported. The aim of the present systematic review and meta-analysis was to investigate the effectiveness of dental pulp stem cells and synthetic block complexes for bone [...] Read more.
Background: Recently a greater interest in tissue engineering for the treatment of large bone defect has been reported. The aim of the present systematic review and meta-analysis was to investigate the effectiveness of dental pulp stem cells and synthetic block complexes for bone defect treatment in preclinical in vivo articles. Methods: The electronic database and manual search was conducted on Pubmed, Scopus, and EMBASE. The papers identified were submitted for risk-of-bias assessment and classified according to new bone formation, bone graft characteristics, dental pulp stem cells (DPSCs) culture passages and amount of experimental data. The meta-analysis assessment was conducted to assess new bone formation in test sites with DPSCs/synthetic blocks vs. synthetic block alone. Results: The database search identified a total of 348 papers. After the initial screening, 30 studies were included, according to the different animal models: 19 papers on rats, 3 articles on rabbits, 2 manuscripts on sheep and 4 papers on swine. The meta-analysis evaluation showed a significantly increase in new bone formation in favor of DPSCs/synthetic scaffold complexes, if compared to the control at 4 weeks (Mean Diff: 17.09%, 95% CI: 15.16–18.91%, p < 0.01) and at 8 weeks (Mean Diff: 14.86%, 95% CI: 1.82–27.91%, p < 0.01) in rats calvaria bone defects. Conclusion: The synthetic scaffolds in association of DPSCs used for the treatment of bone defects showed encouraging results of early new bone formation in preclinical animal studies and could represent a useful resource for regenerative bone augmentation procedures Full article
(This article belongs to the Special Issue Cell Therapy Approaches for Bone and Cartilage Regeneration)
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13 pages, 2261 KiB  
Article
Development of HER2-Specific Aptamer-Drug Conjugate for Breast Cancer Therapy
by Hwa Yeon Jeong, Hyeri Kim, Myunghwa Lee, Jinju Hong, Joo Han Lee, Jeonghyeon Kim, Moon Jung Choi, Yong Serk Park and Sung-Chun Kim
Int. J. Mol. Sci. 2020, 21(24), 9764; https://doi.org/10.3390/ijms21249764 - 21 Dec 2020
Cited by 25 | Viewed by 5687
Abstract
In this study, HER2 RNA aptamers were conjugated to mertansine (DM1) and the anti-cancer effectiveness of the conjugate was evaluated in HER2-overexpressing breast cancer models. The conjugate of HER2 aptamer and anticancer drug DM1 (aptamer-drug conjugate, ApDC) was prepared and analyzed using HPLC [...] Read more.
In this study, HER2 RNA aptamers were conjugated to mertansine (DM1) and the anti-cancer effectiveness of the conjugate was evaluated in HER2-overexpressing breast cancer models. The conjugate of HER2 aptamer and anticancer drug DM1 (aptamer-drug conjugate, ApDC) was prepared and analyzed using HPLC and mass spectrometry. The cell-binding affinity and cytotoxicity of the conjugate were determined using confocal microscopy and WST-1 assay. The in vivo anti-tumoral efficacy of ApDC was also evaluated in mice carrying BT-474 breast tumors overexpressing HER2. The synthesized HER2-specific RNA aptamers were able to specifically and efficiently bind to HER-positive BT-474 breast cancer cells, but not to HER2-negative MDA-MB-231 breast cancer cells. Also, the HER2-specific ApDC showed strong toxicity to the target cells, BT-474, but not to MDA-MB-231 cells. According to the in vivo analyses drawn from the mouse xenografts of BT-747 tumor, the ApDC was able to more effectively inhibit the tumor growth. Compared to the control group, the mice treated with the ApDC showed a significant reduction of tumor growth. Besides, any significant body weight losses or hepatic toxicities were monitored in the ApDC-treated mice. This research suggests the HER2 aptamer-DM1 conjugate as a target-specific anti-cancer modality and provides experimental evidence supporting its enhanced effectiveness for HER2-overexpressing target tumors. This type of aptamer-conjugated anticancer drug would be utilized as a platform structure for the development of versatile targeted high-performance anticancer drugs by adopting the easy deformability and high affinity of aptamers. Full article
(This article belongs to the Special Issue Aptamer-Mediated Cancer Theranostics)
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20 pages, 2993 KiB  
Article
Low Basal CB2R in Dopamine Neurons and Microglia Influences Cannabinoid Tetrad Effects
by Qing-Rong Liu, Ana Canseco-Alba, Ying Liang, Hiroki Ishiguro and Emmanuel S. Onaivi
Int. J. Mol. Sci. 2020, 21(24), 9763; https://doi.org/10.3390/ijms21249763 - 21 Dec 2020
Cited by 16 | Viewed by 3581
Abstract
There are two well-characterized cannabinoid receptors (CB1R and CB2R and other candidates): the central nervous system (CNS) enriched CB1R and peripheral tissue enriched CB2R with a wide dynamic range of expression levels in different cell types of human tissues. Hepatocytes and neurons express [...] Read more.
There are two well-characterized cannabinoid receptors (CB1R and CB2R and other candidates): the central nervous system (CNS) enriched CB1R and peripheral tissue enriched CB2R with a wide dynamic range of expression levels in different cell types of human tissues. Hepatocytes and neurons express low baseline CB1R and CB2R, respectively, and their cell-type-specific functions are not well defined. Here we report inducible expression of CB1R in the liver by high-fat and high sugar diet and CB2R in cortical neurons by methamphetamine. While there is less controversy about hepatocyte CB1R, the presence of functional neuronal CB2R is still debated to date. We found that neuron CB2R basal expression was higher than that of hepatocyte CB1R by measuring mRNA levels of specific isoform CB2A in neurons isolated by fluorescence-activated cell sorting (FACS) and CB1A in hepatocytes isolated by collagenase perfusion of liver. For in vivo studies, we generated hepatocyte, dopaminergic neuron, and microglia-specific conditional knockout mice (Abl-Cnr1Δ, Dat-Cnr2Δ, and Cx3cr1-Cnr2Δ) of CB1R and CB2R by crossing Cnr1f/f and Cnr2f/f strains to Abl-Cre, Dat-Cre, and Cx3cr1-Cre deleter mouse strains, respectively. Our data reveals that neuron and microglia CB2Rs are involved in the “tetrad” effects of the mixed agonist WIN 55212-2, CB1R selective agonist arachidonyl-2′-chloroethylamide (ACEA), and CB2R selective agonist JWH133. Dat-Cnr2Δ and Cx3cr1-Cnr2Δ mice showed genotypic differences in hypomobility, hypothermia, analgesia, and catalepsy induced by the synthetic cannabinoids. Alcohol conditioned place preference was abolished in DAT-Cnr2Δ mice and remained intact in Cx3cr1-Cnr2Δ mice in comparison to WT mice. These Cre-loxP recombinant mouse lines provide unique approaches in cannabinoid research for dissecting the complex endocannabinoid system that is implicated in many chronic disorders. Full article
(This article belongs to the Section Molecular Neurobiology)
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18 pages, 1568 KiB  
Article
Variations in Triterpenoid Deposition in Cuticular Waxes during Development and Maturation of Selected Fruits of Rosaceae Family
by Soyol Dashbaldan, Cezary Pączkowski and Anna Szakiel
Int. J. Mol. Sci. 2020, 21(24), 9762; https://doi.org/10.3390/ijms21249762 - 21 Dec 2020
Cited by 21 | Viewed by 2772
Abstract
The process of fruit ripening involves many chemical changes occurring not only in the mesocarp but also in the epicarp, including changes in the triterpenoid content of fruit cuticular waxes that can modify the susceptibility to pathogens and mechanical properties of the fruit [...] Read more.
The process of fruit ripening involves many chemical changes occurring not only in the mesocarp but also in the epicarp, including changes in the triterpenoid content of fruit cuticular waxes that can modify the susceptibility to pathogens and mechanical properties of the fruit surface. The aim of the study was the determination of the ripening-related changes in the triterpenoid content of fruit cuticular waxes of three plant species from the Rosaceae family, including rugosa rose (Rosa rugosa), black chokeberry (Aronia melanocarpa var. “Galicjanka”) and apple (Malus domestica var. “Antonovka”). The triterpenoid and steroid content in chloroform-soluble cuticular waxes was determined by a GC-MS/FID method at four different phenological stages. The profile of identified compounds was rather similar in selected fruit samples with triterpenoids with ursane-, oleanane- and lupane-type carbon skeletons, prevalence of ursolic acid and the composition of steroids. Increasing accumulation of triterpenoids and steroids, as well as the progressive enrichment of the composition of these compounds in cuticular wax during fruit development, was observed. The changes in triterpenoid content resulted from modifications of metabolic pathways, particularly hydroxylation and esterification, that can alter interactions with complementary functional groups of aliphatic constituents and lead to important changes in fruit surface quality. Full article
(This article belongs to the Special Issue Fruit and Seed Development)
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20 pages, 3879 KiB  
Article
Identification and Physicochemical Characterization of a New Allergen from Ascaris lumbricoides
by Velky Ahumada, María Manotas, Josefina Zakzuk, Lorenz Aglas, Sandra Coronado, Peter Briza, Peter Lackner, Ronald Regino, Galber Araujo, Fatima Ferreira and Luis Caraballo
Int. J. Mol. Sci. 2020, 21(24), 9761; https://doi.org/10.3390/ijms21249761 - 21 Dec 2020
Cited by 6 | Viewed by 3355
Abstract
To analyze the impact of Ascaris lumbricoides infection on the pathogenesis and diagnosis of allergic diseases, new allergens should be identified. We report the identification of a new Ascaris lumbricoides allergen, Asc l 5. The aim of this study was to evaluate the [...] Read more.
To analyze the impact of Ascaris lumbricoides infection on the pathogenesis and diagnosis of allergic diseases, new allergens should be identified. We report the identification of a new Ascaris lumbricoides allergen, Asc l 5. The aim of this study was to evaluate the physicochemical and immunological features of the Asc l 5 allergen. We constructed an A. lumbricoides cDNA library and Asc l 5 was identified by immunoscreening. After purification, rAsc l 5 was physicochemically characterized. Evaluation of its allergenic activity included determination of Immunoglobulin E (IgE) binding frequency (in two populations: 254 children and 298 all-age subjects), CD203c based-basophil activation tests (BAT) and a passive cutaneous anaphylaxis (PCA) mouse model. We found by amino acid sequence analysis that Asc l 5 belongs to the SXP/RAL-2 protein family of nematodes. rAsc l 5 is a monomeric protein with an alpha-helical folding. IgE sensitization to rAsc l 5 was around 52% in general population; positive BAT rate was 60%. rAsc l 5 induced specific IgE production in mice and a positive PCA reaction. These results show that Asc l 5 has structural and immunological characteristics to be considered as a new allergen from A. lumbricoides. Full article
(This article belongs to the Section Molecular Immunology)
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24 pages, 1817 KiB  
Review
Targeting Platelet in Atherosclerosis Plaque Formation: Current Knowledge and Future Perspectives
by Lei Wang and Chaojun Tang
Int. J. Mol. Sci. 2020, 21(24), 9760; https://doi.org/10.3390/ijms21249760 - 21 Dec 2020
Cited by 43 | Viewed by 8499
Abstract
Besides their role in hemostasis and thrombosis, it has become increasingly clear that platelets are also involved in many other pathological processes of the vascular system, such as atherosclerotic plaque formation. Atherosclerosis is a chronic vascular inflammatory disease, which preferentially develops at sites [...] Read more.
Besides their role in hemostasis and thrombosis, it has become increasingly clear that platelets are also involved in many other pathological processes of the vascular system, such as atherosclerotic plaque formation. Atherosclerosis is a chronic vascular inflammatory disease, which preferentially develops at sites under disturbed blood flow with low speeds and chaotic directions. Hyperglycemia, hyperlipidemia, and hypertension are all risk factors for atherosclerosis. When the vascular microenvironment changes, platelets can respond quickly to interact with endothelial cells and leukocytes, participating in atherosclerosis. This review discusses the important roles of platelets in the plaque formation under pro-atherogenic factors. Specifically, we discussed the platelet behaviors under disturbed flow, hyperglycemia, and hyperlipidemia conditions. We also summarized the molecular mechanisms involved in vascular inflammation during atherogenesis based on platelet receptors and secretion of inflammatory factors. Finally, we highlighted the studies of platelet migration in atherogenesis. In general, we elaborated an atherogenic role of platelets and the aspects that should be further studied in the future. Full article
(This article belongs to the Special Issue Mechanisms and Therapeutics of Platelet Thrombus Formation 2020)
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28 pages, 1740 KiB  
Review
Clinical Application of Bone Marrow Mesenchymal Stem/Stromal Cells to Repair Skeletal Tissue
by Agnieszka Arthur and Stan Gronthos
Int. J. Mol. Sci. 2020, 21(24), 9759; https://doi.org/10.3390/ijms21249759 - 21 Dec 2020
Cited by 160 | Viewed by 9844
Abstract
There has been an escalation in reports over the last decade examining the efficacy of bone marrow derived mesenchymal stem/stromal cells (BMSC) in bone tissue engineering and regenerative medicine-based applications. The multipotent differentiation potential, myelosupportive capacity, anti-inflammatory and immune-modulatory properties of BMSC underpins [...] Read more.
There has been an escalation in reports over the last decade examining the efficacy of bone marrow derived mesenchymal stem/stromal cells (BMSC) in bone tissue engineering and regenerative medicine-based applications. The multipotent differentiation potential, myelosupportive capacity, anti-inflammatory and immune-modulatory properties of BMSC underpins their versatile nature as therapeutic agents. This review addresses the current limitations and challenges of exogenous autologous and allogeneic BMSC based regenerative skeletal therapies in combination with bioactive molecules, cellular derivatives, genetic manipulation, biocompatible hydrogels, solid and composite scaffolds. The review highlights the current approaches and recent developments in utilizing endogenous BMSC activation or exogenous BMSC for the repair of long bone and vertebrae fractures due to osteoporosis or trauma. Current advances employing BMSC based therapies for bone regeneration of craniofacial defects is also discussed. Moreover, this review discusses the latest developments utilizing BMSC therapies in the preclinical and clinical settings, including the treatment of bone related diseases such as Osteogenesis Imperfecta. Full article
(This article belongs to the Special Issue Cell Therapy Approaches for Bone and Cartilage Regeneration)
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11 pages, 2963 KiB  
Article
ᶫ-Leucine Loading and Release in MIL-100 Nanoparticles
by Ivan E. Gorban, Mikhail A. Soldatov, Vera V. Butova, Pavel V. Medvedev, Olga A. Burachevskaya, Anna Belanova, Peter Zolotukhin and Alexander V. Soldatov
Int. J. Mol. Sci. 2020, 21(24), 9758; https://doi.org/10.3390/ijms21249758 - 21 Dec 2020
Cited by 10 | Viewed by 3622
Abstract
Synthesis of the MIL-100 metal-organic framework particles was carried out by hydrothermal (HT) and microwave (MW)-assisted methods. Transmission electron microscopy showed formation of microparticles in the course of hydrothermal synthesis and nanoparticles for microwave-assisted synthesis. Powder X-ray diffraction confirmed formation of larger crystallites [...] Read more.
Synthesis of the MIL-100 metal-organic framework particles was carried out by hydrothermal (HT) and microwave (MW)-assisted methods. Transmission electron microscopy showed formation of microparticles in the course of hydrothermal synthesis and nanoparticles for microwave-assisted synthesis. Powder X-ray diffraction confirmed formation of larger crystallites for hydrothermal synthesis. Particle aggregation in aqueous solution was observed by dynamic light scattering. However, the stability of both samples could be improved in acetic acid solution. Nitrogen sorption isotherms showed high porosity of the particles. ᶫ-leucine molecule was used as a model molecule for loading in the porous micro- and nanoparticles. Loading was estimated by FTIR spectroscopy and thermogravimetric analysis. UV-VIS spectroscopy quantified ᶫ-leucine release from the particles in aqueous solution. Cytotoxicity studies using the HeLa cell model showed that the original particles were somewhat toxic, but ᶫ-leucine loading ameliorated the toxic effects, likely due to signaling properties of the amino acid. Full article
(This article belongs to the Special Issue Self-Assembled Polymer Nanoparticles for Tumor Imaging and Therapy)
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15 pages, 4682 KiB  
Article
The Histamine 3 Receptor Is Expressed in the Heart and Its Activation Opposes Adverse Cardiac Remodeling in the Angiotensin II Mouse Model
by Samuel L. McCaffrey, Grace Lim, Martyn Bullock, Ainsley O. Kasparian, Roderick Clifton-Bligh, William B. Campbell, Alexander Widiapradja and Scott P. Levick
Int. J. Mol. Sci. 2020, 21(24), 9757; https://doi.org/10.3390/ijms21249757 - 21 Dec 2020
Cited by 8 | Viewed by 2675
Abstract
Histamine is a basic amine stored in mast cells, with its release capable of activating one of four histamine receptors. The histamine 3 receptor (H3R) is known to be cardioprotective during acute ischemia by acting to limit norepinephrine release. However, a [...] Read more.
Histamine is a basic amine stored in mast cells, with its release capable of activating one of four histamine receptors. The histamine 3 receptor (H3R) is known to be cardioprotective during acute ischemia by acting to limit norepinephrine release. However, a recent study reported that myofibroblasts isolated from the infarct zone of rat hearts responded to H3R activation by up-regulating collagen production. Thus, it is necessary to clarify the potential role of the H3R in relation to fibrosis in the heart. We identified that the mouse left ventricle (LV) expresses the H3R. Isolation of mouse cardiac fibroblasts determined that while angiotensin II (Ang II) increased levels of the H3R, these cells did not produce excess collagen in response to H3R activation. Using the Ang II mouse model of adverse cardiac remodeling, we found that while H3R blockade had little effect on cardiac fibrosis, activation of the H3R reduced cardiac fibrosis and macrophage infiltration. These findings suggest that when activated, the H3R is anti-inflammatory and anti-fibrotic in the mouse heart and may be a promising target for protecting against cardiac fibrosis. Full article
(This article belongs to the Special Issue Extracellular Matrix in Heart Disease 2.0)
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16 pages, 3414 KiB  
Article
Glyceraldehyde-3-Phosphate Dehydrogenase Increases the Adhesion of Lactobacillus reuteri to Host Mucin to Enhance Probiotic Effects
by Zhaoxi Deng, Tian Dai, Wenming Zhang, Junli Zhu, Xin M. Luo, Dongyan Fu, Jianxin Liu and Haifeng Wang
Int. J. Mol. Sci. 2020, 21(24), 9756; https://doi.org/10.3390/ijms21249756 - 21 Dec 2020
Cited by 24 | Viewed by 3515
Abstract
The ability to adhere to the intestinal mucus layer is an important property of probiotic bacteria. Lactobacillus reuteri strains ZJ615 and ZJ617 show low and high adhesion, respectively, to intestinal epithelial cells. In this study, we quantified bacterial cell wall-associated glyceraldehyde-3-phosphate dehydrogenases (cw-GAPDH) [...] Read more.
The ability to adhere to the intestinal mucus layer is an important property of probiotic bacteria. Lactobacillus reuteri strains ZJ615 and ZJ617 show low and high adhesion, respectively, to intestinal epithelial cells. In this study, we quantified bacterial cell wall-associated glyceraldehyde-3-phosphate dehydrogenases (cw-GAPDH) and bacterial cell membrane permeability in both strains using immunoblotting and flow cytometry, respectively. Highly adhesive L. reuteri ZJ617 possessed significantly more cw-GAPDH, higher cell membrane permeability, and significantly higher adhesive ability toward mucin compared with low-adhesive L. reuteri ZJ615. In vitro adhesion studies and analysis of interaction kinetics using the Octet, the system revealed significantly decreased interaction between L. reuteri and mucin when mucin was oxidized when bacterial surface proteins were removed when bacteria were heat-inactivated at 80 °C for 30 min, and when the interaction was blocked with an anti-GAPDH antibody. SWISS-MODEL analysis suggested intensive interactions between mucin glycans (GalNAcα1-O-Ser, GalNAcαSer, and Galβ3GalNAc) and GAPDH. Furthermore, in vivo studies revealed significantly higher numbers of bacteria adhering to the jejunum, ileum, and colon of piglets orally inoculated with L. reuteri ZJ617 compared with those inoculated with L. reuteri ZJ615; this led to a significantly decreased rate of diarrhea in piglets inoculated with L. reuteri ZJ617. In conclusion, there are strong correlations among the abundance of cw-GAPDH in L. reuteri, the ability of the bacterium to adhere to the host, and the health benefits of this probiotic. Full article
(This article belongs to the Special Issue Bacterial Carbohydrates: Structures, Applications, and Structure/Activity Relationships)
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35 pages, 2662 KiB  
Review
Intrinsic Disorder in Plant Transcription Factor Systems: Functional Implications
by Edoardo Salladini, Maria L. M. Jørgensen, Frederik F. Theisen and Karen Skriver
Int. J. Mol. Sci. 2020, 21(24), 9755; https://doi.org/10.3390/ijms21249755 - 21 Dec 2020
Cited by 16 | Viewed by 5761
Abstract
Eukaryotic cells are complex biological systems that depend on highly connected molecular interaction networks with intrinsically disordered proteins as essential components. Through specific examples, we relate the conformational ensemble nature of intrinsic disorder (ID) in transcription factors to functions in plants. Transcription factors [...] Read more.
Eukaryotic cells are complex biological systems that depend on highly connected molecular interaction networks with intrinsically disordered proteins as essential components. Through specific examples, we relate the conformational ensemble nature of intrinsic disorder (ID) in transcription factors to functions in plants. Transcription factors contain large regulatory ID-regions with numerous orphan sequence motifs, representing potential important interaction sites. ID-regions may affect DNA-binding through electrostatic interactions or allosterically as for the bZIP transcription factors, in which the DNA-binding domains also populate ensembles of dynamic transient structures. The flexibility of ID is well-suited for interaction networks requiring efficient molecular adjustments. For example, Radical Induced Cell Death1 depends on ID in transcription factors for its numerous, structurally heterogeneous interactions, and the JAZ:MYC:MED15 regulatory unit depends on protein dynamics, including binding-associated unfolding, for regulation of jasmonate-signaling. Flexibility makes ID-regions excellent targets of posttranslational modifications. For example, the extent of phosphorylation of the NAC transcription factor SOG1 regulates target gene expression and the DNA-damage response, and phosphorylation of the AP2/ERF transcription factor DREB2A acts as a switch enabling heat-regulated degradation. ID-related phase separation is emerging as being important to transcriptional regulation with condensates functioning in storage and inactivation of transcription factors. The applicative potential of ID-regions is apparent, as removal of an ID-region of the AP2/ERF transcription factor WRI1 affects its stability and consequently oil biosynthesis. The highlighted examples show that ID plays essential functional roles in plant biology and has a promising potential in engineering. Full article
(This article belongs to the Special Issue Protein Intrinsic Disorder in Plant Biology)
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15 pages, 2812 KiB  
Article
Identification and Analysis of MicroRNAs Associated with Wing Polyphenism in the Brown Planthopper, Nilaparvata lugens
by Le Xu, Jiao Zhang, Anran Zhan, Yaqin Wang, Xingzhou Ma, Wencai Jie, Zhenghong Cao, Mohamed A. A. Omar, Kang He and Fei Li
Int. J. Mol. Sci. 2020, 21(24), 9754; https://doi.org/10.3390/ijms21249754 - 21 Dec 2020
Cited by 11 | Viewed by 2984
Abstract
Many insects are capable of developing two types of wings (i.e., wing polyphenism) to adapt to various environments. Though the roles of microRNAs (miRNAs) in regulating animal growth and development have been well studied, their potential roles in modulating wing polyphenism remain largely [...] Read more.
Many insects are capable of developing two types of wings (i.e., wing polyphenism) to adapt to various environments. Though the roles of microRNAs (miRNAs) in regulating animal growth and development have been well studied, their potential roles in modulating wing polyphenism remain largely elusive. To identify wing polyphenism-related miRNAs, we isolated small RNAs from 1st to 5th instar nymphs of long-wing (LW) and short-wing (SW) strains of the brown planthopper (BPH), Nilaparvata lugens. Small RNA libraries were then constructed and sequenced, yielding 158 conserved and 96 novel miRNAs. Among these, 122 miRNAs were differentially expressed between the two BPH strains. Specifically, 47, 2, 27 and 41 miRNAs were more highly expressed in the 1st, 3rd, 4th and 5th instars, respectively, of the LW strain compared with the SW strain. In contrast, 47, 3, 29 and 25 miRNAs were more highly expressed in the 1st, 3rd, 4th and 5th instars, respectively, of the SW strain compared with the LW strain. Next, we predicted the targets of these miRNAs and carried out Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis. We found that a number of pathways might be involved in wing form determination, such as the insulin, MAPK, mTOR, FoxO and thyroid hormone signaling pathways and the thyroid hormone synthesis pathway. Thirty and 45 differentially expressed miRNAs targeted genes in the insulin signaling and insect hormone biosynthesis pathways, respectively, which are related to wing dimorphism. Among these miRNAs, Nlu-miR-14-3p, Nlu-miR-9a-5p and Nlu-miR-315-5p, were confirmed to interact with insulin receptors (NlInRs) in dual luciferase reporter assays. These discoveries are helpful for understanding the miRNA-mediated regulatory mechanism of wing polyphenism in BPHs and shed new light on how insects respond to environmental cues through developmental plasticity. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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16 pages, 1254 KiB  
Review
Juvenile Leaves or Adult Leaves: Determinants for Vegetative Phase Change in Flowering Plants
by Darren Manuela and Mingli Xu
Int. J. Mol. Sci. 2020, 21(24), 9753; https://doi.org/10.3390/ijms21249753 - 21 Dec 2020
Cited by 29 | Viewed by 5213
Abstract
Vegetative leaves in Arabidopsis are classified as either juvenile leaves or adult leaves based on their specific traits, such as leaf shape and the presence of abaxial trichomes. The timing of the juvenile-to-adult phase transition during vegetative development, called the vegetative phase change, [...] Read more.
Vegetative leaves in Arabidopsis are classified as either juvenile leaves or adult leaves based on their specific traits, such as leaf shape and the presence of abaxial trichomes. The timing of the juvenile-to-adult phase transition during vegetative development, called the vegetative phase change, is a critical decision for plants, as this transition is associated with crop yield, stress responses, and immune responses. Juvenile leaves are characterized by high levels of miR156/157, and adult leaves are characterized by high levels of miR156/157 targets, SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) transcription factors. The discovery of this miR156/157-SPL module provided a critical tool for elucidating the complex regulation of the juvenile-to-adult phase transition in plants. In this review, we discuss how the traits of juvenile leaves and adult leaves are determined by the miR156/157-SPL module and how different factors, including embryonic regulators, sugar, meristem regulators, hormones, and epigenetic proteins are involved in controlling the juvenile-to-adult phase transition, focusing on recent insights into vegetative phase change. We also highlight outstanding questions in the field that need further investigation. Understanding how vegetative phase change is regulated would provide a basis for manipulating agricultural traits under various conditions. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Leaf Morphogenesis 2.0)
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28 pages, 2856 KiB  
Review
Associations between the Complement System and Choroidal Neovascularization in Wet Age-Related Macular Degeneration
by Emilie Grarup Jensen, Thomas Stax Jakobsen, Steffen Thiel, Anne Louise Askou and Thomas J. Corydon
Int. J. Mol. Sci. 2020, 21(24), 9752; https://doi.org/10.3390/ijms21249752 - 21 Dec 2020
Cited by 16 | Viewed by 5244
Abstract
Age-related macular degeneration (AMD) is the leading cause of blindness affecting the elderly in the Western world. The most severe form of AMD, wet AMD (wAMD), is characterized by choroidal neovascularization (CNV) and acute vision loss. The current treatment for these patients comprises [...] Read more.
Age-related macular degeneration (AMD) is the leading cause of blindness affecting the elderly in the Western world. The most severe form of AMD, wet AMD (wAMD), is characterized by choroidal neovascularization (CNV) and acute vision loss. The current treatment for these patients comprises monthly intravitreal injections of anti-vascular endothelial growth factor (VEGF) antibodies, but this treatment is expensive, uncomfortable for the patient, and only effective in some individuals. AMD is a complex disease that has strong associations with the complement system. All three initiating complement pathways may be relevant in CNV formation, but most evidence indicates a major role for the alternative pathway (AP) and for the terminal complement complex, as well as certain complement peptides generated upon complement activation. Since the complement system is associated with AMD and CNV, a complement inhibitor may be a therapeutic option for patients with wAMD. The aim of this review is to (i) reflect on the possible complement targets in the context of wAMD pathology, (ii) investigate the results of prior clinical trials with complement inhibitors for wAMD patients, and (iii) outline important considerations when developing a future strategy for the treatment of wAMD. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 2.0)
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23 pages, 2013 KiB  
Review
Roles of Lysyl Oxidase Family Members in the Tumor Microenvironment and Progression of Liver Cancer
by Hung-Yu Lin, Chia-Jung Li, Ya-Ling Yang, Ying-Hsien Huang, Ya-Tze Hsiau and Pei-Yi Chu
Int. J. Mol. Sci. 2020, 21(24), 9751; https://doi.org/10.3390/ijms21249751 - 21 Dec 2020
Cited by 26 | Viewed by 4076
Abstract
The lysyl oxidase (LOX) family members are secreted copper-dependent amine oxidases, comprised of five paralogues: LOX and LOX-like l-4 (LOXL1-4), which are characterized by catalytic activity contributing to the remodeling of the cross-linking of the structural extracellular matrix (ECM). ECM remodeling plays a [...] Read more.
The lysyl oxidase (LOX) family members are secreted copper-dependent amine oxidases, comprised of five paralogues: LOX and LOX-like l-4 (LOXL1-4), which are characterized by catalytic activity contributing to the remodeling of the cross-linking of the structural extracellular matrix (ECM). ECM remodeling plays a key role in the angiogenesis surrounding tumors, whereby a corrupt tumor microenvironment (TME) takes shape. Primary liver cancer includes hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), ranked as the seventh most common cancer globally, with limited therapeutic options for advanced stages. In recent years, a growing body of evidence has revealed the key roles of LOX family members in the pathogenesis of liver cancer and the shaping of TME, indicating their notable potential as therapeutic targets. We herein review the clinical value and novel biological roles of LOX family members in tumor progression and the TME of liver cancers. In addition, we highlight recent insights into their mechanisms and their potential involvement in the development of target therapy for liver cancer. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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21 pages, 19233 KiB  
Article
Metabolism of Melatonin Synthesis-Related Indoles in the Turkey Pineal Organ and Its Modification by Monochromatic Light
by Kamila Martyniuk, Maria Hanuszewska and Bogdan Lewczuk
Int. J. Mol. Sci. 2020, 21(24), 9750; https://doi.org/10.3390/ijms21249750 - 21 Dec 2020
Cited by 9 | Viewed by 2518
Abstract
The metabolism of pineal indoles is closely related to alterations in the light and dark phases of a daily cycle. Recent research showed important interspecies differences in the pineal biochemistry, and a strong impact of monochromatic light on many physiological processes in birds. [...] Read more.
The metabolism of pineal indoles is closely related to alterations in the light and dark phases of a daily cycle. Recent research showed important interspecies differences in the pineal biochemistry, and a strong impact of monochromatic light on many physiological processes in birds. Therefore, the aims of study were to characterize the metabolism of melatonin-synthesis indoles in the pineal organ of the domestic turkey, and to determine the changes occurring in this metabolism under the influence of different wavelengths and intensities of light. For this purpose, 3-week-old turkeys were kept under 16 lx white light, or under blue, green, and red light with intensities of 16, 32, and 64 lx during the photophase, and after 7 d were sacrificed at 4 h intervals. The activities of melatonin-synthesizing enzymes and the contents of indoles were measured in the same pineal organ. The results revealed that the activities of tryptophan hydroxylase and arylalkylamine N-acetyltransferase, and the levels of all tryptophan derivatives had significant daily changes in birds kept under each light condition used. The profile of pineal indole metabolism in 4-week-old turkeys was characterized by high-amplitude rhythms in the activity of arylalkylamine N-acetyltransferase and the contents of N-acetylserotonin and melatonin, equal relative amounts of serotonin and 5-hydroxyindoleacetic acid, and higher content of melatonin than N-acetylserotonin. The monochromatic light significantly modified the pineal indole metabolism, and its effects were dependent on the color and intensity of light. Pronounced changes occurred in the level of serotonin synthesis and the daily rhythm course of melatonin synthesis. Full article
(This article belongs to the Special Issue Melatonin: Lessons from Animals to Plants. Experimental and Clinical Studies)
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22 pages, 4585 KiB  
Article
Why the Orientational Mobility in Arginine and Lysine Spacers of Peptide Dendrimers Designed for Gene Delivery Is Different?
by Valeriy V. Bezrodnyi, Oleg V. Shavykin, Sofia E. Mikhtaniuk, Igor M. Neelov, Nadezhda N. Sheveleva and Denis A. Markelov
Int. J. Mol. Sci. 2020, 21(24), 9749; https://doi.org/10.3390/ijms21249749 - 21 Dec 2020
Cited by 10 | Viewed by 2367
Abstract
New peptide dendrimer with Lys-2Arg repeating units was recently studied experimentally by NMR (RSC Advances, 2019, 9, 18018) and tested as gene carrier successfully (Int. J. Mol. Sci., 2020, 21, 3138). The unusual slowing down of the orientational mobility of 2Arg spacers in [...] Read more.
New peptide dendrimer with Lys-2Arg repeating units was recently studied experimentally by NMR (RSC Advances, 2019, 9, 18018) and tested as gene carrier successfully (Int. J. Mol. Sci., 2020, 21, 3138). The unusual slowing down of the orientational mobility of 2Arg spacers in this dendrimer was revealed. It has been suggested that this unexpected behavior is caused by the Arg-Arg pairing effect in water, which leads to entanglements between dendrimer branches. In this paper, we determine the reason for this slowing down using atomistic molecular dynamics simulation of this dendrimer. We present that the structural properties of Lys-2Arg dendrimer are close to those of the Lys-2Lys dendrimer at all temperatures (Polymers, 2020, 12, 1657). However, the orientational mobility of the H-H vector in CH2-N groups of 2Arg spacers in Lys-2Arg dendrimer is significantly slower than the mobility of the same vector in the Lys-2Lys dendrimer. This result is in agreement with the recent NMR experiments for the same systems. We revealed that this difference is not due to the arginine-arginine pairing, but is due to the semiflexibility effect associated with the different contour length from CH2-N group to the end of the side arginine or lysine segment in spacers. Full article
(This article belongs to the Special Issue Polymer and Biopolymer Systems of Complex Architecture and Composition)
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12 pages, 1797 KiB  
Article
The Extraction Solvent Influences the Anti-Inflammatory Effects of Jakyakgamcho-Tang in Lipopolysaccharide-Stimulated Macrophages and Mice with Gouty Arthritis
by Yun Mi Lee and Dong-Seon Kim
Int. J. Mol. Sci. 2020, 21(24), 9748; https://doi.org/10.3390/ijms21249748 - 21 Dec 2020
Cited by 9 | Viewed by 2515
Abstract
Jakyakgamcho-Tang (JGT) is a traditional medicine used to treat muscular tension, spasm, and pain. Several studies have reported its clinical use as an anti-inflammatory and in gynaecological treatment. This study aimed to compare the anti-inflammatory effects of JGT according to extraction solvent, water [...] Read more.
Jakyakgamcho-Tang (JGT) is a traditional medicine used to treat muscular tension, spasm, and pain. Several studies have reported its clinical use as an anti-inflammatory and in gynaecological treatment. This study aimed to compare the anti-inflammatory effects of JGT according to extraction solvent, water (JGTW) and 30% EtOH (JGTE) on lipopolysaccharide (LPS)—stimulated macrophages and in mice with monosodium urate (MSU)—induced gouty arthritis. We evaluated the production of inflammatory mediators and cytokines and the expression of inducible nitric oxide (iNOS) and cyclooxygenase-2 (COX-2) in RAW 264.7 cells. We also examined oedema, pain, and inflammation in MSU-induced mice by measuring affected hind paw swelling, weight-bearing, pro-inflammatory cytokines levels, and myeloperoxidase (MPO) activity. In LPS-stimulated RAW264.7 cells, JGTW and JGTE significantly decreased prostaglandin (PG) E2(PGE2) production via suppressing COX-2 expression and cytokines interleukin-1β and interleukin-6. Only JGTE reduced the production of NO and cytokines and the mRNA levels of iNOS and cytokines. In MSU-induced mice, JGTE and JGTW efficiently decreased paw swelling and attenuated joint pain. JGTE (200 and 300 mg/kg) effectively suppressed inflammation by downregulating pro-inflammatory cytokines (tumour necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6) and MPO activity, which were only slightly reduced by JGTW. Our data demonstrate the anti-inflammatory activity of JGT in macrophage and gouty arthritis animal models and show that JGTE is more effective than JGTW at lower concentrations. Full article
(This article belongs to the Section Molecular Endocrinology and Metabolism)
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